Using multiple decrement models to estimate risk and morbidity from specific AIDS illnesses. Multicenter AIDS Cohort Study (MACS).

PubMed

Hoover, D R; Peng, Y; Saah, A J; Detels, R R; Day, R S; Phair, J P

A simple non-parametric approach is developed to simultaneously estimate net incidence and morbidity time from specific AIDS illnesses in populations at high risk for death from these illnesses and other causes. The disease-death process has four-stages that can be recast as two sandwiching three-state multiple decrement processes. Non-parametric estimation of net incidence and morbidity time with error bounds are achieved from these sandwiching models through modification of methods from Aalen and Greenwood, and bootstrapping. An application to immunosuppressed HIV-1 infected homosexual men reveals that cytomegalovirus disease, Kaposi's sarcoma and Pneumocystis pneumonia are likely to occur and cause significant morbidity time.

Multiple sclerosis pathways: an innovative nursing role in disease management.

PubMed

Madonna, M G; Keating, M M

1999-12-01

Multiple sclerosis (MS), a chronic disease of the central nervous system, is characterized by a variable and unpredictable course. The most common pattern of the disease is the relapsing-remitting form in which clearly defined relapses (also called exacerbations) are followed by complete or incomplete recovery. Interferon beta-1b (Betaseron), a drug that affects the natural course of the disease, was developed for the treatment of relapsing-remitting MS. Multiple Sclerosis Pathways (MSP), a disease management program, was developed to provide comprehensive and personal support to MS patients taking interferon beta-1b and to serve as an information resource for all people with MS, their families, and healthcare professionals. The MSP program includes personal patient assistance, reimbursement services, a 24-hour nurse hotline, training program, educational resources, and injection supplies. The nurse hotline counselor (NHC) utilizes the nursing process in a unique telephone nursing practice in this program. The positive impact of education and support on adherence to therapy has been validated by training and nurse hotline data.

Vicious circles in inflammatory bowel disease.

PubMed

Sonnenberg, Amnon; Collins, Judith F

2006-10-01

Inflammatory bowel disease can present with a bewildering array of disease manifestations whose overall impact on patient health is difficult to disentangle. The multitude of disease complications and therapeutic side effects result in conflicting ideas on how to best manage a patient. The aim of the study is to test the usefulness of influence diagrams in resolving conflicts centered on managing complex disease processes. The influences of a disease process and the ensuing medical interventions on the health of a patient with inflammatory bowel disease are modeled by an influence diagram. Patient health is the focal point of multiple influences affecting its overall strength. Any downstream influence represents the focal point of other preceding upstream influences. The mathematics underlying the influence diagram is similar to that of a decision tree. Its formalism allows one to consider additive and inhibitory influences and include in the same analysis qualitatively different types of parameters, such as diagnoses, complications, side effects, and therapeutic outcomes. Three exemplary cases are presented to illustrate the potential use of influence diagrams. In all three case scenarios, Crohn's disease resulted in disease manifestations that seemingly interfered with its own therapy. The presence of negative feedback loops rendered the management of each case particularly challenging. The analyses by influence diagrams revealed subtle interactions among the multiple influences and their joint contributions to the patient's overall health that would have been difficult to appreciate by verbal reasoning alone. Influence diagrams represent a decision tool that is particularly suited to improve decision-making in inflammatory bowel disease. They highlight key factors of a complex disease process and help to assess their quantitative interactions.

Positive or negative involvement of heat shock proteins in multiple sclerosis pathogenesis: an overview.

PubMed

Turturici, Giuseppina; Tinnirello, Rosaria; Sconzo, Gabriella; Asea, Alexzander; Savettieri, Giovanni; Ragonese, Paolo; Geraci, Fabiana

2014-12-01

Multiple sclerosis (MS) is the most diffuse chronic inflammatory disease of the central nervous system. Both immune-mediated and neurodegenerative processes apparently play roles in the pathogenesis of this disease. Heat shock proteins (HSPs) are a family of highly evolutionarily conserved proteins; their expression in the nervous system is induced in a variety of pathologic states, including cerebral ischemia, neurodegenerative diseases, epilepsy, and trauma. To date, investigators have observed protective effects of HSPs in a variety of brain disease models (e.g. of Alzheimer disease and Parkinson disease). In contrast, unequivocal data have been obtained for their roles in MS that depend on the HSP family and particularly on their localization (i.e. intracellular or extracellular). This article reviews our current understanding of the involvement of the principal HSP families in MS.

Visualization and Measurement of Multiple Components of the Autophagy Flux.

PubMed

Evans, Tracey; Button, Robert; Anichtchik, Oleg; Luo, Shouqing

2018-06-24

Autophagy is an intracellular degradation process that mediates the clearance of cytoplasmic components. As well as being an important function for cellular homeostasis, autophagy also promotes the removal of aberrant protein accumulations, such as those seen in conditions like neurodegeneration. The dynamic nature of autophagy requires precise methods to examine the process at multiple stages. The protocols described herein enable the dissection of the complete autophagy process (the "autophagy flux"). These allow for the elucidation of which stages of autophagy may be altered in response to various diseases and treatments.

Natural products as modulator of autophagy with potential clinical prospects.

PubMed

Wang, Peiqi; Zhu, Lingjuan; Sun, Dejuan; Gan, Feihong; Gao, Suyu; Yin, Yuanyuan; Chen, Lixia

2017-03-01

Natural compounds derived from living organisms are well defined for their remarkable biological and pharmacological properties likely to be translated into clinical use. Therefore, delving into the mechanisms by which natural compounds protect against diverse diseases may be of great therapeutic benefits for medical practice. Autophagy, an intricate lysosome-dependent digestion process, with implications in a wide variety of pathophysiological settings, has attracted extensive attention over the past few decades. Hitherto, accumulating evidence has revealed that a large number of natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways and transcriptional regulators. In this review, we summarize natural compounds regulating autophagy in multifarious diseases including cancer, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and immune diseases, hoping to inspire further investigation of the underlying mechanisms of natural compounds and to facilitate their clinical use for multiple human diseases.

Polycistronic tRNA and CRISPR guide-RNA enables highly efficient multiplexed genome engineering in human cells

PubMed Central

Dong, Fengping; Xie, Kabin; Chen, Yueying; Yang, Yinong; Mao, Yingwei

2016-01-01

CRISPR/Cas9 has been widely used for genomic editing in many organisms. Many human diseases are caused by multiple mutations. The CRISPR/Cas9 system provides a potential tool to introduce multiple mutations in a genome. To mimic complicated genomic variants in human diseases, such as multiple gene deletions or mutations, two or more small guide RNAs (sgRNAs) need to be introduced all together. This can be achieved by separate Pol III promoters in a construct. However, limited enzyme sites and increased insertion size lower the efficiency to make a construct. Here, we report a strategy to quickly assembly multiple sgRNAs in one construct using a polycistronic-tRNA-gRNA (PTG) strategy. Taking advantage of the endogenous tRNA processing system in mammalian cells, we efficiently express multiple sgRNAs driven using only one Pol III promoter. Using an all-in-one construct carrying PTG, we disrupt the deacetylase domain in multiple histone deacetylases (HDACs) in human cells simultaneously. We demonstrate that multiple HDAC deletions significantly affect the activation of the Wnt-signaling pathway. Thus, this method enables to efficiently target multiple genes and provide a useful tool to establish mutated cells mimicking human diseases. PMID:27890617

Polycistronic tRNA and CRISPR guide-RNA enables highly efficient multiplexed genome engineering in human cells.

PubMed

Dong, Fengping; Xie, Kabin; Chen, Yueying; Yang, Yinong; Mao, Yingwei

2017-01-22

CRISPR/Cas9 has been widely used for genomic editing in many organisms. Many human diseases are caused by multiple mutations. The CRISPR/Cas9 system provides a potential tool to introduce multiple mutations in a genome. To mimic complicated genomic variants in human diseases, such as multiple gene deletions or mutations, two or more small guide RNAs (sgRNAs) need to be introduced all together. This can be achieved by separate Pol III promoters in a construct. However, limited enzyme sites and increased insertion size lower the efficiency to make a construct. Here, we report a strategy to quickly assembly multiple sgRNAs in one construct using a polycistronic-tRNA-gRNA (PTG) strategy. Taking advantage of the endogenous tRNA processing system in mammalian cells, we efficiently express multiple sgRNAs driven using only one Pol III promoter. Using an all-in-one construct carrying PTG, we disrupt the deacetylase domain in multiple histone deacetylases (HDACs) in human cells simultaneously. We demonstrate that multiple HDAC deletions significantly affect the activation of the Wnt-signaling pathway. Thus, this method enables to efficiently target multiple genes and provide a useful tool to establish mutated cells mimicking human diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Why infectious disease research needs community ecology

PubMed Central

Johnson, Pieter T. J.; de Roode, Jacobus C.; Fenton, Andy

2016-01-01

Infectious diseases often emerge from interactions among multiple species and across nested levels of biological organization. Threats as diverse as Ebola virus, human malaria, and bat white-nose syndrome illustrate the need for a mechanistic understanding of the ecological interactions underlying emerging infections. We describe how recent advances in community ecology can be adopted to address contemporary challenges in disease research. These analytical tools can identify the factors governing complex assemblages of multiple hosts, parasites, and vectors, and reveal how processes link across scales from individual hosts to regions. They can also determine the drivers of heterogeneities among individuals, species, and regions to aid targeting of control strategies. We provide examples where these principles have enhanced disease management and illustrate how they can be further extended. PMID:26339035

A Practical Methodology for the Systematic Development of Multiple Choice Tests.

ERIC Educational Resources Information Center

Blumberg, Phyllis; Felner, Joel

Using Guttman's facet design analysis, four parallel forms of a multiple-choice test were developed. A mapping sentence, logically representing the universe of content of a basic cardiology course, specified the facets of the course and the semantic structural units linking them. The facets were: cognitive processes, disease priority, specific…

Gut-CNS-Axis as Possibility to Modulate Inflammatory Disease Activity-Implications for Multiple Sclerosis.

PubMed

Fleck, Ann-Katrin; Schuppan, Detlef; Wiendl, Heinz; Klotz, Luisa

2017-07-14

In the last decade the role of environmental factors as modulators of disease activity and progression has received increasing attention. In contrast to classical environmental modulators such as exposure to sun-light or fine dust pollution, nutrition is an ideal tool for a personalized human intervention. Various studies demonstrate a key role of dietary factors in autoimmune diseases including Inflammatory Bowel Disease (IBD), rheumatoid arthritis or inflammatory central nervous system (CNS) diseases such as Multiple Sclerosis (MS). In this review we discuss the connection between diet and inflammatory processes via the gut-CNS-axis. This axis describes a bi-directional communication system and comprises neuronal signaling, neuroendocrine pathways and modulation of immune responses. Therefore, the gut-CNS-axis represents an emerging target to modify CNS inflammatory activity ultimately opening new avenues for complementary and adjunctive treatment of autoimmune diseases such as MS.

The role of information system in multiple sclerosis management

PubMed Central

Ajami, Sima; Ahmadi, Golchehreh; Etemadifar, Masoud

2014-01-01

Multiple sclerosis (MS) is a chronic disease of central nervous system. The multiple sclerosis information system (MSIS), such as other information system (IS), depends on identification, collection and processing of data for producing useful information. Lack of the integrated IS for collecting standard data causes undesirable effects on exchanging, comparing, and managing. The aim of this study was to recognize the role of the IS in the MS management and determine the advantages and barriers in implementing of the MSIS. The present study was a nonsystematized review that was done in order to recognize the role of the IS in the MS management. In this study, electronic scientific resources such as scientific magazines and books and published topics at conferences were used. We used key words (IS, chronic disease management, and multiple sclerosis), their combination or their synonyms in title, key words, abstracts, and text of English articles and published reports from 1980 until 2013, and by using search engines such as Google, Google Scholar and scientific databases and electronic issues such as iPubMed, sufficiently important difference, Scopus, Medlib, and Magiran for gathering information. More than 200 articles and reports were collected and assessed and 139 of them. Findings showed that the MSIS can reduce of disease expenses through continuously collecting correct, accurate, sufficient, and timely patients and disease nature information; recoding; editing; processing; exchanging, and distributing among different health care centers. Although the MSIS has many advantages; but, we cannot ignore cultural, economic, technical, organizational, and managerial barriers. Therefore, it is necessary to do studies for preventing, reducing, and controlling them. One of the ways is to recognize the advantages of the MSIS and usage information technology in optimizing disease management. PMID:25709660

Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases.

PubMed

Sahakyan, Aleksandr B; Balasubramanian, Shankar

2016-03-12

The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases. We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations. Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired.

The role of information system in multiple sclerosis management.

PubMed

Ajami, Sima; Ahmadi, Golchehreh; Etemadifar, Masoud

2014-12-01

Multiple sclerosis (MS) is a chronic disease of central nervous system. The multiple sclerosis information system (MSIS), such as other information system (IS), depends on identification, collection and processing of data for producing useful information. Lack of the integrated IS for collecting standard data causes undesirable effects on exchanging, comparing, and managing. The aim of this study was to recognize the role of the IS in the MS management and determine the advantages and barriers in implementing of the MSIS. The present study was a nonsystematized review that was done in order to recognize the role of the IS in the MS management. In this study, electronic scientific resources such as scientific magazines and books and published topics at conferences were used. We used key words (IS, chronic disease management, and multiple sclerosis), their combination or their synonyms in title, key words, abstracts, and text of English articles and published reports from 1980 until 2013, and by using search engines such as Google, Google Scholar and scientific databases and electronic issues such as iPubMed, sufficiently important difference, Scopus, Medlib, and Magiran for gathering information. More than 200 articles and reports were collected and assessed and 139 of them. Findings showed that the MSIS can reduce of disease expenses through continuously collecting correct, accurate, sufficient, and timely patients and disease nature information; recoding; editing; processing; exchanging, and distributing among different health care centers. Although the MSIS has many advantages; but, we cannot ignore cultural, economic, technical, organizational, and managerial barriers. Therefore, it is necessary to do studies for preventing, reducing, and controlling them. One of the ways is to recognize the advantages of the MSIS and usage information technology in optimizing disease management.

Inflammasomes link vascular disease with neuroinflammation and brain disorders

PubMed Central

Lénárt, Nikolett; Brough, David

2016-01-01

The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer’s or Parkinson’s disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target. PMID:27486046

Disease-specific molecular events in cortical multiple sclerosis lesions

PubMed Central

Wimmer, Isabella; Höftberger, Romana; Gerlach, Susanna; Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Mahad, Don; Binder, Christoph J.; Krumbholz, Markus; Bauer, Jan; Bradl, Monika

2013-01-01

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. PMID:23687122

The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics.

PubMed

Camara-Lemarroy, Carlos R; Metz, Luanne; Meddings, Jonathan B; Sharkey, Keith A; Wee Yong, V

2018-05-30

Biological barriers are essential for the maintenance of homeostasis in health and disease. Breakdown of the intestinal barrier is an essential aspect of the pathophysiology of gastrointestinal inflammatory diseases, such as inflammatory bowel disease. A wealth of recent studies has shown that the intestinal microbiome, part of the brain-gut axis, could play a role in the pathophysiology of multiple sclerosis. However, an essential component of this axis, the intestinal barrier, has received much less attention. In this review, we describe the intestinal barrier as the physical and functional zone of interaction between the luminal microbiome and the host. Besides its essential role in the regulation of homeostatic processes, the intestinal barrier contains the gut mucosal immune system, a guardian of the integrity of the intestinal tract and the whole organism. Gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, and content of the intestinal microbiome entering into the circulation can impact the functions of CNS microglia. We highlight currently available studies suggesting that there is intestinal barrier dysfunction in multiple sclerosis. Finally, we address the mechanisms by which commonly used disease-modifying drugs in multiple sclerosis could alter the intestinal barrier and the microbiome, and we discuss the potential of barrier-stabilizing strategies, including probiotics and stabilization of tight junctions, as novel therapeutic avenues in multiple sclerosis.

The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.

PubMed

Pardo, Gabriel; Jones, David E

2017-12-01

The treatment landscape for relapsing forms of multiple sclerosis (RMS) has expanded considerably over the last 10 years with the approval of multiple new disease-modifying therapies (DMTs), and others in late-stage clinical development. All DMTs for RMS are believed to reduce central nervous system immune-mediated inflammatory processes, which translate into demonstrable improvement in clinical and radiologic outcomes. However, some DMTs are associated with long-lasting effects on the immune system and/or serious adverse events, both of which may complicate the use of subsequent therapies. When customizing a treatment program, a benefit-risk assessment must consider multiple factors, including the efficacy of the DMT to reduce disease activity, the short- and long-term safety and immunologic profiles of each DMT, the criteria used to define switching treatment, and the risk tolerance of each patient. A comprehensive benefit-risk assessment can only be achieved by evaluating the immunologic, safety, and efficacy data for DMTs in the controlled clinical trial environment and the postmarketing clinical practice setting. This review is intended to help neurologists make informed decisions when treating RMS by summarizing the known data for each DMT and raising awareness of the multiple considerations involved in treating people with RMS throughout the entire course of their disease.

Design and analysis of multiple diseases genome-wide association studies without controls.

PubMed

Chen, Zhongxue; Huang, Hanwen; Ng, Hon Keung Tony

2012-11-15

In genome-wide association studies (GWAS), multiple diseases with shared controls is one of the case-control study designs. If data obtained from these studies are appropriately analyzed, this design can have several advantages such as improving statistical power in detecting associations and reducing the time and cost in the data collection process. In this paper, we propose a study design for GWAS which involves multiple diseases but without controls. We also propose corresponding statistical data analysis strategy for GWAS with multiple diseases but no controls. Through a simulation study, we show that the statistical association test with the proposed study design is more powerful than the test with single disease sharing common controls, and it has comparable power to the overall test based on the whole dataset including the controls. We also apply the proposed method to a real GWAS dataset to illustrate the methodologies and the advantages of the proposed design. Some possible limitations of this study design and testing method and their solutions are also discussed. Our findings indicate that the proposed study design and statistical analysis strategy could be more efficient than the usual case-control GWAS as well as those with shared controls. Copyright © 2012 Elsevier B.V. All rights reserved.

Quantifying cause-related mortality by weighting multiple causes of death

PubMed Central

Moreno-Betancur, Margarita; Lamarche-Vadel, Agathe; Rey, Grégoire

2016-01-01

Abstract Objective To investigate a new approach to calculating cause-related standardized mortality rates that involves assigning weights to each cause of death reported on death certificates. Methods We derived cause-related standardized mortality rates from death certificate data for France in 2010 using: (i) the classic method, which considered only the underlying cause of death; and (ii) three novel multiple-cause-of-death weighting methods, which assigned weights to multiple causes of death mentioned on death certificates: the first two multiple-cause-of-death methods assigned non-zero weights to all causes mentioned and the third assigned non-zero weights to only the underlying cause and other contributing causes that were not part of the main morbid process. As the sum of the weights for each death certificate was 1, each death had an equal influence on mortality estimates and the total number of deaths was unchanged. Mortality rates derived using the different methods were compared. Findings On average, 3.4 causes per death were listed on each certificate. The standardized mortality rate calculated using the third multiple-cause-of-death weighting method was more than 20% higher than that calculated using the classic method for five disease categories: skin diseases, mental disorders, endocrine and nutritional diseases, blood diseases and genitourinary diseases. Moreover, this method highlighted the mortality burden associated with certain diseases in specific age groups. Conclusion A multiple-cause-of-death weighting approach to calculating cause-related standardized mortality rates from death certificate data identified conditions that contributed more to mortality than indicated by the classic method. This new approach holds promise for identifying underrecognized contributors to mortality. PMID:27994280

Similar autobiographical memory impairment in long-term secondary progressive multiple sclerosis and Alzheimer's disease.

PubMed

Müller, S; Saur, R; Greve, B; Melms, A; Hautzinger, M; Fallgatter, A J; Leyhe, T

2013-02-01

Memory disturbance is a common symptom of multiple sclerosis (MS), but little is known about autobiographical memory deficits in the long-term course of different MS subtypes. Inflammatory activity and demyelination is pronounced in relapsing-remitting multiple sclerosis (RRMS) whereas, similar to Alzheimer's disease, neurodegeneration affecting autobiographical memory-associated areas is seen in secondary progressive multiple sclerosis (SPMS). In light of distinct disease mechanisms, we evaluated autobiographical memory in different MS subtypes and hypothesized similarities between elderly patients with SPMS and Alzheimer's disease. We used the Autobiographical Memory Interview to assess episodic and semantic autobiographical memory in 112 education- and gender-matched participants, including healthy controls and patients with RRMS, SPMS, amnesic mild cognitive impairment (aMCI) and early Alzheimer's dementia (AD). Patients with SPMS, AD, and aMCI, but not with RRMS, exhibited a pattern of episodic autobiographical memory impairment that followed Ribot's Law; older memories were better preserved than more recent memories. In contrast to aMCI and AD, neither SPMS nor RRMS was associated with semantic autobiographical memory impairment. Our neuropsychological findings suggest that episodic autobiographical memory is affected in long-term patients with SPMS, possibly due to neurodegenerative processes in functional relevant brain regions.

Are microRNAs true sensors of ageing and cellular senescence?

PubMed

Williams, Justin; Smith, Flint; Kumar, Subodh; Vijayan, Murali; Reddy, P Hemachandra

2017-05-01

All living beings are programmed to death due to aging and age-related processes. Aging is a normal process of every living species. While all cells are inevitably progressing towards death, many disease processes accelerate the aging process, leading to senescence. Pathologies such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, cardiovascular disease, cancer, and skin diseases have been associated with deregulated aging. Healthy aging can delay onset of all age-related diseases. Genetics and epigenetics are reported to play large roles in accelerating and/or delaying the onset of age-related diseases. Cellular mechanisms of aging and age-related diseases are not completely understood. However, recent molecular biology discoveries have revealed that microRNAs (miRNAs) are potential sensors of aging and cellular senescence. Due to miRNAs capability to bind to the 3' untranslated region (UTR) of mRNA of specific genes, miRNAs can prevent the translation of specific genes. The purpose of our article is to highlight recent advancements in miRNAs and their involvement in cellular changes in aging and senescence. Our article discusses the current understanding of cellular senescence, its interplay with miRNAs regulation, and how they both contribute to disease processes. Copyright © 2016 Elsevier B.V. All rights reserved.

Multiparametric Imaging of Organ System Interfaces

PubMed Central

Vandoorne, Katrien; Nahrendorf, Matthias

2017-01-01

Cardiovascular diseases are a consequence of genetic and environmental risk factors that together generate arterial wall and cardiac pathologies. Blood vessels connect multiple systems throughout the entire body and allow organs to interact via circulating messengers. These same interactions facilitate nervous and metabolic system influence on cardiovascular health. Multiparametric imaging offers the opportunity to study these interfacing systems’ distinct processes, to quantify their interactions and to explore how these contribute to cardiovascular disease. Noninvasive multiparametric imaging techniques are emerging tools that can further our understanding of this complex and dynamic interplay. PET/MRI and multichannel optical imaging are particularly promising because they can simultaneously sample multiple biomarkers. Preclinical multiparametric diagnostics could help discover clinically relevant biomarker combinations pivotal for understanding cardiovascular disease. Interfacing systems important to cardiovascular disease include the immune, nervous and hematopoietic systems. These systems connect with ‘classical’ cardiovascular organs, like the heart and vasculature, and with the brain. The dynamic interplay between these systems and organs enables processes such as hemostasis, inflammation, angiogenesis, matrix remodeling, metabolism and fibrosis. As the opportunities provided by imaging expand, mapping interconnected systems will help us decipher the complexity of cardiovascular disease and monitor novel therapeutic strategies. PMID:28360260

Calcium Dysregulation and Homeostasis of Neural Calcium in the Molecular Mechanisms of Neurodegenerative Diseases Provide Multiple Targets for Neuroprotection

PubMed Central

Zündorf, Gregor

2011-01-01

Abstract The intracellular free calcium concentration subserves complex signaling roles in brain. Calcium cations (Ca2+) regulate neuronal plasticity underlying learning and memory and neuronal survival. Homo- and heterocellular control of Ca2+ homeostasis supports brain physiology maintaining neural integrity. Ca2+ fluxes across the plasma membrane and between intracellular organelles and compartments integrate diverse cellular functions. A vast array of checkpoints controls Ca2+, like G protein-coupled receptors, ion channels, Ca2+ binding proteins, transcriptional networks, and ion exchangers, in both the plasma membrane and the membranes of mitochondria and endoplasmic reticulum. Interactions between Ca2+ and reactive oxygen species signaling coordinate signaling, which can be either beneficial or detrimental. In neurodegenerative disorders, cellular Ca2+-regulating systems are compromised. Oxidative stress, perturbed energy metabolism, and alterations of disease-related proteins result in Ca2+-dependent synaptic dysfunction, impaired plasticity, and neuronal demise. We review Ca2+ control processes relevant for physiological and pathophysiological conditions in brain tissue. Dysregulation of Ca2+ is decisive for brain cell death and degeneration after ischemic stroke, long-term neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, inflammatory processes, such as in multiple sclerosis, epileptic sclerosis, and leucodystrophies. Understanding the underlying molecular processes is of critical importance for the development of novel therapeutic strategies to prevent neurodegeneration and confer neuroprotection. Antioxid. Redox Signal. 14, 1275–1288. PMID:20615073

Evidence-based patient information about treatment of multiple sclerosis--a phase one study on comprehension and emotional responses.

PubMed

Kasper, Jürgen; Köpke, Sascha; Mühlhauser, Ingrid; Heesen, Christoph

2006-07-01

This study analysis the comprehension and emotional responses of people suffering from multiple sclerosis when provided with an evidence-based information module. It is a core module of a comprehensive decision aid about immunotherapy. The core module is designed to enable patients to process scientific uncertainty without adverse effects. It considers existing standards for risk communication and presentation of data. Using a mailing approach we investigated 169 patients with differing courses of disease in a before-after design. Items addressed the competence in processing relative and absolute risk information and patients' emotional response to the tool, comprising grade of familiarity with the information, understanding, relevance, emotional arousal, and certainty. Overall, numeracy improved (p < 0.001), although 99 of 169 patients did not complete the numeracy task correctly. Understanding depended on the relevance related to the course of disease. A moderate level of uncertainty was induced. No adverse emotional responses could be shown, neither in those who did comprehend the information, nor in those who did not develop numeracy skills. In conclusion, the tool supports people suffering from multiple sclerosis to process evidence-based medical information and scientific uncertainty without burdening them emotionally. This study is an example for the documentation of an important step in the development process of a complex intervention.

Pathways leading to an immunological disease: systemic lupus erythematosus

PubMed Central

Zharkova, Olga; Celhar, Teja; Cravens, Petra D.; Satterthwaite, Anne B.; Fairhurst, Anna-Marie

2017-01-01

Abstract SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes. We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in SLE and highlight new findings. We describe the immunological changes that characterize this form of autoimmunity. The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE. PMID:28375453

Alternative Splicing in the Hippo Pathway—Implications for Disease and Potential Therapeutic Targets

PubMed Central

Porazinski, Sean; Ladomery, Michael

2018-01-01

Alternative splicing is a well-studied gene regulatory mechanism that produces biological diversity by allowing the production of multiple protein isoforms from a single gene. An involvement of alternative splicing in the key biological signalling Hippo pathway is emerging and offers new therapeutic avenues. This review discusses examples of alternative splicing in the Hippo pathway, how deregulation of these processes may contribute to disease and whether these processes offer new potential therapeutic targets. PMID:29534050

Multiple Sclerosis: Epidemiologic, Clinical, and Therapeutic Aspects.

PubMed

Vidal-Jordana, Angela; Montalban, Xavier

2017-05-01

Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system that affects young people. MS develops in genetically susceptible individuals exposed to different unknown triggering factors. Different phenotypes are described. About 15% of patients present with a primary progressive course and 85% with a relapsing-remitting course. An increasing number of disease-modifying treatments has emerged. Although encouraging, the number of drugs challenges the neurologist because each treatment has its own risk-benefit profile. Patients should be involved in the decision-making process to ensure good treatment and safety monitoring adherence. Copyright © 2016 Elsevier Inc. All rights reserved.

Predictive Models for Tomato Spotted Wilt Virus Spread Dynamics, Considering Frankliniella occidentalis Specific Life Processes as Influenced by the Virus

PubMed Central

Ogada, Pamella Akoth; Moualeu, Dany Pascal; Poehling, Hans-Michael

2016-01-01

Several models have been studied on predictive epidemics of arthropod vectored plant viruses in an attempt to bring understanding to the complex but specific relationship between the three cornered pathosystem (virus, vector and host plant), as well as their interactions with the environment. A large body of studies mainly focuses on weather based models as management tool for monitoring pests and diseases, with very few incorporating the contribution of vector’s life processes in the disease dynamics, which is an essential aspect when mitigating virus incidences in a crop stand. In this study, we hypothesized that the multiplication and spread of tomato spotted wilt virus (TSWV) in a crop stand is strongly related to its influences on Frankliniella occidentalis preferential behavior and life expectancy. Model dynamics of important aspects in disease development within TSWV-F. occidentalis-host plant interactions were developed, focusing on F. occidentalis’ life processes as influenced by TSWV. The results show that the influence of TSWV on F. occidentalis preferential behaviour leads to an estimated increase in relative acquisition rate of the virus, and up to 33% increase in transmission rate to healthy plants. Also, increased life expectancy; which relates to improved fitness, is dependent on the virus induced preferential behaviour, consequently promoting multiplication and spread of the virus in a crop stand. The development of vector–based models could further help in elucidating the role of tri-trophic interactions in agricultural disease systems. Use of the model to examine the components of the disease process could also boost our understanding on how specific epidemiological characteristics interact to cause diseases in crops. With this level of understanding we can efficiently develop more precise control strategies for the virus and the vector. PMID:27159134

Predictive Models for Tomato Spotted Wilt Virus Spread Dynamics, Considering Frankliniella occidentalis Specific Life Processes as Influenced by the Virus.

PubMed

Ogada, Pamella Akoth; Moualeu, Dany Pascal; Poehling, Hans-Michael

2016-01-01

Several models have been studied on predictive epidemics of arthropod vectored plant viruses in an attempt to bring understanding to the complex but specific relationship between the three cornered pathosystem (virus, vector and host plant), as well as their interactions with the environment. A large body of studies mainly focuses on weather based models as management tool for monitoring pests and diseases, with very few incorporating the contribution of vector's life processes in the disease dynamics, which is an essential aspect when mitigating virus incidences in a crop stand. In this study, we hypothesized that the multiplication and spread of tomato spotted wilt virus (TSWV) in a crop stand is strongly related to its influences on Frankliniella occidentalis preferential behavior and life expectancy. Model dynamics of important aspects in disease development within TSWV-F. occidentalis-host plant interactions were developed, focusing on F. occidentalis' life processes as influenced by TSWV. The results show that the influence of TSWV on F. occidentalis preferential behaviour leads to an estimated increase in relative acquisition rate of the virus, and up to 33% increase in transmission rate to healthy plants. Also, increased life expectancy; which relates to improved fitness, is dependent on the virus induced preferential behaviour, consequently promoting multiplication and spread of the virus in a crop stand. The development of vector-based models could further help in elucidating the role of tri-trophic interactions in agricultural disease systems. Use of the model to examine the components of the disease process could also boost our understanding on how specific epidemiological characteristics interact to cause diseases in crops. With this level of understanding we can efficiently develop more precise control strategies for the virus and the vector.

Rare inflammatory diseases of the white matter and mimics of multiple sclerosis and related disorders.

PubMed

Tardieu, Marc; Deiva, Kumaran

2013-12-01

The spectra of white matter neuroinflammatory diseases and pathological processes inducing inflammatory lesions in the white matter of the central nervous system are wider in children than in adults. The definitions of multiple sclerosis (MS) and of the related clinically isolated syndromes (CIS) and acute disseminated encephalomyelitis (ADEM) have been recently revised leading to a new consensus definition. However, other entities with similarities to these diseases may also develop with monophasic or relapsing white matter inflammation. These conditions include congenital immunogenetic diseases (such as hemophagocytic lymphohistiocytosis), vasculitis, and autoantibody-mediated encephalopathies (Hashimoto encephalopathy, encephalitis with anti-N-methyl-D-aspartate receptor antibodies and neuromyelitis optica). Moreover, infectious diseases, such as Lyme disease, tumors (oligodendroglioma and lymphoma), and even genetic or metabolic diseases should also be considered if the clinical course of the disease does not follow the typical pattern for ADEM or MS. This short review describes these different entities and provides information for the differential diagnosis of inflammatory diseases of the white matter. Georg Thieme Verlag KG Stuttgart · New York.

Behavioral Relaxation Training for Parkinson's Disease Related Dyskinesia and Comorbid Social Anxiety

ERIC Educational Resources Information Center

Lundervold, Duane A.; Pahwa, Rajesh; Lyons, Kelly E.

2013-01-01

Effects of brief Behavioral Relaxation Training (BRT) on anxiety and dyskinesia of a 57-year-old female, with an 11-year history of Parkinson's disease (PD) and 18-months post-deep brain stimulation of the subthalamic nucleus, were evaluated. Multiple process and outcome measures were used including the Clinical Anxiety Scale (CAS), Subjective…

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

PubMed

Studer, Valeria; Rocchi, Camilla; Motta, Caterina; Lauretti, Benedetta; Perugini, Jacopo; Brambilla, Laura; Pareja-Gutierrez, Lorena; Camera, Giorgia; Barbieri, Francesca Romana; Marfia, Girolama A; Centonze, Diego; Rossi, Silvia

2017-01-01

Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

PubMed

Correale, Jorge; Gaitán, María I; Ysrraelit, María C; Fiol, Marcela P

2017-03-01

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Can discrete event simulation be of use in modelling major depression?

PubMed Central

Le Lay, Agathe; Despiegel, Nicolas; François, Clément; Duru, Gérard

2006-01-01

Background Depression is among the major contributors to worldwide disease burden and adequate modelling requires a framework designed to depict real world disease progression as well as its economic implications as closely as possible. Objectives In light of the specific characteristics associated with depression (multiple episodes at varying intervals, impact of disease history on course of illness, sociodemographic factors), our aim was to clarify to what extent "Discrete Event Simulation" (DES) models provide methodological benefits in depicting disease evolution. Methods We conducted a comprehensive review of published Markov models in depression and identified potential limits to their methodology. A model based on DES principles was developed to investigate the benefits and drawbacks of this simulation method compared with Markov modelling techniques. Results The major drawback to Markov models is that they may not be suitable to tracking patients' disease history properly, unless the analyst defines multiple health states, which may lead to intractable situations. They are also too rigid to take into consideration multiple patient-specific sociodemographic characteristics in a single model. To do so would also require defining multiple health states which would render the analysis entirely too complex. We show that DES resolve these weaknesses and that its flexibility allow patients with differing attributes to move from one event to another in sequential order while simultaneously taking into account important risk factors such as age, gender, disease history and patients attitude towards treatment, together with any disease-related events (adverse events, suicide attempt etc.). Conclusion DES modelling appears to be an accurate, flexible and comprehensive means of depicting disease progression compared with conventional simulation methodologies. Its use in analysing recurrent and chronic diseases appears particularly useful compared with Markov processes. PMID:17147790

Can discrete event simulation be of use in modelling major depression?

PubMed

Le Lay, Agathe; Despiegel, Nicolas; François, Clément; Duru, Gérard

2006-12-05

Depression is among the major contributors to worldwide disease burden and adequate modelling requires a framework designed to depict real world disease progression as well as its economic implications as closely as possible. In light of the specific characteristics associated with depression (multiple episodes at varying intervals, impact of disease history on course of illness, sociodemographic factors), our aim was to clarify to what extent "Discrete Event Simulation" (DES) models provide methodological benefits in depicting disease evolution. We conducted a comprehensive review of published Markov models in depression and identified potential limits to their methodology. A model based on DES principles was developed to investigate the benefits and drawbacks of this simulation method compared with Markov modelling techniques. The major drawback to Markov models is that they may not be suitable to tracking patients' disease history properly, unless the analyst defines multiple health states, which may lead to intractable situations. They are also too rigid to take into consideration multiple patient-specific sociodemographic characteristics in a single model. To do so would also require defining multiple health states which would render the analysis entirely too complex. We show that DES resolve these weaknesses and that its flexibility allow patients with differing attributes to move from one event to another in sequential order while simultaneously taking into account important risk factors such as age, gender, disease history and patients attitude towards treatment, together with any disease-related events (adverse events, suicide attempt etc.). DES modelling appears to be an accurate, flexible and comprehensive means of depicting disease progression compared with conventional simulation methodologies. Its use in analysing recurrent and chronic diseases appears particularly useful compared with Markov processes.

The emergence of designed multiple ligands for neurodegenerative disorders.

PubMed

Geldenhuys, Werner J; Youdim, Moussa B H; Carroll, Richard T; Van der Schyf, Cornelis J

2011-09-01

The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline. Copyright © 2011. Published by Elsevier Ltd.

Interleukin 35 and Hepatocyte Growth Factor; as a novel combined immune gene therapy for Multiple Sclerosis disease.

PubMed

Moghadam, Samira; Erfanmanesh, Maryam; Esmaeilzadeh, Abdolreza

2017-11-01

An autoimmune demyelination disease of the Central Nervous System, Multiple Sclerosis, is a chronic inflammation which mostly involves young adults. Suffering people face functional loss with a severe pain. Most current MS treatments are focused on the immune response suppression. Approved drugs suppress the inflammatory process, but factually, there is no definite cure for Multiple Sclerosis. Recently developed knowledge has demonstrated that gene and cell therapy as a hopeful approach in tissue regeneration. The authors propose a novel combined immune gene therapy for Multiple Sclerosis treatment using anti-inflammatory and remyelination of Interleukine-35 and Hepatocyte Growth Factor properties, respectively. In this hypothesis Interleukine-35 and Hepatocyte Growth Factor introduce to Mesenchymal Stem Cells of EAE mouse model via an adenovirus based vector. It is expected that Interleukine-35 and Hepatocyte Growth Factor genes expressed from MSCs could effectively perform in immunotherapy of Multiple Sclerosis. Copyright © 2017. Published by Elsevier Ltd.

Human Chagas Disease and Migration in the Context of Globalization: Some Particular Aspects

PubMed Central

Pinto Dias, João Carlos

2013-01-01

Human Chagas disease originated in Latin America, being spread around the world in relation with multiple bioecological, sociocultural, and political factors. The process of the disease production and dispersion is discussed, emphasizing the human migration and correlated aspects, in the context of globalization. Positive and negative consequences concern the future of this trypanosomiasis, mainly in terms of the ecologic and sociopolitical characteristics of the endemic and nonendemic countries. PMID:23606862

[Cormorbidity in multiple sclerosis and its therapeutic approach].

PubMed

Estruch, Bonaventura Casanova

2014-12-01

Multiple sclerosis (MS) is a long-term chronic disease, in which intercurrent processes develop three times more frequently in affected individuals than in persons without MS. Knowledge of the comorbidity of MS, its definition and measurement (Charlson index) improves patient management. Acting on comorbid conditions delays the progression of disability, which is intimately linked to the number of concurrent processes and with health states and habits. Moreover, the presence of comorbidities delays the diagnosis of MS, which in turn delays the start of treatment. The main comorbidity found in MS includes other autoimmune diseases (thyroiditis, systemic lupus erythematosus, or pemphigus) but can also include general diseases, such as asthma or osteomuscular alterations, and, in particular, psychiatric disturbances. All these alterations should be evaluated with multidimensional scales (Disability Expectancy Table, DET), which allow more accurate determination of the patient's real clinical course and quality of life. These scales also allow identification of how MS, concurrent and intercurrent processes occurring during the clinical course, and the treatment provided affect patients with MS. An overall approach to patients' health status helps to improve quality of life. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Diagnosis and treatment of latent tuberculosis in patients with multiple sclerosis, expert consensus. On behalf of the Colombian Association of Neurology, Committee of Multiple Sclerosis.

PubMed

Navas, Carlos; Torres-Duque, Carlos A; Munoz-Ceron, Joe; Álvarez, Carlos; García, Juan R; Zarco, Luis; Vélez, Lázaro A; Awad, Carlos; Castro, Carlos Alberto

2018-01-01

Multiple sclerosis is an inflammatory and neurodegenerative demyelinating disease. Current treatment of multiple sclerosis focuses on the use of immunomodulatory, immunosuppressant, and selective immunosuppressant agents. Some of these medications may result in high risk of opportunistic infections including tuberculosis. The purpose of this study was to obtain consensus from a panel of neurologists, pulmonologists, infectious disease specialists, and epidemiology experts regarding the diagnosis, treatment, and monitoring of latent tuberculosis in patients with multiple sclerosis. A panel of experts in multiple sclerosis and tuberculosis was established. The methodological process was performed in three phases: definition of questions, answer using Delphi methodology, and the discussion of questions not agreed. Tuberculosis screening is suggested when multiple sclerosis drugs are prescribed. The recommended tests for latent tuberculosis are tuberculin and interferon gamma release test. When an anti-tuberculosis treatment is indicated, monitoring should be performed to determine liver enzyme values with consideration of age as well as comorbid conditions such as a history of alcoholism, age, obesity, concomitant hepatotoxic drugs, and history of liver disease. Latent tuberculosis should be considered in patients with multiple sclerosis who are going to be treated with immunomodulatory and immunosuppressant medications. Transaminase level monitoring is required on a periodic basis depending on clinical and laboratory characteristics. In addition to the liver impairment, other side effects should be considered when Isoniazid is prescribed.

A qualitative study assessing patient perspectives in the process of decision-making on disease modifying therapies (DMT's) in multiple sclerosis (MS).

PubMed

Ceuninck van Capelle, Archibald de; Meide, Hanneke van der; Vosman, Frans J H; Visser, Leo H

2017-01-01

Physicians commonly advise patients to begin disease modifying therapies (DMT's) shortly after the establishment of a diagnosis of Multiple Sclerosis (MS) to prevent further relapses and disease progression. However, little is known about the meaning for patients going through the process of the diagnosis of MS and of making decisions on DMT's in early MS. To explore the patient perspective on using DMT's for MS. Methods: Ten participants with a recent (< 2 years) relapsing-remitting MS diagnosis were interviewed. Seven of them were using DMT's at the time of the interview. All interviews were transcribed and analyzed using a hermeneutical-phenomenological approach. The analysis revealed the following themes: (1) Constant confrontation with the disease, (2) Managing inevitable decline, (3) Hope of delaying the progression of the disease, and, (4) The importance of social support. The themes show that patients associate the recommendation to begin DMT's (especially injectable DMT's) with views about their bodies as well as their hopes about the future. Both considering and adhering to treatment are experienced by patients as not only matters of individual and rational deliberation, but also as activities that are lived within a web of relationships with relatives and friends. From the patient perspective, the use of DMT's is not a purely rational and individual experience. More attention to the use of DMT's as relational and lived phenomena will improve the understanding of the process of decision-making for DMT's in MS.

Systems thinking in combating infectious diseases.

PubMed

Xia, Shang; Zhou, Xiao-Nong; Liu, Jiming

2017-09-11

The transmission of infectious diseases is a dynamic process determined by multiple factors originating from disease pathogens and/or parasites, vector species, and human populations. These factors interact with each other and demonstrate the intrinsic mechanisms of the disease transmission temporally, spatially, and socially. In this article, we provide a comprehensive perspective, named as systems thinking, for investigating disease dynamics and associated impact factors, by means of emphasizing the entirety of a system's components and the complexity of their interrelated behaviors. We further develop the general steps for performing systems approach to tackling infectious diseases in the real-world settings, so as to expand our abilities to understand, predict, and mitigate infectious diseases.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C; Otto, Markus; Tumani, Hayrettin

2015-07-31

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed Central

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C.; Otto, Markus; Tumani, Hayrettin

2015-01-01

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs. PMID:26263977

Dietary Phosphorus Intake and the Kidney

PubMed Central

Chang, Alex R.; Anderson, Cheryl

2017-01-01

Although phosphorus is an essential nutrient required for multiple physiological functions, recent research raises concerns that high phosphorus intake could have detrimental effects on health. Phosphorus is abundant in the food supply of developed countries, occurring naturally in protein-rich foods and as an additive in processed foods. High phosphorus intake can cause vascular and renal calcification, renal tubular injury, and premature death in multiple animal models. Small studies in human suggest that high phosphorus intake may result in positive phosphorus balance and correlate with renal calcification and albuminuria. Although serum phosphorus is strongly associated with cardiovascular disease, progression of kidney disease, and death, limited data exist linking high phosphorus intake directly to adverse clinical outcomes. Further prospective studies are needed to determine whether phosphorus intake is a modifiable risk factor for kidney disease. PMID:28613982

Framework for Infectious Disease Analysis: A comprehensive and integrative multi-modeling approach to disease prediction and management.

PubMed

Erraguntla, Madhav; Zapletal, Josef; Lawley, Mark

2017-12-01

The impact of infectious disease on human populations is a function of many factors including environmental conditions, vector dynamics, transmission mechanics, social and cultural behaviors, and public policy. A comprehensive framework for disease management must fully connect the complete disease lifecycle, including emergence from reservoir populations, zoonotic vector transmission, and impact on human societies. The Framework for Infectious Disease Analysis is a software environment and conceptual architecture for data integration, situational awareness, visualization, prediction, and intervention assessment. Framework for Infectious Disease Analysis automatically collects biosurveillance data using natural language processing, integrates structured and unstructured data from multiple sources, applies advanced machine learning, and uses multi-modeling for analyzing disease dynamics and testing interventions in complex, heterogeneous populations. In the illustrative case studies, natural language processing from social media, news feeds, and websites was used for information extraction, biosurveillance, and situation awareness. Classification machine learning algorithms (support vector machines, random forests, and boosting) were used for disease predictions.

Software to Facilitate Remote Sensing Data Access for Disease Early Warning Systems

PubMed Central

Liu, Yi; Hu, Jiameng; Snell-Feikema, Isaiah; VanBemmel, Michael S.; Lamsal, Aashis; Wimberly, Michael C.

2015-01-01

Satellite remote sensing produces an abundance of environmental data that can be used in the study of human health. To support the development of early warning systems for mosquito-borne diseases, we developed an open-source, client based software application to enable the Epidemiological Applications of Spatial Technologies (EASTWeb). Two major design decisions were full automation of the discovery, retrieval and processing of remote sensing data from multiple sources, and making the system easily modifiable in response to changes in data availability and user needs. Key innovations that helped to achieve these goals were the implementation of a software framework for data downloading and the design of a scheduler that tracks the complex dependencies among multiple data processing tasks and makes the system resilient to external errors. EASTWeb has been successfully applied to support forecasting of West Nile virus outbreaks in the United States and malaria epidemics in the Ethiopian highlands. PMID:26644779

Pathways leading to an immunological disease: systemic lupus erythematosus.

PubMed

Zharkova, Olga; Celhar, Teja; Cravens, Petra D; Satterthwaite, Anne B; Fairhurst, Anna-Marie; Davis, Laurie S

2017-04-01

SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes. We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in SLE and highlight new findings. We describe the immunological changes that characterize this form of autoimmunity. The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.

How do immune cells support and shape the brain in health, disease, and aging?

PubMed

Schwartz, Michal; Kipnis, Jonathan; Rivest, Serge; Prat, Alexandre

2013-11-06

For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed.

Clinical Outcome Assessments: Use of Normative Data in a Pediatric Rare Disease.

PubMed

Phillips, Dawn; Leiro, Beth

2018-05-01

Pediatric rare diseases present unique challenges in clinical trial design and in selection of clinical outcome assessments (COAs) used to support claims in medical product labeling. COAs that discriminate level of function relative to a normative sample are particularly important in the pediatric rare disease setting because the literature is often void of natural history data. Pediatric rare disease clinical trials will often include a wide age distribution. Gross and fine motor skills, communication, cognition, and independence in activities of daily living vary by age, and it may be difficult to distinguish between treatment effect and change due to developmental maturation. Asfotase alfa was granted breakthrough therapy designation and subsequently approved for the treatment of hypophosphatasia (HPP; a genetic metabolic musculoskeletal disorder) and is used in this discussion to illustrate COA selection in a pediatric rare disease. Multiple COAs with normative data in HPP clinical trials for asfotase alfa are presented. The assessment instruments included the Bayley Scales of Infant and Toddler Development-Third Edition, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, the Childhood Health Assessment Questionnaire, the Pediatric Outcomes Data Collection Instrument, handheld dynamometry, the 6-minute walk test, and the Modified Performance-Oriented Mobility Assessment-Gait scale. Multiple end points were required to adequately capture the impact of asfotase alfa treatment on the multiple systems affected in HPP. These data illustrate the importance of using multiple COAs that provide normative data and to use COAs early in the drug development process for rare pediatric disease. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

[Coincidence of juvenile idiopathic arthritis and multiple sclerosis: case report].

PubMed

Puszczewicz, Mariusz J; Tuchocka-Piotrowska, Aleksandra; Majewski, Dominik; Kołczewska, Aleksandra

2006-01-01

Juvenile idiopathic arthritis is a systemic pathology of connective tissue characterized by a chronic inflammatory process with an autoimmune background whereas multiple sclerosis is a demyelination disease with an important role of immune disorders in its pathogenesis. The etiology in both cases remains unknown. The coincidence of juvenile idiopathic arthritis and multiple sclerosis was described a just a few patients. We now report on a 31-year-old woman with juvenile idiopathic arthritis and multiple sclerosis. In the present case, the main problem was to find the right proper medication for a very, aggressive course of multiple sclerosis and for arthritis. Treatment with interferon-beta and methylprednisolone led to remission with just minor side-effects.

Role of Proangiogenic Factors in Immunopathogenesis of Multiple Sclerosis.

PubMed

Hamid, Kabir Magaji; Mirshafiey, Abbas

2016-02-01

Angiogenesis is a complex and balanced process in which new blood vessels form from preexisting ones by sprouting, splitting, growth and remodeling. This phenomenon plays a vital role in many physiological and pathological processes. However, the disturbance in physiological process can play a role in pathogenesis of some chronic inflammatory diseases, including multiple sclerosis (MS) in human and its animal model. Although the relation between abnormal blood vessels and MS lesions was established in previous studies, but the role of pathological angiogenesis remains unclear. In this study, the link between proangiogenic factors and multiple sclerosis pathogenesis was examined by conducting a systemic review. Thus we searched the English medical literature via PubMed, ISI web of knowledge, Medline and virtual health library (VHL) databases. In this review, we describe direct and indirect roles of some proangiogenic factors in MS pathogenesis and report the association of these factors with pathological and inflammatory angiogenesis.

Development of anti-inflammatory drugs - the research and development process.

PubMed

Knowles, Richard Graham

2014-01-01

The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti-inflammatory medicines. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

Omics analysis of mouse brain models of human diseases.

PubMed

Paban, Véronique; Loriod, Béatrice; Villard, Claude; Buee, Luc; Blum, David; Pietropaolo, Susanna; Cho, Yoon H; Gory-Faure, Sylvie; Mansour, Elodie; Gharbi, Ali; Alescio-Lautier, Béatrice

2017-02-05

The identification of common gene/protein profiles related to brain alterations, if they exist, may indicate the convergence of the pathogenic mechanisms driving brain disorders. Six genetically engineered mouse lines modelling neurodegenerative diseases and neuropsychiatric disorders were considered. Omics approaches, including transcriptomic and proteomic methods, were used. The gene/protein lists were used for inter-disease comparisons and further functional and network investigations. When the inter-disease comparison was performed using the gene symbol identifiers, the number of genes/proteins involved in multiple diseases decreased rapidly. Thus, no genes/proteins were shared by all 6 mouse models. Only one gene/protein (Gfap) was shared among 4 disorders, providing strong evidence that a common molecular signature does not exist among brain diseases. The inter-disease comparison of functional processes showed the involvement of a few major biological processes indicating that brain diseases of diverse aetiologies might utilize common biological pathways in the nervous system, without necessarily involving similar molecules. Copyright © 2016 Elsevier B.V. All rights reserved.

Advances of Molecular Imaging for Monitoring the Anatomical and Functional Architecture of the Olfactory System.

PubMed

Zhang, Xintong; Bi, Anyao; Gao, Quansheng; Zhang, Shuai; Huang, Kunzhu; Liu, Zhiguo; Gao, Tang; Zeng, Wenbin

2016-01-20

The olfactory system of organisms serves as a genetically and anatomically model for studying how sensory input can be translated into behavior output. Some neurologic diseases are considered to be related to olfactory disturbance, especially Alzheimer's disease, Parkinson's disease, multiple sclerosis, and so forth. However, it is still unclear how the olfactory system affects disease generation processes and olfaction delivery processes. Molecular imaging, a modern multidisciplinary technology, can provide valid tools for the early detection and characterization of diseases, evaluation of treatment, and study of biological processes in living subjects, since molecular imaging applies specific molecular probes as a novel approach to produce special data to study biological processes in cellular and subcellular levels. Recently, molecular imaging plays a key role in studying the activation of olfactory system, thus it could help to prevent or delay some diseases. Herein, we present a comprehensive review on the research progress of the imaging probes for visualizing olfactory system, which is classified on different imaging modalities, including PET, MRI, and optical imaging. Additionally, the probes' design, sensing mechanism, and biological application are discussed. Finally, we provide an outlook for future studies in this field.

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases

PubMed Central

Davalli, Pierpaola; Mitic, Tijana; Caporali, Andrea; Lauriola, Angela; D'Arca, Domenico

2016-01-01

The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS) and/or Reactive Nitrosative Species (RNS). Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging. PMID:27247702

Multiple biomarkers in molecular oncology. I. Molecular diagnostics applications in cervical cancer detection.

PubMed

Malinowski, Douglas P

2007-03-01

The screening for cervical carcinoma and its malignant precursors (cervical neoplasia) currently employs morphology-based detection methods (Papanicolaou [Pap] smear) in addition to the detection of high-risk human papillomavirus. The combination of the Pap smear with human papillomavirus testing has achieved significant improvements in sensitivity for the detection of cervical disease. Diagnosis of cervical neoplasia is dependent upon histology assessment of cervical biopsy specimens. Attempts to improve the specificity of cervical disease screening have focused on the investigation of molecular biomarkers for adjunctive use in combination with the Pap smear. Active research into the genomic and proteomic alterations that occur during human papillomavirus-induced neoplastic transformation have begun to characterize some of the basic mechanisms inherent to the disease process of cervical cancer development. This research continues to demonstrate the complexity of multiple genomic and proteomic alterations that accumulate during the tumorigenesis process. Despite this diversity, basic patterns of uncontrolled signal transduction, cell cycle deregulation, activation of DNA replication and altered extracellular matrix interactions are beginning to emerge as common features inherent to cervical cancer development. Some of these gene or protein expression alterations have been investigated as potential biomarkers for screening and diagnostics applications. The contribution of multiple gene alterations in the development of cervical cancer suggests that the application of multiple biomarker panels has the potential to develop clinically useful molecular diagnostics. In this review, the application of biomarkers for the improvement of sensitivity and specificity of the detection of cervical neoplasia within cytology specimens will be discussed.

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

PubMed

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

2000-07-01

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

Optimizing the antioxidant activity of Kelakai (Stenochlaena palustris) through multiplestage extraction process

NASA Astrophysics Data System (ADS)

Wijaya, Elza; Widiputri, Diah Indriani; Rahmawati, Della

2017-11-01

Kelakai is known as traditional remedy for treating several diseases, such as fever, anemia, and stimulate the production of breast milk for breastfeeding mother. Instead of those benefits, kelakai also proved has several kinds of antioxidant properties. Therefore, extracting antioxidant properties from kelakai is one way to discover the amount of antioxidant activity contained in kelakai. In this research, the multiple-stage extraction process was done in order to optimize the antioxidant activity. Moreover, based on data obtained from single stage extraction process, the most suitable condition was discovered. It turns out that the use of milled sample in water solvent for 12 hours at 44°C produce the highest antioxidant activity, which is 919.95 mg to inhibit 50% of DPPH. Referred to the experiment, the antioxidant activity of the extract which gained from multiple-stage was higher than from single stage. Multiple-stage process has proven the increasing of antioxidant activity up to 72.43%, which is need 404 mg to inhibit 50% of DPPH.

Renal redox stress and remodeling in metabolic syndrome, type 2 diabetes mellitus, and diabetic nephropathy: paying homage to the podocyte.

PubMed

Hayden, Melvin R; Whaley-Connell, Adam; Sowers, James R

2005-01-01

Type 2 diabetes mellitus has reached epidemic proportions and diabetic nephropathy is the leading cause of end-stage renal disease. The metabolic syndrome constitutes a milieu conducive to tissue redox stress. This loss of redox homeostasis contributes to renal remodeling and parallels the concurrent increased vascular redox stress associated with the cardiometabolic syndrome. The multiple metabolic toxicities, redox stress and endothelial dysfunction combine to weave the complicated mosaic fabric of diabetic glomerulosclerosis and diabetic nephropathy. A better understanding may provide both the clinician and researcher tools to unravel this complicated disease process. Cellular remodeling of podocyte foot processes in the Ren-2 transgenic rat model of tissue angiotensin II overexpression (TG(mREN-2)27) and the Zucker diabetic fatty model of type 2 diabetes mellitus have been observed in preliminary studies. Importantly, angiotensin II receptor blockers have been shown to abrogate these ultrastructural changes in the foot processes of the podocyte in preliminary studies. An integrated, global risk reduction, approach in therapy addressing the multiple metabolic abnormalities combined with attempts to reach therapeutic goals at an earlier stage could have a profound effect on the development and progressive nature to end-stage renal disease and ultimately renal replacement therapy.

Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS).

PubMed

Glatigny, Simon; Bettelli, Estelle

2018-01-08

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system (CNS) leading to the progressive destruction of the myelin sheath surrounding axons. It can present with variable clinical and pathological manifestations, which might reflect the involvement of distinct pathogenic processes. Although the mechanisms leading to the development of the disease are not fully understood, numerous evidences indicate that MS is an autoimmune disease, the initiation and progression of which are dependent on an autoimmune response against myelin antigens. In addition, genetic susceptibility and environmental triggers likely contribute to the initiation of the disease. At this time, there is no cure for MS, but several disease-modifying therapies (DMTs) are available to control and slow down disease progression. A good number of these DMTs were identified and tested using animal models of MS referred to as experimental autoimmune encephalomyelitis (EAE). In this review, we will recapitulate the characteristics of EAE models and discuss how they help shed light on MS pathogenesis and help test new treatments for MS patients. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

PubMed

Coll, Rebecca C; Robertson, Avril A B; Chae, Jae Jin; Higgins, Sarah C; Muñoz-Planillo, Raúl; Inserra, Marco C; Vetter, Irina; Dungan, Lara S; Monks, Brian G; Stutz, Andrea; Croker, Daniel E; Butler, Mark S; Haneklaus, Moritz; Sutton, Caroline E; Núñez, Gabriel; Latz, Eicke; Kastner, Daniel L; Mills, Kingston H G; Masters, Seth L; Schroder, Kate; Cooper, Matthew A; O'Neill, Luke A J

2015-03-01

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

Immunomodulation of multiple myeloma.

PubMed

Tohnya, Tanyifor M; Figg, William D

2004-11-01

Multiple myeloma is a multi-process disease, and these different processes are responsible for the reduced sensitivity to chemotherapy and radiotherapy, hence the relapse and refractory nature of multiple myeloma. Emphasis is now placed on the hypothesis that myeloma cell growth, inhibition of apoptosis and drug resistance are dependent on immunomodulatory cytokines such as IL-6 and pro-angiogenic factors such as VEGF. In addition to its anti-angiogenic effects, the immunomodulatory properties of thalidomide make it a possible therapy for patients with advanced multiple myeloma. This has lead to the clinical development of a number of immunomodulatory thalidomide analogues (IMiDs) which are more potent and have less side effects than the parent drug, thalidomide. In the August 15(th) issue of Journal of Clinical Oncology, Schey SA et al. suggested that an IMiD (CC-4047) maybe efficacious due to T-cell co-stimulation, and safe in patients with relapsed or refractory multiple myeloma. This article demonstrates a supporting role for IMiDs as immunomodulatory adjuvant therapy.

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

PubMed Central

Hametner, Simon; Yao, Bing; van Gelderen, Peter; Merkle, Hellmut; Cantor, Fredric K.; Lassmann, Hans; Duyn, Jeff H.

2011-01-01

Previous authors have shown that the transverse relaxivity R2* and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R2* and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3- to 5-µm thick paraffin sections. Iron was detected with Perl's staining and 3,3′-diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining. In multiple sclerosis tissue, iron presence invariably matched with an increase in R2*. Conversely, R2* increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history. PMID:22171355

May Diet and Dietary Supplements Improve the Wellness of Multiple Sclerosis Patients? A Molecular Approach

PubMed Central

Riccio, Paolo; Rossano, Rocco; Liuzzi, Grazia Maria

2010-01-01

Multiple sclerosis is a complex and multifactorial neurological disease, and nutrition is one of the environmental factors possibly involved in its pathogenesis. At present, the role of nutrition is unclear, and MS therapy is not associated to a particular diet. MS clinical trials based on specific diets or dietary supplements are very few and in some cases controversial. To understand how diet can influence the course of MS and improve the wellness of MS patients, it is necessary to identify the dietary molecules, their targets and the molecular mechanisms involved in the control of the disease. The aim of this paper is to provide a molecular basis for the nutritional intervention in MS by evaluating at molecular level the effect of dietary molecules on the inflammatory and autoimmune processes involved in the disease. PMID:21461338

Inflammasome and Autophagy Regulation: A Two-way Street

PubMed Central

Qian, Sun; Fan, Jie; Billiar, Timothy R; Scott, Melanie J

2017-01-01

Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. The inflammasome is a major innate immune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a protein complex including a nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines interleukin (IL)-1β and IL-18 from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation is linked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer’s disease and multiple sclerosis. So there is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy has now been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeostasis, recycling and removal of damaged organelles (eg, mitochondria) and intracellular pathogens. Autophagy is regulated by proteins that are important in endosomal/phagosomal pathways, as well as by specific autophagy proteins coded for by autophagy-related genes. Cytosolic components are surrounded and contained by a double-membraned vesicle, which then fuses with lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome components or cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing for a two-way mutual regulation of inflammation that may hold the key for treatment of multiple diseases. PMID:28741645

[Neuropsychology of mildly disabled patients with relapsing-remitting multiple sclerosis].

PubMed

Santiago Rolanía, Olga; Guàrdia Olmos, Joan; Arbizu Urdiain, Txomin

2006-02-01

Previous papers have mainly demonstrated the presence of cognitive impairment in patients with multiple sclerosis (MS), these changes have been traditionally associated with the later stages of the disease. In the current study, a comprehensive neuropsychological battery was administered to 216 relapsing-remitting MS patients with mild clinical disability (EDSS

Calvarial sarcoid mimicking metastatic disease.

PubMed

Bodie, B F; Kheir, S M; Omura, E F

1980-10-01

A 61-year-old white woman presented with localized cutaneous Boeck's sarcoid and multiple lytic skull lesions mimicking metastatic carcinoma. Complete workup revealed no neoplastic process; biopsy of the skull lesions showed noncaseating granulomas consistent with sarcoid. Although rare, calvarial sarcoid can occur.

Second-Order Analysis of Semiparametric Recurrent Event Processes

PubMed Central

Guan, Yongtao

2011-01-01

Summary A typical recurrent event dataset consists of an often large number of recurrent event processes, each of which contains multiple event times observed from an individual during a followup period. Such data have become increasingly available in medical and epidemiological studies. In this paper, we introduce novel procedures to conduct second-order analysis for a flexible class of semiparametric recurrent event processes. Such an analysis can provide useful information regarding the dependence structure within each recurrent event process. Specifically, we will use the proposed procedures to test whether the individual recurrent event processes are all Poisson processes and to suggest sensible alternative models for them if they are not. We apply these procedures to a well-known recurrent event dataset on chronic granulomatous disease and an epidemiological dataset on Meningococcal disease cases in Merseyside, UK to illustrate their practical value. PMID:21361885

Resting-state functional connectivity in multiple sclerosis: an examination of group differences and individual differences.

PubMed

Janssen, Alisha L; Boster, Aaron; Patterson, Beth A; Abduljalil, Amir; Prakash, Ruchika Shaurya

2013-11-01

Multiple sclerosis (MS) is a neurodegenerative, inflammatory disease of the central nervous system, resulting in physical and cognitive disturbances. The goal of the current study was to examine the association between network integrity and composite measures of cognition and disease severity in individuals with relapsing-remitting MS (RRMS), relative to healthy controls. All participants underwent a neuropsychological and neuroimaging session, where resting-state data was collected. Independent component analysis and dual regression were employed to examine network integrity in individuals with MS, relative to healthy controls. The MS sample exhibited less connectivity in the motor and visual networks, relative to healthy controls, after controlling for group differences in gray matter volume. However, no alterations were observed in the frontoparietal, executive control, or default-mode networks, despite previous evidence of altered neuronal patterns during tasks of exogenous processing. Whole-brain, voxel-wise regression analyses with disease severity and processing speed composites were also performed to elucidate the brain-behavior relationship with neuronal network integrity. Individuals with higher levels of disease severity demonstrated reduced intra-network connectivity of the motor network, and the executive control network, while higher disease burden was associated with greater inter-network connectivity between the medial visual network and areas involved in visuomotor learning. Our findings underscore the importance of examining resting-state oscillations in this population, both as a biomarker of disease progression and a potential target for therapeutic intervention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Cognitive status in patients with multiple sclerosis in Lanzarote.

PubMed

Pérez-Martín, María Yaiza; Eguia-Del Río, Pablo; González-Platas, Montserrat; Jiménez-Sosa, Alejandro

2016-01-01

Cognitive impairment is a common feature in multiple sclerosis affecting ~43%-72% of patients, which involves cognitive functions such as memory, processing speed, attention, and executive function. The aim of this study was to describe the extent and pattern of the involvement of cognitive impairment and psychological status in all patients with multiple sclerosis on a small Spanish island. In all, 70 patients and 56 healthy controls were included in the study between February 2013 and May 2013. All participants were assessed using the Brief Repeatable Battery of Neuropsychological Test. The patients also completed instruments to evaluate the presence of fatigue, perceived cognitive dysfunction, and symptoms of anxiety and depression. All procedures were performed in a single session. Cognitive impairment, defined as a score <1.5 standard deviation on two subtests of the battery, was present in 35% of the participants. The most frequently affected domain was working memory, followed by verbal memory and processing speed. Disease duration showed a moderate correlation with visuospatial memory and processing speed. The Expanded Disability Status Scale score correlated with verbal and processing speed. Verbal memory was correlated with depression symptoms and fatigue. Cognitive impairment was present in 35% of the study population. The most affected domains were working memory and verbal memory. Working memory and verbal fluency deficit are independent factors of disease evolution. Cognitive decline is related to clinical variables and psychological measures such as fatigue or depression but not to anxiety.

Cognitive status in patients with multiple sclerosis in Lanzarote

PubMed Central

Pérez-Martín, María Yaiza; Eguia-del Río, Pablo; González-Platas, Montserrat; Jiménez-Sosa, Alejandro

2016-01-01

Objectives Cognitive impairment is a common feature in multiple sclerosis affecting ~43%–72% of patients, which involves cognitive functions such as memory, processing speed, attention, and executive function. The aim of this study was to describe the extent and pattern of the involvement of cognitive impairment and psychological status in all patients with multiple sclerosis on a small Spanish island. Patients and methods In all, 70 patients and 56 healthy controls were included in the study between February 2013 and May 2013. All participants were assessed using the Brief Repeatable Battery of Neuropsychological Test. The patients also completed instruments to evaluate the presence of fatigue, perceived cognitive dysfunction, and symptoms of anxiety and depression. All procedures were performed in a single session. Results Cognitive impairment, defined as a score <1.5 standard deviation on two subtests of the battery, was present in 35% of the participants. The most frequently affected domain was working memory, followed by verbal memory and processing speed. Disease duration showed a moderate correlation with visuospatial memory and processing speed. The Expanded Disability Status Scale score correlated with verbal and processing speed. Verbal memory was correlated with depression symptoms and fatigue. Conclusion Cognitive impairment was present in 35% of the study population. The most affected domains were working memory and verbal memory. Working memory and verbal fluency deficit are independent factors of disease evolution. Cognitive decline is related to clinical variables and psychological measures such as fatigue or depression but not to anxiety. PMID:27418825

Impaired neurosteroid synthesis in multiple sclerosis

PubMed Central

Noorbakhsh, Farshid; Ellestad, Kristofor K.; Maingat, Ferdinand; Warren, Kenneth G.; Han, May H.; Steinman, Lawrence; Baker, Glen B.

2011-01-01

High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcription–polymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to impaired neurosteroidogenesis in both multiple sclerosis and experimental autoimmune encephalomyelitis. The findings also indicate that allopregnanolone and perhaps other neurosteroid-like compounds might represent potential biomarkers or therapies for multiple sclerosis. PMID:21908875

B cell biology: implications for treatment of systemic lupus erythematosus.

PubMed

Anolik, J H

2013-04-01

B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread utilization of B cell depletion therapy in autoimmune diseases and the need for new therapeutic approaches in SLE, a better understanding of human B cell subsets and the balance of pathogenic and regulatory functions is of the essence.

Realizing drug repositioning by adapting a recommendation system to handle the process.

PubMed

Ozsoy, Makbule Guclin; Özyer, Tansel; Polat, Faruk; Alhajj, Reda

2018-04-12

Drug repositioning is the process of identifying new targets for known drugs. It can be used to overcome problems associated with traditional drug discovery by adapting existing drugs to treat new discovered diseases. Thus, it may reduce associated risk, cost and time required to identify and verify new drugs. Nowadays, drug repositioning has received more attention from industry and academia. To tackle this problem, researchers have applied many different computational methods and have used various features of drugs and diseases. In this study, we contribute to the ongoing research efforts by combining multiple features, namely chemical structures, protein interactions and side-effects to predict new indications of target drugs. To achieve our target, we realize drug repositioning as a recommendation process and this leads to a new perspective in tackling the problem. The utilized recommendation method is based on Pareto dominance and collaborative filtering. It can also integrate multiple data-sources and multiple features. For the computation part, we applied several settings and we compared their performance. Evaluation results show that the proposed method can achieve more concentrated predictions with high precision, where nearly half of the predictions are true. Compared to other state of the art methods described in the literature, the proposed method is better at making right predictions by having higher precision. The reported results demonstrate the applicability and effectiveness of recommendation methods for drug repositioning.

The roles of inoculants' carbon source use in the biocontrol of potato scab disease.

PubMed

Sun, Pingping; Zhao, Xinbei; Shangguan, Nini; Chang, Dongwei; Ma, Qing

2015-04-01

Despite the application of multiple strains in the biocontrol of plant diseases, multistrain inoculation is still constrained by its inconsistency in the field. Nutrients, especially carbons, play an important role in the biocontrol processes. However, little work has been done on the systematic estimation of inoculants' carbon source use on biocontrol efficacies in vivo. In the present study, 7 nonpathogenic Streptomyces strains alone and in different combinations were inoculated as biocontrol agents against the potato scab disease, under field conditions and greenhouse treatments. The influence of the inoculants' carbon source use properties on biocontrol efficacies was investigated. The results showed that increasing the number of inoculated strains did not necessarily result in greater biocontrol efficacy in vivo. However, single strains with higher growth rates or multiple strains with less carbon source competition had positive effects on the biocontrol efficacies. These findings may shed light on optimizing the consistent biocontrol of plant disease with the consideration of inoculants' carbon source use properties.

Acute and chronic hepatobiliary manifestations of sickle cell disease: A review

PubMed Central

Shah, Rushikesh; Taborda, Cesar; Chawla, Saurabh

2017-01-01

Sickle cell disease (SCD) is a common hemoglobinopathy which can affect multiple organ systems in the body. Within the digestive tract, the hepatobiliary system is most commonly affected in SCD. The manifestations range from benign hyperbilirubinemia to overt liver failure, with the spectrum of acute clinical presentations often referred to as “sickle cell hepatopathy”. This is an umbrella term referring to liver dysfunction and hyperbilirubinemia due to intrahepatic sickling process during SCD crisis leading to ischemia, sequestration and cholestasis. In this review, we detail the pathophysiology, clinical presentation and biochemical features of various acute and chronic hepatobiliary manifestations of SCD and present and evaluate existing evidence with regards to management of this disease process. We also discuss recent advances and controversies such as the role of liver transplantation in sickle cell hepatopathy and highlight important questions in this field which would require further research. Our aim with this review is to help increase the understanding, aid in early diagnosis and improve management of this important disease process. PMID:28868180

Clinical performance improvement series. Classic CQI integrated with comprehensive disease management as a model for performance improvement.

PubMed

Joshi, M S; Bernard, D B

1999-08-01

In recent years, health and disease management has emerged as an effective means of delivering, integrating, and improving care through a population-based approach. Since 1997 the University of Pennsylvania Health System (UPHS) has utilized the key principles and components of continuous quality improvement (CQI) and disease management to form a model for health care improvement that focuses on designing best practices, using best practices to influence clinical decision making, changing processes and systems to deploy and deliver best practices, and measuring outcomes to improve the process. Experience with 28 programs and more than 14,000 patients indicates significant improvement in outcomes, including high physician satisfaction, increased patient satisfaction, reduced costs, and improved clinical process and outcome measures across multiple diseases. DIABETES DISEASE MANAGEMENT: In three months a UPHS multidisciplinary diabetes disease management team developed a best practice approach for the treatment of all patients with diabetes in the UPHS. After the program was pilot tested in three primary care physician sites, it was then introduced progressively to additional practice sites throughout the health system. The establishment of the role of the diabetes nurse care managers (certified diabetes educators) was central to successful program deployment. Office-based coordinators ensure incorporation of the best practice protocols into routine flow processes. A disease management intranet disseminates programs electronically. Outcomes of the UPHS health and disease management programs so far demonstrate success across multiple dimensions of performance-service, clinical quality, access, and value. The task of health care leadership today is to remove barriers and enable effective implementation of key strategies, such as health and disease management. Substantial effort and resources must be dedicated to gain physician buy-in and achieve compliance. The challenge is to provide leadership support, to reward and recognize best practice performers, and to emphasize the use of data for feedback and improvement. As these processes are implemented successfully, and evidence of improved outcomes is documented, it is likely that this approach will be more widely embraced and that organizationwide performance improvement will increase significantly. Health care has traditionally invested extraordinary resources in developing best practice approaches, including guidelines, education programs, or other tangible products and services. Comparatively little time, effort, and resources have been targeted to implementation and use, the stage at which most efforts fail. CQI's emphasis on data, rapid diffusion of innovative programs, and rapid cycle improvements enhance the implementation and effectiveness of disease management.

A small molecule inhibitior of the NLRP3 inflammasome is a potential therapeutic for inflammatory diseases

PubMed Central

Coll, Rebecca C.; Robertson, Avril A. B.; Chae, Jae Jin; Higgins, Sarah C.; Muñoz-Planillo, Raúl; Inserra, Marco C.; Vetter, Irina; Dungan, Lara S.; Monks, Brian G.; Stutz, Andrea; Croker, Daniel E.; Butler, Mark S.; Haneklaus, Moritz; Sutton, Caroline E.; Núñez, Gabriel; Latz, Eicke; Kastner, Daniel L.; Mills, Kingston H. G.; Masters, Seth L.; Schroder, Kate; Cooper, Matthew A.; O’Neill, Luke A. J.

2015-01-01

The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes and atherosclerosis. We describe the development of MCC950, a potent, selective, small molecule inhibitor of NLRP3. MCC950 blocks canonical and non-canonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibits NLRP3 but not AIM2, NLRC4 or NLRP1 activation. MCC950 reduces Interleukin-1p (IL-1β) production in vivo and attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescues neonatal lethality in a mouse model of CAPS and is active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for the further study of the NLRP3 inflammasome in human health and disease. PMID:25686105

Demyelination of vestibular nerve axons in unilateral Ménière's disease.

PubMed

Spencer, Robert F; Sismanis, Aristides; Kilpatrick, Jefferson K; Shaia, Wayne T

2002-11-01

We conducted a study to determine whether vestibular nerves in patients with unilateral Ménière's disease whose symptoms are refractory to medical management exhibit neuropathologic changes. We also endeavored to determine whether retrocochlear abnormalities are primary or secondary factors in the disease process. To these ends, we obtained vestibular nerve segments from five patients during retrosigmoid (posterior fossa) neurectomy, immediately fixed them, and processed them for light and electron microscopy. We found that all five segments exhibited moderate to severe demyelination with axonal sparing. Moreover, we noted that reactive astrocytes produced an extensive proliferation of fibrous processes and that the microglia assumed a phagocytic role. We conclude that the possible etiologies of demyelination include viral and/or immune-mediated factors similar to those seen in other demyelinating diseases, such as multiple sclerosis and Guillain-Barré syndrome. Our findings suggest that some forms of Ménière's disease that are refractory to traditional medical management might be the result of retrocochlear pathology that affects the neuroglial portion of the vestibular nerve.

Detecting disease-predisposing variants: the haplotype method.

PubMed Central

Valdes, A M; Thomson, G

1997-01-01

For many HLA-associated diseases, multiple alleles-- and, in some cases, multiple loci--have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some--compared with none--of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1#52 (Arg predisposing) DQB1#57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class II DRB1 data, the results were consistent with the shared-epitope hypothesis. PMID:9042931

Protocol for a randomised controlled trial of chronic disease self-management support for older Australians with multiple chronic diseases.

PubMed

Reed, Richard L; Battersby, Malcolm; Osborne, Richard H; Bond, Malcolm J; Howard, Sara L; Roeger, Leigh

2011-11-01

The prevalence of older Australians with multiple chronic diseases is increasing and now accounts for a large proportion of total health care utilisation. Chronic disease self-management support (CDSMS) has become a core service component of many community based health programs because it is considered a useful tool in improving population health outcomes and reducing the financial burden of chronic disease care. However, the evidence base to justify these support programs is limited, particularly for older people with multiple chronic diseases. We describe an ongoing trial examining the effectiveness of a particular CDSMS approach called the Flinders Program. The Flinders Program is a clinician-led generic self-management intervention that provides a set of tools and a structured process that enables health workers and patients to collaboratively assess self-management behaviours, identify problems, set goals, and develop individual care plans covering key self-care, medical, psychosocial and carer issues. A sample of 252 older Australians that have two or more chronic conditions will be randomly assigned to receive either CDSMS or an attention control intervention (health information only) for 6 months. Outcomes will be assessed using self-reported health measures taken at baseline and post-intervention. This project will be the first comprehensive evaluation of CDSMS in this population. Findings are expected to guide consumers, clinicians and policymakers in the use of CDSMS, as well as facilitate prioritisation of public monies towards evidence-based services. Copyright © 2011 Elsevier Inc. All rights reserved.

Docosahexaenoic Acid Reduces Amyloid β Production via Multiple Pleiotropic Mechanisms*

PubMed Central

Grimm, Marcus O. W.; Kuchenbecker, Johanna; Grösgen, Sven; Burg, Verena K.; Hundsdörfer, Benjamin; Rothhaar, Tatjana L.; Friess, Petra; de Wilde, Martijn C.; Broersen, Laus M.; Penke, Botond; Péter, Mária; Vígh, László; Grimm, Heike S.; Hartmann, Tobias

2011-01-01

Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing β- and γ-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in γ-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release. DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects. PMID:21324907

A MULTIPLE-PURPOSE DESIGN APPROACH TO THE EVALUATION OF RISKS FROM COMPLEX MIXTURES OF DISINFECTION BY-PRODUCTS

EPA Science Inventory

Drinking water disinfection has effectively eliminated much of the morbidity and mortality associated with waterborne infectious diseases in the United States. Various disinfection processes, however, produce certain types and amounts of disinfection by-products (DBPs), including...

Second-order analysis of semiparametric recurrent event processes.

PubMed

Guan, Yongtao

2011-09-01

A typical recurrent event dataset consists of an often large number of recurrent event processes, each of which contains multiple event times observed from an individual during a follow-up period. Such data have become increasingly available in medical and epidemiological studies. In this article, we introduce novel procedures to conduct second-order analysis for a flexible class of semiparametric recurrent event processes. Such an analysis can provide useful information regarding the dependence structure within each recurrent event process. Specifically, we will use the proposed procedures to test whether the individual recurrent event processes are all Poisson processes and to suggest sensible alternative models for them if they are not. We apply these procedures to a well-known recurrent event dataset on chronic granulomatous disease and an epidemiological dataset on meningococcal disease cases in Merseyside, United Kingdom to illustrate their practical value. © 2011, The International Biometric Society.

Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data.

PubMed

Cha, Kihoon; Hwang, Taeho; Oh, Kimin; Yi, Gwan-Su

2015-01-01

It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation.

Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data

PubMed Central

2015-01-01

Background It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. Results In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. Conclusions This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation. PMID:26043779

Impaired autophagy in macrophages promotes inflammatory eye disease.

PubMed

Santeford, Andrea; Wiley, Luke A; Park, Sunmin; Bamba, Sonya; Nakamura, Rei; Gdoura, Abdelaziz; Ferguson, Thomas A; Rao, P Kumar; Guan, Jun-Lin; Saitoh, Tatsuya; Akira, Shizuo; Xavier, Ramnik; Virgin, Herbert W; Apte, Rajendra S

2016-10-02

Autophagy is critical for maintaining cellular homeostasis. Organs such as the eye and brain are immunologically privileged. Here, we demonstrate that autophagy is essential for maintaining ocular immune privilege. Deletion of multiple autophagy genes in macrophages leads to an inflammation-mediated eye disease called uveitis that can cause blindness. Loss of autophagy activates inflammasome-mediated IL1B secretion that increases disease severity. Inhibition of caspase activity by gene deletion or pharmacological means completely reverses the disease phenotype. Of interest, experimental uveitis was also increased in a model of Crohn disease, a systemic autoimmune disease in which patients often develop uveitis, offering a potential mechanistic link between macrophage autophagy and systemic disease. These findings directly implicate the homeostatic process of autophagy in blinding eye disease and identify novel pathways for therapeutic intervention in uveitis.

Voxelwise multivariate analysis of multimodality magnetic resonance imaging

PubMed Central

Naylor, Melissa G.; Cardenas, Valerie A.; Tosun, Duygu; Schuff, Norbert; Weiner, Michael; Schwartzman, Armin

2015-01-01

Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remains a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer's disease, in which data from three MRI modalities are available. PMID:23408378

Matrix Metalloproteinases and Neurotrauma: Evolving Roles in Injury and Reparative Processes

PubMed Central

Zhang, Haoqian; Adwanikar, Hita; Werb, Zena; Noble-Haeusslein, Linda J.

2010-01-01

Matrix metalloproteinases (MMPs) are involved in a wide range of proteolytic events in fetal development and normal tissue remodeling as well as wound healing and inflammation. In the CNS, they have been implicated in a variety of neurodegenerative diseases ranging from multiple sclerosis to Alzheimer disease and are integral to stroke-related cell damage. Although studies implicate increased activity of MMPs in pathogenesis in the CNS, there is also a growing literature to support their participation in events that support recovery processes. Here the authors provide a brief overview of MMPs and their regulation, address their complex roles following traumatic injuries to the adult and developing CNS, and consider their time- and context-dependent signatures that influence both injury and reparative processes. PMID:20400713

GLIS1-3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases.

PubMed

Jetten, Anton M

2018-05-19

Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-similar 1-3 (GLIS1-3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1-3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while a little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

Proteomic Profiling of Cranial (Superior) Cervical Ganglia Reveals Beta-Amyloid and Ubiquitin Proteasome System Perturbations in an Equine Multiple System Neuropathy.

PubMed

McGorum, Bruce C; Pirie, R Scott; Eaton, Samantha L; Keen, John A; Cumyn, Elizabeth M; Arnott, Danielle M; Chen, Wenzhang; Lamont, Douglas J; Graham, Laura C; Llavero Hurtado, Maica; Pemberton, Alan; Wishart, Thomas M

2015-11-01

Equine grass sickness (EGS) is an acute, predominantly fatal, multiple system neuropathy of grazing horses with reported incidence rates of ∼2%. An apparently identical disease occurs in multiple species, including but not limited to cats, dogs, and rabbits. Although the precise etiology remains unclear, ultrastructural findings have suggested that the primary lesion lies in the glycoprotein biosynthetic pathway of specific neuronal populations. The goal of this study was therefore to identify the molecular processes underpinning neurodegeneration in EGS. Here, we use a bottom-up approach beginning with the application of modern proteomic tools to the analysis of cranial (superior) cervical ganglion (CCG, a consistently affected tissue) from EGS-affected patients and appropriate control cases postmortem. In what appears to be the proteomic application of modern proteomic tools to equine neuronal tissues and/or to an inherent neurodegenerative disease of large animals (not a model of human disease), we identified 2,311 proteins in CCG extracts, with 320 proteins increased and 186 decreased by greater than 20% relative to controls. Further examination of selected proteomic candidates by quantitative fluorescent Western blotting (QFWB) and subcellular expression profiling by immunohistochemistry highlighted a previously unreported dysregulation in proteins commonly associated with protein misfolding/aggregation responses seen in a myriad of human neurodegenerative conditions, including but not limited to amyloid precursor protein (APP), microtubule associated protein (Tau), and multiple components of the ubiquitin proteasome system (UPS). Differentially expressed proteins eligible for in silico pathway analysis clustered predominantly into the following biofunctions: (1) diseases and disorders, including; neurological disease and skeletal and muscular disorders and (2) molecular and cellular functions, including cellular assembly and organization, cell-to-cell signaling and interaction (including epinephrine, dopamine, and adrenergic signaling and receptor function), and small molecule biochemistry. Interestingly, while the biofunctions identified in this study may represent pathways underpinning EGS-induced neurodegeneration, this is also the first demonstration of potential molecular conservation (including previously unreported dysregulation of the UPS and APP) spanning the degenerative cascades from an apparently unrelated condition of large animals, to small animal models with altered neuronal vulnerability, and human neurological conditions. Importantly, this study highlights the feasibility and benefits of applying modern proteomic techniques to veterinary investigations of neurodegenerative processes in diseases of large animals. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Inflammatory responses and intestinal injury development during acute Trypanosoma cruzi infection are associated with the parasite load.

PubMed

Vazquez, Bruna Perez; Vazquez, Thaís Perez; Miguel, Camila Botelho; Rodrigues, Wellington Francisco; Mendes, Maria Tays; de Oliveira, Carlo José Freire; Chica, Javier Emílio Lazo

2015-04-03

Chagas disease is caused by the protozoan Trypanosoma cruzi and is characterized by cardiac, gastrointestinal, and nervous system disorders. Although much about the pathophysiological process of Chagas disease is already known, the influence of the parasite burden on the inflammatory process and disease progression remains uncertain. We used an acute experimental disease model to evaluate the effect of T. cruzi on intestinal lesions and assessed correlations between parasite load and inflammation and intestinal injury at 7 and 14 days post-infection. Low (3 × 10(2)), medium (3 × 10(3)), and high (3 × 10(4)) parasite loads were generated by infecting C57BL/6 mice with "Y"-strain trypomastigotes. Statistical analysis was performed using analysis of variance with Tukey's multiple comparison post-test, Kruskal-Wallis test with Dunn's multiple comparison, χ2 test and Spearman correlation. High parasite load-bearing mice more rapidly and strongly developed parasitemia. Increased colon width, inflammatory infiltration, myositis, periganglionitis, ganglionitis, pro-inflammatory cytokines (e.g., TNF-α, INF-γ, IL-2, IL-17, IL-6), and intestinal amastigote nests were more pronounced in high parasite load-bearing animals. These results were remarkable because a positive correlation was observed between parasite load, inflammatory infiltrate, amastigote nests, and investigated cytokines. These experimental data support the idea that the parasite load considerably influences the T. cruzi-induced intestinal inflammatory response and contributes to the development of the digestive form of the disease.

Adipose, Bone and Myeloma: Contributions from the Microenvironment

PubMed Central

McDonald, Michelle; Fairfield, Heather; Falank, Carolyne; Reagan, Michaela R.

2017-01-01

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide [1]. Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90% of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies. PMID:27343063

Coexistence of Multiple Sclerosis and Brain Tumor: An Uncommon Diagnostic Challenge.

PubMed

Abrishamchi, Fatemeh; Khorvash, Fariborz

2017-01-01

Nonneoplastic demyelinating processes of the brain with mass effect on magnetic resonance imaging can cause diagnostic difficulties. It requires differential diagnosis between the tumefactive demyelinating lesion and the coexistence of neoplasm. We document the case of 41-year-old woman with clinical and radiological findings suggestive of multiple sclerosis. Additional investigations confirmed the coexistence of astrocytoma. This report emphasizes the importance of considering brain tumors in the differential diagnosis of primary demyelinating disease presenting with a cerebral mass lesion.

A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system.

PubMed

Kim, Hee Jin; Kim, Pitna; Shin, Chan Young

2013-03-01

Ginseng is one of the most widely used herbal medicines in human. Central nervous system (CNS) diseases are most widely investigated diseases among all others in respect to the ginseng's therapeutic effects. These include Alzheimer's disease, Parkinson's disease, cerebral ischemia, depression, and many other neurological disorders including neurodevelopmental disorders. Not only the various types of diseases but also the diverse array of target pathways or molecules ginseng exerts its effect on. These range, for example, from neuroprotection to the regulation of synaptic plasticity and from regulation of neuroinflammatory processes to the regulation of neurotransmitter release, too many to mention. In general, ginseng and even a single compound of ginsenoside produce its effects on multiple sites of action, which make it an ideal candidate to develop multi-target drugs. This is most important in CNS diseases where multiple of etiological and pathological targets working together to regulate the final pathophysiology of diseases. In this review, we tried to provide comprehensive information on the pharmacological and therapeutic effects of ginseng and ginsenosides on neurodegenerative and other neurological diseases. Side by side comparison of the therapeutic effects in various neurological disorders may widen our understanding of the therapeutic potential of ginseng in CNS diseases and the possibility to develop not only symptomatic drugs but also disease modifying reagents based on ginseng.

A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system

PubMed Central

Kim, Hee Jin; Kim, Pitna; Shin, Chan Young

2013-01-01

Ginseng is one of the most widely used herbal medicines in human. Central nervous system (CNS) diseases are most widely investigated diseases among all others in respect to the ginseng’s therapeutic effects. These include Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, depression, and many other neurological disorders including neurodevelopmental disorders. Not only the various types of diseases but also the diverse array of target pathways or molecules ginseng exerts its effect on. These range, for example, from neuroprotection to the regulation of synaptic plasticity and from regulation of neuroinflammatory processes to the regulation of neurotransmitter release, too many to mention. In general, ginseng and even a single compound of ginsenoside produce its effects on multiple sites of action, which make it an ideal candidate to develop multi-target drugs. This is most important in CNS diseases where multiple of etiological and pathological targets working together to regulate the final pathophysiology of diseases. In this review, we tried to provide comprehensive information on the pharmacological and therapeutic effects of ginseng and ginsenosides on neurodegenerative and other neurological diseases. Side by side comparison of the therapeutic effects in various neurological disorders may widen our understanding of the therapeutic potential of ginseng in CNS diseases and the possibility to develop not only symptomatic drugs but also disease modifying reagents based on ginseng. PMID:23717153

Wilms' tumour 1 (WT1) in development, homeostasis and disease.

PubMed

Hastie, Nicholas D

2017-08-15

The study of genes mutated in human disease often leads to new insights into biology as well as disease mechanisms. One such gene is Wilms' tumour 1 ( WT1 ), which plays multiple roles in development, tissue homeostasis and disease. In this Primer, I summarise how this multifaceted gene functions in various mammalian tissues and organs, including the kidney, gonads, heart and nervous system. This is followed by a discussion of our current understanding of the molecular mechanisms by which WT1 and its two major isoforms regulate these processes at the transcriptional and post-transcriptional levels. © 2017. Published by The Company of Biologists Ltd.

The intricate mechanisms of neurodegeneration in prion diseases

PubMed Central

Soto, Claudio; Satani, Nikunj

2010-01-01

Prion diseases are a group of infectious neurodegenerative diseases with an entirely novel mechanism of transmission, involving a protein-only infectious agent that propagates the disease by transmitting protein conformational changes. The disease results from extensive and progressive brain degeneration. The molecular mechanisms involved in neurodegeneration are not entirely known but involve multiple processes operating simultaneously and synergistically in the brain, including spongiform degeneration, synaptic alterations, brain inflammation, neuronal death and the accumulation of protein aggregates. Here, we review the pathways implicated in prion-induced brain damage and put the pieces together into a possible model of neurodegeneration in prion disorders. A more comprehensive understanding of the molecular basis of brain degeneration is essential to develop a much needed therapy for these devastating diseases. PMID:20889378

A Tol2 Gateway-Compatible Toolbox for the Study of the Nervous System and Neurodegenerative Disease.

PubMed

Don, Emily K; Formella, Isabel; Badrock, Andrew P; Hall, Thomas E; Morsch, Marco; Hortle, Elinor; Hogan, Alison; Chow, Sharron; Gwee, Serene S L; Stoddart, Jack J; Nicholson, Garth; Chung, Roger; Cole, Nicholas J

2017-02-01

Currently there is a lack in fundamental understanding of disease progression of most neurodegenerative diseases, and, therefore, treatments and preventative measures are limited. Consequently, there is a great need for adaptable, yet robust model systems to both investigate elementary disease mechanisms and discover effective therapeutics. We have generated a Tol2 Gateway-compatible toolbox to study neurodegenerative disorders in zebrafish, which includes promoters for astrocytes, microglia and motor neurons, multiple fluorophores, and compatibility for the introduction of genes of interest or disease-linked genes. This toolbox will advance the rapid and flexible generation of zebrafish models to discover the biology of the nervous system and the disease processes that lead to neurodegeneration.

A Chronic Disease Prevention and Management Corridor© to Supporting System-Level Transformations for Chronic Conditions.

PubMed

Sampalli, Tara; Christian, Erin; Edwards, Lynn; Ryer, Ashley

2015-01-01

Improving care for chronic conditions requires system-level transformations to ensure multiple levels of adoption and sustainability of the implemented improvements. These comprehensive solutions require transformations and supports at various levels, leadership and process changes at service/program level. Recognizing the importance of an organization-wide strategy to mitigate the growing issue of chronic disease prevention and management, a novel system-level approach has been developed in a district health authority in Nova Scotia, Canada. In this paper, the contextual factors and efforts that led to the conceptual framework of the Chronic Disease Prevention and Management (CDPM) "Corridor©" to management of chronic conditions are discussed. The CDPM Corridor© essentially constitutes a system-level redesign process; common elements, tools and resources; and a hub of supports for chronic disease prevention and management. The CDPM Corridor © will include a toolkit to guide the implementation of the proposed transformations.

SR-BI as target in atherosclerosis and cardiovascular disease - A comprehensive appraisal of the cellular functions of SR-BI in physiology and disease.

PubMed

Hoekstra, Menno

2017-03-01

High-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein species due to its role in reverse cholesterol transport. HDL delivers cholesterol esters to the liver through selective uptake by scavenger receptor class B type I (SR-BI). In line with the protective role for HDL in the context of cardiovascular disease, studies in mice and recently also in humans have shown that a disruption of normal SR-BI function predisposes subjects to the development of atherosclerotic lesions and cardiovascular disease. Although SR-BI function has been studied primarily in the liver, it should be acknowledged that the SR-BI protein is expressed in multiple tissues and cell types across the body, albeit at varying levels between the different tissues. Given that SR-BI is widely expressed throughout the body, multiple cell types and tissues can theoretically contribute to the atheroprotective effect of SR-BI. In this review the different functions of SR-BI in normal physiology are highlighted and the (potential) consequences of cell type-specific disruption of SR-BI function for atherosclerosis and cardiovascular disease susceptibility discussed. It appears that hepatocyte and platelet SR-BI inhibit respectively the development of atherosclerotic lesions and thrombosis, suggesting that SR-BI located on these cell compartments should be regarded as being a protective factor in the context of cardiovascular disease. The relative contribution of SR-BI present on endothelial cells, steroidogenic cells, adipocytes and macrophages to the pathogenesis of atherosclerosis and cardiovascular disease remains less clear, although proper SR-BI function in these cells does appear to influence multiple processes that impact on cardiovascular disease susceptibility. Copyright © 2017 The Author. Published by Elsevier B.V. All rights reserved.

[Daily practice and pulp diseases].

PubMed

Calmein, S; Claisse, A

1990-09-01

Constructive or destructive processes of pulp tissue depend on many factors: anatomic topography, particular physiology, or intensity and duration of infectious, mechanical and chemical aggression. Also irritation of the pulpo-dentinal complex induce histologic and physiologic changes. The positive diagnosis of hyperemia, acute or chronic pulpitis, pulpal necrosis and acute or chronic apical abscess is performed by clinical investigations which allow a differential diagnosis with other dental or extra-dental diseases. These multiple steps lead to an adapted and appropriate treatment.

Gene Therapy for Skin Diseases

PubMed Central

Gorell, Emily; Nguyen, Ngon; Lane, Alfred; Siprashvili, Zurab

2014-01-01

The skin possesses qualities that make it desirable for gene therapy, and studies have focused on gene therapy for multiple cutaneous diseases. Gene therapy uses a vector to introduce genetic material into cells to alter gene expression, negating a pathological process. This can be accomplished with a variety of viral vectors or nonviral administrations. Although results are promising, there are several potential pitfalls that must be addressed to improve the safety profile to make gene therapy widely available clinically. PMID:24692191

Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice.

PubMed

Zhou, Qiong; Wang, Man; Du, Ying; Zhang, Wei; Bai, Miao; Zhang, Zhuo; Li, Zhuyi; Miao, Jianting

2015-04-01

Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. Using behavioral, histological, and biochemical methods, outcomes of SP600125 treatment on neuropathology and cognitive deficits were studied in APPswe/PS1dE9 mice. Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, β-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD. © 2015 American Neurological Association.

Rab7: roles in membrane trafficking and disease.

PubMed

Zhang, Ming; Chen, Li; Wang, Shicong; Wang, Tuanlao

2009-06-01

The endocytosis pathway controls multiple cellular and physiological events. The lysosome is the destination of newly synthesized lysosomal hydrolytic enzymes. Internalized molecules or particles are delivered to the lysosome for degradation through sequential transport along the endocytic pathway. The endocytic pathway is also emerging as a signalling platform, in addition to the well-known role of the plasma membrane for signalling. Rab7 is a late endosome-/lysosome-associated small GTPase, perhaps the only lysosomal Rab protein identified to date. Rab7 plays critical roles in the endocytic processes. Through interaction with its partners (including upstream regulators and downstream effectors), Rab7 participates in multiple regulation mechanisms in endosomal sorting, biogenesis of lysosome [or LRO (lysosome-related organelle)] and phagocytosis. These processes are closely related to substrates degradation, antigen presentation, cell signalling, cell survival and microbial pathogen infection. Consistently, mutations or dysfunctions of Rab7 result in traffic disorders, which cause various diseases, such as neuropathy, cancer and lipid metabolism disease. Rab7 also plays important roles in microbial pathogen infection and survival, as well as in participating in the life cycle of viruses. Here, we give a brief review on the central role of Rab7 in endosomal traffic and summarize the studies focusing on the participation of Rab7 in disease pathogenesis. The underlying mechanism governed by Rab7 and its partners will also be discussed.

Pathogenesis of the limb manifestations and exercise limitations in peripheral artery disease.

PubMed

Hiatt, William R; Armstrong, Ehrin J; Larson, Christopher J; Brass, Eric P

2015-04-24

Patients with peripheral artery disease have a marked reduction in exercise performance and daily ambulatory activity irrespective of their limb symptoms of classic or atypical claudication. This review will evaluate the multiple pathophysiologic mechanisms underlying the exercise impairment in peripheral artery disease based on an evaluation of the current literature and research performed by the authors. Peripheral artery disease results in atherosclerotic obstructions in the major conduit arteries supplying the lower extremities. This arterial disease process impairs the supply of oxygen and metabolic substrates needed to match the metabolic demand generated by active skeletal muscle during walking exercise. However, the hemodynamic impairment associated with the occlusive disease process does not fully account for the reduced exercise impairment, indicating that additional pathophysiologic mechanisms contribute to the limb manifestations. These mechanisms include a cascade of pathophysiological responses during exercise-induced ischemia and reperfusion at rest that are associated with endothelial dysfunction, oxidant stress, inflammation, and muscle metabolic abnormalities that provide opportunities for targeted therapeutic interventions to address the complex pathophysiology of the exercise impairment in peripheral artery disease. © 2015 American Heart Association, Inc.

Challenges in personalised management of chronic diseases-heart failure as prominent example to advance the care process.

PubMed

Brunner-La Rocca, Hans-Peter; Fleischhacker, Lutz; Golubnitschaja, Olga; Heemskerk, Frank; Helms, Thomas; Hoedemakers, Thom; Allianses, Sandra Huygen; Jaarsma, Tiny; Kinkorova, Judita; Ramaekers, Jan; Ruff, Peter; Schnur, Ivana; Vanoli, Emilio; Verdu, Jose; Zippel-Schultz, Bettina

2015-01-01

Chronic diseases are the leading causes of morbidity and mortality in Europe, accounting for more than 2/3 of all death causes and 75 % of the healthcare costs. Heart failure is one of the most prominent, prevalent and complex chronic conditions and is accompanied with multiple other chronic diseases. The current approach to care has important shortcomings with respect to diagnosis, treatment and care processes. A critical aspect of this situation is that interaction between stakeholders is limited and chronic diseases are usually addressed in isolation. Health care in Western countries requires an innovative approach to address chronic diseases to provide sustainability of care and to limit the excessive costs that may threaten the current systems. The increasing prevalence of chronic diseases combined with their enormous economic impact and the increasing shortage of healthcare providers are among the most critical threats. Attempts to solve these problems have failed, and future limitations in financial resources will result in much lower quality of care. Thus, changing the approach to care for chronic diseases is of utmost social importance.

Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype.

PubMed

Adebola, Adijat A; Di Castri, Theo; He, Chui-Zhen; Salvatierra, Laura A; Zhao, Jian; Brown, Kristy; Lin, Chyuan-Sheng; Worman, Howard J; Liem, Ronald K H

2015-04-15

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited neurological disorder with a prevalence of 1 in 2500 people worldwide. Patients suffer from degeneration of the peripheral nerves that control sensory information of the foot/leg and hand/arm. Multiple mutations in the neurofilament light polypeptide gene, NEFL, cause CMT2E. Previous studies in transfected cells showed that expression of disease-associated neurofilament light chain variants results in abnormal intermediate filament networks associated with defects in axonal transport. We have now generated knock-in mice with two different point mutations in Nefl: P8R that has been reported in multiple families with variable age of onset and N98S that has been described as an early-onset, sporadic mutation in multiple individuals. Nefl(P8R/+) and Nefl(P8R/P8R) mice were indistinguishable from Nefl(+/+) in terms of behavioral phenotype. In contrast, Nefl(N98S/+) mice had a noticeable tremor, and most animals showed a hindlimb clasping phenotype. Immunohistochemical analysis revealed multiple inclusions in the cell bodies and proximal axons of spinal cord neurons, disorganized processes in the cerebellum and abnormal processes in the cerebral cortex and pons. Abnormal processes were observed as early as post-natal day 7. Electron microscopic analysis of sciatic nerves showed a reduction in the number of neurofilaments, an increase in the number of microtubules and a decrease in the axonal diameters. The Nefl(N98S/+) mice provide an excellent model to study the pathogenesis of CMT2E and should prove useful for testing potential therapies. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Fibroblast growth factor signaling in oligodendrocyte-lineage cells facilitates recovery of chronically demyelinated lesions but is redundant in acute lesions

PubMed Central

Furusho, M; Roulois, A; Franklin, RJM; Bansal, R

2015-01-01

Remyelination is a potent regenerative process in demyelinating diseases, such as multiple sclerosis, the effective therapeutic promotion of which will fill an unmet clinical need. The development of pro-regenerative therapies requires the identification of key regulatory targets that are likely to be involved in the integration of multiple signaling mechanisms. Fibroblast growth factor (FGF) signaling system, which comprises multiple ligands and receptors, potentially provides one such target. Since the FGF/FGF receptor (FGFR) interactions are complex and regulate multiple diverse functions of oligodendrocyte lineage cells, it is difficult to predict their overall therapeutic potential in the regeneration of oligodendrocytes and myelin. Therefore, to assess the integrated effects of FGFR signaling on this process, we simultaneously inactivated both FGFR1 and FGFR2 in oligodendrocytes and their precursors using two Cre-driver mouse lines. Acute and chronic cuprizone-induced or lysolecithin-induced demyelination was established in Fgfr1/Fgfr2 double knockout mice (dKO). We found that in the acute cuprizone model, there was normal differentiation of oligodendrocytes and recovery of myelin in the corpus callosum of both control and dKO mice. Similarly, in the spinal cord, lysolecithin-induced demyelinated lesions regenerated similarly in the dKO and control mice. In contrast, in the chronic cuprizone model, fewer differentiated oligodendrocytes and less efficient myelin recovery were observed in the dKO compared to control mice. These data suggest that while cell-autonomous FGF signaling is redundant during recovery of acute demyelinated lesions, it facilitates regenerative processes in chronic demyelination. Thus, FGF-based therapies have potential value in stimulating oligodendrocyte and myelin regeneration in late-stage disease. PMID:25913734

Multiprotocol MR image segmentation in multiple sclerosis: experience with over 1000 studies

NASA Astrophysics Data System (ADS)

Udupa, Jayaram K.; Nyul, Laszlo G.; Ge, Yulin; Grossman, Robert I.

2000-06-01

Multiple Sclerosis (MS) is an acquired disease of the central nervous system. Subjective cognitive and ambulatory test scores on a scale called EDSS are currently utilized to assess the disease severity. Various MRI protocols are being investigated to study the disease based on how it manifests itself in the images. In an attempt to eventually replace EDSS by an objective measure to assess the natural course of the disease and its response to therapy, we have developed image segmentation methods based on fuzzy connectedness to quantify various objects in multiprotocol MRI. These include the macroscopic objects such as lesions, the gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and brain parenchyma as well as the microscopic aspects of the diseased WM. Over 1000 studies have been processed to date. By far the strongest correlations with the clinical measures were demonstrated by the Magnetization Transfer Ratio (MTR) histogram parameters obtained for the various segmented tissue regions emphasizing the importance of considering the microscopic/diffused nature of the disease in the individual tissue regions. Brain parenchymal volume also demonstrated a strong correlation with the clinical measures indicating that brain atrophy is an important indicator of the disease. Fuzzy connectedness is a viable segmentation method for studying MS.

Light Controlled Modulation of Gene Expression by Chemical Optoepigenetic Probes

PubMed Central

Reis, Surya A.; Ghosh, Balaram; Hendricks, J. Adam; Szantai-Kis, D. Miklos; Törk, Lisa; Ross, Kenneth N.; Lamb, Justin; Read-Button, Willis; Zheng, Baixue; Wang, Hongtao; Salthouse, Christopher; Haggarty, Stephen J.; Mazitschek, Ralph

2016-01-01

Epigenetic gene regulation is a dynamic process orchestrated by chromatin-modifying enzymes. Many of these master regulators exert their function through covalent modification of DNA and histone proteins. Aberrant epigenetic processes have been implicated in the pathophysiology of multiple human diseases. Small-molecule inhibitors have been essential to advancing our understanding of the underlying molecular mechanisms of epigenetic processes. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatio-temporal control. Here, we present a novel and generalizable approach, referred to as ‘Chemo-Optical Modulation of Epigenetically-regulated Transcription’ (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light. COMET probes may translate into novel therapeutic strategies for diseases where conditional and selective epigenome modulation is required. PMID:26974814

Urine metabolic profiling for the pathogenesis research of erosive oral lichen planus.

PubMed

Li, Xu-Zhao; Yang, Xu-Yan; Wang, Yu; Zhang, Shuai-Nan; Zou, Wei; Wang, Yan; Li, Xiao-Nan; Wang, Ling-Shu; Zhang, Zhi-Gang; Xie, Liang-Zhen

2017-01-01

Oral lichen planus (OLP) is a relatively common chronic immune-pathological and inflammatory disease and potentially oral precancerous lesion. Erosive OLP patients show the higher rate of malignant transformation than patients with non-erosive OLP. Identifying the potential biomarkers related to erosive OLP may help to understand the pathogenesis of the diseases. Metabolic profiles were compared in control and patient subjects with erosive OLP by using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods An integrative analysis was used to identify the perturbed metabolic pathways and pathological processes that may be associated with the disease. In total, 12 modulated metabolites were identified and considered as the potential biomarkers of erosive OLP. Multiple metabolic pathways and pathological processes were involved in erosive OLP. The dysregulations of these metabolites could be used to explain the pathogenesis of the disease, which could also be the potential therapeutic targets for the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Expression profiling of cardiovascular disease

PubMed Central

2004-01-01

Cardiovascular disease is the most important cause of morbidity and mortality in developed countries, causing twice as many deaths as cancer in the USA. The major cardiovascular diseases, including coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF) and common congenital heart disease (CHD), are caused by multiple genetic and environmental factors, as well as the interactions between them. The underlying molecular pathogenic mechanisms for these disorders are still largely unknown, but gene expression may play a central role in the development and progression of cardiovascular disease. Microarrays are high-throughput genomic tools that allow the comparison of global expression changes in thousands of genes between normal and diseased cells/tissues. Microarrays have recently been applied to CAD/MI, CHF and CHD to profile changes in gene expression patterns in diseased and non-diseased patients. This same technology has also been used to characterise endothelial cells, vascular smooth muscle cells and inflammatory cells, with or without various treatments that mimic disease processes involved in CAD/MI. These studies have led to the identification of unique subsets of genes associated with specific diseases and disease processes. Ongoing microarray studies in the field will provide insights into the molecular mechanism of cardiovascular disease and may generate new diagnostic and therapeutic markers. PMID:15588496

Electronic-nose devices - Potential for noninvasive early disease-detection applications

Treesearch

Alphus Dan Wilson

2017-01-01

Significant progress in the development of portable electronic devices is showing considerable promise to facilitate clinical diagnostic processes. The increasing global trend of shifts in healthcare policies and priorities toward shortening and improving the effectiveness of diagnostic procedures by utilizing non-invasive methods should provide multiple benefits of...

Symptomatic Therapy and Rehabilitation in Primary Progressive Multiple Sclerosis

PubMed Central

Khan, Fary; Amatya, Bhasker; Turner-Stokes, Lynne

2011-01-01

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system and a major cause of chronic neurological disability in young adults. Primary progressive MS (PPMS) constitutes about 10% of cases, and is characterized by a steady decline in function with no acute attacks. The rate of deterioration from disease onset is more rapid than relapsing remitting and secondary progressive MS types. Multiple system involvement at onset and rapid early progression have a worse prognosis. PPMS can cause significant disability and impact on quality of life. Recent studies are biased in favour of relapsing remitting patients as treatment is now available for them and they are more likely to be seen at MS clinics. Since prognosis for PPMS is worse than other types of MS, the focus of rehabilitation is on managing disability and enhancing participation, and application of a “neuropalliative” approach as the disease progresses. This chapter presents the symptomatic treatment and rehabilitation for persons with MS, including PPMS. A multidisciplinary approach optimizes the intermediate and long-term medical, psychological and social outcomes in this population. Restoration and maintenance of functional independence and societal reintegration, and issues relating to quality of life are addressed in rehabilitation processes. PMID:22013521

Performance evaluation for volumetric segmentation of multiple sclerosis lesions using MATLAB and computing engine in the graphical processing unit (GPU)

NASA Astrophysics Data System (ADS)

Le, Anh H.; Park, Young W.; Ma, Kevin; Jacobs, Colin; Liu, Brent J.

2010-03-01

Multiple Sclerosis (MS) is a progressive neurological disease affecting myelin pathways in the brain. Multiple lesions in the white matter can cause paralysis and severe motor disabilities of the affected patient. To solve the issue of inconsistency and user-dependency in manual lesion measurement of MRI, we have proposed a 3-D automated lesion quantification algorithm to enable objective and efficient lesion volume tracking. The computer-aided detection (CAD) of MS, written in MATLAB, utilizes K-Nearest Neighbors (KNN) method to compute the probability of lesions on a per-voxel basis. Despite the highly optimized algorithm of imaging processing that is used in CAD development, MS CAD integration and evaluation in clinical workflow is technically challenging due to the requirement of high computation rates and memory bandwidth in the recursive nature of the algorithm. In this paper, we present the development and evaluation of using a computing engine in the graphical processing unit (GPU) with MATLAB for segmentation of MS lesions. The paper investigates the utilization of a high-end GPU for parallel computing of KNN in the MATLAB environment to improve algorithm performance. The integration is accomplished using NVIDIA's CUDA developmental toolkit for MATLAB. The results of this study will validate the practicality and effectiveness of the prototype MS CAD in a clinical setting. The GPU method may allow MS CAD to rapidly integrate in an electronic patient record or any disease-centric health care system.

Patient autonomy in multiple sclerosis--possible goals and assessment strategies.

PubMed

Heesen, C; Köpke, S; Solari, A; Geiger, F; Kasper, J

2013-08-15

Patient autonomy has been increasingly acknowledged as prerequisite for successful medical decision making in Western countries. In medical decisions with a need to involve a health professional, patient autonomy becomes apparent in the extent of patients' participation in the communication as described in the concept of shared decision making. Patient autonomy can be derived from different perspectives or goals and the focus of evaluation approaches may vary accordingly. Multiple sclerosis (MS) is a paradigmatic disease to study patient autonomy mainly because MS patients are highly disease competent and due to ambiguous evidence on many aspects of disease-related medical decision making. This review gives an overview on measurement issues in studying decision making in MS, categorized according to prerequisites, process measures and outcomes of patient autonomy. As relevant prerequisites role preferences, risk attribution, risk tolerance, and risk knowledge are discussed. Regarding processes, we distinguish intra-psychic and interpersonal aspects. Intra-psychic processes are elucidated using the theory of planned behavior, which guided development of a 30-item scale to capture decisions about immunotherapy. Moreover, a theory of uncertainty management has been created resulting in the development of a corresponding measurement concept. Interpersonal processes evolving between physician and patient can be thoroughly analyzed from different perspectives by use of the newly developed comprehensive MAPPIN'SDM inventory. Concerning outcomes, besides health related outcomes, we discuss match of preferred roles during the decision encounters (preference match), decisional conflict as well as an application of the multidimensional measure of informed choice to decisions of MS patients. These approaches provide an overview on patient-inherent and interpersonal factors and processes modulating medical decision making and health behavior in MS and beyond. Copyright © 2013. Published by Elsevier B.V.

Recent developments in the surgical management of perianal fistula for Crohn’s disease

PubMed Central

Geltzeiler, Cristina B.; Wieghard, Nicole; Tsikitis, Vassiliki L.

2014-01-01

Perianal manifestations of Crohn’s disease (CD) are common and, of them, fistulas are the most common. Perianal fistulas can be extremely debilitating for patients and are often very challenging for clinicians to treat. CD perianal fistulas usually require multidisciplinary and multimodality treatment, including both medical and surgical approaches. The majority of patients require multiple surgical interventions. CD patients with perianal fistulas have a high rate of primary non-healing, surgical morbidity, and high recurrence rates. This has led to constant efforts to improve surgical management of this disease process. PMID:25331917

Rehabilitation in multiple sclerosis.

PubMed

Kubsik-Gidlewska, Anna M; Klimkiewicz, Paulina; Klimkiewicz, Robert; Janczewska, Katarzyna; Woldańska-Okońska, Marta

2017-07-01

The aim of the study is to present a strategy of rehabilitation in multiple sclerosis on the basis of the latest developments in the field of physiotherapy. The publications on the problem discuss a wide range of methods of physiotherapy that can be used in order to reduce the degree of disability and alleviate the symptoms associated with the disease. The complexity of the disease, the difficulty in determining the appropriate treatment and a wide range of symptoms require a comprehensive approach to the patient, which would include both pharmacology and neurorehabilitation. Rehabilitation, which includes psychotherapy and symptomatic therapy, is regarded nowadays as the best form of treatment for multiple sclerosis. An indepth diagnostic assessment of functional status and prognosis should be carried out before the start of the rehabilitation process. The prognosis should take into account the mental state, the neurological status and the awareness of the patient. The kinesiotherapy program in multiple sclerosis is based on a gradation of physiotherapy which assumes a gradual transition from basic movements to more complex ones till global functions are obtained. The most appropriate form of treatment is functional rehabilitation combined with physical procedures. Recent reports indicate the need for aerobic training to be included in the rehabilitation program. The introduction of physical activities, regardless of the severity of the disease, will reduce the negative effects of akinesia, and thus increase the functional capabilities of all body systems.

Cat-scratch disease presenting as multiple hepatic lesions: case report and literature review.

PubMed

Baptista, Mariana Andrade; Lo, Denise Swei; Hein, Noely; Hirose, Maki; Yoshioka, Cristina Ryoka Miyao; Ragazzi, Selma Lopes Betta; Gilio, Alfredo Elias; Ferronato, Angela Esposito

2014-01-01

Although infectious diseases are the most prevalent cause of fevers of unknown origin (FUO), this diagnosis remains challenging in some pediatric patients. Imaging exams, such as computed tomography (CT) are frequently required during the diagnostic processes. The presence of multiple hypoattenuating scattered images throughout the liver associated with the history of cohabitation with cats should raise the suspicion of the diagnosis of cat-scratch disease (CSD), although the main etiologic agent of liver abscesses in childhood is S taphylococcus aureus . Differential diagnosis by clinical and epidemiological data with Bartonella henselae is often advisable. The authors report the case of a boy aged 2 years and 9 months with 16-day history of daily fever accompanied by intermittent abdominal pain. Physical examination was unremarkable. Abdominal ultrasound performed in the initial work up was unrevealing, but an abdominal CT that was performed afterwards disclosed multiple hypoattenuating hepatic images compatible with the diagnosis of micro abscesses. Initial antibiotic regimen included cefotaxime, metronidazole, and oxacillin. Due to the epidemiology of close contact with kittens, diagnosis of CSD was considered and confirmed by serologic tests. Therefore, the initial antibiotics were replaced by clarithromycin orally for 14 days followed by fever defervescence and clinical improvement. The authors call attention to this uncommon diagnosis in a child presenting with FUO and multiple hepatic images suggestive of micro abscesses.

A systematic review of integrated use of disease-management interventions in asthma and COPD.

PubMed

Lemmens, Karin M M; Nieboer, Anna P; Huijsman, Robbert

2009-05-01

The effectiveness of multiple interventions in asthma and chronic obstructive pulmonary disease (COPD) is unclear. To examine the effectiveness of multiple interventions as compared to single interventions or usual care on health outcomes and health care utilisation within the context of integrated disease management in asthma and COPD. MEDLINE and the Cochrane Library (1995-May 2008) were searched for controlled trials. Two reviewers independently extracted data and assessed study quality. Meta-analyses were performed on quality of life and health care utilisation data. Furthermore, the effects of multiple interventions versus single interventions and usual care were assessed qualitatively. Of the 36 studies included, 17 targeted double interventions (patient-related and organisational interventions); 19 studies performed triple interventions (patient-related, professional-directed and organisational interventions). They were heterogeneous in terms of (combinations of) interventions, outcomes measured, study design and setting. Pooled data showed that studied disease management programmes significantly improved quality of life on several domains. Patients within triple intervention programmes had less chance of at least one hospital admission compared with usual care. No significant effects were found in number of emergency department visits. Qualitative analyses revealed positive trends on process improvements and satisfaction. Inconclusive results were reported on symptoms; no effects were found in lung function. In spite of the heterogeneity of disease management studies in asthma and COPD care, this review showed promising improvements in quality of life and reductions in hospitalisations, especially for triple intervention programmes.

[Association of Kaposi sarcoma--multiple myeloma. A new case].

PubMed

Cohen, J D; Thomas, E; Garnier, N; Hellier, I; Durand, L; Guilhou, J J; Baldet, P; Blotman, F

2000-11-01

Kaposi's disease is an angiogenic multifocal cancer process that has several forms, namely Mediterranean, African, HIV-associated, and secondary to a preexisting immunodepressive state (hematological disorder, corticosteroid therapy, immunodepressive treatment). Whatever its form, Kaposi's sarcoma is probably associated with a chronic viral human herpes type 8 infection (HHV8). This virus has been implicated in the pathogenesis of multiple myeloma (17 cases recorded to date). In the present study, a further case of Kaposi's sarcoma associated with multiple myeloma has been reported. However, Epstein-Barr virus, cytomegalovirus, hepatitis B and C, HIV and HHV8 serologies were negative. Radiotherapy on the lower limbs was initiated. It is concluded that HHV8 does not appear to play a pathogenic role in cases of multiple myeloma, given the rarity of the association between Kaposi's sarcoma/multiple myeloma/HHV8.

Intestinal microbiota in primary sclerosing cholangitis.

PubMed

Hov, Johannes R; Kummen, Martin

2017-03-01

Alterations of the gut-liver axis have been linked to the pathogenesis of primary sclerosing cholangitis (PSC) since the disease was first described. The purpose of this review is to discuss multiple recent studies on the intestinal microbiota in human PSC and experimental models of this disease. Data are available from eight cross-sectional studies of human PSC, which include a variable number of patients (n = 11-85), material (mucosal or fecal), and microbiota profiling methodology. Despite the heterogeneity of the studies, a pattern of differences is observed that could represent a theme or signature of the PSC gut microbiota, characterized by low diversity and with alterations in multiple bacterial taxa. In experimental models of PSC, re-derivation of animals into germ-free facilities may either aggravate or attenuate the disease, depending on host genetics and putative disease mechanisms (e.g., fibrotic or immune-driven processes, respectively). The present data provide a strong rationale to explore the functional consequences of the observed gut microbial alterations and their influence on the pathogenesis in PSC. Studies of gut microbiota as biomarker and treatment target may potentially also lead to early translation into clinical practice.

The MiRNA Journey from Theory to Practice as a CNS Biomarker.

PubMed

Stoicea, Nicoleta; Du, Amy; Lakis, D Christie; Tipton, Courtney; Arias-Morales, Carlos E; Bergese, Sergio D

2016-01-01

MicroRNAs (miRNAs), small nucleotide sequences that control gene transcription, have the potential to serve an expanded function as indicators in the diagnosis and progression of neurological disorders. Studies involving debilitating neurological diseases such as, Alzheimer's disease, multiple sclerosis, traumatic brain injuries, Parkinson's disease and CNS tumors, already provide validation for their clinical diagnostic use. These small nucleotide sequences have several features, making them favorable candidates as biomarkers, including function in multiple tissues, stability in bodily fluids, a role in pathogenesis, and the ability to be detected early in the disease course. Cerebrospinal fluid, with its cell-free environment, collection process that minimizes tissue damage, and direct contact with the brain and spinal cord, is a promising source of miRNA in the diagnosis of many neurological disorders. Despite the advantages of miRNA analysis, current analytic technology is not yet affordable as a clinically viable diagnostic tool and requires standardization. The goal of this review is to explore the prospective use of CSF miRNA as a reliable and affordable biomarker for different neurological disorders.

The MiRNA Journey from Theory to Practice as a CNS Biomarker

PubMed Central

Stoicea, Nicoleta; Du, Amy; Lakis, D. Christie; Tipton, Courtney; Arias-Morales, Carlos E.; Bergese, Sergio D.

2016-01-01

MicroRNAs (miRNAs), small nucleotide sequences that control gene transcription, have the potential to serve an expanded function as indicators in the diagnosis and progression of neurological disorders. Studies involving debilitating neurological diseases such as, Alzheimer's disease, multiple sclerosis, traumatic brain injuries, Parkinson's disease and CNS tumors, already provide validation for their clinical diagnostic use. These small nucleotide sequences have several features, making them favorable candidates as biomarkers, including function in multiple tissues, stability in bodily fluids, a role in pathogenesis, and the ability to be detected early in the disease course. Cerebrospinal fluid, with its cell-free environment, collection process that minimizes tissue damage, and direct contact with the brain and spinal cord, is a promising source of miRNA in the diagnosis of many neurological disorders. Despite the advantages of miRNA analysis, current analytic technology is not yet affordable as a clinically viable diagnostic tool and requires standardization. The goal of this review is to explore the prospective use of CSF miRNA as a reliable and affordable biomarker for different neurological disorders. PMID:26904099

SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease

PubMed Central

Li, Darrick K.; Tisdale, Sarah; Lotti, Francesco; Pellizzoni, Livio

2014-01-01

At the post-transcriptional level, expression of protein-coding genes is controlled by a series of RNA regulatory events including nuclear processing of primary transcripts, transport of mature mRNAs to specific cellular compartments, translation and ultimately, turnover. These processes are orchestrated through the dynamic association of mRNAs with RNA binding proteins and ribonucleoprotein (RNP) complexes. Accurate formation of RNPs in vivo is fundamentally important to cellular development and function, and its impairment often leads to human disease. The survival motor neuron (SMN) protein is key to this biological paradigm: SMN is essential for the biogenesis of various RNPs that function in mRNA processing, and genetic mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP assembly. We discuss advances in our understanding of SMN activity as a chaperone of RNPs and how disruption of SMN-dependent RNA pathways can cause motor neuron disease. PMID:24769255

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

PubMed

Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C A; Patsopoulos, Nikolaos A; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E; Edkins, Sarah; Gray, Emma; Booth, David R; Potter, Simon C; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Céline; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D'alfonso, Sandra; Blackburn, Hannah; Martinelli Boneschi, Filippo; Liddle, Jennifer; Harbo, Hanne F; Perez, Marc L; Spurkland, Anne; Waller, Matthew J; Mycko, Marcin P; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J; Barcellos, Lisa F; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P; Brassat, David; Broadley, Simon A; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M; Cavalla, Paola; Celius, Elisabeth G; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Françoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B; Cozen, Wendy; Cree, Bruce A C; Cross, Anne H; Cusi, Daniele; Daly, Mark J; Davis, Emma; de Bakker, Paul I W; Debouverie, Marc; D'hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Bénédicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F A; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G; Kilpatrick, Trevor J; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S; Leone, Maurizio A; Leppä, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R; Link, Jenny; Liu, Jianjun; Lorentzen, Aslaug R; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L; Ramsay, Patricia P; Reunanen, Mauri; Reynolds, Richard; Rioux, John D; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P; Rückert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J; Sellebjerg, Finn; Selmaj, Krzysztof W; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M A; Smestad, Cathrine; Sørensen, Per Soelberg; Søndergaard, Helle Bach; Stankovich, Jim; Strange, Richard C; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvänen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A; Tronczynska, Ewa; Casas, Juan P; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S; Wang, Kai; Mathew, Christopher G; Wason, James; Palmer, Colin N A; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C; Yaouanq, Jacqueline; Viswanathan, Ananth C; Zhang, Haitao; Wood, Nicholas W; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R; Pericak-Vance, Margaret A; Haines, Jonathan L; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J; De Jager, Philip L; Peltonen, Leena; Stewart, Graeme J; Hafler, David A; Hauser, Stephen L; McVean, Gil; Donnelly, Peter; Compston, Alastair

2011-08-10

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

GLADIATOR: a global approach for elucidating disease modules.

PubMed

Silberberg, Yael; Kupiec, Martin; Sharan, Roded

2017-05-26

Understanding the genetic basis of disease is an important challenge in biology and medicine. The observation that disease-related proteins often interact with one another has motivated numerous network-based approaches for deciphering disease mechanisms. In particular, protein-protein interaction networks were successfully used to illuminate disease modules, i.e., interacting proteins working in concert to drive a disease. The identification of these modules can further our understanding of disease mechanisms. We devised a global method for the prediction of multiple disease modules simultaneously named GLADIATOR (GLobal Approach for DIsease AssociaTed mOdule Reconstruction). GLADIATOR relies on a gold-standard disease phenotypic similarity to obtain a pan-disease view of the underlying modules. To traverse the search space of potential disease modules, we applied a simulated annealing algorithm aimed at maximizing the correlation between module similarity and the gold-standard phenotypic similarity. Importantly, this optimization is employed over hundreds of diseases simultaneously. GLADIATOR's predicted modules highly agree with current knowledge about disease-related proteins. Furthermore, the modules exhibit high coherence with respect to functional annotations and are highly enriched with known curated pathways, outperforming previous methods. Examination of the predicted proteins shared by similar diseases demonstrates the diverse role of these proteins in mediating related processes across similar diseases. Last, we provide a detailed analysis of the suggested molecular mechanism predicted by GLADIATOR for hyperinsulinism, suggesting novel proteins involved in its pathology. GLADIATOR predicts disease modules by integrating knowledge of disease-related proteins and phenotypes across multiple diseases. The predicted modules are functionally coherent and are more in line with current biological knowledge compared to modules obtained using previous disease-centric methods. The source code for GLADIATOR can be downloaded from http://www.cs.tau.ac.il/~roded/GLADIATOR.zip .

A Community-Based Participatory Planning Process and Multilevel Intervention Design: Toward Eliminating Cardiovascular Health Inequities

PubMed Central

Schulz, Amy J.; Israel, Barbara A.; Coombe, Chris M.; Gaines, Causandra; Reyes, Angela G.; Rowe, Zachary; Sand, Sharon; Strong, Larkin L.; Weir, Sheryl

2010-01-01

The elimination of persistent health inequities requires the engagement of multiple perspectives, resources and skills. Community-based participatory research is one approach to developing action strategies that promote health equity by addressing contextual as well as individual level factors, and that can contribute to addressing more fundamental factors linked to health inequity. Yet many questions remain about how to implement participatory processes that engage local insights and expertise, are informed by the existing public health knowledge base, and build support across multiple sectors to implement solutions. We describe a CBPR approach used to conduct a community assessment and action planning process, culminating in development of a multilevel intervention to address inequalities in cardiovascular disease in Detroit, Michigan. We consider implications for future efforts to engage communities in developing strategies toward eliminating health inequities. PMID:21873580

Profile of Circulatory Metabolites in a Relapsing-remitting Animal Model of Multiple Sclerosis using Global Metabolomics

PubMed Central

Mangalam, AK; Poisson, LM; Nemutlu, E; Datta, I; Denic, A; Dzeja, P; Rodriguez, M; Rattan, R; Giri, S

2013-01-01

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Although, MS is well characterized in terms of the role played by immune cells, cytokines and CNS pathology, nothing is known about the metabolic alterations that occur during the disease process in circulation. Recently, metabolic aberrations have been defined in various disease processes either as contributing to the disease, as potential biomarkers, or as therapeutic targets. Thus in an attempt to define the metabolic alterations that may be associated with MS disease progression, we profiled the plasma metabolites at the chronic phase of disease utilizing relapsing remitting-experimental autoimmune encephalomyelitis (RR-EAE) model in SJL mice. At the chronic phase of the disease (day 45), untargeted global metabolomic profiling of plasma collected from EAE diseased SJL and healthy mice was performed, using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry. A total of 282 metabolites were identified, with significant changes observed in 44 metabolites (32 up-regulated and 12 down-regulated), that mapped to lipid, amino acid, nucleotide and xenobiotic metabolism and distinguished EAE from healthy group (p<0.05, false discovery rate (FDR)<0.23). Mapping the differential metabolite signature to their respective biochemical pathways using the Kyoto Encyclopedia of Genes and Genomics (KEGG) database, we found six major pathways that were significantly altered (containing concerted alterations) or impacted (containing alteration in key junctions). These included bile acid biosynthesis, taurine metabolism, tryptophan and histidine metabolism, linoleic acid and D-arginine metabolism pathways. Overall, this study identified a 44 metabolite signature drawn from various metabolic pathways which correlated well with severity of the EAE disease, suggesting that these metabolic changes could be exploited as (1) biomarkers for EAE/MS progression and (2) to design new treatment paradigms where metabolic interventions could be combined with present and experimental therapeutics to achieve better treatment of MS. PMID:24273690

Etiology and pathogenesis of inflammatory bowel disease.

PubMed

Schmidt, C; Stallmach, A

2005-06-01

Despite of scientific efforts during the last decades, etiology and pathogenesis of the two major inflammatory bowel diseases, namely Crohn's disease and ulcerative colitis, remain rather unclear. According to the results of multiple studies it is accepted that the development of either disease is the result of an exaggerated or insufficiently suppressed immune response to a hitherto undefined luminal antigen, probably derived from the microbial flora. This inflammatory process leads to the well-known mucosal damage and therefore a further disturbance of the epithelial barrier function, resulting in an increased influx of bacteria into the intestinal wall, even further accelerating the inflammatory process. However, these immunological disturbances that have been investigated extensively during the past years have to be considered on the genetic background of the individual patient and the environmental factors the patient is exposed to. In this review we will attempt to summarize the current knowledge about risk factors for inflammatory bowel diseases, genetic and environmental factors of IBD and focus on the immunological alterations of innate and acquired immune system underlying Crohn's disease and ulcerative colitis.

Abnormal pain perception in patients with Multiple System Atrophy.

PubMed

Ory-Magne, F; Pellaprat, J; Harroch, E; Galitzsky, M; Rousseau, V; Pavy-Le Traon, A; Rascol, O; Gerdelat, A; Brefel-Courbon, C

2018-03-01

Patients with Parkinson's disease or Multiple System Atrophy frequently experience painful sensations. The few studies investigating pain mechanisms in Multiple System Atrophy patients have reported contradictory results. In our study, we compared pain thresholds in Multiple System Atrophy and Parkinson's disease patients and healthy controls and evaluated the effect of l-DOPA on pain thresholds. We assessed subjective and objective pain thresholds (using a thermotest and RIII reflex), and pain tolerance in OFF and ON conditions, clinical pain, motor and psychological evaluation. Pain was reported in 78.6% of Multiple System Atrophy patients and in 37.5% of Parkinson's disease patients. In the OFF condition, subjective and objective pain thresholds were significantly lower in Multiple System Atrophy patients than in healthy controls (43.8 °C ± 1.3 vs 45.7 °C ± 0.8; p = 0.0005 and 7.4 mA ± 3.8 vs 13.7 mA ± 2.8; p = 0.002, respectively). They were also significantly reduced in Multiple System Atrophy compared to Parkinson's disease patients. No significant difference was found in pain tolerance for the 3 groups and in the effect of l-DOPA on pain thresholds in Multiple System Atrophy and Parkinson's disease patients. In the ON condition, pain tolerance tended to be reduced in Multiple System Atrophy versus Parkinson's disease patients (p = 0.05). Multiple System Atrophy patients had an increase in pain perception compared to Parkinson's disease patients and healthy controls. The l-DOPA effect was similar for pain thresholds in Multiple System Atrophy and Parkinson's disease patients, but tended to worsen pain tolerance in Multiple System Atrophy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Potential use of multiple surveillance data in the forecast of hospital admissions

PubMed Central

Lau, Eric H.Y.; Ip, Dennis K.M.; Cowling, Benjamin J.

2013-01-01

Objective This paper describes the potential use of multiple influenza surveillance data to forecast hospital admissions for respiratory diseases. Introduction A sudden surge in hospital admissions in public hospital during influenza peak season has been a challenge to healthcare and manpower planning. In Hong Kong, the timing of influenza peak seasons are variable and early short-term indication of possible surge may facilitate preparedness which could be translated into strategies such as early discharge or reallocation of extra hospital beds. In this study we explore the potential use of multiple routinely collected syndromic data in the forecast of hospital admissions. Methods A multivariate dynamic linear time series model was fitted to multiple syndromic data including influenza-like illness (ILI) rates among networks of public and private general practitioners (GP), and school absenteeism rates, plus drop-in fever count data from designated flu clinics (DFC) that were created during the pandemic. The latent process derived from the model has been used as a measure of the influenza activity [1]. We compare the cross-correlations between estimated influenza level based on multiple surveillance data and GP ILI data, versus accident and emergency hospital admissions with principal diagnoses of respiratory diseases and pneumonia & influenza (P&I). Results The estimated influenza activity has higher cross-correlation with respiratory and P&I admissions (ρ=0.66 and 0.73 respectively) compared to that of GP ILI rates (Table 1). Cross correlations drop distinctly after lag 2 for both estimated influenza activity and GP ILI rates. Conclusions The use of a multivariate method to integrate information from multiple sources of influenza surveillance data may have the potential to improve forecasting of admission surge of respiratory diseases.

Survey of diagnostic and treatment practices for multiple sclerosis in Europe.

PubMed

Fernández, O; Delvecchio, M; Edan, G; Fredrikson, S; Gionvannoni, G; Hartung, H-P; Havrdova, E; Kappos, L; Pozzilli, C; Soerensen, P S; Tackenberg, B; Vermersch, P; Comi, G

2017-03-01

Up-to-date information is needed on the extent to which neurologists treating multiple sclerosis (MS) in Europe are integrating rapidly evolving diagnostic criteria, disease-modifying therapies and recommendations for monitoring disease activity into their clinical practice. A steering committee of MS neurologists used a modified Delphi process to develop case- and practice-based questions for two sequential surveys distributed to MS neurologists throughout Europe. Case-based questions were developed for radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS) and RRMS with breakthrough disease. Multiple sclerosis neurologists from 11 European countries responded to survey 1 (n = 233) and survey 2 (n = 171). Respondents agreed that they would not treat the patients in the RIS or CIS cases but would treat a patient with a relatively mild form of RRMS. Choice of treatment was evenly distributed among first-line injectables and oral treatments for mild RRMS, and moved to second-line treatment as the RRMS case increased in severity. Additional results on RRMS with breakthrough disease are presented. Although there was general agreement on some aspects of treatment, responses to other management and clinical practice questions varied considerably. These results, which reflect current clinical practice patterns, highlight the need for additional MS treatment education and awareness and may help inform the development of MS practice guidelines in Europe. © 2017 EAN.

Perspectives on the role of mobility, behavior, and time scales in the spread of diseases.

PubMed

Castillo-Chavez, Carlos; Bichara, Derdei; Morin, Benjamin R

2016-12-20

The dynamics, control, and evolution of communicable and vector-borne diseases are intimately connected to the joint dynamics of epidemiological, behavioral, and mobility processes that operate across multiple spatial, temporal, and organizational scales. The identification of a theoretical explanatory framework that accounts for the pattern regularity exhibited by a large number of host-parasite systems, including those sustained by host-vector epidemiological dynamics, is but one of the challenges facing the coevolving fields of computational, evolutionary, and theoretical epidemiology. Host-parasite epidemiological patterns, including epidemic outbreaks and endemic recurrent dynamics, are characteristic to well-identified regions of the world; the result of processes and constraints such as strain competition, host and vector mobility, and population structure operating over multiple scales in response to recurrent disturbances (like El Niño) and climatological and environmental perturbations over thousands of years. It is therefore important to identify and quantify the processes responsible for observed epidemiological macroscopic patterns: the result of individual interactions in changing social and ecological landscapes. In this perspective, we touch on some of the issues calling for the identification of an encompassing theoretical explanatory framework by identifying some of the limitations of existing theory, in the context of particular epidemiological systems. Fostering the reenergizing of research that aims at disentangling the role of epidemiological and socioeconomic forces on disease dynamics, better understood as complex adaptive systems, is a key aim of this perspective.

Chronic Pain in Inflammatory Arthritis: Mechanisms, Metrology, and Emerging Targets—A Focus on the JAK-STAT Pathway

PubMed Central

Salaffi, Fausto; Giacobazzi, Giovanni

2018-01-01

Chronic pain is nowadays considered not only the mainstay symptom of rheumatic diseases but also “a disease itself.” Pain is a multidimensional phenomenon, and in inflammatory arthritis, it derives from multiple mechanisms, involving both synovitis (release of a great number of cytokines) and peripheral and central pain-processing mechanisms (sensitization). In the last years, the JAK-STAT pathway has been recognized as a pivotal component both in the inflammatory process and in pain amplification in the central nervous system. This paper provides a summary on pain in inflammatory arthritis, from pathogenesis to clinimetric instruments and treatment, with a focus on the JAK-STAT pathway. PMID:29623147

A Systematic Review and Meta-Analysis of Strength Training in Individuals With Multiple Sclerosis Or Parkinson Disease

PubMed Central

Cruickshank, Travis M.; Reyes, Alvaro R.; Ziman, Melanie R.

2015-01-01

Abstract Strength training has, in recent years, been shown to be beneficial for people with Parkinson disease and multiple sclerosis. Consensus regarding its utility for these disorders nevertheless remains contentious among healthcare professionals. Greater clarity is required, especially in regards to the type and magnitude of effects as well as the response differences to strength training between individuals with Parkinson disease or multiple sclerosis. This study examines the effects, magnitude of those effects, and response differences to strength training between patients with Parkinson disease or multiple sclerosis. A comprehensive search of electronic databases including Physiotherapy Evidence Database scale, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL was conducted from inception to July 2014. English articles investigating the effect of strength training for individuals with neurodegenerative disorders were selected. Strength training trials that met the inclusion criteria were found for individuals with Parkinson disease or multiple sclerosis. Individuals with Parkinson disease or multiple sclerosis were included in the study. Strength training interventions included traditional (free weights/machine exercises) and nontraditional programs (eccentric cycling). Included articles were critically appraised using the Physiotherapy Evidence Database scale. Of the 507 articles retrieved, only 20 articles met the inclusion criteria. Of these, 14 were randomized and 6 were nonrandomized controlled articles in Parkinson disease or multiple sclerosis. Six randomized and 2 nonrandomized controlled articles originated from 3 trials and were subsequently pooled for systematic analysis. Strength training was found to significantly improve muscle strength in people with Parkinson disease (15%–83.2%) and multiple sclerosis (4.5%–36%). Significant improvements in mobility (11.4%) and disease progression were also reported in people with Parkinson disease after strength training. Furthermore, significant improvements in fatigue (8.2%), functional capacity (21.5%), quality of life (8.3%), power (17.6%), and electromyography activity (24.4%) were found in individuals with multiple sclerosis after strength training. The limitations of the study were the heterogeneity of interventions and study outcomes in Parkinson disease and multiple sclerosis trials. Strength training is useful for increasing muscle strength in Parkinson disease and to a lesser extent multiple sclerosis. PMID:25634170

A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or Parkinson disease.

PubMed

Cruickshank, Travis M; Reyes, Alvaro R; Ziman, Melanie R

2015-01-01

Strength training has, in recent years, been shown to be beneficial for people with Parkinson disease and multiple sclerosis. Consensus regarding its utility for these disorders nevertheless remains contentious among healthcare professionals. Greater clarity is required, especially in regards to the type and magnitude of effects as well as the response differences to strength training between individuals with Parkinson disease or multiple sclerosis. This study examines the effects, magnitude of those effects, and response differences to strength training between patients with Parkinson disease or multiple sclerosis. A comprehensive search of electronic databases including Physiotherapy Evidence Database scale, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL was conducted from inception to July 2014. English articles investigating the effect of strength training for individuals with neurodegenerative disorders were selected. Strength training trials that met the inclusion criteria were found for individuals with Parkinson disease or multiple sclerosis. Individuals with Parkinson disease or multiple sclerosis were included in the study. Strength training interventions included traditional (free weights/machine exercises) and nontraditional programs (eccentric cycling). Included articles were critically appraised using the Physiotherapy Evidence Database scale. Of the 507 articles retrieved, only 20 articles met the inclusion criteria. Of these, 14 were randomized and 6 were nonrandomized controlled articles in Parkinson disease or multiple sclerosis. Six randomized and 2 nonrandomized controlled articles originated from 3 trials and were subsequently pooled for systematic analysis. Strength training was found to significantly improve muscle strength in people with Parkinson disease (15%-83.2%) and multiple sclerosis (4.5%-36%). Significant improvements in mobility (11.4%) and disease progression were also reported in people with Parkinson disease after strength training. Furthermore, significant improvements in fatigue (8.2%), functional capacity (21.5%), quality of life (8.3%), power (17.6%), and electromyography activity (24.4%) were found in individuals with multiple sclerosis after strength training. The limitations of the study were the heterogeneity of interventions and study outcomes in Parkinson disease and multiple sclerosis trials. Strength training is useful for increasing muscle strength in Parkinson disease and to a lesser extent multiple sclerosis.

Adipose, Bone, and Myeloma: Contributions from the Microenvironment.

PubMed

McDonald, Michelle M; Fairfield, Heather; Falank, Carolyne; Reagan, Michaela R

2017-05-01

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.

Voxelwise multivariate analysis of multimodality magnetic resonance imaging.

PubMed

Naylor, Melissa G; Cardenas, Valerie A; Tosun, Duygu; Schuff, Norbert; Weiner, Michael; Schwartzman, Armin

2014-03-01

Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remain a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer's disease, in which data from three MRI modalities are available. Copyright © 2013 Wiley Periodicals, Inc.

Differences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease.

PubMed

Huh, Young Eun; Park, Jongkyu; Suh, Mee Kyung; Lee, Sang Eun; Kim, Jumin; Jeong, Yuri; Kim, Hee-Tae; Cho, Jin Whan

2015-08-01

In Parkinson variant of multiple system atrophy (MSA-P), patterns of early speech impairment and their distinguishing features from Parkinson's disease (PD) require further exploration. Here, we compared speech data among patients with early-stage MSA-P, PD, and healthy subjects using quantitative acoustic and perceptual analyses. Variables were analyzed for men and women in view of gender-specific features of speech. Acoustic analysis revealed that male patients with MSA-P exhibited more profound speech abnormalities than those with PD, regarding increased voice pitch, prolonged pause time, and reduced speech rate. This might be due to widespread pathology of MSA-P in nigrostriatal or extra-striatal structures related to speech production. Although several perceptual measures were mildly impaired in MSA-P and PD patients, none of these parameters showed a significant difference between patient groups. Detailed speech analysis using acoustic measures may help distinguish between MSA-P and PD early in the disease process. Copyright © 2015 Elsevier Inc. All rights reserved.

Iron deposition and inflammation in multiple sclerosis. Which one comes first?

PubMed Central

2011-01-01

Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor. PMID:21699686

Development of partial ontogenic resistance to powdery mildew in Hop cones and its management implications

USDA-ARS?s Scientific Manuscript database

Knowledge of processes leading to crop damage is central to devising rational approaches to disease management. Multiple experiments established that infection of hop cones by Podosphaera macularis was most severe if inoculation occurred within 15 to 21 days after bloom. This period of infection was...

Using Behavioral Interventions to Assist Children with Type 1 Diabetes Manage Blood Glucose Levels

ERIC Educational Resources Information Center

Lasecki, Kim; Olympia, Daniel; Clark, Elaine; Jenson, William; Heathfield, Lora Tuesday

2008-01-01

Treatment and management of chronic disease processes on children occurs across multiple settings, placing demands for consultation and expertise on school personnel, including school psychologists. One such chronic condition in children is type I diabetes. Children with type I insulin dependent diabetes mellitus exhibit high rates of…

Text-based Analytics for Biosurveillance

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

Charles, Lauren E.; Smith, William P.; Rounds, Jeremiah

The ability to prevent, mitigate, or control a biological threat depends on how quickly the threat is identified and characterized. Ensuring the timely delivery of data and analytics is an essential aspect of providing adequate situational awareness in the face of a disease outbreak. This chapter outlines an analytic pipeline for supporting an advanced early warning system that can integrate multiple data sources and provide situational awareness of potential and occurring disease situations. The pipeline, includes real-time automated data analysis founded on natural language processing (NLP), semantic concept matching, and machine learning techniques, to enrich content with metadata related tomore » biosurveillance. Online news articles are presented as an example use case for the pipeline, but the processes can be generalized to any textual data. In this chapter, the mechanics of a streaming pipeline are briefly discussed as well as the major steps required to provide targeted situational awareness. The text-based analytic pipeline includes various processing steps as well as identifying article relevance to biosurveillance (e.g., relevance algorithm) and article feature extraction (who, what, where, why, how, and when). The ability to prevent, mitigate, or control a biological threat depends on how quickly the threat is identified and characterized. Ensuring the timely delivery of data and analytics is an essential aspect of providing adequate situational awareness in the face of a disease outbreak. This chapter outlines an analytic pipeline for supporting an advanced early warning system that can integrate multiple data sources and provide situational awareness of potential and occurring disease situations. The pipeline, includes real-time automated data analysis founded on natural language processing (NLP), semantic concept matching, and machine learning techniques, to enrich content with metadata related to biosurveillance. Online news articles are presented as an example use case for the pipeline, but the processes can be generalized to any textual data. In this chapter, the mechanics of a streaming pipeline are briefly discussed as well as the major steps required to provide targeted situational awareness. The text-based analytic pipeline includes various processing steps as well as identifying article relevance to biosurveillance (e.g., relevance algorithm) and article feature extraction (who, what, where, why, how, and when).« less

Rodent Models of Experimental Endometriosis: Identifying Mechanisms of Disease and Therapeutic Targets

PubMed Central

Bruner-Tran, Kaylon L.; Mokshagundam, Shilpa; Herington, Jennifer L.; Ding, Tianbing; Osteen, Kevin G.

2018-01-01

Background: Although it has been more than a century since endometriosis was initially described in the literature, understanding the etiology and natural history of the disease has been challenging. However, the broad utility of murine and rat models of experimental endometriosis has enabled the elucidation of a number of potentially targetable processes which may otherwise promote this disease. Objective: To review a variety of studies utilizing rodent models of endometriosis to illustrate their utility in examining mechanisms associated with development and progression of this disease. Results: Use of rodent models of endometriosis has provided a much broader understanding of the risk factors for the initial development of endometriosis, the cellular pathology of the disease and the identification of potential therapeutic targets. Conclusion: Although there are limitations with any animal model, the variety of experimental endometriosis models that have been developed has enabled investigation into numerous aspects of this disease. Thanks to these models, our under-standing of the early processes of disease development, the role of steroid responsiveness, inflammatory processes and the peritoneal environment has been advanced. More recent models have begun to shed light on how epigenetic alterations con-tribute to the molecular basis of this disease as well as the multiple comorbidities which plague many patients. Continued de-velopments of animal models which aid in unraveling the mechanisms of endometriosis development provide the best oppor-tunity to identify therapeutic strategies to prevent or regress this enigmatic disease.

Data-model fusion to better understand emerging pathogens and improve infectious disease forecasting.

PubMed

LaDeau, Shannon L; Glass, Gregory E; Hobbs, N Thompson; Latimer, Andrew; Ostfeld, Richard S

2011-07-01

Ecologists worldwide are challenged to contribute solutions to urgent and pressing environmental problems by forecasting how populations, communities, and ecosystems will respond to global change. Rising to this challenge requires organizing ecological information derived from diverse sources and formally assimilating data with models of ecological processes. The study of infectious disease has depended on strategies for integrating patterns of observed disease incidence with mechanistic process models since John Snow first mapped cholera cases around a London water pump in 1854. Still, zoonotic and vector-borne diseases increasingly affect human populations, and methods used to successfully characterize directly transmitted diseases are often insufficient. We use four case studies to demonstrate that advances in disease forecasting require better understanding of zoonotic host and vector populations, as well of the dynamics that facilitate pathogen amplification and disease spillover into humans. In each case study, this goal is complicated by limited data, spatiotemporal variability in pathogen transmission and impact, and often, insufficient biological understanding. We present a conceptual framework for data-model fusion in infectious disease research that addresses these fundamental challenges using a hierarchical state-space structure to (1) integrate multiple data sources and spatial scales to inform latent parameters, (2) partition uncertainty in process and observation models, and (3) explicitly build upon existing ecological and epidemiological understanding. Given the constraints inherent in the study of infectious disease and the urgent need for progress, fusion of data and expertise via this type of conceptual framework should prove an indispensable tool.

An epigenetic view of developmental diseases: new targets, new therapies.

PubMed

Xie, Pei; Zang, Li-Qun; Li, Xue-Kun; Shu, Qiang

2016-08-01

Function of epigenetic modifications is one of the most competitive fields in life science. Over the past several decades, it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental diseases. In the present review, we summarize the recent progress about the function of epigenetic regulation, especially DNA and RNA modifications in developmental diseases. Original research articles and literature reviews published in PubMed-indexed journals. DNA modifications including methylation and demethylation can regulate gene expression, and are involved in development and multiple diseases including Rett syndrome, Autism spectrum disorders, congenital heart disease and cancer, etc. RNA methylation and demethylation play important roles in RNA processing, reprogramming, circadian, and neuronal activity, and then modulate development. DNA and RNA modifications play important roles in development and diseases through regulating gene expression. Epigenetic components could serve as novel targets for the treatment of developmental diseases.

Bioerodible System for Sequential Release of Multiple Drugs

PubMed Central

Sundararaj, Sharath C.; Thomas, Mark V.; Dziubla, Thomas D.; Puleo, David A.

2013-01-01

Because many complex physiological processes are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the objective of the present research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. The polymers used were cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule. PMID:24096151

Genomic and Epigenomic Insights into Nutrition and Brain Disorders

PubMed Central

Dauncey, Margaret Joy

2013-01-01

Considerable evidence links many neuropsychiatric, neurodevelopmental and neurodegenerative disorders with multiple complex interactions between genetics and environmental factors such as nutrition. Mental health problems, autism, eating disorders, Alzheimer’s disease, schizophrenia, Parkinson’s disease and brain tumours are related to individual variability in numerous protein-coding and non-coding regions of the genome. However, genotype does not necessarily determine neurological phenotype because the epigenome modulates gene expression in response to endogenous and exogenous regulators, throughout the life-cycle. Studies using both genome-wide analysis of multiple genes and comprehensive analysis of specific genes are providing new insights into genetic and epigenetic mechanisms underlying nutrition and neuroscience. This review provides a critical evaluation of the following related areas: (1) recent advances in genomic and epigenomic technologies, and their relevance to brain disorders; (2) the emerging role of non-coding RNAs as key regulators of transcription, epigenetic processes and gene silencing; (3) novel approaches to nutrition, epigenetics and neuroscience; (4) gene-environment interactions, especially in the serotonergic system, as a paradigm of the multiple signalling pathways affected in neuropsychiatric and neurological disorders. Current and future advances in these four areas should contribute significantly to the prevention, amelioration and treatment of multiple devastating brain disorders. PMID:23503168

Psychosocial Intervention for Young Children With Chronic Tics

ClinicalTrials.gov

2018-06-18

Tourette's Syndrome; Tourette's Disorder; Tourette's Disease; Tourette Disorder; Tourette Disease; Tic Disorder, Combined Vocal and Multiple Motor; Multiple Motor and Vocal Tic Disorder, Combined; Gilles de La Tourette's Disease; Gilles de la Tourette Syndrome; Gilles De La Tourette's Syndrome; Combined Vocal and Multiple Motor Tic Disorder; Combined Multiple Motor and Vocal Tic Disorder; Chronic Motor and Vocal Tic Disorder

Clinical Holistic Medicine: The Patient with Multiple Diseases

PubMed Central

Ventegodt, Søren; Merrick, Joav

2005-01-01

In clinical practice, patients can present with many different diseases, often both somatic and mental. Holistic medicine will try to see the diseases as a whole, as symptoms of a more fundamental imbalance in the state of being. The holistic physician must help the patient to recover existence and a good relationship with self. According to the life mission theory, theory of character, and holistic process theory of healing, recovering the purpose of life (the life mission) is essential for the patient to regain life, love, and trust in order to find happiness and realize the true purpose of life. We illustrate the power of the holistic medical approach with a case study of an invalidated female artist, aged 42 years, who suffered from multiple severe health problems, many of which had been chronic for years. She had a combination of neurological disturbances (tinnitus, migraine, minor hallucinations), immunological disturbances (recurrent herpes simplex, phlegm in the throat, fungal infection in the crotch), hormonal disturbances (14 days of menstruation in each cycle), muscle disturbances (neck tensions), mental disturbances (tendency to cry, inferiority feeling, mild depression, desolation, anxiety), abdominal complaints, hemorrhoids, and more. The treatment was a combined strategy of improving the general quality of life, recovering her human character and purpose of life (“renewing the patients life energy”, “balancing her global information system”), and processing the local blockages, thus healing most of her many different diseases in a treatment using 30 h of intense holistic therapy over a period of 18 months. PMID:15962199

Mathematical Modeling of Protein Misfolding Mechanisms in Neurological Diseases: A Historical Overview.

PubMed

Carbonell, Felix; Iturria-Medina, Yasser; Evans, Alan C

2018-01-01

Protein misfolding refers to a process where proteins become structurally abnormal and lose their specific 3-dimensional spatial configuration. The histopathological presence of misfolded protein (MP) aggregates has been associated as the primary evidence of multiple neurological diseases, including Prion diseases, Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease. However, the exact mechanisms of MP aggregation and propagation, as well as their impact in the long-term patient's clinical condition are still not well understood. With this aim, a variety of mathematical models has been proposed for a better insight into the kinetic rate laws that govern the microscopic processes of protein aggregation. Complementary, another class of large-scale models rely on modern molecular imaging techniques for describing the phenomenological effects of MP propagation over the whole brain. Unfortunately, those neuroimaging-based studies do not take full advantage of the tremendous capabilities offered by the chemical kinetics modeling approach. Actually, it has been barely acknowledged that the vast majority of large-scale models have foundations on previous mathematical approaches that describe the chemical kinetics of protein replication and propagation. The purpose of the current manuscript is to present a historical review about the development of mathematical models for describing both microscopic processes that occur during the MP aggregation and large-scale events that characterize the progression of neurodegenerative MP-mediated diseases.

Bridging paradigms: hybrid mechanistic-discriminative predictive models.

PubMed

Doyle, Orla M; Tsaneva-Atansaova, Krasimira; Harte, James; Tiffin, Paul A; Tino, Peter; Díaz-Zuccarini, Vanessa

2013-03-01

Many disease processes are extremely complex and characterized by multiple stochastic processes interacting simultaneously. Current analytical approaches have included mechanistic models and machine learning (ML), which are often treated as orthogonal viewpoints. However, to facilitate truly personalized medicine, new perspectives may be required. This paper reviews the use of both mechanistic models and ML in healthcare as well as emerging hybrid methods, which are an exciting and promising approach for biologically based, yet data-driven advanced intelligent systems.

Ubiquitin-dependent and independent roles of SUMO in proteostasis.

PubMed

Liebelt, Frauke; Vertegaal, Alfred C O

2016-08-01

Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options. Copyright © 2016 the American Physiological Society.

Feature tracking cardiac magnetic resonance imaging: A review of a novel non-invasive cardiac imaging technique

PubMed Central

Rahman, Zia Ur; Sethi, Pooja; Murtaza, Ghulam; Virk, Hafeez Ul Hassan; Rai, Aitzaz; Mahmod, Masliza; Schoondyke, Jeffrey; Albalbissi, Kais

2017-01-01

Cardiovascular disease is a leading cause of morbidity and mortality globally. Early diagnostic markers are gaining popularity for better patient care disease outcomes. There is an increasing interest in noninvasive cardiac imaging biomarkers to diagnose subclinical cardiac disease. Feature tracking cardiac magnetic resonance imaging is a novel post-processing technique that is increasingly being employed to assess global and regional myocardial function. This technique has numerous applications in structural and functional diagnostics. It has been validated in multiple studies, although there is still a long way to go for it to become routine standard of care. PMID:28515849

8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications

PubMed Central

Prachayasittikul, Veda; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

2013-01-01

Metal ions play an important role in biological processes and in metal homeostasis. Metal imbalance is the leading cause for many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. 8-Hydroxyquinoline (8HQ) is a small planar molecule with a lipophilic effect and a metal chelating ability. As a result, 8HQ and its derivatives hold medicinal properties such as antineurodegenerative, anticancer, antioxidant, antimicrobial, anti-inflammatory, and antidiabetic activities. Herein, diverse bioactivities of 8HQ and newly synthesized 8HQ-based compounds are discussed together with their mechanisms of actions and structure–activity relationships. PMID:24115839

The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity

PubMed Central

Satoh, Akiko; Stein, Liana

2013-01-01

Ever since the discovery of sirtuins a decade ago, interest in this family of NAD-dependent deacetylases has exploded, generating multiple lines of evidence implicating sirtuins as evolutionarily conserved regulators of lifespan. In mammals, it has been established that sirtuins regulate physiological responses to metabolism and stress, two key factors that affect the process of aging. Further investigation into the intimate connection among sirtuins, metabolism, and aging has implicated the activation of SIRT1 as both preventative and therapeutic measures against multiple age-associated disorders including type 2 diabetes and Alzheimer’s disease. SIRT1 activation has clear potential to not only prevent age-associated diseases but also to extend healthspan and perhaps lifespan. Sirtuin activating compounds and NAD intermediates are two promising ways to achieve these elusive goals. PMID:21879449

A gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging

PubMed Central

Louapre, Céline; Govindarajan, Sindhuja T.; Giannì, Costanza; Nielsen, A. Scott; Cohen-Adad, Julien; Sloane, Jacob; Kinkel, Revere P.

2015-01-01

We used a surface-based analysis of T2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2* throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (≥4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2* maps were registered to anatomical cortical surfaces for sampling T2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2* was compared with patients’ normal-appearing cortical grey matter T2* (paired t-test) and with mean cortical T2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2*, consistent with cortical myelin and iron loss. In early disease, T2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10−10 and P < 10−7), and mean cortical T2* in controls (P < 10−5 and P < 10−6). In secondary progressive multiple sclerosis, T2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface. PMID:25681411

Microarray profiling analysis uncovers common molecular mechanisms of rubella virus, human cytomegalovirus, and herpes simplex virus type 2 infections in ECV304 cells.

PubMed

Mo, X; Xu, L; Yang, Q; Feng, H; Peng, J; Zhang, Y; Yuan, W; Wang, Y; Li, Y; Deng, Y; Wan, Y; Chen, Z; Li, F; Wu, X

2011-08-01

To study the common molecular mechanisms of various viruses infections that might result in congential cardiovascular diseases in perinatal period, changes in mRNA expression levels of ECV304 cells infected by rubella virus (RUBV), human cytomegalovirus (HCMV), and herpes simplex virus type 2 (HSV-2) were analyzed using a microarray system representing 18,716 human genes. 99 genes were found to exhibit differential expression (80 up-regulated and 19 down-regulated). Biological process analysis showed that 33 signaling pathways including 22 genes were relevant significantly to RV, HCMV and HSV-II infections. Of these 33 biological processes, 28 belong to one-gene biological processes and 5 belong to multiple-gene biological processes. Gene annotation indicated that the 5 multiple-gene biological processes including regulation of cell growth, collagen fibril organization, mRNA transport, cell adhesion and regulation of cell shape, and seven down- or up-regulated genes [CRIM1 (cysteine rich transmembrane BMP regulator 1), WISP2 (WNT1 inducible signaling pathway protein 2), COL12A1 (collagen, type XII, alpha 1), COL11A2 (collagen, type XI, alpha 2), CNTN5 (contactin 5), DDR1 (discoidin domain receptor tyrosine kinase 1), VEGF (vascular endothelial growth factor precursor)], are significantly correlated to RUBV, HCMV and HSV-2 infections in ECV304 cells. The results obtained in this study suggested the common molecular mechanisms of viruses infections that might result in congential cardiovascular diseases.

Lung disease and coal mining: what pulmonologists need to know.

PubMed

Go, Leonard H T; Krefft, Silpa D; Cohen, Robert A; Rose, Cecile S

2016-03-01

Coal mine workers are at risk for a range of chronic respiratory diseases including coal workers' pneumoconiosis, diffuse dust-related fibrosis, and chronic obstructive pulmonary disease. The purpose of this review is to describe coal mining processes and associated exposures to inform the diagnostic evaluation of miners with respiratory symptoms. Although rates of coal workers' pneumoconiosis declined after regulations were enacted in the 1970s, more recent data shows a reversal in this downward trend. Rapidly progressive pneumoconiosis with progressive massive fibrosis (complicated coal workers' pneumoconiosis) is being observed with increased frequency in United States coal miners, with histologic findings of silicosis and mixed-dust pneumoconiosis. There is increasing evidence of decline in lung function in individuals with pneumoconiosis. Multiple recent cohort studies suggest increased risk of lung cancer in coal miners. A detailed understanding of coal mining methods and processes allows clinicians to better evaluate and confirm chronic lung diseases caused by inhalational hazards in the mine atmosphere.

Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes

NASA Astrophysics Data System (ADS)

Habchi, Johnny; Chia, Sean; Galvagnion, Céline; Michaels, Thomas C. T.; Bellaiche, Mathias M. J.; Ruggeri, Francesco Simone; Sanguanini, Michele; Idini, Ilaria; Kumita, Janet R.; Sparr, Emma; Linse, Sara; Dobson, Christopher M.; Knowles, Tuomas P. J.; Vendruscolo, Michele

2018-06-01

Alzheimer's disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-β peptide. Although increasing evidence implicates cholesterol in the pathogenesis of Alzheimer's disease, the detailed mechanistic link between this lipid molecule and the disease process remains to be fully established. To address this problem, we adopt a kinetics-based strategy that reveals a specific catalytic role of cholesterol in the aggregation of Aβ42 (the 42-residue form of the amyloid-β peptide). More specifically, we demonstrate that lipid membranes containing cholesterol promote Aβ42 aggregation by enhancing its primary nucleation rate by up to 20-fold through a heterogeneous nucleation pathway. We further show that this process occurs as a result of cooperativity in the interaction of multiple cholesterol molecules with Aβ42. These results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of Aβ42 aggregation, thereby helping rationalize the link between Alzheimer's disease and the impairment of cholesterol homeostasis.

Splicing regulatory factors, ageing and age-related disease.

PubMed

Latorre, Eva; Harries, Lorna W

2017-07-01

Alternative splicing is a co-transcriptional process, which allows for the production of multiple transcripts from a single gene and is emerging as an important control point for gene expression. Alternatively expressed isoforms often have antagonistic function and differential temporal or spatial expression patterns, yielding enormous plasticity and adaptability to cells and increasing their ability to respond to environmental challenge. The regulation of alternative splicing is critical for numerous cellular functions in both pathological and physiological conditions, and deregulated alternative splicing is a key feature of common chronic diseases. Isoform choice is controlled by a battery of splicing regulatory proteins, which include the serine arginine rich (SRSF) proteins and the heterogeneous ribonucleoprotein (hnRNP) classes of genes. These important splicing regulators have been implicated in age-related disease, and in the ageing process itself. This review will outline the important contribution of splicing regulator proteins to ageing and age-related disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Potential of PET-MRI for imaging of non-oncologic musculoskeletal disease.

PubMed

Kogan, Feliks; Fan, Audrey P; Gold, Garry E

2016-12-01

Early detection of musculoskeletal disease leads to improved therapies and patient outcomes, and would benefit greatly from imaging at the cellular and molecular level. As it becomes clear that assessment of multiple tissues and functional processes are often necessary to study the complex pathogenesis of musculoskeletal disorders, the role of multi-modality molecular imaging becomes increasingly important. New positron emission tomography-magnetic resonance imaging (PET-MRI) systems offer to combine high-resolution MRI with simultaneous molecular information from PET to study the multifaceted processes involved in numerous musculoskeletal disorders. In this article, we aim to outline the potential clinical utility of hybrid PET-MRI to these non-oncologic musculoskeletal diseases. We summarize current applications of PET molecular imaging in osteoarthritis (OA), rheumatoid arthritis (RA), metabolic bone diseases and neuropathic peripheral pain. Advanced MRI approaches that reveal biochemical and functional information offer complementary assessment in soft tissues. Additionally, we discuss technical considerations for hybrid PET-MR imaging including MR attenuation correction, workflow, radiation dose, and quantification.

Cholinesterases as biomarkers for parasympathetic dysfunction and inflammation-related disease.

PubMed

Shenhar-Tsarfaty, Shani; Berliner, Shlomo; Bornstein, Natan M; Soreq, Hermona

2014-07-01

Accumulating evidence suggests parasympathetic dysfunction and elevated inflammation as underlying processes in multiple peripheral and neurological diseases. Acetylcholine, the main parasympathetic neurotransmitter and inflammation regulator, is hydrolyzed by the two closely homologous enzymes, acetylcholinesterase and butyrylcholinesterase (AChE and BChE, respectively), which are also expressed in the serum. Here, we consider the potential value of both enzymes as possible biomarkers in diseases associated with parasympathetic malfunctioning. We cover the modulations of cholinesterase activities in inflammation-related events as well as by cholinesterase-targeted microRNAs. We further discuss epigenetic control over cholinesterase gene expression and the impact of single-nucleotide polymorphisms on the corresponding physiological and pathological processes. In particular, we focus on measurements of circulation cholinesterases as a readily quantifiable readout for changes in the sympathetic/parasympathetic balance and the implications of changes in this readout in health and disease. Taken together, this cumulative know-how calls for expanding the use of cholinesterase activity measurements for both basic research and as a clinical assessment tool.

Impact of age on markers of HIV-1 disease

PubMed Central

Pirrone, Vanessa; Libon, David J; Sell, Christian; Lerner, Chad A; Nonnemacher, Michael R; Wigdahl, Brian

2013-01-01

Aging is a complicated process characterized by a progressive loss of homeostasis, which results in an increased vulnerability to multiple diseases. HIV-1-infected patients demonstrate a premature aging phenotype and develop certain age-related diseases earlier in their lifespan than what is seen in the general population. Age-related comorbidities may include the development of bone disease, metabolic disorders, neurologic impairment and immunosenescence. Age also appears to have an effect on traditional markers of HIV-1 disease progression, including CD4+ T-cell count and viral load. These effects are not only a consequence of HIV-1 infection, but in many cases, are also linked to antiretroviral therapy. This review summarizes the complex interplay between HIV-1 infection and aging, and the impact that aging has on markers of HIV-1 disease. PMID:23596462

Primary care clinicians' experiences with treatment decision making for older persons with multiple conditions.

PubMed

Fried, Terri R; Tinetti, Mary E; Iannone, Lynne

2011-01-10

Clinicians are caring for an increasing number of older patients with multiple diseases in the face of uncertainty concerning the benefits and harms associated with guideline-directed interventions. Understanding how primary care clinicians approach treatment decision making for these patients is critical to the design of interventions to improve the decision-making process. Focus groups were conducted with 40 primary care clinicians (physicians, nurse practitioners, and physician assistants) in academic, community, and Veterans Affairs-affiliated primary care practices. Participants were given open-ended questions about their approach to treatment decision making for older persons with multiple medical conditions. Responses were organized into themes using qualitative content analysis. The participants were concerned about their patients' ability to adhere to complex regimens derived from guideline-directed care. There was variability in beliefs regarding, and approaches to balancing, the benefits and harms of guideline-directed care. There was also variability regarding how the participants involved patients in the process of decision making, with clinicians describing conflicts between their own and their patients' goals. The participants listed a number of barriers to making good treatment decisions, including the lack of outcome data, the role of specialists, patient and family expectations, and insufficient time and reimbursement. The experiences of practicing clinicians suggest that they struggle with the uncertainties of applying disease-specific guidelines to their older patients with multiple conditions. To improve decision making, they need more data, alternative guidelines, approaches to reconciling their own and their patients' priorities, the support of their subspecialist colleagues, and an altered reimbursement system.

Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition.

PubMed

Goos, Jeroen D C; Kester, M I; Barkhof, Frederik; Klein, Martin; Blankenstein, Marinus A; Scheltens, Philip; van der Flier, Wiesje M

2009-11-01

Microbleeds (MBs) are commonly observed in Alzheimer disease. A minority of patients has multiple MBs. We aimed to investigate associations of multiple MBs in Alzheimer disease with clinical and MRI characteristics and cerebrospinal fluid biomarkers. Patients with Alzheimer disease with multiple (>or=8) MBs on T2*-weighted MRI were matched for age, sex, and field strength with patients with Alzheimer disease without MBs on a 1:2 basis. We included 21 patients with multiple MBs (73+/-7 years, 33% female) and 42 patients without MBs (72+/-7 years, 38% female). Mini-Mental State Examination was used to assess dementia severity. Cognitive functions were assessed using neuropsychological tests. Medial temporal lobe atrophy (0 to 4), global cortical atrophy (0 to 3), and white matter hyperintensities (0 to 30) were assessed using visual rating scales. In a subset, apolipoprotein E genotype and cerebrospinal fluid amyloid beta 1-42, total tau and tau phosphorylated at threonine 181 were determined. Patients with multiple MBs performed worse on Mini-Mental State Examination (multiple MB: 17+/-7; no MB: 22+/-4, P<0.05) despite similar disease duration. Atrophy was not related to presence of MBs, but patients with multiple MBs had more white matter hyperintensities (multiple MB: 8.8+/-4.8; no MB: 3.2+/-3.6, P<0.05). Adjusted for age, sex, white matter hyperintensities, and medial temporal lobe atrophy, the multiple MB group additionally performed worse on Visual Association Test object naming and animal fluency. Patients with multiple MBs had lower cerebrospinal fluid amyloid beta 1-42 levels (307+/-61) than patients without MBs (505+/-201, P<0.05). Adjusted for the same covariates, total tau, and tau phosphorylated at threonine 181 were higher in the multiple MB group. Microbleeds are associated with the clinical manifestation and biochemical hallmarks of Alzheimer disease, suggesting possible involvement of MBs in the pathogenesis of Alzheimer disease.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

PubMed Central

Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C.A.; Patsopoulos, Nikolaos A.; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Booth, David R.; Potter, Simon C.; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Céline; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D’alfonso, Sandra; Blackburn, Hannah; Boneschi, Filippo Martinelli; Liddle, Jennifer; Harbo, Hanne F.; Perez, Marc L.; Spurkland, Anne; Waller, Matthew J; Mycko, Marcin P.; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T.; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J.; Barcellos, Lisa F.; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E.; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P.; Brassat, David; Broadley, Simon A.; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M.; Cavalla, Paola; Celius, Elisabeth G.; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Françoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B.; Cozen, Wendy; Cree, Bruce A.C.; Cross, Anne H.; Cusi, Daniele; Daly, Mark J.; Davis, Emma; de Bakker, Paul I.W.; Debouverie, Marc; D’hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Bénédicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F.A.; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N.; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G.; Kilpatrick, Trevor J.; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S.; Leone, Maurizio A.; Leppä, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R.; Link, Jenny; Liu, Jianjun; Lorentzen, Åslaug R.; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L.; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L.; Ramsay, Patricia P.; Reunanen, Mauri; Reynolds, Richard; Rioux, John D.; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P.; Rückert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A.; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J.; Sellebjerg, Finn; Selmaj, Krzysztof W.; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M.A.; Smestad, Cathrine; Sørensen, Per Soelberg; Søndergaard, Helle Bach; Stankovich, Jim; Strange, Richard C.; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvänen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M.; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A.; Tronczynska, Ewa; Casas, Juan P.; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S.; Wang, Kai; Mathew, Christopher G.; Wason, James; Palmer, Colin N.A.; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C.; Yaouanq, Jacqueline; Viswanathan, Ananth C.; Zhang, Haitao; Wood, Nicholas W.; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J.; De Jager, Philip L.; Peltonen, Leena; Stewart, Graeme J.; Hafler, David A.; Hauser, Stephen L.; McVean, Gil; Donnelly, Peter; Compston, Alastair

2011-01-01

Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis. PMID:21833088

Synaptic Activity and Bioenergy Homeostasis: Implications in Brain Trauma and Neurodegenerative Diseases

PubMed Central

Khatri, Natasha; Man, Heng-Ye

2013-01-01

Powered by glucose metabolism, the brain is the most energy-demanding organ in our body. Adequate ATP production and regulation of the metabolic processes are essential for the maintenance of synaptic transmission and neuronal function. Glutamatergic synaptic activity utilizes the largest portion of bioenergy for synaptic events including neurotransmitter synthesis, vesicle recycling, and most importantly, the postsynaptic activities leading to channel activation and rebalancing of ionic gradients. Bioenergy homeostasis is coupled with synaptic function via activities of the sodium pumps, glutamate transporters, glucose transport, and mitochondria translocation. Energy insufficiency is sensed by the AMP-activated protein kinase (AMPK), a master metabolic regulator that stimulates the catalytic process to enhance energy production. A decline in energy supply and a disruption in bioenergy homeostasis play a critical role in multiple neuropathological conditions including ischemia, stroke, and neurodegenerative diseases including Alzheimer’s disease and traumatic brain injuries. PMID:24376435

Correlation of proteome-wide changes with social immunity behaviors provides insight into resistance to the parasitic mite, Varroa destructor, in the honey bee (Apis mellifera)

PubMed Central

2012-01-01

Background Disease is a major factor driving the evolution of many organisms. In honey bees, selection for social behavioral responses is the primary adaptive process facilitating disease resistance. One such process, hygienic behavior, enables bees to resist multiple diseases, including the damaging parasitic mite Varroa destructor. The genetic elements and biochemical factors that drive the expression of these adaptations are currently unknown. Proteomics provides a tool to identify proteins that control behavioral processes, and these proteins can be used as biomarkers to aid identification of disease tolerant colonies. Results We sampled a large cohort of commercial queen lineages, recording overall mite infestation, hygiene, and the specific hygienic response to V. destructor. We performed proteome-wide correlation analyses in larval integument and adult antennae, identifying several proteins highly predictive of behavior and reduced hive infestation. In the larva, response to wounding was identified as a key adaptive process leading to reduced infestation, and chitin biosynthesis and immune responses appear to represent important disease resistant adaptations. The speed of hygienic behavior may be underpinned by changes in the antenna proteome, and chemosensory and neurological processes could also provide specificity for detection of V. destructor in antennae. Conclusions Our results provide, for the first time, some insight into how complex behavioural adaptations manifest in the proteome of honey bees. The most important biochemical correlations provide clues as to the underlying molecular mechanisms of social and innate immunity of honey bees. Such changes are indicative of potential divergence in processes controlling the hive-worker maturation. PMID:23021491

Correlation of proteome-wide changes with social immunity behaviors provides insight into resistance to the parasitic mite, Varroa destructor, in the honey bee (Apis mellifera).

PubMed

Parker, Robert; Guarna, M Marta; Melathopoulos, Andony P; Moon, Kyung-Mee; White, Rick; Huxter, Elizabeth; Pernal, Stephen F; Foster, Leonard J

2012-06-29

Disease is a major factor driving the evolution of many organisms. In honey bees, selection for social behavioral responses is the primary adaptive process facilitating disease resistance. One such process, hygienic behavior, enables bees to resist multiple diseases, including the damaging parasitic mite Varroa destructor. The genetic elements and biochemical factors that drive the expression of these adaptations are currently unknown. Proteomics provides a tool to identify proteins that control behavioral processes, and these proteins can be used as biomarkers to aid identification of disease tolerant colonies. We sampled a large cohort of commercial queen lineages, recording overall mite infestation, hygiene, and the specific hygienic response to V. destructor. We performed proteome-wide correlation analyses in larval integument and adult antennae, identifying several proteins highly predictive of behavior and reduced hive infestation. In the larva, response to wounding was identified as a key adaptive process leading to reduced infestation, and chitin biosynthesis and immune responses appear to represent important disease resistant adaptations. The speed of hygienic behavior may be underpinned by changes in the antenna proteome, and chemosensory and neurological processes could also provide specificity for detection of V. destructor in antennae. Our results provide, for the first time, some insight into how complex behavioural adaptations manifest in the proteome of honey bees. The most important biochemical correlations provide clues as to the underlying molecular mechanisms of social and innate immunity of honey bees. Such changes are indicative of potential divergence in processes controlling the hive-worker maturation.

System Dynamics Modeling for Public Health: Background and Opportunities

PubMed Central

Homer, Jack B.; Hirsch, Gary B.

2006-01-01

The systems modeling methodology of system dynamics is well suited to address the dynamic complexity that characterizes many public health issues. The system dynamics approach involves the development of computer simulation models that portray processes of accumulation and feedback and that may be tested systematically to find effective policies for overcoming policy resistance. System dynamics modeling of chronic disease prevention should seek to incorporate all the basic elements of a modern ecological approach, including disease outcomes, health and risk behaviors, environmental factors, and health-related resources and delivery systems. System dynamics shows promise as a means of modeling multiple interacting diseases and risks, the interaction of delivery systems and diseased populations, and matters of national and state policy. PMID:16449591

Smart cloud system with image processing server in diagnosing brain diseases dedicated for hospitals with limited resources.

PubMed

Fahmi, Fahmi; Nasution, Tigor H; Anggreiny, Anggreiny

2017-01-01

The use of medical imaging in diagnosing brain disease is growing. The challenges are related to the big size of data and complexity of the image processing. High standard of hardware and software are demanded, which can only be provided in big hospitals. Our purpose was to provide a smart cloud system to help diagnosing brain diseases for hospital with limited infrastructure. The expertise of neurologists was first implanted in cloud server to conduct an automatic diagnosis in real time using image processing technique developed based on ITK library and web service. Users upload images through website and the result, in this case the size of tumor was sent back immediately. A specific image compression technique was developed for this purpose. The smart cloud system was able to measure the area and location of tumors, with average size of 19.91 ± 2.38 cm2 and an average response time 7.0 ± 0.3 s. The capability of the server decreased when multiple clients accessed the system simultaneously: 14 ± 0 s (5 parallel clients) and 27 ± 0.2 s (10 parallel clients). The cloud system was successfully developed to process and analyze medical images for diagnosing brain diseases in this case for tumor.

Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.

PubMed

Jurynczyk, Maciej; Geraldes, Ruth; Probert, Fay; Woodhall, Mark R; Waters, Patrick; Tackley, George; DeLuca, Gabriele; Chandratre, Saleel; Leite, Maria I; Vincent, Angela; Palace, Jacqueline

2017-03-01

Brain imaging characteristics of MOG antibody disease are largely unknown and it is unclear whether they differ from those of multiple sclerosis and AQP4 antibody disease. The aim of this study was to identify brain imaging discriminators between those three inflammatory central nervous system diseases in adults and children to support diagnostic decisions, drive antibody testing and generate disease mechanism hypotheses. Clinical brain scans of 83 patients with brain lesions (67 in the training and 16 in the validation cohort, 65 adults and 18 children) with MOG antibody (n = 26), AQP4 antibody disease (n = 26) and multiple sclerosis (n = 31) recruited from Oxford neuromyelitis optica and multiple sclerosis clinical services were retrospectively and anonymously scored on a set of 29 predefined magnetic resonance imaging features by two independent raters. Principal component analysis was used to perform an overview of patients without a priori knowledge of the diagnosis. Orthogonal partial least squares discriminant analysis was used to build models separating diagnostic groups and identify best classifiers, which were then tested on an independent cohort set. Adults and children with MOG antibody disease frequently had fluffy brainstem lesions, often located in pons and/or adjacent to fourth ventricle. Children across all conditions showed more frequent bilateral, large, brainstem and deep grey matter lesions. MOG antibody disease spontaneously separated from multiple sclerosis but overlapped with AQP4 antibody disease. Multiple sclerosis was discriminated from MOG antibody disease and from AQP4 antibody disease with high predictive values, while MOG antibody disease could not be accurately discriminated from AQP4 antibody disease. Best classifiers between MOG antibody disease and multiple sclerosis were similar in adults and children, and included ovoid lesions adjacent to the body of lateral ventricles, Dawson's fingers, T1 hypointense lesions (multiple sclerosis), fluffy lesions and three lesions or less (MOG antibody). In the validation cohort patients with antibody-mediated conditions were differentiated from multiple sclerosis with high accuracy. Both antibody-mediated conditions can be clearly separated from multiple sclerosis on conventional brain imaging, both in adults and children. The overlap between MOG antibody oligodendrocytopathy and AQP4 antibody astrocytopathy suggests that the primary immune target is not the main substrate for brain lesion characteristics. This is also supported by the clear distinction between multiple sclerosis and MOG antibody disease both considered primary demyelinating conditions. We identify discriminatory features, which may be useful in classifying atypical multiple sclerosis, seronegative neuromyelitis optica spectrum disorders and relapsing acute disseminated encephalomyelitis, and characterizing cohorts for antibody discovery. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Ying and Yang of STAT3 in Human Disease.

PubMed

Vogel, Tiphanie P; Milner, Joshua D; Cooper, Megan A

2015-10-01

The transcription factor signal transducer and activator of transcription 3 (STAT3) is a critical regulator of multiple, diverse cellular processes. Heterozgyous, germline, loss-of-function mutations in STAT3 lead to the primary immune deficiency Hyper-IgE syndrome. Heterozygous, somatic, gain-of-function mutations in STAT3 have been reported in malignancy. Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity. This review summarizes what is known about the role of STAT3 in human disease.

Multiple sclerosis (MS) for the urologist: What should urologists know about MS?

PubMed

Aharony, Shachar; Lam, Ornella; Lapierre, Yves; Corcos, Jacques

2016-02-01

Multiple sclerosis (MS) is a unique central nervous system (CNS) inflammatory disease with a broad spectrum of clinical presentations, which are time- and disease progression-related. It usually affects young adults, with a female predominance of 3:1. Men are more likely to develop symptoms at a slightly older age with a more progressive disease course. Diagnosis relies on a combination of clinical, radiological, and laboratory investigations, with a central role of magnetic resonance imaging (MRI). Although the exact etiology is still obscure, the leading hypothesis behind MS relapses is acute inflammatory attacks on CNS myelin and axons. This complex process involves B and T cells together with macrophages and microglia. Genetic and environmental factors are thought to be major contributors to the disease's evolution. MS therapies consist of long-term (immunomodulatory) management, focusing on disease modification, and short-term symptomatic control. Symptomatic treatment includes pharmacological and non-pharmacological methods to protect function and restore quality of life (QoL). The introduction and development of disease-modifying medications provide opportunities to change the face of this disease, enhancing QoL over the long-term. Interferon (INF) and Glatiramer acetate (GLAT) represent first line medications with limited effect and relatively fair safety profile. Newer medications with improved efficacy along with a more hazardous side effect profile are now considered second line therapy. The present review summarizes current knowledge of this frequent disease. Urologists must acquire a deeper understanding for better integration of practice recommendations. © 2015 Wiley Periodicals, Inc.

The lung mycobiome in the next-generation sequencing era

PubMed Central

Tipton, Laura; Ghedin, Elodie; Morris, Alison

2017-01-01

ABSTRACT The fungi that reside in the human lungs represent an understudied, but medically relevant comm-unity. From the few studies published on the lung mycobiome, we find that there are fungi in both the healthy and diseased respiratory tract, that these fungi vary widely between individuals, and that there is a trend toward lower fungal diversity among individuals with disease. This review discusses the few studies of the lung mycobiome and details the challenges that accompany lung mycobiome studies. These challenges include sample collection and processing, sequence amplification and processing, and a history of multiple names for species. Some challenges may never be solved, but others can be solved with more data and additional studies of the lung mycobiome. PMID:27687858

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

PubMed

Cooper, Colin S; Eeles, Rosalind; Wedge, David C; Van Loo, Peter; Gundem, Gunes; Alexandrov, Ludmil B; Kremeyer, Barbara; Butler, Adam; Lynch, Andrew G; Camacho, Niedzica; Massie, Charlie E; Kay, Jonathan; Luxton, Hayley J; Edwards, Sandra; Kote-Jarai, ZSofia; Dennis, Nening; Merson, Sue; Leongamornlert, Daniel; Zamora, Jorge; Corbishley, Cathy; Thomas, Sarah; Nik-Zainal, Serena; O'Meara, Sarah; Matthews, Lucy; Clark, Jeremy; Hurst, Rachel; Mithen, Richard; Bristow, Robert G; Boutros, Paul C; Fraser, Michael; Cooke, Susanna; Raine, Keiran; Jones, David; Menzies, Andrew; Stebbings, Lucy; Hinton, Jon; Teague, Jon; McLaren, Stuart; Mudie, Laura; Hardy, Claire; Anderson, Elizabeth; Joseph, Olivia; Goody, Victoria; Robinson, Ben; Maddison, Mark; Gamble, Stephen; Greenman, Christopher; Berney, Dan; Hazell, Steven; Livni, Naomi; Fisher, Cyril; Ogden, Christopher; Kumar, Pardeep; Thompson, Alan; Woodhouse, Christopher; Nicol, David; Mayer, Erik; Dudderidge, Tim; Shah, Nimish C; Gnanapragasam, Vincent; Voet, Thierry; Campbell, Peter; Futreal, Andrew; Easton, Douglas; Warren, Anne Y; Foster, Christopher S; Stratton, Michael R; Whitaker, Hayley C; McDermott, Ultan; Brewer, Daniel S; Neal, David E

2015-04-01

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.

Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma

PubMed Central

Calcinotto, Arianna; Ponzoni, Maurilio; Ria, Roberto; Grioni, Matteo; Cattaneo, Elena; Villa, Isabella; Sabrina Bertilaccio, Maria Teresa; Chesi, Marta; Rubinacci, Alessandro; Tonon, Giovanni; Bergsagel, P Leif; Vacca, Angelo; Bellone, Matteo

2015-01-01

While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8+ and CD4+ T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206+Tie2+ macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease. PMID:26155424

[Current approaches in multiple myeloma and other cancer-related bone diseases].

PubMed

Engelhardt, M; Kleber, M; Udi, J; Wäsch, R

2012-05-01

Multiple myeloma (MM) ranges second of all hematological malignancies and occurs most commonly in elderly patients. Almost all MM patients develop bone lesions in the course of their disease or have evidence of bone loss at initial diagnosis. Whole-body conventional radiography remains the gold standard in the diagnostic evaluation, albeit computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly used as complementary techniques in the more sensitive detection of osteolytic processes. Bisphosphonates like zoledronate or pamidronate represent the cornerstone therapeutics in osteolytic disease, and are effective supportives to potent anti-myeloma therapies, including novel agents such as the proteasome inhibitor bortezomib or immunomodulatory drugs (IMIDs, e. g. thalidomide or lenalidomide). Several studies are ongoing to investigate the effects of alternative bone-seeking agents and their therapeutic potential for the management of myeloma bone disease, such as denosumab (RANKL-neutralizing antibody), anti-sclerostin (monoclonal antibody, generated against sclerostin) or sotatercept (potent activin-A inhibitor). This review summarizes the most prominent data on myeloma bone disease pathogenesis, the role of imaging techniques as well as therapy and prevention of lytic complications in myeloma which may similarly or equally be true for other bone metastases-inducing solid tumors. © Georg Thieme Verlag KG Stuttgart · New York.

Gene–environment interactions: key to unraveling the mystery of Parkinson’s disease

PubMed Central

Gao, Hui-Ming; Hong, Jau-shyong

2011-01-01

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The gradual, irreversible loss of dopamine neurons in the substantia nigra isthe signature lesion of PD. Clinical symptoms of PD become apparent when 50–60% of nigral dopamine neurons are lost. PD progresses insidiously for 5–7 years (preclinical period) and then continues to worsen even under the symptomatic treatment. To determine what triggers the disease onset and what drives the chronic, self-propelling neurodegenerative process becomes critical and urgent, since lack of such knowledge impedes the discovery of effective treatments to retard PD progression. At present, available therapeutics only temporarily relieve PD symptoms. While the identification of causative gene defects in familial PD uncovers important genetic influences in this disease, the majority of PD cases are sporadic and idiopathic. The current consensus suggests that PD develops from multiple risk factors including aging, genetic predisposition, and environmental exposure. Here, we briefly review research on the genetic and environmental causes of PD. We also summarize very recent genome-wide association studies on risk gene polymorphisms in the emergence of PD. We highlight the new converging evidence on gene-environment interplay in the development of PD with an emphasis on newly developed multiple-hit PD models involving both genetic lesions and environmental triggers. PMID:21439347

Undiagnosed neurological disease as a potential cause of male lower urinary tract symptoms.

PubMed

Wei, Diana Y; Drake, Marcus J

2016-01-01

In the central nervous system there are many regulatory processes controlling the lower urinary tract. This review considers the possibility that urinary dysfunction may precede diagnosis of neurological disease. Lower urinary tract symptoms (LUTS) occur early in multiple system atrophy, Parkinson's disease and normal pressure hydrocephalus, and may present before neurological diagnosis. Some people present with LUTS and subsequently are diagnosed with multiple sclerosis or a spinal condition. In male LUTS, the symptoms could reflect early stages of a neurological disease, which has not yet been diagnosed ('occult neurology'). Key symptoms include erectile dysfunction, retrograde ejaculation, enuresis, loss of filling sensation or unexplained stress urinary incontinence. Directed questioning should enquire about visual symptoms, back pain, anosmia, bowel dysfunction and incontinence, or memory loss. Examination features can include resting tremor, 'croaky' speech, abnormal gait, orthostatic hypotension, ataxia, or altered perineal sensation. Imaging, such as MRI scan, should only be requested after expert neurological examination, to ensure the correct parts of the central nervous system are scanned with appropriate radiological protocols. Urologists should consider an undiagnosed neurological condition can be present in a few cases. Any finding should be further evaluated by colleagues with relevant expertise.

Centenarian Rates and Life Expectancy Related to the Death Rates of Multiple Sclerosis, Asthma, and Rheumatoid Arthritis and the Incidence of Type 1 Diabetes in Children.

PubMed

Lens-Pechakova, Lilia S

2016-02-01

The autoimmune diseases are among the 10 leading causes of death for women and the number two cause of chronic illness in America as well as a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter life span and are a model of accelerated immunosenescence. Conversely, centenarians are used as a model of successful aging and have shown several immune parameters that are better preserved and lower levels of autoantibodies. The study reported here focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed Organisation for Economic Co-operation and Development (OECD) countries, because multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relationship pattern, help to identify common factors, and determine new important factors that contribute to longevity and healthy aging. The relationships between the mortality rates data of multiple sclerosis (MS), rheumatoid arthritis (RA), asthma, the incidence of type 1 diabetes (T1D) from one side and centenarian rates (two sets) as well as life expectancy data from the other side were assessed using regression models and Pearson correlation coefficients. The data obtained correspond to an inverse linear correlation with different degrees of linearity. This is the first observation of a clear tendency of diminishing centenarian rates or life expectancy in countries having higher death rates of asthma, MS, and RA and a higher incidence of T1D in children. The conclusion is that most probably there are common mechanistic pathways and factors affecting the above diseases and at the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways, and other factors connected to autoimmune diseases with those of longevity could clarify the processes involved, so as to promote longevity and limit the expansion of those diseases in the younger and older population.

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

PubMed Central

Pessoa de Magalhães, Roberto J.; Vidriales, María-Belén; Paiva, Bruno; Fernandez-Gimenez, Carlos; García-Sanz, Ramón; Mateos, Maria-Victoria; Gutierrez, Norma C.; Lecrevisse, Quentin; Blanco, Juan F; Hernández, Jose; de las Heras, Natalia; Martinez-Lopez, Joaquin; Roig, Monica; Costa, Elaine Sobral; Ocio, Enrique M.; Perez-Andres, Martin; Maiolino, Angelo; Nucci, Marcio; De La Rubia, Javier; Lahuerta, Juan-Jose; San-Miguel, Jesús F.; Orfao, Alberto

2013-01-01

Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+ T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting improved immune surveillance. PMID:22773604

Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis.

PubMed

Disanto, Giulio; Hall, Carolina; Lucas, Robyn; Ponsonby, Anne-Louise; Berlanga-Taylor, Antonio J; Giovannoni, Gavin; Ramagopalan, Sreeram V

2013-09-01

Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.

Lost productivity and burden of illness in cancer survivors with and without other chronic conditions.

PubMed

Dowling, Emily C; Chawla, Neetu; Forsythe, Laura P; de Moor, Janet; McNeel, Timothy; Rozjabek, Heather M; Ekwueme, Donatus U; Yabroff, K Robin

2013-09-15

Cancer survivors may experience long-term and late effects from treatment that adversely affect health and limit functioning. Few studies examine lost productivity and disease burden in cancer survivors compared with individuals who have other chronic conditions or by cancer type. We identified 4960 cancer survivors and 64,431 other individuals from the 2008-2010 Medical Expenditure Panel Survey and compared multiple measures of disease burden, including health status and lost productivity, between conditions and by cancer site for cancer survivors. All analyses controlled for the effects of age, sex, race/ethnicity, and number of comorbid conditions. Overall, in adjusted analyses in multiple models, cancer survivors with another chronic disease (heart disease or diabetes) experienced higher levels of burden compared with individuals with a history of cancer only, chronic disease only, and neither cancer, heart disease, nor diabetes across multiple measures (P < .05). Among cancer survivors, individuals with short survival cancers and multiple cancers consistently had the highest levels of burden across multiple measures (P < .0001). Cancer survivors who have another chronic disease experience more limitations and higher levels of burden across multiple measures. Limitations are particularly severe in cancer survivors with short survival cancer and multiple cancers. © 2013 American Cancer Society.

Lost Productivity and Burden of Illness in Cancer Survivors With and Without Other Chronic Conditions

PubMed Central

Dowling, Emily C.; Chawla, Neetu; Forsythe, Laura P.; de Moor, Janet; McNeel, Timothy; Rozjabek, Heather M.; Ekwueme, Donatus U.; Yabroff, K. Robin

2018-01-01

BACKGROUND Cancer survivors may experience long-term and late effects from treatment that adversely affect health and limit functioning. Few studies examine lost productivity and disease burden in cancer survivors compared with individuals who have other chronic conditions or by cancer type. METHODS We identified 4960 cancer survivors and 64,431 other individuals from the 2008–2010 Medical Expenditure Panel Survey and compared multiple measures of disease burden, including health status and lost productivity, between conditions and by cancer site for cancer survivors. All analyses controlled for the effects of age, sex, race/ethnicity, and number of comorbid conditions. RESULTS Overall, in adjusted analyses in multiple models, cancer survivors with another chronic disease (heart disease or diabetes) experienced higher levels of burden compared with individuals with a history of cancer only, chronic disease only, and neither cancer, heart disease, nor diabetes across multiple measures (P <.05). Among cancer survivors, individuals with short survival cancers and multiple cancers consistently had the highest levels of burden across multiple measures (P <.0001). CONCLUSIONS Cancer survivors who have another chronic disease experience more limitations and higher levels of burden across multiple measures. Limitations are particularly severe in cancer survivors with short survival cancer and multiple cancers. PMID:23794146

Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process.

PubMed

Ponsioen, Cyriel Y; Chapman, Roger W; Chazouillères, Olivier; Hirschfield, Gideon M; Karlsen, Tom H; Lohse, Ansgar W; Pinzani, Massimo; Schrumpf, Erik; Trauner, Michael; Gores, Gregory J

2016-04-01

Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. © 2015 by the American Association for the Study of Liver Diseases.

[Axonopathy in the pathogenesis of multiple sclerosis, peripheral diffuse and local motor neuropathies and motor neuron disease].

PubMed

Merkulov, Iu A; Merkulova, D M; Iosifova, O A; Zavalishin, I A

2010-01-01

Two hundreds and seventy-six patients including 43 patients with multiple sclerosis, 24 - with acute inflammatory demyelinating polyneuropathy (AIDP), 144 - with chronic inflammatory demyelinating polyneuropathy (CIDP), 27 - with motor multifocal neuropathy (MMN), 38 - with lateral amyotrophic sclerosis (LAS) have been examined. Symptoms of axonal degeneration, manifested in denervation phenomena in both clinical and instrumental studies (electromyography, transcranial magnetic stimulation, MRT), were revealed in all groups of patients. The formation of excitation conduction blocks is an universal pathophysiological mechanism of the axonopathy development in AIDP, CIDP, MMN and LAS. Symptoms of axonopathy and peripheral demyelinization in patients with multiple sclerosis and LAS suggest the possibility of transformation of immunopathological process from the central nervous system to the peripheral one.

Plasma Endothelial Microparticles in Multiple Sclerosis: A Novel Metric Assay of Disease Activity and Response to Treatment

DTIC Science & Technology

2011-09-01

direct link to a source of increased tissue iron deposition which is characteristic for multiple sclerosis . The results of these data and their... Multiple Sclerosis : A Novel Metric Assay of Disease Activity and Response to Treatment PRINCIPAL INVESTIGATOR: Jonathan Steven...SUBTITLE 5a. CONTRACT NUMBER Plasma Endothelial Microparticles in Multiple Sclerosis : A Novel Metric Assay of Disease Activity and Response to

Neural Dynamics of Multiple Object Processing in Mild Cognitive Impairment and Alzheimer's Disease: Future Early Diagnostic Biomarkers?

PubMed

Bagattini, Chiara; Mazza, Veronica; Panizza, Laura; Ferrari, Clarissa; Bonomini, Cristina; Brignani, Debora

2017-01-01

The aim of this study was to investigate the behavioral and electrophysiological dynamics of multiple object processing (MOP) in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to test whether its neural signatures may represent reliable diagnostic biomarkers. Behavioral performance and event-related potentials [N2pc and contralateral delay activity (CDA)] were measured in AD, MCI, and healthy controls during a MOP task, which consisted in enumerating a variable number of targets presented among distractors. AD patients showed an overall decline in accuracy for both small and large target quantities, whereas in MCI patients, only enumeration of large quantities was impaired. N2pc, a neural marker of attentive individuation, was spared in both AD and MCI patients. In contrast, CDA, which indexes visual short term memory abilities, was altered in both groups of patients, with a non-linear pattern of amplitude modulation along the continuum of the disease: a reduction in AD and an increase in MCI. These results indicate that AD pathology shows a progressive decline in MOP, which is associated to the decay of visual short-term memory mechanisms. Crucially, CDA may be considered as a useful neural signature both to distinguish between healthy and pathological aging and to characterize the different stages along the AD continuum, possibly becoming a reliable candidate for an early diagnostic biomarker of AD pathology.

Library of molecular associations: curating the complex molecular basis of liver diseases.

PubMed

Buchkremer, Stefan; Hendel, Jasmin; Krupp, Markus; Weinmann, Arndt; Schlamp, Kai; Maass, Thorsten; Staib, Frank; Galle, Peter R; Teufel, Andreas

2010-03-20

Systems biology approaches offer novel insights into the development of chronic liver diseases. Current genomic databases supporting systems biology analyses are mostly based on microarray data. Although these data often cover genome wide expression, the validity of single microarray experiments remains questionable. However, for systems biology approaches addressing the interactions of molecular networks comprehensive but also highly validated data are necessary. We have therefore generated the first comprehensive database for published molecular associations in human liver diseases. It is based on PubMed published abstracts and aimed to close the gap between genome wide coverage of low validity from microarray data and individual highly validated data from PubMed. After an initial text mining process, the extracted abstracts were all manually validated to confirm content and potential genetic associations and may therefore be highly trusted. All data were stored in a publicly available database, Library of Molecular Associations http://www.medicalgenomics.org/databases/loma/news, currently holding approximately 1260 confirmed molecular associations for chronic liver diseases such as HCC, CCC, liver fibrosis, NASH/fatty liver disease, AIH, PBC, and PSC. We furthermore transformed these data into a powerful resource for molecular liver research by connecting them to multiple biomedical information resources. Together, this database is the first available database providing a comprehensive view and analysis options for published molecular associations on multiple liver diseases.

Mediators and mechanisms of herpes simplex virus entry into ocular cells.

PubMed

Farooq, Asim V; Valyi-Nagy, Tibor; Shukla, Deepak

2010-06-01

The entry of herpes simplex virus into cells was once thought to be a general process. It is now understood that the virus is able to use multiple mechanisms for entry and spread, including the use of receptors and co-receptors that have been determined to be cell-type specific. This is certainly true for ocular cell types, which is important as the virus may use different mechanisms to gain access to multiple anatomic structures in close proximity, leading to various ocular diseases. There are some patterns that may be utilized by the virus in the eye and elsewhere, including surfing along filopodia in moving from cell to cell. There are common themes as well as intriguing differences in the entry mechanisms of herpes simplex virus into ocular cells. We discuss these issues in the context of conjunctivitis, keratitis, acute retinal necrosis, and other ocular diseases.

Mediators and Mechanisms of Herpes Simplex Virus Entry into Ocular Cells

PubMed Central

Farooq, Asim V.; Valyi-Nagy, Tibor; Shukla, Deepak

2010-01-01

The entry of herpes simplex virus (HSV) into cells was once thought to be a general process. It is now understood that the virus is able to use multiple mechanisms for entry and spread, including the use of receptors and co-receptors that have been determined to be cell-type specific. This is certainly true for ocular cell types, which is important as the virus may use different mechanisms to gain access to multiple anatomic structures in close proximity, leading to various ocular diseases. There are some patterns that may be utilized by the virus in the eye and elsewhere, including surfing along filopodia in moving from cell to cell. There are common themes as well as intriguing differences in the entry mechanisms of HSV into ocular cells. We discuss these issues in the context of conjunctivitis, keratitis, acute retinal necrosis and other ocular diseases. PMID:20465436

Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing using next-generation sequencer.

PubMed

Mitsui, Jun; Fukuda, Yoko; Azuma, Kyo; Tozaki, Hirokazu; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Tsuji, Shoji

2010-07-01

We have recently found that multiple rare variants of the glucocerebrosidase gene (GBA) confer a robust risk for Parkinson disease, supporting the 'common disease-multiple rare variants' hypothesis. To develop an efficient method of identifying rare variants in a large number of samples, we applied multiplexed resequencing using a next-generation sequencer to identification of rare variants of GBA. Sixteen sets of pooled DNAs from six pooled DNA samples were prepared. Each set of pooled DNAs was subjected to polymerase chain reaction to amplify the target gene (GBA) covering 6.5 kb, pooled into one tube with barcode indexing, and then subjected to extensive sequence analysis using the SOLiD System. Individual samples were also subjected to direct nucleotide sequence analysis. With the optimization of data processing, we were able to extract all the variants from 96 samples with acceptable rates of false-positive single-nucleotide variants.

An IT Architecture for Systems Medicine.

PubMed

Ganzinger, Matthias; Gietzelt, Matthias; Karmen, Christian; Firnkorn, Daniel; Knaup, Petra

2015-01-01

Systems medicine aims to support treatment of complex diseases like cancer by integrating all available data for the disease. To provide such a decision support in clinical practice, a suitable IT architecture is necessary. We suggest a generic architecture comprised of the following three layers: data representation, decision support, and user interface. For the systems medicine research project "Clinically-applicable, omics-based assessment of survival, side effects, and targets in multiple myeloma" (CLIOMMICS) we developed a concrete instance of the generic architecture. We use i2b2 for representing the harmonized data. Since no deterministic model exists for multiple myeloma we use case-based reasoning for decision support. For clinical practice, visualizations of the results must be intuitive and clear. At the same time, they must communicate the uncertainty immanent in stochastic processes. Thus, we develop a specific user interface for systems medicine based on the web portal software Liferay.

A Bayesian system to detect and characterize overlapping outbreaks.

PubMed

Aronis, John M; Millett, Nicholas E; Wagner, Michael M; Tsui, Fuchiang; Ye, Ye; Ferraro, Jeffrey P; Haug, Peter J; Gesteland, Per H; Cooper, Gregory F

2017-09-01

Outbreaks of infectious diseases such as influenza are a significant threat to human health. Because there are different strains of influenza which can cause independent outbreaks, and influenza can affect demographic groups at different rates and times, there is a need to recognize and characterize multiple outbreaks of influenza. This paper describes a Bayesian system that uses data from emergency department patient care reports to create epidemiological models of overlapping outbreaks of influenza. Clinical findings are extracted from patient care reports using natural language processing. These findings are analyzed by a case detection system to create disease likelihoods that are passed to a multiple outbreak detection system. We evaluated the system using real and simulated outbreaks. The results show that this approach can recognize and characterize overlapping outbreaks of influenza. We describe several extensions that appear promising. Copyright © 2017 Elsevier Inc. All rights reserved.

Repulsive Guidance Molecules (RGMs) and Neogenin in Bone Morphogenetic Protein (BMP) signaling

PubMed Central

Tian, Chenxi; Liu, Jun

2015-01-01

Summary Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGFβ) superfamily. BMPs mediate a highly conserved signal transduction cascade through the type I and type II serine/threonine kinase receptors and intracellular Smad proteins. The BMP pathway regulates multiple developmental and homeostatic processes. Mutations in this pathway can cause various diseases in humans, such as skeletal disorders, cardiovascular diseases and various cancers. Multiple levels of regulation, including extracellular regulation, help to ensure proper spatiotemporal control of BMP signaling in the right cellular context. The family of repulsive guidance molecules (RGMs) and the type I trans-membrane protein neogenin, a paralog of DCC (Deleted in Colorectal Cancer), have been implicated in modulating the BMP pathway. In this review, we discuss the properties and functions of RGM proteins and neogenin, focusing on their roles in the modulation of BMP signal transduction. PMID:23740870

The World Hypertension League: where now and where to in salt reduction

PubMed Central

Lackland, Daniel T.; Lisheng, Liu; Zhang, Xin-Hua; Nilsson, Peter M.; Niebylski, Mark L.

2015-01-01

High dietary salt is a leading risk for death and disability largely by causing increased blood pressure. Other associated health risks include gastric and renal cell cancers, osteoporosis, renal stones, and increased disease activity in multiple sclerosis, headache, increased body fat and Meniere’s disease. The World Hypertension League (WHL) has prioritized advocacy for salt reduction. WHL resources and actions include a non-governmental organization policy statement, dietary salt fact sheet, development of standardized nomenclature, call for quality research, collaboration in a weekly salt science update, development of a process to set recommended dietary salt research standards and regular literature reviews, development of adoptable power point slide sets to support WHL positions and resources, and critic of weak research studies on dietary salt. The WHL plans to continue to work with multiple governmental and non-governmental organizations to promote dietary salt reduction towards the World Health Organization (WHO) recommendations. PMID:26090335

The fuzzy cube and causal efficacy: representation of concomitant mechanisms in stroke.

PubMed

Jobe, Thomas H.; Helgason, Cathy M.

1998-04-01

Twentieth century medical science has embraced nineteenth century Boolean probability theory based upon two-valued Aristotelian logic. With the later addition of bit-based, von Neumann structured computational architectures, an epistemology based on randomness has led to a bivalent epidemiological methodology that dominates medical decision making. In contrast, fuzzy logic, based on twentieth century multi-valued logic, and computational structures that are content addressed and adaptively modified, has advanced a new scientific paradigm for the twenty-first century. Diseases such as stroke involve multiple concomitant causal factors that are difficult to represent using conventional statistical methods. We tested which paradigm best represented this complex multi-causal clinical phenomenon-stroke. We show that the fuzzy logic paradigm better represented clinical complexity in cerebrovascular disease than current probability theory based methodology. We believe this finding is generalizable to all of clinical science since multiple concomitant causal factors are involved in nearly all known pathological processes.

SORL1 variants and risk of late-onset Alzheimer's disease.

PubMed

Li, Yonghong; Rowland, Charles; Catanese, Joseph; Morris, John; Lovestone, Simon; O'Donovan, Michael C; Goate, Alison; Owen, Michael; Williams, Julie; Grupe, Andrew

2008-02-01

A recent study reported significant association of late-onset Alzheimer's disease (LOAD) with multiple single nucleotide polymorphisms (SNPs) and haplotypes in SORL1, a neuronal sortilin-related receptor protein known to be involved in the trafficking and processing of amyloid precursor protein. Here we attempted to validate this finding in three large, well characterized case-control series. Approximately 2000 samples from the three series were individually genotyped for 12 SNPs, including the 10 reported significant SNPs and 2 that constitute the reported significant haplotypes. A total of 25 allelic and haplotypic association tests were performed. One SNP rs2070045 was marginally replicated in the three sample sets combined (nominal P=0.035); however, this result does not remain significant when accounting for multiple comparisons. Further validation in other sample sets will be required to assess the true effects of SORL1 variants in LOAD.

Review: the role of vitamin D in nervous system health and disease.

PubMed

DeLuca, G C; Kimball, S M; Kolasinski, J; Ramagopalan, S V; Ebers, G C

2013-08-01

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis. © 2013 British Neuropathological Society.

Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders.

PubMed

Islam, Md Torequl

2017-01-01

Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.

Adenosine A2B receptor: from cell biology to human diseases

NASA Astrophysics Data System (ADS)

Sun, Ying; Huang, Pingbo

2016-08-01

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

Clonal evolution in myelodysplastic syndromes

PubMed Central

da Silva-Coelho, Pedro; Kroeze, Leonie I.; Yoshida, Kenichi; Koorenhof-Scheele, Theresia N.; Knops, Ruth; van de Locht, Louis T.; de Graaf, Aniek O.; Massop, Marion; Sandmann, Sarah; Dugas, Martin; Stevens-Kroef, Marian J.; Cermak, Jaroslav; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; de Witte, Theo; Blijlevens, Nicole M. A.; Muus, Petra; Huls, Gerwin; van der Reijden, Bert A.; Ogawa, Seishi; Jansen, Joop H.

2017-01-01

Cancer development is a dynamic process during which the successive accumulation of mutations results in cells with increasingly malignant characteristics. Here, we show the clonal evolution pattern in myelodysplastic syndrome (MDS) patients receiving supportive care, with or without lenalidomide (follow-up 2.5–11 years). Whole-exome and targeted deep sequencing at multiple time points during the disease course reveals that both linear and branched evolutionary patterns occur with and without disease-modifying treatment. The application of disease-modifying therapy may create an evolutionary bottleneck after which more complex MDS, but also unrelated clones of haematopoietic cells, may emerge. In addition, subclones that acquired an additional mutation associated with treatment resistance (TP53) or disease progression (NRAS, KRAS) may be detected months before clinical changes become apparent. Monitoring the genetic landscape during the disease may help to guide treatment decisions. PMID:28429724

VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease.

PubMed

Barratt, Shaney L; Flower, Victoria A; Pauling, John D; Millar, Ann B

2018-04-24

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.

The Apollo Structured Vocabulary: an OWL2 ontology of phenomena in infectious disease epidemiology and population biology for use in epidemic simulation.

PubMed

Hogan, William R; Wagner, Michael M; Brochhausen, Mathias; Levander, John; Brown, Shawn T; Millett, Nicholas; DePasse, Jay; Hanna, Josh

2016-08-18

We developed the Apollo Structured Vocabulary (Apollo-SV)-an OWL2 ontology of phenomena in infectious disease epidemiology and population biology-as part of a project whose goal is to increase the use of epidemic simulators in public health practice. Apollo-SV defines a terminology for use in simulator configuration. Apollo-SV is the product of an ontological analysis of the domain of infectious disease epidemiology, with particular attention to the inputs and outputs of nine simulators. Apollo-SV contains 802 classes for representing the inputs and outputs of simulators, of which approximately half are new and half are imported from existing ontologies. The most important Apollo-SV class for users of simulators is infectious disease scenario, which is a representation of an ecosystem at simulator time zero that has at least one infection process (a class) affecting at least one population (also a class). Other important classes represent ecosystem elements (e.g., households), ecosystem processes (e.g., infection acquisition and infectious disease), censuses of ecosystem elements (e.g., censuses of populations), and infectious disease control measures. In the larger project, which created an end-user application that can send the same infectious disease scenario to multiple simulators, Apollo-SV serves as the controlled terminology and strongly influences the design of the message syntax used to represent an infectious disease scenario. As we added simulators for different pathogens (e.g., malaria and dengue), the core classes of Apollo-SV have remained stable, suggesting that our conceptualization of the information required by simulators is sound. Despite adhering to the OBO Foundry principle of orthogonality, we could not reuse Infectious Disease Ontology classes as the basis for infectious disease scenarios. We thus defined new classes in Apollo-SV for host, pathogen, infection, infectious disease, colonization, and infection acquisition. Unlike IDO, our ontological analysis extended to existing mathematical models of key biological phenomena studied by infectious disease epidemiology and population biology. Our ontological analysis as expressed in Apollo-SV was instrumental in developing a simulator-independent representation of infectious disease scenarios that can be run on multiple epidemic simulators. Our experience suggests the importance of extending ontological analysis of a domain to include existing mathematical models of the phenomena studied by the domain. Apollo-SV is freely available at: http://purl.obolibrary.org/obo/apollo_sv.owl .

Combined Diffusion Tensor Imaging and Apparent Transverse Relaxation Rate Differentiate Parkinson Disease and Atypical Parkinsonism.

PubMed

Du, G; Lewis, M M; Kanekar, S; Sterling, N W; He, L; Kong, L; Li, R; Huang, X

2017-05-01

Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms. © 2017 by American Journal of Neuroradiology.

The role of the amygdala during emotional processing in Huntington's disease: from pre-manifest to late stage disease.

PubMed

Mason, Sarah L; Zhang, Jiaxiang; Begeti, Faye; Guzman, Natalie Valle; Lazar, Alpar S; Rowe, James B; Barker, Roger A; Hampshire, Adam

2015-04-01

Deficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis. We investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: "the Reading the Mind in the Eyes Test" which has been previously been shown to be amygdala dependent. Psychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, p<0.05). Furthermore, performance on the "Reading the Mind in the Eyes Test" correlated negatively with proximity to disease onset and became progressively worse with each stage of disease. Abnormalities in the neural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis. Furthermore, the "Reading the Mind in the Eyes Test" is a surrogate measure of amygdala function that is clinically useful across the entire cross-section of disease stages in HD. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Modeling Studying the Role of Bacteria on ice Nucleation Processes

NASA Astrophysics Data System (ADS)

Sun, J.

2006-12-01

Certain air-borne bacteria have been recognized as active ice nuclei at the temperatures warm than - 10°C. Ice nucleating bacteria commonly found in plants and ocean surface. These ice nucleating bacteria are readily disseminated into the atmosphere and have been observed in clouds and hailstones, and their importance in cloud formation process and precipitation, as well as causing diseases in plants and animal kingdom, have been considered for over two decades, but their significance in atmospheric processes are yet to be understood. A 1.5-D non-hydrostatic cumulus cloud model with bin-resolved microphysics is developed and is to used to examine the relative importance of sulphate aerosol concentrations on the evolution of cumulus cloud droplet spectra and ice multiplication process, as well as ice initiation process by ice nucleating bacteria in the growing stage of cumulus clouds and the key role of this process on the ice multiplication in the subsequent dissipating stage of cumulus clouds. In this paper, we will present some sensitivity test results of the evolution of cumulus cloud spectra, ice concentrations at various concentrations of sulfate aerosols, and at different ideal sounding profiles. We will discuss the implication of our results in understanding of ice nucleation processes.

AgMIP: Next Generation Models and Assessments

NASA Astrophysics Data System (ADS)

Rosenzweig, C.

2014-12-01

Next steps in developing next-generation crop models fall into several categories: significant improvements in simulation of important crop processes and responses to stress; extension from simplified crop models to complex cropping systems models; and scaling up from site-based models to landscape, national, continental, and global scales. Crop processes that require major leaps in understanding and simulation in order to narrow uncertainties around how crops will respond to changing atmospheric conditions include genetics; carbon, temperature, water, and nitrogen; ozone; and nutrition. The field of crop modeling has been built on a single crop-by-crop approach. It is now time to create a new paradigm, moving from 'crop' to 'cropping system.' A first step is to set up the simulation technology so that modelers can rapidly incorporate multiple crops within fields, and multiple crops over time. Then the response of these more complex cropping systems can be tested under different sustainable intensification management strategies utilizing the updated simulation environments. Model improvements for diseases, pests, and weeds include developing process-based models for important diseases, frameworks for coupling air-borne diseases to crop models, gathering significantly more data on crop impacts, and enabling the evaluation of pest management strategies. Most smallholder farming in the world involves integrated crop-livestock systems that cannot be represented by crop modeling alone. Thus, next-generation cropping system models need to include key linkages to livestock. Livestock linkages to be incorporated include growth and productivity models for grasslands and rangelands as well as the usual annual crops. There are several approaches for scaling up, including use of gridded models and development of simpler quasi-empirical models for landscape-scale analysis. On the assessment side, AgMIP is leading a community process for coordinated contributions to IPCC AR6 that involves the key modeling groups from around the world including North America, Europe, South America, Sub-Saharan Africa, South Asia, East Asia, and Australia and Oceania. This community process will lead to mutually agreed protocols for coordinated global and regional assessments.

In vivo imaging of the neurovascular unit in CNS disease

PubMed Central

Merlini, Mario; Davalos, Dimitrios; Akassoglou, Katerina

2014-01-01

The neurovascular unit—comprised of glia, pericytes, neurons and cerebrovasculature—is a dynamic interface that ensures physiological central nervous system (CNS) functioning. In disease dynamic remodeling of the neurovascular interface triggers a cascade of responses that determine the extent of CNS degeneration and repair. The dynamics of these processes can be adequately captured by imaging in vivo, which allows the study of cellular responses to environmental stimuli and cell-cell interactions in the living brain in real time. This perspective focuses on intravital imaging studies of the neurovascular unit in stroke, multiple sclerosis (MS) and Alzheimer disease (AD) models and discusses their potential for identifying novel therapeutic targets. PMID:25197615

Chronic morbidities after traumatic brain injury: an update for the advanced practice nurse.

PubMed

Bay, Esther H; Chartier, Kattlynn S

2014-06-01

Emerging data suggest that traumatic brain injury (TBI) is a disease process with considerable long-range morbidities requiring lifelong monitoring and treatment. Multiple chronic morbidities develop across the life span after TBI, including mental health disorders, headaches, seizures, and neuroendocrine imbalances as well as chronic diseases. Still, there has been limited focus on effective guides and strategies for helping persons with TBI meet their chronic health needs as they live with the consequences of TBI. The advanced practice nurse is well positioned to participate collaboratively in practices that promote health screening and chronic disease management after TBI to ameliorate distress and enhance quality of life as persons with TBI live with lifelong consequences.

Neurocognitive and executive functioning in adult survivors of congenital heart disease.

PubMed

Klouda, Leda; Franklin, Wayne J; Saraf, Anita; Parekh, Dhaval R; Schwartz, David D

2017-01-01

Congenital heart disease (CHD) can affect the developing central nervous system, resulting in neurocognitive and behavioral deficits. Preoperative neurological abnormalities as well as sequelae of the open heart operations required to correct structural abnormalities of the heart contribute to these deficits. There are few studies examining the neurocognitive functioning of adults with CHD. This study sought to investigate multiple domains of neurocognitive functioning in adult survivors of CHD who had childhood cardiac surgery with either moderate or severe disease complexity. A total of 48 adults (18-49 years of age) who had undergone cardiac surgery for CHD prior to five years of age participated in the study. CHD severity was classified as moderate or severe according to the 32nd Bethesda Guidelines. A computerized battery of standardized neurocognitive tests (CNS-Vital Signs), a validated rating scale of executive functioning, and demographic questionnaires were administered. There were no significant differences between the moderate CHD group and normative data on any cognitive measure. In contrast, the severe CHD group differed from norms in multiple domains: psychomotor speed, processing speed, complex attention, reaction time, and on the overall neurocognitive index. Number of surgeries was strongly related to worse executive functioning. There was no association between age at first surgery or time since last surgery and neuropsychological functioning. Number of surgeries was also unrelated to neurocognitive test performance. Patients with severe CHD performed significantly worse on measures of processing speed, attention, and executive functioning. These findings may be useful in the long-term care of adults with congenital heart disease. © 2016 Wiley Periodicals, Inc.

A case report of unexpected pathology within an incarcerated ventral hernia.

PubMed

Kane, Erica D; Bittner, Katharine R; Bennett, Michelle; Romanelli, John R; Seymour, Neal E; Wu, Jacqueline J

2017-01-01

Incidence of hernial appendicitis is 0.008%, most frequently within inguinal and femoral hernias. Up to 2.5% of appendectomy patients are found to have Crohn's disease. Elucidating the etiology of inflammation is essential for directing management. A 51-year-old female with achondroplastic dwarfism, multiple cesarean sections, and subsequent massive incisional hernia, presented with ruptured appendicitis within her incarcerated hernia. She underwent diagnostic laparoscopy, appendectomy, intra-abdominal abscess drainage, and complete reduction of ventral hernia contents. She developed a nonhealing colocutaneous fistula, causing major disruptions to her daily life. She elected to undergo hernia repair with component separation for anticipated lack of domain secondary to her body habitus. Her operative course consisted of open abdominal exploration, adhesiolysis, colocutaneous fistula repair, ileocolic resection and anastomosis, and hernia repair with bioresorbable mesh. She tolerated the procedure well. Unexpectedly, ileocolic pathology demonstrated chronic active ileitis, diagnostic of Crohn's disease. Only two cases of hernial Crohn's appendicitis have been reported, both within Spigelian hernias. Appendiceal inflammation inside a hernia sac may be attributed to ischemia from extraluminal compression of the hernia neck. This case demonstrates a rare presentation of multiple concurrent surgical disease processes, each of which impact the patient's treatment plan. This is the first report of incisional hernia appendicitis with nonhealing colocutaneous fistulas secondary to Crohn's. It is a lesson in developing a differential diagnosis of an inflammatory process within an incarcerated hernia and management of the complications related to laparoscopic hernial appendectomy in a patient with undiagnosed Crohn's disease. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Area variations in multiple morbidity using a life table methodology.

PubMed

Congdon, Peter

Analysis of healthy life expectancy is typically based on a binary distinction between health and ill-health. By contrast, this paper considers spatial modelling of disease free life expectancy taking account of the number of chronic conditions. Thus the analysis is based on population sub-groups with no disease, those with one disease only, and those with two or more diseases (multiple morbidity). Data on health status is accordingly modelled using a multinomial likelihood. The analysis uses data for 258 small areas in north London, and shows wide differences in the disease burden related to multiple morbidity. Strong associations between area socioeconomic deprivation and multiple morbidity are demonstrated, as well as strong spatial clustering.

Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.

PubMed

Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas

2017-10-01

Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease.

PubMed

Lafaille, J J; Keere, F V; Hsu, A L; Baron, J L; Haas, W; Raine, C S; Tonegawa, S

1997-07-21

Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4(+) Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in alphabeta T cell-deficient mice, albeit after a longer preclinical phase. Normal or gammadelta T cell-deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.

Autophagy in alcohol-induced liver diseases

PubMed Central

Dolganiuc, Angela; Thomes, Paul G.; Ding, Wen-Xing; Lemasters, John J.; Donohue, Terrence M.

2013-01-01

Alcohol is the most abused substance worldwide and a significant source of liver injury; the mechanisms of alcohol-induced liver disease are not fully understood. Significant cellular toxicity and impairment of protein synthesis and degradation occur in alcohol-exposed liver cells, along with changes in energy balance and modified responses to pathogens. Autophagy is the process of cellular catabolism through the lysosomal-dependent machinery, which maintains a balance among protein synthesis, degradation, and recycling of self. Autophagy is part of normal homeostasis and it can be triggered by multiple factors that threaten cell integrity including starvation, toxins, or pathogens. Multiple factors regulate autophagy; survival and preservation of cellular integrity at the expense of inadequately-folded proteins and damaged high energy-generating intracellular organelles are prominent targets of autophagy in pathologic conditions. Coincidentally, inadequately-folded proteins accumulate and high energy-generating intracellular organelles, such as mitochondria, are damaged by alcohol abuse; these alcohol-induced pathological findings prompted investigation of the role of autophagy in the pathogenesis of alcohol-induced liver damage. Our review summarizes the current knowledge about the role and implications of autophagy in alcohol-induced liver disease. PMID:22551004

Prophylaxis and Immunization in Mice by Use of Virus-Free Defective T Particles to Protect Against Intracerebral Infection by Vesicular Stomatitis Virus

PubMed Central

Doyle, Michael; Holland, John J.

1973-01-01

Defective interfering T particles of vesicular stomatitis virus provide remarkable protection against viral disease and death when introduced intracerebrally in large numbers along with an otherwise rapidly fatal low dose of standard infectious virus. This profound prophylactic effect of defective T particles is due to homologous autointerference since it is serotype-specific and interferon is not induced. This protective effect can be demonstrated only with preparations of T particles that have been purified completely free of infectious virions. When pure T particles are injected intracerebrally along with large doses of infectious virus, they convert an otherwise rapidly fatal disease process to a slowly progressing virus infection that generally terminates in death after many days of wasting disease and paralysis. Intracerebral injection of virus-free T particles alone is apparently innocuous to mice and stimulates immunity to massive doses of homologous infectious virus. In vitro, virus-free T particles at extremely high multiplicities depress cellular RNA and protein synthesis and kill BHK21 cells in culture, but do not exhibit such effects at moderately high multiplicities. PMID:4352972

[Disease concept, etiology and mechanisms of multiple sclerosis].

PubMed

Kira, Jun-Ichi

2014-11-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system(CNS). MS is assumed to be caused by a complex interplay between genes and environments. Autoimmune mechanisms targeting CNS myelin has long been proposed, yet it has not been proved. Th17 cells producing interleukin-17 and Th1 cells producing interferon-gamma are postulated to play major roles in initiating inflammation while regulatory T cell functions are dampened. The forth nationwide survey of MS in Japan revealed that MS prevalence showed four-folds increase over 30 years and the increase was especially prominent in female. Thus, westernized life style and improved sanitation are suspected to increase MS susceptibility. Genome-wide association studies in Western MS patients disclosed more than 100 disease-susceptibility genes, most of which are immune-related genes. It therefore supports immune-mediated mechanisms to be operative. Detailed magnetic resonance imaging studies revealed an early atrophy of the cerebral gray matter where T cell infiltration is pathologically scarce. Therefore, neurodegenerative process also takes place in the early course beside neuroinflammation.

Alkaline Phosphatase, an Unconventional Immune Protein.

PubMed

Rader, Bethany A

2017-01-01

Recent years have seen an increase in the number of studies focusing on alkaline phosphatases (APs), revealing an expanding complexity of function of these enzymes. Of the four human AP (hAP) proteins, most is known about tissue non-specific AP (TNAP) and intestinal AP (IAP). This review highlights current understanding of TNAP and IAP in relation to human health and disease. TNAP plays a role in multiple processes, including bone mineralization, vitamin B6 metabolism, and neurogenesis, is the genetic cause of hypophosphatasia, influences inflammation through regulation of purinergic signaling, and has been implicated in Alzheimer's disease. IAP regulates fatty acid absorption and has been implicated in the regulation of diet-induced obesity and metabolic syndrome. IAP and TNAP can dephosphorylate bacterial-derived lipopolysaccharide, and IAP has been identified as a potential regulator of the composition of the intestinal microbiome, an evolutionarily conserved function. Endogenous and recombinant bovine APs and recombinant hAPs are currently being explored for their potential as pharmacological agents to treat AP-associated diseases and mitigate multiple sources of inflammation. Continued research on these versatile proteins will undoubtedly provide insight into human pathophysiology, biochemistry, and the human holobiont.

Database integration of protocol-specific neurological imaging datasets

PubMed Central

Pacurar, Emil E.; Sethi, Sean K.; Habib, Charbel; Laze, Marius O.; Martis-Laze, Rachel; Haacke, E. Mark

2016-01-01

For many years now, Magnetic Resonance Innovations (MR Innovations), a magnetic resonance imaging (MRI) software development, technology, and research company, has been aggregating a multitude of MRI data from different scanning sites through its collaborations and research contracts. The majority of the data has adhered to neuroimaging protocols developed by our group which has helped ensure its quality and consistency. The protocols involved include the study of: traumatic brain injury, extracranial venous imaging for multiple sclerosis and Parkinson's disease, and stroke. The database has proven invaluable in helping to establish disease biomarkers, validate findings across multiple data sets, develop and refine signal processing algorithms, and establish both public and private research collaborations. Myriad Masters and PhD dissertations have been possible thanks to the availability of this database. As an example of a project that cuts across diseases, we have used the data and specialized software to develop new guidelines for detecting cerebral microbleeds. Ultimately, the database has been vital in our ability to provide tools and information for researchers and radiologists in diagnosing their patients, and we encourage collaborations and welcome sharing of similar data in this database. PMID:25959660

Protein Tyrosine Phosphatase 1B (PTP1B): A Potential Target for Alzheimer's Therapy?

PubMed

Vieira, Marcelo N N; Lyra E Silva, Natalia M; Ferreira, Sergio T; De Felice, Fernanda G

2017-01-01

Despite significant advances in current understanding of mechanisms of pathogenesis in Alzheimer's disease (AD), attempts at drug development based on those discoveries have failed to translate into effective, disease-modifying therapies. AD is a complex and multifactorial disease comprising a range of aberrant cellular/molecular processes taking part in different cell types and brain regions. As a consequence, therapeutics for AD should be able to block or compensate multiple abnormal pathological events. Here, we examine recent evidence that inhibition of protein tyrosine phosphatase 1B (PTP1B) may represent a promising strategy to combat a variety of AD-related detrimental processes. Besides its well described role as a negative regulator of insulin and leptin signaling, PTB1B recently emerged as a modulator of various other processes in the central nervous system (CNS) that are also implicated in AD. These include signaling pathways germane to learning and memory, regulation of synapse dynamics, endoplasmic reticulum (ER) stress and microglia-mediated neuroinflammation. We propose that PTP1B inhibition may represent an attractive and yet unexplored therapeutic approach to correct aberrant signaling pathways linked to AD.

Infections on the move: how transient phases of host movement influence disease spread

PubMed Central

Fenton, A.; Dell, A. I.

2017-01-01

Animal movement impacts the spread of human and wildlife diseases, and there is significant interest in understanding the role of migrations, biological invasions and other wildlife movements in spatial infection dynamics. However, the influence of processes acting on infections during transient phases of host movement is poorly understood. We propose a conceptual framework that explicitly considers infection dynamics during transient phases of host movement to better predict infection spread through spatial host networks. Accounting for host transient movement captures key processes that occur while hosts move between locations, which together determine the rate at which hosts spread infections through networks. We review theoretical and empirical studies of host movement and infection spread, highlighting the multiple factors that impact the infection status of hosts. We then outline characteristics of hosts, parasites and the environment that influence these dynamics. Recent technological advances provide disease ecologists unprecedented ability to track the fine-scale movement of organisms. These, in conjunction with experimental testing of the factors driving infection dynamics during host movement, can inform models of infection spread based on constituent biological processes. PMID:29263283

Painting a new picture of personalised medicine for diabetes.

PubMed

McCarthy, Mark I

2017-05-01

The current focus on delivery of personalised (or precision) medicine reflects the expectation that developments in genomics, imaging and other domains will extend our diagnostic and prognostic capabilities, and enable more effective targeting of current and future preventative and therapeutic options. The clinical benefits of this approach are already being realised in rare diseases and cancer but the impact on management of complex diseases, such as type 2 diabetes, remains limited. This may reflect reliance on inappropriate models of disease architecture, based around rare, high-impact genetic and environmental exposures that are poorly suited to our emerging understanding of type 2 diabetes. This review proposes an alternative 'palette' model, centred on a molecular taxonomy that focuses on positioning an individual with respect to the major pathophysiological processes that contribute to diabetes risk and progression. This model anticipates that many individuals with diabetes will have multiple parallel defects that affect several of these processes. One corollary of this model is that research efforts should, at least initially, be targeted towards identifying and characterising individuals whose adverse metabolic trajectory is dominated by perturbation in a restricted set of processes.

A national survey of organizational transfer practices in chronic disease prevention in Canada.

PubMed

Hanusaik, Nancy; O'Loughlin, Jennifer L; Paradis, Gilles; Kishchuk, Natalie

2011-08-01

Underuse of best practices in chronic disease prevention (CDP) represents missed opportunities to promote healthy living and prevent chronic disease. Better understanding of how CDP programs, practices and policies (PPPs) are transferred from 'resource' organizations that develop them to 'user' organizations that implement them is crucial. The objectives of this work were to develop psychometrically sound measures of transfer practices occurring within resource organizations; describe the use of these transfer practices and identify correlates of the transfer process. Cross-sectional data were collected in structured telephone interviews with the person most knowledgeable about PPP transfer in 77 Canadian organizations that develop PPPs. Independent correlates of transfer were identified using multiple linear regression. The transfer practices most commonly used included: identification of barriers to PPP adoption/implementation, tailoring transfer strategies and designing a transfer plan. Skill at planning/implementing transfer, external sources of funding specifically allocated for transfer, type of resource organization, attitude toward process of collaboration and user-centeredness were all positively associated with the transfer process. These factors represent possible targets for interventions to improve transfer of CDP PPPs.

Coexistence of multiple sclerosis and ankylosing spondylitis: Report of four cases from Russia and review of the literature.

PubMed

Fominykh, Vera; Shevtsova, Tatyana; Arzumanian, Narine; Brylev, Lev

2017-10-01

Multiple sclerosis is a chronic demyelinating disorder of the central nervous system. There are many cases of multiple sclerosis - like syndrome and demyelinating disorders in systemic lupus erythematosus, Sjogren disease, Behcet disease and other autoimmune conditions. Coexistence of ankylosing spondylitis and multiple sclerosis usually is rare but in this article we report 4 Russian patients with concomitant multiple sclerosis and ankylosing spondylitis diseases. None of these patients received anti-tumor necrosis factor alpha therapy prior to diagnosis of multiple sclerosis. Pathogenesis, diagnostic and treatment challenges are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of acute dieldrin exposure on neurotransmitters and global gene transcription in largemouth bass (Micropterus salmoides) hypothalamus

PubMed Central

Martyniuk, Christopher J.; Feswick, April; Spade, Daniel J.; Kroll, Kevin J.; Barber, David S.; Denslow, Nancy D.

2010-01-01

Exposure to dieldrin induces neurotoxic effects in the vertebrate CNS and disrupts reproductive processes in teleost fish. Reproductive impairment observed in fish by dieldrin is likely the result of multiple effects along the hypothalamic-pituitary-gonadal axis but the molecular signaling cascades are not well characterized. To better elucidate the mode of action of dieldrin in the hypothalamus, this study measured neurotransmitter levels and examined the transcriptomic response in female largemouth bass (LMB) to an acute treatment of dieldrin. Male and female LMB were injected with either vehicle or 10 mg dieldrin/kg and sacrificed after seven days. There were no significant changes in dopamine or DOPAC concentrations in the neuroendocrine brain of males and females after treatment but GABA levels in females were moderately increased 20–30% in the hypothalamus and cerebellum. In the female hypothalamus, there were 227 transcripts (p<0.001) identified as being differentially regulated by dieldrin. Functional enrichment analysis revealed transcription, DNA repair, ubiquitin-proteasome pathway, and cell communication, as biological processes over-represented in the microarray analysis. Pathway analysis identified DNA damage, inflammation, regeneration, and Alzheimer’s disease as major cell processes and diseases affected by dieldrin. Using multiple bioinformatics approaches, this study demonstrates that the teleostean hypothalamus is a target for dieldrin-induced neurotoxicity and provides mechanistic evidence that dieldrin activates similar cell pathways and biological processes that are also associated with the etiology of human neurological disorders. PMID:20438755

Automating quantum dot barcode assays using microfluidics and magnetism for the development of a point-of-care device.

PubMed

Gao, Yali; Lam, Albert W Y; Chan, Warren C W

2013-04-24

The impact of detecting multiple infectious diseases simultaneously at point-of-care with good sensitivity, specificity, and reproducibility would be enormous for containing the spread of diseases in both resource-limited and rich countries. Many barcoding technologies have been introduced for addressing this need as barcodes can be applied to detecting thousands of genetic and protein biomarkers simultaneously. However, the assay process is not automated and is tedious and requires skilled technicians. Barcoding technology is currently limited to use in resource-rich settings. Here we used magnetism and microfluidics technology to automate the multiple steps in a quantum dot barcode assay. The quantum dot-barcoded microbeads are sequentially (a) introduced into the chip, (b) magnetically moved to a stream containing target molecules, (c) moved back to the original stream containing secondary probes, (d) washed, and (e) finally aligned for detection. The assay requires 20 min, has a limit of detection of 1.2 nM, and can detect genetic targets for HIV, hepatitis B, and syphilis. This study provides a simple strategy to automate the entire barcode assay process and moves barcoding technologies one step closer to point-of-care applications.

The role of the striatum in rule application: the model of Huntington's disease at early stage.

PubMed

Teichmann, Marc; Dupoux, Emmanuel; Kouider, Sid; Brugières, Pierre; Boissé, Marie-Françoise; Baudic, Sophie; Cesaro, Pierre; Peschanski, Marc; Bachoud-Lévi, Anne-Catherine

2005-05-01

The role of the basal ganglia, and more specifically of the striatum, in language is still debated. Recent studies have proposed that linguistic abilities involve two distinct types of processes: the retrieving of stored information, implicating temporal lobe areas, and the application of combinatorial rules, implicating fronto-striatal circuits. Studies of patients with focal lesions and neurodegenerative diseases have suggested a role for the striatum in morphological rule application, but functional imaging studies found that the left caudate was involved in syntactic processing and not morphological processing. In the present study, we tested the view that the basal ganglia are involved in rule application and not in lexical retrieving in a model of striatal dysfunction, namely Huntington's disease at early stages. We assessed the rule-lexicon dichotomy in the linguistic domain with morphology (conjugation of non-verbs and verbs) and syntax (sentence comprehension) and in a non-linguistic domain with arithmetic operations (subtraction and multiplication). Thirty Huntington's disease patients (15 at stage I and 15 at stage II) and 20 controls matched for their age and cultural level were included in this study. Huntington's disease patients were also assessed using the Unified Huntington's Disease Rating Scale (UHDRS) and MRI. We found that early Huntington's disease patients were impaired in rule application in the linguistic and non-linguistic domains (morphology, syntax and subtraction), whereas they were broadly spared with lexical processing. The pattern of performance was similar in patients at stage I and stage II, except that stage II patients were more impaired in all tasks assessing rules and had in addition a very slight impairment in the lexical condition of conjugation. Finally, syntactic rule abilities correlated with all markers of the disease evolution including bicaudate ratio and performance in executive function, whereas there was no correlation with arithmetic and morphological abilities. Together, this suggests that the striatum is involved in rule processing more than in lexical processing and that it extends to linguistic and non-linguistic domains. These results are discussed in terms of domain-specific versus domain-general processes of rule application.

An Assessment of Information Exchange Practices, Challenges, and Opportunities to Support US Disease Surveillance in 3 States.

PubMed

Garcia, Macarena C; Garrett, Nedra Y; Singletary, Vivian; Brown, Sheereen; Hennessy-Burt, Tamara; Haney, Gillian; Link, Kimberly; Tripp, Jennifer; Mac Kenzie, William R; Yoon, Paula

2017-12-07

State and local public health agencies collect and use surveillance data to identify outbreaks, track cases, investigate causes, and implement measures to protect the public-s health through various surveillance systems and data exchange practices. The purpose of this assessment was to better understand current practices at state and local public health agencies for collecting, managing, processing, reporting, and exchanging notifiable disease surveillance information. Over an 18-month period (January 2014-June 2015), we evaluated the process of data exchange between surveillance systems, reporting burdens, and challenges within 3 states (California, Idaho, and Massachusetts) that were using 3 different reporting systems. All 3 states use a combination of paper-based and electronic information systems for managing and exchanging data on reportable conditions within the state. The flow of data from local jurisdictions to the state health departments varies considerably. When state and local information systems are not interoperable, manual duplicative data entry and other work-arounds are often required. The results of the assessment show the complexity of disease reporting at the state and local levels and the multiple systems, processes, and resources engaged in preparing, processing, and transmitting data that limit interoperability and decrease efficiency. Through this structured assessment, the Centers for Disease Control and Prevention (CDC) has a better understanding of the complexities for surveillance of using commercial off-the-shelf data systems (California and Massachusetts), and CDC-developed National Electronic Disease Surveillance System Base System. More efficient data exchange and use of data will help facilitate interoperability between National Notifiable Diseases Surveillance Systems.

[Model of multiple seasonal autoregressive integrated moving average model and its application in prediction of the hand-foot-mouth disease incidence in Changsha].

PubMed

Tan, Ting; Chen, Lizhang; Liu, Fuqiang

2014-11-01

To establish multiple seasonal autoregressive integrated moving average model (ARIMA) according to the hand-foot-mouth disease incidence in Changsha, and to explore the feasibility of the multiple seasonal ARIMA in predicting the hand-foot-mouth disease incidence. EVIEWS 6.0 was used to establish multiple seasonal ARIMA according to the hand-foot- mouth disease incidence from May 2008 to August 2013 in Changsha, and the data of the hand- foot-mouth disease incidence from September 2013 to February 2014 were served as the examined samples of the multiple seasonal ARIMA, then the errors were compared between the forecasted incidence and the real value. Finally, the incidence of hand-foot-mouth disease from March 2014 to August 2014 was predicted by the model. After the data sequence was handled by smooth sequence, model identification and model diagnosis, the multiple seasonal ARIMA (1, 0, 1)×(0, 1, 1)12 was established. The R2 value of the model fitting degree was 0.81, the root mean square prediction error was 8.29 and the mean absolute error was 5.83. The multiple seasonal ARIMA is a good prediction model, and the fitting degree is good. It can provide reference for the prevention and control work in hand-foot-mouth disease.

[Rheumatoid arthritis as a connective tissue disease].

PubMed

Targońska-Stępniak, Bożena

2018-01-01

The available data indicate that seropositive rheumatoid arthritis (RA) develops as a result of systemic, autoimmune reaction directed against a range of "self" peptides/proteins that have undergone specific forms of post-translational modification. The development and progress of autoimmunity may be triggered by non-specific, local inflammatory processes outside the joints, for example in the oral or respiratory mucous membrane. The disease occurs in genetically susceptible individuals under the influence of environmental risk factors that promote autoimmunity and consequently the inflammatory process. Smoking is particularly linked with RA pathogenesis. Synovitis of multiple, symmetrical, peripheral joints is the most typical feature of RA which results in irreversible damage to joints structure and as a consequence in disability of patients. However, the inflammatory process in the course of RA has a systemic, constitutional nature. Therefore, extra-articular symptoms with internal organ involvement may occur additionally to synovitis, what is an unfavorable prognostic factor. Extra-articular manifestations of RA are associated with the high disease activity both inflammatory and immunological. They occur in patients with severe form of the disease and contribute to a significant lifespan reduction. This is usually associated with progressive atherosclerosis and cardiovascular complications. The systemic inhibition of an abnormal immune system activity is the mainstay of the effective RA treatment. The currently used disease modifying antirheumatic drugs affect the activity and function of different constituents of the immune system, including B and T lymphocytes and the main pro-inflammatory cytokines, and contribute to autoimmune and inflammatory processes.

Diagnosis - the limiting focus of taxonomy.

PubMed

Sturmberg, Joachim P; Martin, Carmel M

2016-02-01

The focus on the diagnosis is a pivotal aspect of medical practice since antiquity. Diagnostic taxonomy helped to categorize ailments to improve medical care, and in its social sense resulted in validation of the sick role for some, but marginalization or stigmatization for others. In the medical industrial complex, diagnostic taxonomy structured health care financing, management and practitioner remuneration. However, with increasing demands from multiple agencies, there are increasing unintended and unwarranted consequences of our current taxonomies and diagnostic processes resulting from the conglomeration of underpinning concepts, theories, information and motivations. We argue that the increasing focus on the diagnosis resulted in excessive compartmentalization - 'partialism' - of medical practice, diminishing medical care and being naively simplistic in light of the emerging understanding of the interconnected nature of the diseasome. The human is a complex organic system of interconnecting dynamics and feedback loops responding to internal and external forces including genetic, epigenetic and environmental attractors, rather than the sum of multiple discrete organs which can develop isolated diseases or multiple morbidities. Solutions to these unintended consequences of many contemporary health system processes involve revisiting the nature of diagnostic taxonomies and the processes of their construction. A dynamic taxonomic framework would shift to more relevant attractors at personal, clinical and health system levels recognizing the non-linear nature of health and disease. Human health at an individual, group and population level is the ability to adapt to internal and external stressors with resilience throughout the life course, yet diagnostic taxonomies are increasingly constructed around fixed anchors. Understanding diagnosis as dissecting, pigeonholing or bean counting (learning by dividing) is no longer useful, the challenge for the future is to understand the big picture (learning by connecting). Diagnostic categorization needs to embrace a meta-learning approach open to human variability. © 2014 John Wiley & Sons, Ltd.

Generation of gene-targeted mice using embryonic stem cells derived from a transgenic mouse model of Alzheimer's disease.

PubMed

Yamamoto, Satoshi; Ooshima, Yuki; Nakata, Mitsugu; Yano, Takashi; Matsuoka, Kunio; Watanabe, Sayuri; Maeda, Ryouta; Takahashi, Hideki; Takeyama, Michiyasu; Matsumoto, Yoshio; Hashimoto, Tadatoshi

2013-06-01

Gene-targeting technology using mouse embryonic stem (ES) cells has become the "gold standard" for analyzing gene functions and producing disease models. Recently, genetically modified mice with multiple mutations have increasingly been produced to study the interaction between proteins and polygenic diseases. However, introduction of an additional mutation into mice already harboring several mutations by conventional natural crossbreeding is an extremely time- and labor-intensive process. Moreover, to do so in mice with a complex genetic background, several years may be required if the genetic background is to be retained. Establishing ES cells from multiple-mutant mice, or disease-model mice with a complex genetic background, would offer a possible solution. Here, we report the establishment and characterization of novel ES cell lines from a mouse model of Alzheimer's disease (3xTg-AD mouse, Oddo et al. in Neuron 39:409-421, 2003) harboring 3 mutated genes (APPswe, TauP301L, and PS1M146V) and a complex genetic background. Thirty blastocysts were cultured and 15 stable ES cell lines (male: 11; female: 4) obtained. By injecting these ES cells into diploid or tetraploid blastocysts, we generated germline-competent chimeras. Subsequently, we confirmed that F1 mice derived from these animals showed similar biochemical and behavioral characteristics to the original 3xTg-AD mice. Furthermore, we introduced a gene-targeting vector into the ES cells and successfully obtained gene-targeted ES cells, which were then used to generate knockout mice for the targeted gene. These results suggest that the present methodology is effective for introducing an additional mutation into mice already harboring multiple mutated genes and/or a complex genetic background.

Systems and precision medicine approaches to diabetes heterogeneity: a Big Data perspective.

PubMed

Capobianco, Enrico

2017-12-01

Big Data, and in particular Electronic Health Records, provide the medical community with a great opportunity to analyze multiple pathological conditions at an unprecedented depth for many complex diseases, including diabetes. How can we infer on diabetes from large heterogeneous datasets? A possible solution is provided by invoking next-generation computational methods and data analytics tools within systems medicine approaches. By deciphering the multi-faceted complexity of biological systems, the potential of emerging diagnostic tools and therapeutic functions can be ultimately revealed. In diabetes, a multidimensional approach to data analysis is needed to better understand the disease conditions, trajectories and the associated comorbidities. Elucidation of multidimensionality comes from the analysis of factors such as disease phenotypes, marker types, and biological motifs while seeking to make use of multiple levels of information including genetics, omics, clinical data, and environmental and lifestyle factors. Examining the synergy between multiple dimensions represents a challenge. In such regard, the role of Big Data fuels the rise of Precision Medicine by allowing an increasing number of descriptions to be captured from individuals. Thus, data curations and analyses should be designed to deliver highly accurate predicted risk profiles and treatment recommendations. It is important to establish linkages between systems and precision medicine in order to translate their principles into clinical practice. Equivalently, to realize their full potential, the involved multiple dimensions must be able to process information ensuring inter-exchange, reducing ambiguities and redundancies, and ultimately improving health care solutions by introducing clinical decision support systems focused on reclassified phenotypes (or digital biomarkers) and community-driven patient stratifications.

Recent discoveries on absorption of dietary fat: Presence, synthesis, and metabolism of cytoplasmic lipid droplets within enterocytes.

PubMed

D'Aquila, Theresa; Hung, Yu-Han; Carreiro, Alicia; Buhman, Kimberly K

2016-08-01

Dietary fat provides essential nutrients, contributes to energy balance, and regulates blood lipid concentrations. These functions are important to health, but can also become dysregulated and contribute to diseases such as obesity, diabetes, cardiovascular disease, and cancer. Within enterocytes, the digestive products of dietary fat are re-synthesized into triacylglycerol, which is either secreted on chylomicrons or stored within cytoplasmic lipid droplets (CLDs). CLDs were originally thought to be inert stores of neutral lipids, but are now recognized as dynamic organelles that function in multiple cellular processes in addition to lipid metabolism. This review will highlight recent discoveries related to dietary fat absorption with an emphasis on the presence, synthesis, and metabolism of CLDs within this process. Copyright © 2016 Elsevier B.V. All rights reserved.

Malarial pathocoenosis: beneficial and deleterious interactions between malaria and other human diseases

PubMed Central

Faure, Eric

2014-01-01

In nature, organisms are commonly infected by an assemblage of different parasite species or by genetically distinct parasite strains that interact in complex ways. Linked to co-infections, pathocoenosis, a term proposed by M. Grmek in 1969, refers to a pathological state arising from the interactions of diseases within a population and to the temporal and spatial dynamics of all of the diseases. In the long run, malaria was certainly one of the most important component of past pathocoenoses. Today this disease, which affects hundreds of millions of individuals and results in approximately one million deaths each year, is always highly endemic in over 20% of the world and is thus co-endemic with many other diseases. Therefore, the incidences of co-infections and possible direct and indirect interactions with Plasmodium parasites are very high. Both positive and negative interactions between malaria and other diseases caused by parasites belonging to numerous taxa have been described and in some cases, malaria may modify the process of another disease without being affected itself. Interactions include those observed during voluntary malarial infections intended to cure neuro-syphilis or during the enhanced activations of bacterial gastro-intestinal diseases and HIV infections. Complex relationships with multiple effects should also be considered, such as those observed during helminth infections. Moreover, reports dating back over 2000 years suggested that co- and multiple infections have generally deleterious consequences and analyses of historical texts indicated that malaria might exacerbate both plague and cholera, among other diseases. Possible biases affecting the research of etiological agents caused by the protean manifestations of malaria are discussed. A better understanding of the manner by which pathogens, particularly Plasmodium, modulate immune responses is particularly important for the diagnosis, cure, and control of diseases in human populations. PMID:25484866

Remote sensing of multiple vital signs using a CMOS camera-equipped infrared thermography system and its clinical application in rapidly screening patients with suspected infectious diseases.

PubMed

Sun, Guanghao; Nakayama, Yosuke; Dagdanpurev, Sumiyakhand; Abe, Shigeto; Nishimura, Hidekazu; Kirimoto, Tetsuo; Matsui, Takemi

2017-02-01

Infrared thermography (IRT) is used to screen febrile passengers at international airports, but it suffers from low sensitivity. This study explored the application of a combined visible and thermal image processing approach that uses a CMOS camera equipped with IRT to remotely sense multiple vital signs and screen patients with suspected infectious diseases. An IRT system that produced visible and thermal images was used for image acquisition. The subjects' respiration rates were measured by monitoring temperature changes around the nasal areas on thermal images; facial skin temperatures were measured simultaneously. Facial blood circulation causes tiny color changes in visible facial images that enable the determination of the heart rate. A logistic regression discriminant function predicted the likelihood of infection within 10s, based on the measured vital signs. Sixteen patients with an influenza-like illness and 22 control subjects participated in a clinical test at a clinic in Fukushima, Japan. The vital-sign-based IRT screening system had a sensitivity of 87.5% and a negative predictive value of 91.7%; these values are higher than those of conventional fever-based screening approaches. Multiple vital-sign-based screening efficiently detected patients with suspected infectious diseases. It offers a promising alternative to conventional fever-based screening. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Analysis of the New Zealand Black contribution to lupus-like renal disease

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

Drake, C.G.; Rozzo, S.J.; Hirschfeld, H.F.

1995-03-01

F{sub 1} progeny of New Zealand Black (NZB) and New Zealand White (NZW) mice spontaneously develop an autoimmune process remarkably similar to human systemic lupus erythematosus. Previous studies have implicated major genetic contributions from the NZW MHC and from a dominant NZB gene on chromosome 4. To identify additional NZB contributions to lupus-like disease, (NZB x SM/J)F{sub 1} x NZW backcross mice were followed for the development of severe renal disease and were comprehensively genotyped. Despite a 50% incidence of disease significant associations between the presence of the NZB genotype and disease were noted on chromosomes 1, 4, 7, 10,more » 13, and 19. The data indicated that multiple NZB genes, in different combinations, contribute to severe renal disease, and that no single gene is required. To further investigate this NZB contribution, NZB x SM/J (NXSM) recombinant inbred (RI) strains were crossed with NZW mice, and F{sub 1} progeny were analyzed for the presence of lupus-like renal disease. Interestingly, nearly all of the (RI x NZW)F{sub 1} cohorts studies expressed some level of disease. Five RI strains generated a high incidence of disease, similar to (NZB x NZW)F{sub 1} mice, and nearly one-half of the cohorts developed disease at intermediate levels. Only two cohorts demonstrated very little disease, supporting the conclusion that multiple genes are capable of disease induction. Experiments correlating the genotypes of these RI strains with their ability to generate disease revealed that none of the disease-associated loci defined by the backcross analysis were present in all five RI strains that generated disease at high levels. Overall, both the backcross data and RI analysis provide additional support for the genetic complexity of lupus nephritis and uphold the conclusion that heterogeneous combinations of contributing NZB genes seem to operate in a threshold manner to generate the disease phenotype. 31 refs., 3 figs., 2 tabs.« less

Information processing efficiency in patients with multiple sclerosis.

PubMed

Archibald, C J; Fisk, J D

2000-10-01

Reduced information processing efficiency, consequent to impaired neural transmission, has been proposed as underlying various cognitive problems in patients with Multiple Sclerosis (MS). This study employed two measures developed from experimental psychology that control for the potential confound of perceptual-motor abnormalities (Salthouse, Babcock, & Shaw, 1991; Sternberg, 1966, 1969) to assess the speed of information processing and working memory capacity in patients with mild to moderate MS. Although patients had significantly more cognitive complaints than neurologically intact matched controls, their performance on standard tests of immediate memory span did not differ from control participants and their word list learning was within normal limits. On the experimental measures, both relapsing-remitting and secondary-progressive patients exhibited significantly slowed information processing speed relative to controls. However, only the secondary-progressive patients had an additional decrement in working memory capacity. Depression, fatigue, or neurologic disability did not account for performance differences on these measures. While speed of information processing may be slowed early in the disease process, deficits in working memory capacity may appear only as there is progression of MS. It is these latter deficits, however, that may underlie the impairment of new learning that patients with MS demonstrate.

Huntingtons Disease: The Value of Transcranial Meganetic Stimulation

PubMed

Medina, F J; Túnez, I

2010-01-01

Huntington's disease (HD) is a genetic neurodegenerative process whose etiology is based on a localized disturbance in the short arm of chromosome 4 that encodes the huntingtin protein (Htt). The elongation of triple CAG for glutamine characterizes this change. Mutated Htt (mHtt) causes the appearance of intracellular aggregates inducing alterations in mitochondrial metabolism in the form of reactive oxygen species (ROS) and ATP depletion. The oxidative imbalance caused by mHtt leads the neurons to a state of oxidative stress resulting in damage to macromolecules and cellular death. Since the discovery of certain mechanisms underlying the pathogenesis of HD, several therapeutic procedures have been shown to delay or slow the evolution of the condition and have demonstrated the biochemical and molecular mechanism involved. The studies have reported that transcranial magnetic stimulation (TMS) may improve motor and other symptoms associated with neurodegenerative and neuropsychiatric processes such as major depression, schizophrenia, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, progressive muscle atrophy, multiple sclerosis, stroke, Alzheimer's disease, Parkinson's disease or HD. This study focuses on the effect of TMS on oxidative stress and neurogenesis in studies and its possible usefulness in HD.

Design of peptide mimetics to block pro-inflammatory functions of HA fragments.

PubMed

Hauser-Kawaguchi, Alexandra; Luyt, Leonard G; Turley, Eva

2018-01-31

Hyaluronan is a simple extracellular matrix polysaccharide that actively regulates inflammation in tissue repair and disease processes. The native HA polymer, which is large (>500 kDa), contributes to the maintenance of homeostasis. In remodeling and diseased tissues, polymer size is strikingly polydisperse, ranging from <10 kDa to >500 kDa. In a diseased or stressed tissue context, both smaller HA fragments and high molecular weight HA polymers can acquire pro-inflammatory functions, which result in the activation of multiple receptors, triggering pro-inflammatory signaling to diverse stimuli. Peptide mimics that bind and scavenge HA fragments have been developed, which show efficacy in animal models of inflammation. These studies indicate both that HA fragments are key to driving inflammation and that scavenging these is a viable therapeutic approach to blunting inflammation in disease processes. This mini-review summarizes the peptide-based methods that have been reported to date for blocking HA signaling events as an anti-inflammatory therapeutic approach. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer's disease.

PubMed

Kovacech, B; Novak, M

2010-12-01

Deposits of the misfolded neuronal protein tau are major hallmarks of neurodegeneration in Alzheimer's disease (AD) and other tauopathies. The etiology of the transformation process of the intrinsically disordered soluble protein tau into the insoluble misordered aggregate has attracted much attention. Tau undergoes multiple modifications in AD, most notably hyperphosphorylation and truncation. Hyperphosphorylation is widely regarded as the hottest candidate for the inducer of the neurofibrillary pathology. However, the true nature of the impetus that initiates the whole process in the human brains remains unknown. In AD, several site-specific tau cleavages were identified and became connected to the progression of the disease. In addition, western blot analyses of tau species in AD brains reveal multitudes of various truncated forms. In this review we summarize evidence showing that tau truncation alone is sufficient to induce the complete cascade of neurofibrillary pathology, including hyperphosphorylation and accumulation of misfolded insoluble forms of tau. Therefore, proteolytical abnormalities in the stressed neurons and production of aberrant tau cleavage products deserve closer attention and should be considered as early therapeutic targets for Alzheimer's disease.

Mantle Cell Hyperplasia of Peripheral Lymph Nodes as Initial Manifestation of Sickle Cell Disease.

PubMed

Monabbati, Ahmad; Noori, Sadat; Safaei, Akbar; Ramzi, Mani; Eghbali, Seyedsajjad; Adib, Ali

2016-01-01

Sickle cell disease (SCD) is a well known hemoglobinopathy with usual manifestations including anemia, hyperbilirubinemia, and vasoocclusive complications. Despite presence of mild splenomegaly in early phase of the disease, lymphadenopathy is not an often finding of SCD. We introduce an undiagnosed case of SCD who presented in third decade of his life with multiple cervical lymphadenopathies and mild splenomegaly persistent for about five years. Histopathologic examination of the resected lymph nodes showed expansion of the mantle cell layers of secondary follicles as well as several monomorphic mantle cell nodules. To rule out possibility of a malignant process involving lymph nodes, an immunohistochemical panel was ordered which was in favor of benign mantle cell hyperplasia. Immunoglobulin gene rearrangement study showed no clonal bands and confirmed benign nature of the process. Respecting mild abnormalities on Complete Blood Count, peripheral blood smear was reviewed revealing some typical sickle red blood cells as well as rare nucleated red blood cells. Solubility test for hemoglobin (HB) S was positive. Hemoglobin electrophoresis confirmed diagnosis of homozygous HbS disease.

The Role of Ephs and Ephrins in Memory Formation

PubMed Central

Dines, Monica

2016-01-01

The ability to efficiently store memories in the brain is a fundamental process and its impairment is associated with multiple human mental disorders. Evidence indicates that long-term memory formation involves alterations of synaptic efficacy produced by modifications in neural transmission and morphology. The Eph receptors and their cognate ephrin ligands have been shown to be involved in these key neuronal processes by regulating events such as presynaptic transmitter release, postsynaptic glutamate receptor conductance and trafficking, synaptic glutamate reuptake, and dendritic spine morphogenesis. Recent findings show that Ephs and ephrins are needed for memory formation in different organisms. These proteins participate in the formation of various types of memories that are subserved by different neurons and brain regions. Ephs and ephrins are involved in brain disorders and diseases with memory impairment symptoms, including Alzheimer’s disease and anxiety. Drugs that agonize or antagonize Ephs/ephrins signaling have been developed and could serve as therapeutic agents to treat such diseases. Ephs and ephrins may therefore induce cellular alterations mandatory for memory formation and serve as a target for pharmacological intervention for treatment of memory-related brain diseases. PMID:26371183

A Review of Podocyte Biology.

PubMed

Garg, Puneet

2018-05-31

Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria. Proteinuria in nephrotic syndrome has been linked to mechanistic dysfunctions in the renal glomerulus involving the function of podocyte epithelial cells, including podocyte foot process effacement. Developments in imaging technology are improving knowledge of the detailed structure of the human renal glomerulus and cortex. Podocyte foot processes attach themselves to the glomerular capillaries at the glomerular basement membrane (GBM) forming intercellular junctions that form slit diaphragm filtration barriers that help maintain normal renal function. Damage in this area has been implicated in glomerular disease. Injured podocytes undergo effacement whereby they lose their structure and spread out, leading to a reduction in filtration barrier function. Effacement is typically associated with the presence of proteinuria in focal segmental glomerulosclerosis, minimal change disease, and diabetes. It is thought to be due to a breakdown in the actin cytoskeleton of the foot processes, complex contractile apparatuses that allow podocytes to dynamically reorganize according to changes in filtration requirements. The process of podocyte depletion correlates with the development of glomerular sclerosis and chronic kidney disease. Focal adhesion complexes that interact with the underlying GBM bind the podocytes within the glomerular structure and prevent their detachment. Key Messages: Knowledge of glomerular podocyte biology is helping to advance our understanding of the science and mechanics of the glomerular filtering process, opening the way to a variety of new potential applications for clinical targeting. © 2018 S. Karger AG, Basel.

Advances in assessment, diagnosis, and treatment of hyperthyroidism in children.

PubMed

Amer, Kim Siarkowski

2005-04-01

The thyroid gland is responsible for regulating multiple complex metabolic processes that affect most organs. Physical growth and cognitive development are dependent on proper levels of thyroid hormone. This article will review common challenges in the diagnosis of hyperthyroidism in children, the approaches to treatment, and the nursing interventions guided toward child and family responses to thyroid disease. A comparison of signs and symptoms of hypothyroidism and hyperthyroidism is also included. The nursing interventions addressed in the article integrate the biological, psychological, social, and environmental stresses and adaptations necessary to cope with hyperthyroid disease.

Contemporary disease management in Quebec.

PubMed

Gogovor, Amédé; Savoie, Michelle; Moride, Yola; Krelenbaum, Marilyn; Montague, Terrence

2008-01-01

Health or disease management (DM) has emerged as a promising solution to improve the quality of healthcare and patient outcomes in a cost-efficient way. This solution is particularly relevant in the care of our increasing, and aging, patient populations with multiple chronic diseases. This article reviews the recent history and current status of DM in the province of Quebec and summarizes its evolving perspectives and future prospects. Most DM projects in Quebec have developed from a public-private partnership, and they have addressed several disease states. The results of completed programs confirmed the presence of care gaps--the differences between best and usual care in several disease states. They also identified process changes leading to improved practices and enhanced professional satisfaction among stakeholders. Priorities identified for further research include increased knowledge of the underlying causes of care gaps and greater concentration on the measurement of clinical, humanistic and fiscal outcomes and their causal links to DM structures and processes. Although still embryonic in Quebec and Canada, the available evidence suggests that DM partnerships are practical and functional vehicles to expedite knowledge creation and transfer in the care of whole populations of patients. Future projects offer the promise of updated knowledge and continuously improved care and outcomes.

Effect of gene polymorphisms on periodontal diseases

PubMed Central

Tarannum, Fouzia; Faizuddin, Mohamed

2012-01-01

Periodontal diseases are inflammatory diseases of supporting structures of the tooth. It results in the destruction of the supporting structures and most of the destructive processes involved are host derived. The processes leading to destruction and regeneration of the destroyed tissues are of great interest to both researchers and clinicians. The selective susceptibility of subjects for periodontitis has remained an enigma and wide varieties of risk factors have been implicated for the manifestation and progression of periodontitis. Genetic factors have been a new addition to the list of risk factors for periodontal diseases. With the availability of human genome sequence and the knowledge of the complement of the genes, it should be possible to identify the metabolic pathways involved in periodontal destruction and regeneration. Most forms of periodontitis represent a life-long account of interactions between the genome, behaviour, and environment. The current practical utility of genetic knowledge in periodontitis is limited. The information contained within the human genome can potentially lead to a better understanding of the control mechanisms modulating the production of inflammatory mediators as well as provides potential therapeutic targets for periodontal disease. Allelic variants at multiple gene loci probably influence periodontitis susceptibility. PMID:22754216

Disease Modeling Using 3D Organoids Derived from Human Induced Pluripotent Stem Cells.

PubMed

Ho, Beatrice Xuan; Pek, Nicole Min Qian; Soh, Boon-Seng

2018-03-21

The rising interest in human induced pluripotent stem cell (hiPSC)-derived organoid culture has stemmed from the manipulation of various combinations of directed multi-lineage differentiation and morphogenetic processes that mimic organogenesis. Organoids are three-dimensional (3D) structures that are comprised of multiple cell types, self-organized to recapitulate embryonic and tissue development in vitro. This model has been shown to be superior to conventional two-dimensional (2D) cell culture methods in mirroring functionality, architecture, and geometric features of tissues seen in vivo. This review serves to highlight recent advances in the 3D organoid technology for use in modeling complex hereditary diseases, cancer, host-microbe interactions, and possible use in translational and personalized medicine where organoid cultures were used to uncover diagnostic biomarkers for early disease detection via high throughput pharmaceutical screening. In addition, this review also aims to discuss the advantages and shortcomings of utilizing organoids in disease modeling. In summary, studying human diseases using hiPSC-derived organoids may better illustrate the processes involved due to similarities in the architecture and microenvironment present in an organoid, which also allows drug responses to be properly recapitulated in vitro.

Tachykinins and Their Receptors: Contributions to Physiological Control and the Mechanisms of Disease

PubMed Central

Steinhoff, Martin S.; von Mentzer, Bengt; Geppetti, Pierangelo; Pothoulakis, Charalabos; Bunnett, Nigel W.

2014-01-01

The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists. PMID:24382888

The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS.

PubMed

Martínez-Lapiscina, Elena H; Fraga-Pumar, Elena; Gabilondo, Iñigo; Martínez-Heras, Eloy; Torres-Torres, Ruben; Ortiz-Pérez, Santiago; Llufriu, Sara; Tercero, Ana; Andorra, Magi; Roca, Marc Figueras; Lampert, Erika; Zubizarreta, Irati; Saiz, Albert; Sanchez-Dalmau, Bernardo; Villoslada, Pablo

2014-12-15

Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway. The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients.

Immunogenetic mechanisms for the coexistence of organ-specific and systemic autoimmune diseases.

PubMed

Fridkis-Hareli, Masha

2008-02-15

Organ-specific autoimmune diseases affect particular targets in the body, whereas systemic diseases engage multiple organs. Both types of autoimmune diseases may coexist in the same patient, either sequentially or concurrently, sustained by the presence of autoantibodies directed against the corresponding autoantigens. Multiple factors, including those of immunological, genetic, endocrine and environmental origin, contribute to the above condition. Due to association of certain autoimmune disorders with HLA alleles, it has been intriguing to examine the immunogenetic basis for autoantigen presentation leading to the production of two or more autoantibodies, each distinctive of an organ-specific or systemic disease. This communication offers the explanation for shared autoimmunity as illustrated by organ-specific blistering diseases and the connective tissue disorders of systemic nature. Several hypothetical mechanisms implicating HLA determinants, autoantigenic peptides, T cells, and B cells have been proposed to elucidate the process by which two autoimmune diseases are induced in the same individual. One of these scenarios, based on the assumption that the patient carries two disease-susceptible HLA genes, arises when a single T cell epitope of each autoantigen recognizes its HLA protein, leading to the generation of two types of autoreactive B cells, which produce autoantibodies. Another mechanism functioning whilst an epitope derived from either autoantigen binds each of the HLA determinants, resulting in the induction of both diseases by cross-presentation. Finally, two discrete epitopes originating from the same autoantigen may interact with each of the HLA specificities, eliciting the production of both types of autoantibodies. Despite the lack of immediate or unequivocal experimental evidence supporting the present hypothesis, several approaches may secure a better understanding of shared autoimmunity. Among these are animal models expressing the transgenes of human disease-associated HLA determinants and T or B cell receptors, as well as in vitro binding studies employing purified HLA proteins, synthetic peptides, and cellular assays with antigen-presenting cells and patient's lymphocytes. Indisputably, a bioinformatics-based search for peptide motifs and the modeling of the conformation of bound autoantigenic peptides associated with their respective HLA alleles will reveal some of these important processes. The elucidation of HLA-restricted immune recognition mechanisms prompting the production of two or more disease-specific autoantibodies holds significant clinical ramifications and implications for the development of more effective treatment protocols.

Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.

PubMed

Orsucci, D; Rocchi, A; Caldarazzo Ienco, E; Alì, G; LoGerfo, A; Petrozzi, L; Scarpelli, M; Filosto, M; Carlesi, C; Siciliano, G; Bonuccelli, U; Mancuso, M

2014-01-01

Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.

Shaking Out Clues to Autoimmune Disease

MedlinePlus

... include type 1 diabetes, inflammatory bowel diseases and multiple sclerosis. Researchers have found many genetic variants that affect ... they examined a mouse disease that resembles human multiple sclerosis. Mice lacking SGK1 had less severe symptoms and ...

Timing of Acute Palliative Care Consultation in Critically Ill Patients

ClinicalTrials.gov

2016-08-03

Multiple Organ Failure; End Stage Cardiac Failure; End Stage Chronic Obstructive Airways Disease; Chronic Kidney Disease Stage 5; Hepatic Encephalopathy; Sepsis; Dementia; Multiple Sclerosis; Parkinson's Disease; In-Hospital Cardiac Arrest; Solid Organ Cancer

[Globalization, inequity and Chagas disease].

PubMed

Dias, João Carlos Pinto

2007-01-01

Chagas disease (American trypanosomiasis) bears a close relationship to multiple social and political aspects involving issues of globalization and inequity. Such relations concern the process of disease production and control in parallel with medical management. Despite the poverty in Latin America and various problems related to inequities and globalization, Chagas disease has been controlled in several areas, a fact that reinforces the countries' self-reliance. Several problems and challenges related to the disease can be expected in the future, mainly concerning medical care for already infected individuals and the sustainability of effective epidemiological surveillance. Both points depend heavily on improved performance by the national health systems, principally in terms of their efficiency and their capacity to overcome inequity. A particularly important role has been attributed to the Latin American scientific and academic community in the implementation and sustainability of efficient control policies. Control activities have now evolved towards internationally shared initiatives, a major new stride forward in the region's political context.

Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20.

PubMed

Rexiati, Maimaiti; Sun, Mingming; Guo, Wei

2018-01-05

Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease.

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

PubMed Central

Jope, Richard S.; Yuskaitis, Christopher J.; Beurel, Eléonore

2007-01-01

Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions. PMID:16944320

Towards an integrated approach in surveillance of vector-borne diseases in Europe

PubMed Central

2011-01-01

Vector borne disease (VBD) emergence is a complex and dynamic process. Interactions between multiple disciplines and responsible health and environmental authorities are often needed for an effective early warning, surveillance and control of vectors and the diseases they transmit. To fully appreciate this complexity, integrated knowledge about the human and the vector population is desirable. In the current paper, important parameters and terms of both public health and medical entomology are defined in order to establish a common language that facilitates collaboration between the two disciplines. Special focus is put on the different VBD contexts with respect to the current presence or absence of the disease, the pathogen and the vector in a given location. Depending on the context, whether a VBD is endemic or not, surveillance activities are required to assess disease burden or threat, respectively. Following a decision for action, surveillance activities continue to assess trends. PMID:21967706

Polybacterial human disease: the ills of social networking.

PubMed

Short, Francesca L; Murdoch, Sarah L; Ryan, Robert P

2014-09-01

Polybacterial diseases involve multiple organisms that act collectively to facilitate disease progression. Although this phenomenon was highlighted early in the 20th century, recent technological advances in diagnostics have led to the appreciation that many infections are far more complex than originally believed. Furthermore, it is apparent that although most treatments focus on the dominant bacterial species in an infection, other microbes, including commensals, can have a profound impact on both the response to therapy and virulence. Very little is known about the molecular mechanisms that underpin interactions between bacteria during such infections. Here, we discuss recent studies identifying and characterizing mechanisms of bacterial interaction and the biological processes they govern during certain diseases. We also highlight how possible strategies for targeting these interbacterial interactions may afford a route towards development of new therapies, with consequences for disease control. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Insulin resistance, glycemic control and adiposity: key determinants of healthy lifespan.

PubMed

DiStefano, Peter S; Curtis, Rory; Geddes, Bradley J

2007-04-01

Identification of genes and pathways that alter lifespan has allowed for new insights into factors that control the aging process as well as disease. While strong molecular links exist between aging and metabolism, we hypothesize that targeting the mechanisms involved in aging will also give rise to therapeutics that treat other devastating age-related diseases, such as neurodegeneration, cancer, inflammation and cardiovascular disease. Insulin sensitivity, glycemic control and adiposity are not only hallmarks of the major metabolic diseases, type 2 diabetes and obesity, but they also represent significant risk factors for the development of Alzheimer's Disease and cognitive impairment. Insulin/IGF-1 signaling is an important pathway regulating aging and disease in a variety of species, including mammals. Here we describe an important role for the gut-derived peptide ghrelin in upstream signaling through the insulin/IGF-1 pathway and exemplify modulation of ghrelin signaling as an approach to mechanistic treatment of multiple age-related diseases by virtue of its ability to regulate key metabolic functions.

A framework for a diabetes mellitus disease management system in southern Israel.

PubMed

Fox, Matthew A; Harman-Boehm, Ilana; Weitzman, Shimon; Zelingher, Julian

2002-01-01

Chronic diseases are a significant burden on western healthcare systems and national economies. It has been suggested that automated disease management for chronic disease, like diabetes mellitus (DM), improves the quality of care and reduces inappropriate utilization of diagnostic and therapeutic measures. We have designed a comprehensive DM Disease Management system for the Negev region in southern Israel. This system takes advantage of currently used clinical and administrative information systems. Algorithms for DM disease management have been created based on existing and accepted Israeli guidelines. All data fields and tables in the source information systems have been analyzed, and interfaces for periodic data loads from these systems have been specified. Based on this data, four subsets of decision support algorithms have been developed. The system generates alerts in these domains to multiple end users. We plan to use the products of this information system analysis and disease management specification in the actual development process of such a system shortly.

MALDI imaging mass spectrometry analysis-A new approach for protein mapping in multiple sclerosis brain lesions.

PubMed

Maccarrone, Giuseppina; Nischwitz, Sandra; Deininger, Sören-Oliver; Hornung, Joachim; König, Fatima Barbara; Stadelmann, Christine; Turck, Christoph W; Weber, Frank

2017-03-15

Multiple sclerosis is a disease of the central nervous system characterized by recurrent inflammatory demyelinating lesions in the early disease stage. Lesion formation and mechanisms leading to lesion remyelination are not fully understood. Matrix Assisted Laser Desorption Ionisation Mass Spectrometry imaging (MALDI-IMS) is a technology which analyses proteins and peptides in tissue, preserves their spatial localization, and generates molecular maps within the tissue section. In a pilot study we employed MALDI imaging mass spectrometry to profile and identify peptides and proteins expressed in normal-appearing white matter, grey matter and multiple sclerosis brain lesions with different extents of remyelination. The unsupervised clustering analysis of the mass spectra generated images which reflected the tissue section morphology in luxol fast blue stain and in myelin basic protein immunohistochemistry. Lesions with low remyelination extent were defined by compounds with molecular weight smaller than 5300Da, while more completely remyelinated lesions showed compounds with molecular weights greater than 15,200Da. An in-depth analysis of the mass spectra enabled the detection of cortical lesions which were not seen by routine luxol fast blue histology. An ion mass, mainly distributed at the rim of multiple sclerosis lesions, was identified by liquid chromatography and tandem mass spectrometry as thymosin beta-4, a protein known to be involved in cell migration and in restorative processes. The ion mass of thymosin beta-4 was profiled by MALDI imaging mass spectrometry in brain slides of 12 multiple sclerosis patients and validated by immunohistochemical analysis. In summary, our results demonstrate the ability of the MALDI-IMS technology to map proteins within the brain parenchyma and multiple sclerosis lesions and to identify potential markers involved in multiple sclerosis pathogenesis and/or remyelination. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuroinflamm-aging and neurodegenerative diseases: an overview.

PubMed

Pizza, Vincenzo; Agresta, Anella; D'Acunto, Cosimo W; Festa, Michela; Capasso, Anna

2011-08-01

Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, age has a powerful effect on enhanced susceptibility to neurodegenerative diseases and age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases This review will address current understanding of the relationship between ageing, neuroinflammation and neurodegenerative disease by focusing on the principal mechanisms by which the immune system influences the brain plastic phenomena. Also, the present review considers the principal human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders caused by aging and neuroinflammation.

Current Concepts of Neurodegenerative Mechanisms in Alzheimer's Disease.

PubMed

Magalingam, Kasthuri Bai; Radhakrishnan, Ammu; Ping, Ng Shee; Haleagrahara, Nagaraja

2018-01-01

Neurodegenerative diseases are hereditary or sporadic conditions that result in the progressive loss of the structure and function of neurons as well as neuronal death. Although a range of diseases lie under this umbrella term, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases that affect a large population around the globe. Alzheimer's disease is characterized by the abnormal accumulation of extracellular amyloid- β plaques and intraneuronal neurofibrillary tangles in brain regions and manifests as a type of dementia in aged individuals that results in memory loss, multiple cognitive abnormalities, and intellectual disabilities that interfere with quality of life. Since the discovery of AD, a wealth of new information has emerged that delineates the causes, mechanisms of disease, and potential therapeutic agents, but an effective remedy to cure the diseases has not been identified yet. This could be because of the complexity of the disease process, as it involves various contributing factors that include environmental factors and genetic predispositions. This review summarizes the current understanding on neurodegenerative mechanisms that lead to the emergence of the pathology of AD.

Transmission dynamics: critical questions and challenges

PubMed Central

2017-01-01

This article overviews the dynamics of disease transmission in one-host–one-parasite systems. Transmission is the result of interacting host and pathogen processes, encapsulated with the environment in a ‘transmission triangle’. Multiple transmission modes and their epidemiological consequences are often not understood because the direct measurement of transmission is difficult. However, its different components can be analysed using nonlinear transmission functions, contact matrices and networks. A particular challenge is to develop such functions for spatially extended systems. This is illustrated for vector transmission where a ‘perception kernel’ approach is developed that incorporates vector behaviour in response to host spacing. A major challenge is understanding the relative merits of the large number of approaches to quantifying transmission. The evolution of transmission mode itself has been a rather neglected topic, but is important in the context of understanding disease emergence and genetic variation in pathogens. Disease impacts many biological processes such as community stability, the evolution of sex and speciation, yet the importance of different transmission modes in these processes is not understood. Broader approaches and ideas to disease transmission are important in the public health realm for combating newly emerging infections. This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’. PMID:28289255

Introducing the chronic disease self-management program in Switzerland and other German-speaking countries: findings of a cross-border adaptation using a multiple-methods approach.

PubMed

Haslbeck, Jörg; Zanoni, Sylvie; Hartung, Uwe; Klein, Margot; Gabriel, Edith; Eicher, Manuela; Schulz, Peter J

2015-12-28

Stanford's Chronic Disease Self-Management Program (CDSMP) stands out as having a large evidence-base and being broadly disseminated across various countries. To date, neither evidence nor practice exists of its systematic adaptation into a German-speaking context. The objective of this paper is to describe the systematic German adaptation and implementation process of the CDSMP (2010-2014), report the language-specific adaptation of Franco-Canadian CDSMP for the French-speaking part of Switzerland and report findings from the initial evaluation process. Multiple research methods were integrated to explore the perspective of workshop attendees, combining a longitudinal quantitative survey with self-report questionnaires, qualitative focus groups, and interviews. The evaluation process was conducted in for both the German and French adapted versions to gain insights into participants' experiences in the program and to evaluate its impact. Perceived self-efficacy was measured using the German version of the Self-Efficacy for Managing Chronic Disease 6-Item Scale (SES6G). Two hundred seventy eight people attending 35 workshops in Switzerland and Austria participated in the study. The study participants were receptive to the program content, peer-led approach and found principal methods useful, yet the structured approach did not address all their needs or expectations. Both short and long-term impact on self-efficacy were observed following the workshop participation (albeit with a minor decrease at 6-months). Participants reported positive impacts on aspects of coping and self-care, but limited effects on healthcare service utilization. Our findings suggest that the process for cross-border adaptation was effective, and that the CDSMP can successfully be implemented in diverse healthcare and community settings. The adapted CDSMP can be considered an asset for supporting self-management in both German-and French-speaking central European countries. It could have meaningful, wide-ranging implications for chronic illness care and primary prevention and potentially tertiary prevention of chronic disease. Further investigations are needed to tailor the program for better access to vulnerable and disadvantaged groups who might benefit the most, in terms of facilitating their health literacy in chronic illness.

Disease and Stem Cell-Based Analysis of the 2014 ASNTR Meeting

PubMed Central

Eve, David J.

2015-01-01

A wide variety of subjects are presented at the annual American Society of Neural Therapy and Repair meeting every year, as typified by this summary of the 2014 meeting. Parkinson’s disease-related presentations were again the most popular topic, with traumatic brain injury, spinal cord injury, and stroke being close behind. Other disorders included Huntington’s disease, brain cancer, and bipolar disorders. Several studies were related to multiple diseases, and many studies attempted to reveal more about the disease process. The use of scaffolds, drugs, and gene therapy as disease models and/or potential therapies were also featured. An increasing proportion of presentations related to stem cells, with the study of multiple stem cell types being the most common. Induced pluripotent stem cells were increasingly popular, including two presentations each on a muscle-derived dedifferentiated cell type and cells derived from bipolar patients. Other stem cells, including neural stem cells, mesenchymal stem cells, umbilical cord blood cells, and embryonic stem cells, were featured. More than 55% of the stem cell studies involved transplantation, with human-derived cells being the most frequently transplanted, while rats were the most common recipient. Two human autologous studies for spinal cord injury and hypoxia-derived encephalopathy, while a further three allogenic studies for stroke and spinal cord injury, were also featured. This year’s meeting highlights the increasing promise of stem cells and other therapies for the treatment of neurodegenerative disorders. PMID:26858901

Signaling Pathways in Cardiac Myocyte Apoptosis

PubMed Central

Xia, Peng; Liu, Yuening

2016-01-01

Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

Diverse exocytic pathways for mast cell mediators.

PubMed

Xu, Hao; Bin, Na-Ryum; Sugita, Shuzo

2018-04-17

Mast cells play pivotal roles in innate and adaptive immunities but are also culprits in allergy, autoimmunity, and cardiovascular diseases. Mast cells respond to environmental changes by initiating regulated exocytosis/secretion of various biologically active compounds called mediators (e.g. proteases, amines, and cytokines). Many of these mediators are stored in granules/lysosomes and rely on intricate degranulation processes for release. Mast cell stabilizers (e.g. sodium cromoglicate), which prevent such degranulation processes, have therefore been clinically employed to treat asthma and allergic rhinitis. However, it has become increasingly clear that different mast cell diseases often involve multiple mediators that rely on overlapping but distinct mechanisms for release. This review illustrates existing evidence that highlights the diverse exocytic pathways in mast cells. We also discuss strategies to delineate these pathways so as to identify unique molecular components which could serve as new drug targets for more effective and specific treatments against mast cell-related diseases. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.

PubMed

Shimano, Hitoshi; Sato, Ryuichiro

2017-12-01

Cellular lipid metabolism and homeostasis are controlled by sterol regulatory-element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels.

Narcissistic rage: The Achilles’ heel of the patient with chronic physical illness

PubMed Central

Hyphantis, Thomas; Almyroudi, Augustina; Paika, Vassiliki; Goulia, Panagiota; Arvanitakis, Konstantinos

2009-01-01

Based on the psychoanalytic reading of Homer’s Iliad whose principal theme is “Achilles’ rage” (the semi-mortal hero invulnerable in all of his body except for his heel, hence “Achilles’ heel” has come to mean a person’s principal weakness), we aimed to assess whether “narcissistic rage” has an impact on several psychosocial variables in patients with severe physical illness across time. In 878 patients with cancer, rheumatological diseases, multiple sclerosis, inflammatory bowel disease, and glaucoma, we assessed psychological distress (SCL-90 and GHQ-28), quality of life (WHOQOL-BREF), interpersonal difficulties (IIP-40), hostility (HDHQ), and defense styles (DSQ). Narcissistic rage comprised DSQ “omnipotence” and HDHQ “extraverted hostility”. Hierarchical multiple regressions analyses were performed. We showed that, in patients with disease duration less than one year, narcissistic rage had a minor impact on psychosocial variables studied, indicating that the rage was rather part of a “normal” mourning process. On the contrary, in patients with longer disease duration, increased rates of narcissistic rage had a great impact on all outcome variables, and the opposite was true for patients with low rates of narcissistic rage, indicating that narcissistic rage constitutes actually an “Achilles’ Heel” for patients with long-term physical illness. These findings may have important clinical implications. PMID:19936167

Matrix factorization reveals aging-specific co-expression gene modules in the fat and muscle tissues in nonhuman primates

NASA Astrophysics Data System (ADS)

Wang, Yongcui; Zhao, Weiling; Zhou, Xiaobo

2016-10-01

Accurate identification of coherent transcriptional modules (subnetworks) in adipose and muscle tissues is important for revealing the related mechanisms and co-regulated pathways involved in the development of aging-related diseases. Here, we proposed a systematically computational approach, called ICEGM, to Identify the Co-Expression Gene Modules through a novel mathematical framework of Higher-Order Generalized Singular Value Decomposition (HO-GSVD). ICEGM was applied on the adipose, and heart and skeletal muscle tissues in old and young female African green vervet monkeys. The genes associated with the development of inflammation, cardiovascular and skeletal disorder diseases, and cancer were revealed by the ICEGM. Meanwhile, genes in the ICEGM modules were also enriched in the adipocytes, smooth muscle cells, cardiac myocytes, and immune cells. Comprehensive disease annotation and canonical pathway analysis indicated that immune cells, adipocytes, cardiomyocytes, and smooth muscle cells played a synergistic role in cardiac and physical functions in the aged monkeys by regulation of the biological processes associated with metabolism, inflammation, and atherosclerosis. In conclusion, the ICEGM provides an efficiently systematic framework for decoding the co-expression gene modules in multiple tissues. Analysis of genes in the ICEGM module yielded important insights on the cooperative role of multiple tissues in the development of diseases.

Dupuytren's: a systems biology disease

PubMed Central

2011-01-01

Dupuytren's disease (DD) is an ill-defined fibroproliferative disorder of the palm of the hands leading to digital contracture. DD commonly occurs in individuals of northern European extraction. Cellular components and processes associated with DD pathogenesis include altered gene and protein expression of cytokines, growth factors, adhesion molecules, and extracellular matrix components. Histology has shown increased but varying levels of particular types of collagen, myofibroblasts and myoglobin proteins in DD tissue. Free radicals and localised ischaemia have been suggested to trigger the proliferation of DD tissue. Although the existing available biological information on DD may contain potentially valuable (though largely uninterpreted) information, the precise aetiology of DD remains unknown. Systems biology combines mechanistic modelling with quantitative experimentation in studies of networks and better understanding of the interaction of multiple components in disease processes. Adopting systems biology may be the ideal approach for future research in order to improve understanding of complex diseases of multifactorial origin. In this review, we propose that DD is a disease of several networks rather than of a single gene, and show that this accounts for the experimental observations obtained to date from a variety of sources. We outline how DD may be investigated more effectively by employing a systems biology approach that considers the disease network as a whole rather than focusing on any specific single molecule. PMID:21943049

The Neuropathology of Obesity: Insights from Human Disease

PubMed Central

Lee, Edward B.; Mattson, Mark P.

2013-01-01

Obesity, a pathologic state defined by excess adipose tissue, is a significant public health problem as it affects a large proportion of individuals and is linked with increased risk for numerous chronic diseases. Obesity is the result of fundamental changes associated with modern society including overnutrition and sedentary lifestyles. Proper energy homeostasis is dependent on normal brain function as the master metabolic regulator which integrates peripheral signals, modulates autonomic outflow and controls feeding behavior. Therefore, many human brain diseases are associated with obesity. This review explores the neuropathology of obesity by examining brain diseases which either cause or are influenced by obesity. First, several genetic and acquired brain diseases are discussed as a means to understand the central regulation of peripheral metabolism. These diseases range from monogenetic causes of obesity (leptin deficiency, MC4R deficiency, Bardet-Biedl syndrome and others) to complex neurodevelopmental disorders (Prader-Willi syndrome and Sim1 deficiency) and neurodegenerative conditions (frontotemporal dementia and Gourmand’s syndrome) and serve to highlight the central regulatory mechanisms which have evolved to maintain energy homeostasis. Next, to examine the effect of obesity on the brain, chronic neuropathologic conditions (epilepsy, multiple sclerosis and Alzheimer’s disease) are discussed as examples of obesity leading to maladaptive processes which exacerbate chronic disease. Thus obesity is associated with multiple pathways including abnormal metabolism, altered hormonal signaling and increased inflammation which act in concert to promote downstream neuropathology. Finally, the effect of anti-obesity interventions is discussed in terms of brain structure and function. Together, understanding human diseases and anti-obesity interventions leads to insights into the bidirectional interaction between peripheral metabolism and central brain function, highlighting the need for continued clinicopathologic and mechanistic studies of the neuropathology of obesity. PMID:24096619

Using whole disease modeling to inform resource allocation decisions: economic evaluation of a clinical guideline for colorectal cancer using a single model.

PubMed

Tappenden, Paul; Chilcott, Jim; Brennan, Alan; Squires, Hazel; Glynne-Jones, Rob; Tappenden, Janine

2013-06-01

To assess the feasibility and value of simulating whole disease and treatment pathways within a single model to provide a common economic basis for informing resource allocation decisions. A patient-level simulation model was developed with the intention of being capable of evaluating multiple topics within National Institute for Health and Clinical Excellence's colorectal cancer clinical guideline. The model simulates disease and treatment pathways from preclinical disease through to detection, diagnosis, adjuvant/neoadjuvant treatments, follow-up, curative/palliative treatments for metastases, supportive care, and eventual death. The model parameters were informed by meta-analyses, randomized trials, observational studies, health utility studies, audit data, costing sources, and expert opinion. Unobservable natural history parameters were calibrated against external data using Bayesian Markov chain Monte Carlo methods. Economic analysis was undertaken using conventional cost-utility decision rules within each guideline topic and constrained maximization rules across multiple topics. Under usual processes for guideline development, piecewise economic modeling would have been used to evaluate between one and three topics. The Whole Disease Model was capable of evaluating 11 of 15 guideline topics, ranging from alternative diagnostic technologies through to treatments for metastatic disease. The constrained maximization analysis identified a configuration of colorectal services that is expected to maximize quality-adjusted life-year gains without exceeding current expenditure levels. This study indicates that Whole Disease Model development is feasible and can allow for the economic analysis of most interventions across a disease service within a consistent conceptual and mathematical infrastructure. This disease-level modeling approach may be of particular value in providing an economic basis to support other clinical guidelines. Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

L-Arginine and Alzheimer's Disease

PubMed Central

Yi, Jing; Horky, Laura L.; Friedlich, Avi L.; Shi, Ying; Rogers, Jack T.; Huang, Xudong

2009-01-01

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive neurodegeneration and loss of cognitive and memory functions. Although the exact causes of AD are still unclear, evidence suggests that atherosclerosis, redox stress, inflammation, neurotransmitter dysregulation, and impaired brain energy metabolism may all be associated with AD pathogenesis. Herein, we explore a possible role for L-arginine (L-arg) in AD, taking into consideration known functions for L-arg in atherosclerosis, redox stress and the inflammatory process, regulation of synaptic plasticity and neurogenesis, and modulation of glucose metabolism and insulin activity. L-arg, a precursor of nitric oxide and polyamine, exhibits multiple functions in human health and may play a prominent role in age-related degenerative diseases such as AD. PMID:19079617

Bio-effectiveness of the main flavonoids of Achillea millefolium in the pathophysiology of neurodegenerative disorders- a review

PubMed Central

Ayoobi, Fatemeh; Shamsizadeh, Ali; Fatemi, Iman; Vakilian, Alireza; Allahtavakoli, Mohammad; Hassanshahi, Gholamhossein; Moghadam-Ahmadi, Amir

2017-01-01

The Achillea millefolium L. (Yarrow) is a common herb which is widely being used, worldwide. Achillea is being used for treatment of many disorders since centuries. It is considered safe for supplemental use and flavonoids such as kaempferol, luteolin and apigenin are of main constituents present in Achillea. Most of both antioxidant and anti-inflammatory properties of this herb have been attributed to its flavonoid content. Oxidative and inflammatory processes play important roles in pathogenesis of neurodegenerative diseases. Present review was aimed to review the latest literature evidences regarding application of Achillea and/or its three main flavonoid constituents on epilepsy, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease and stroke. PMID:28868116

Implication of the nutritional and nonnutritional factors in the context of preservation of cognitive performance in patients with dementia/depression and Alzheimer disease.

PubMed

Aliev, Gjumrakch; Ashraf, Ghulam Md; Kaminsky, Yury G; Sheikh, Ishfaq Ahmed; Sudakov, Sergey K; Yakhno, Nikolay N; Benberin, Valery V; Bachurin, Sergey O

2013-11-01

It has been postulated that Alzheimer disease (AD) is a systemic process, which involves multiple pathophysiological factors. A combination of pharmacotherapy and nonpharmacological interventions has been proposed to treat AD and other dementia. The nonpharmacological interventions include but are not limited to increasing sensory input through physical and mental activities, in order to modify cerebral blood flow and implementing nutritional interventions such as diet modification and vitamins and nutraceuticals therapy to vitalize brain functioning. This article highlights the recent research findings regarding novel treatment strategies aimed at modifying natural course of the disease and delaying cognitive decline through simultaneous implementation of pharmacological and nonpharmacological modulators as standardized treatment protocols.

A spatial scan statistic for multiple clusters.

PubMed

Li, Xiao-Zhou; Wang, Jin-Feng; Yang, Wei-Zhong; Li, Zhong-Jie; Lai, Sheng-Jie

2011-10-01

Spatial scan statistics are commonly used for geographical disease surveillance and cluster detection. While there are multiple clusters coexisting in the study area, they become difficult to detect because of clusters' shadowing effect to each other. The recently proposed sequential method showed its better power for detecting the second weaker cluster, but did not improve the ability of detecting the first stronger cluster which is more important than the second one. We propose a new extension of the spatial scan statistic which could be used to detect multiple clusters. Through constructing two or more clusters in the alternative hypothesis, our proposed method accounts for other coexisting clusters in the detecting and evaluating process. The performance of the proposed method is compared to the sequential method through an intensive simulation study, in which our proposed method shows better power in terms of both rejecting the null hypothesis and accurately detecting the coexisting clusters. In the real study of hand-foot-mouth disease data in Pingdu city, a true cluster town is successfully detected by our proposed method, which cannot be evaluated to be statistically significant by the standard method due to another cluster's shadowing effect. Copyright © 2011 Elsevier Inc. All rights reserved.

Pathogenic implications of iron accumulation in multiple sclerosis

PubMed Central

Williams, Rachel; Buchheit, Cassandra L.; Berman, Nancy E. J.; LeVine, Steven M.

2011-01-01

Iron, an essential element used for a multitude of biochemical reactions, abnormally accumulates in the central nervous system of patients with multiple sclerosis (MS). The mechanisms of abnormal iron deposition in MS are not fully understood, nor do we know whether these deposits have adverse consequences, i.e., contribute to pathogenesis. With some exceptions, excess levels of iron are represented concomitantly in multiple deep gray matter structures often with bilateral representation, while in white matter pathological iron deposits are usually located at sites of inflammation that are associated with veins. These distinct spatial patterns suggest disparate mechanisms of iron accumulation between these regions. Iron has been postulated to promote disease activity in MS by various means: 1) iron can amplify the activated state of microglia resulting in the increased production of proinflammatory mediators; 2) excess intracellular iron deposits could promote mitochondria dysfunction; and 3) improperly managed iron could catalyze the production of damaging reactive oxygen species. The pathological consequences of abnormal iron deposits may be dependent on the affected brain region and/or accumulation process. Here we review putative mechanisms of enhanced iron uptake in MS and address the likely roles of iron in the pathogenesis of this disease. PMID:22004421

Infectious Disease Stigmas: Maladaptive in Modern Society

PubMed Central

Smith, Rachel A.; Hughes, David

2014-01-01

At multiple times in human history people have asked if there are good stigmas. Is there some useful function stigmas serve in the context of our evolutionary history; is stigma adaptive? This essay discusses stigmas as a group-selection strategy and the human context in which stigmas likely appeared. The next section explores how human patterns have changed in modern society and the consequences for infectious disease (ID) stigmas in the modern age. The concluding section suggests that while social-living species may be particularly apt to create and communicate ID stigmas and enact ID-related stigmatization, such stigma-related processes no longer function to protect human communities. Stigmas do not increase the ability of modern societies to survive infectious diseases, but in fact may be important drivers of problematic disease dynamics and act as catalysts for failures in protecting public health. PMID:25477728

Immunomodulators as Therapeutic Agents in Mitigating the Progression of Parkinson’s Disease

PubMed Central

Grimmig, Bethany; Morganti, Josh; Nash, Kevin; Bickford, Paula C

2016-01-01

Parkinson’s disease (PD) is a common neurodegenerative disorder that primarily afflicts the elderly. It is characterized by motor dysfunction due to extensive neuron loss in the substantia nigra pars compacta. There are multiple biological processes that are negatively impacted during the pathogenesis of PD, and are implicated in the cell death in this region. Neuroinflammation is evidently involved in PD pathology and mitigating the inflammatory cascade has been a therapeutic strategy. Age is the number one risk factor for PD and thus needs to be considered in the context of disease pathology. Here, we discuss the role of neuroinflammation within the context of aging as it applies to the development of PD, and the potential for two representative compounds, fractalkine and astaxanthin, to attenuate the pathophysiology that modulates neurodegeneration that occurs in Parkinson’s disease. PMID:27669315

Estimating comparable English healthcare costs for multiple diseases and unrelated future costs for use in health and public health economic modelling.

PubMed

Briggs, Adam D M; Scarborough, Peter; Wolstenholme, Jane

2018-01-01

Healthcare interventions, and particularly those in public health may affect multiple diseases and significantly prolong life. No consensus currently exists for how to estimate comparable healthcare costs across multiple diseases for use in health and public health cost-effectiveness models. We aim to describe a method for estimating comparable disease specific English healthcare costs as well as future healthcare costs from diseases unrelated to those modelled. We use routine national datasets including programme budgeting data and cost curves from NHS England to estimate annual per person costs for diseases included in the PRIMEtime model as well as age and sex specific costs due to unrelated diseases. The 2013/14 annual cost to NHS England per prevalent case varied between £3,074 for pancreatic cancer and £314 for liver disease. Costs due to unrelated diseases increase with age except for a secondary peak at 30-34 years for women reflecting maternity resource use. The methodology described allows health and public health economic modellers to estimate comparable English healthcare costs for multiple diseases. This facilitates the direct comparison of different health and public health interventions enabling better decision making.

[Chronic disease, mortality and disability in an elderly Spanish population: the FRADEA study].

PubMed

Alfonso Silguero, Sergio A; Martínez-Reig, Marta; Gómez Arnedo, Llanos; Juncos Martínez, Gema; Romero Rizos, Luis; Abizanda Soler, Pedro

2014-01-01

The objective of this study was to analyse the relationships between the major chronic diseases and multiple morbidity, with mortality, incident disability in basic activities of daily living, and loss of mobility in the elderly. A total of 943 participants were selected from the FRADEA Study, using available baseline data of chronic diseases, and at the follow-up visit of mortality, incident disability, and loss of mobility. The analysis was made of the unadjusted and adjusted association between the number of chronic diseases, the number of 14 pre-selected diseases, and the presence of two or more chronic diseases (multiple morbidity) with adverse health events recorded. Participants with a higher number of diseases (OR 1.11; 95% CI: 1.02-1.22), and 14 pre-selected diseases (OR 1.19; 95% CI: 1.03-1.38) had a higher adjusted mortality risk, but not a higher incident disease or mobility loss risk. Subjects with multiple morbidity had a higher non-significant mortality risk (HR 1.45; 95% CI: 0.87-2.43), than those without multiple morbidity. Disability-free mean time in participants with and without multiple morbidity was 846±34 and 731±17 days, respectively (Log-rank χ(2) 7.45. P=.006), and with our without mobility loss was 818±32 and 696±13 days, respectively (Log rank χ(2) 10.99. P=.001). Multiple morbidity was not associated with mortality, incident disability in ADL, or mobility loss in adults older than 70 years, although if mortality is taken into account, the number of chronic diseases is linear. Copyright © 2013 SEGG. Published by Elsevier Espana. All rights reserved.

An automatic quantification system for MS lesions with integrated DICOM structured reporting (DICOM-SR) for implementation within a clinical environment

NASA Astrophysics Data System (ADS)

Jacobs, Colin; Ma, Kevin; Moin, Paymann; Liu, Brent

2010-03-01

Multiple Sclerosis (MS) is a common neurological disease affecting the central nervous system characterized by pathologic changes including demyelination and axonal injury. MR imaging has become the most important tool to evaluate the disease progression of MS which is characterized by the occurrence of white matter lesions. Currently, radiologists evaluate and assess the multiple sclerosis lesions manually by estimating the lesion volume and amount of lesions. This process is extremely time-consuming and sensitive to intra- and inter-observer variability. Therefore, there is a need for automatic segmentation of the MS lesions followed by lesion quantification. We have developed a fully automatic segmentation algorithm to identify the MS lesions. The segmentation algorithm is accelerated by parallel computing using Graphics Processing Units (GPU) for practical implementation into a clinical environment. Subsequently, characterized quantification of the lesions is performed. The quantification results, which include lesion volume and amount of lesions, are stored in a structured report together with the lesion location in the brain to establish a standardized representation of the disease progression of the patient. The development of this structured report in collaboration with radiologists aims to facilitate outcome analysis and treatment assessment of the disease and will be standardized based on DICOM-SR. The results can be distributed to other DICOM-compliant clinical systems that support DICOM-SR such as PACS. In addition, the implementation of a fully automatic segmentation and quantification system together with a method for storing, distributing, and visualizing key imaging and informatics data in DICOM-SR for MS lesions improves the clinical workflow of radiologists and visualizations of the lesion segmentations and will provide 3-D insight into the distribution of lesions in the brain.

Mechanisms and use of neural transplants for brain repair.

PubMed

Dunnett, Stephen B; Björklund, Anders

2017-01-01

Under appropriate conditions, neural tissues transplanted into the adult mammalian brain can survive, integrate, and function so as to influence the behavior of the host, opening the prospect of repairing neuronal damage, and alleviating symptoms associated with neuronal injury or neurodegenerative disease. Alternative mechanisms of action have been postulated: nonspecific effects of surgery; neurotrophic and neuroprotective influences on disease progression and host plasticity; diffuse or locally regulated pharmacological delivery of deficient neurochemicals, neurotransmitters, or neurohormones; restitution of the neuronal and glial environment necessary for proper host neuronal support and processing; promoting local and long-distance host and graft axon growth; formation of reciprocal connections and reconstruction of local circuits within the host brain; and up to full integration and reconstruction of fully functional host neuronal networks. Analysis of neural transplants in a broad range of anatomical systems and disease models, on simple and complex classes of behavioral function and information processing, have indicated that all of these alternative mechanisms are likely to contribute in different circumstances. Thus, there is not a single or typical mode of graft function; rather grafts can and do function in multiple ways, specific to each particular context. Consequently, to develop an effective cell-based therapy, multiple dimensions must be considered: the target disease pathogenesis; the neurodegenerative basis of each type of physiological dysfunction or behavioral symptom; the nature of the repair required to alleviate or remediate the functional impairments of particular clinical relevance; and identification of a suitable cell source or delivery system, along with the site and method of implantation, that can achieve the sought for repair and recovery. © 2017 Elsevier B.V. All rights reserved.

Intellectual Enrichment Is Linked to Cerebral Efficiency in Multiple Sclerosis: Functional Magnetic Resonance Imaging Evidence for Cognitive Reserve

ERIC Educational Resources Information Center

Sumowski, James F.; Wylie, Glenn R.; DeLuca, John; Chiaravalloti, Nancy

2010-01-01

The cognitive reserve hypothesis helps to explain the incomplete relationship between brain disease and cognitive status in people with neurologic diseases, including Alzheimer's; disease and multiple sclerosis. Lifetime intellectual enrichment (estimated with education or vocabulary knowledge) lessens the negative impact of brain disease on…

Characterization and production of multifunctional cationic peptides derived from rice proteins.

PubMed

Taniguchi, Masayuki; Ochiai, Akihito

2017-04-01

Food proteins have been identified as a source of bioactive peptides. These peptides are inactive within the sequence of the parent protein and must be released during gastrointestinal digestion, fermentation, or food processing. Of bioactive peptides, multifunctional cationic peptides are more useful than other peptides that have specific activity in promotion of health and/or the treatment of diseases. We have identified and characterized cationic peptides from rice enzymes and proteins that possess multiple functions, including antimicrobial, endotoxin-neutralizing, arginine gingipain-inhibitory, and/or angiogenic activities. In particular, we have elucidated the contribution of cationic amino acids (arginine and lysine) in the peptides to their bioactivities. Further, we have discussed the critical parameters, particularly proteinase preparations and fractionation or purification, in the enzymatic hydrolysis process for producing bioactive peptides from food proteins. Using an ampholyte-free isoelectric focusing (autofocusing) technique as a tool for fractionation, we successfully prepared fractions containing cationic peptides with multiple functions.

New biological agents in the treatment of multiple sclerosis.

PubMed

Buc, M

2018-01-01

Multiple sclerosis (MS) is an inflammatory disease induced by autoimmune processes. Their understanding has resulted in an introduction of biological agents to its treatment. Interferon beta and glatiramer acetate have been in clinical practice for more than 20 years. Nowadays, novel biologics, which target molecules involved in immunopathological processes more specifically have entered the scene. They are represented by monoclonal antibodies binding to molecules VLA4 (natalizumab), CD20 (ocrelizumab), CD52 (alemtuzumab) or alpha subunit of IL-2 receptor (daclizumab) or by small molecules such as those modulating the receptors involved in regulation of lymphocyte migration (fingolimod, ozanimod) or in induction of lymphopenia by apoptosis (dimethyl fumarate, cladribine). In the article, we shortly describe their efficacies, adverse reactions and perspectives of a future development in MS biologics. A treatment of neuromyelitis optica by monoclonal antibodies (rituximab, aquaporumab) is given too (Tab. 1, Fig. 2, Ref. 71).

Modulation of inflammation and disease tolerance by DNA damage response pathways.

PubMed

Neves-Costa, Ana; Moita, Luis F

2017-03-01

The accurate replication and repair of DNA is central to organismal survival. This process is challenged by the many factors that can change genetic information such as replication errors and direct damage to the DNA molecule by chemical and physical agents. DNA damage can also result from microorganism invasion as an integral step of their life cycle or as collateral damage from host defense mechanisms against pathogens. Here we review the complex crosstalk of DNA damage response and immune response pathways that might be evolutionarily connected and argue that DNA damage response pathways can be explored therapeutically to induce disease tolerance through the activation of tissue damage control processes. Such approach may constitute the missing pillar in the treatment of critical illnesses caused by multiple organ failure, such as sepsis and septic shock. © 2016 Federation of European Biochemical Societies.

Intergenerational epigenetic inheritance in models of developmental programming of adult disease

PubMed Central

Fernandez-Twinn, Denise S.; Constância, Miguel; Ozanne, Susan E.

2018-01-01

It is now well established that the environment to which we are exposed during fetal and neonatal life can have a long-term impact on our health. This has been termed the developmental origins of health and disease. Factors known to have such programming effects include intrauterine nutrient availability, (determined by maternal nutrition and placental function), endocrine disruptors, toxins and infectious agents. Epigenetic processes have emerged as a key mechanism by which the early environment can permanently influence cell function and metabolism after multiple rounds of cell division. More recently it has been suggested that programmed effects can be observed beyond the first generation and that therefore epigenetic mechanisms could form the basis of transmission of phenotype from parent to child to grandchild and beyond. Here we review the evidence for such processes. PMID:26135290

Commensal or pathogen – a challenge to fulfil Koch’s Postulates

PubMed Central

Hess, M.

2017-01-01

ABSTRACT 1. Infectious diseases have a large impact on poultry health and economics. Elucidating the pathogenesis of a certain disease is crucial to implement control strategies. 2. Multiplication of a pathogen and its characterisation in vitro are basic requirements to perform experimental studies. However, passaging of the pathogen in vitro can influence the pathogenicity, a process targeted for live vaccine development, but limits the reproduction of clinical signs. 3. Numerous factors can influence the outcome of experimental infections with some importance on the pathogen, application route and host as exemplarily outlined for Histomonas meleagridis, Gallibacterium anatis and fowl aviadenoviruses (FAdVs). 4. In future, more comprehensive and detailed settings are needed to obtain as much information as possible from animal experiments. Processing of samples with modern diagnostic tools provides the option to closely monitor the host–pathogen interaction. PMID:27724044

[Effect of pharmacologic treatment of the nutritional status of neurologic patients].

PubMed

Piñeiro Corrales, Guadalupe; Vázquez López, Cristina; Álvarez Payero, Miriam

2014-01-01

Clinical manifestations accompanying neurological diseases are diverse and affect multiple organs. Nutritional status of patients with certain neurological diseases such as stroke, Alzheimer's disease, Parkinson's disease, Epilepsy and Multiple Sclerosis can be altered because of symptoms associated with disease course, including certain micronutrient deficiency (folic acid, zinc, vitamin B6 and B12, vitamin D, vitamin E and vitamin C), changes in energy expenditure, intake decreased, gastrointestinal disorders and dysfunction of the bone mass. Also, we have to take in account other factors as: advanced age, multiple co morbidities, polypharmacy, the use of herbal products, social habits, diet and pharmacological treatments effect. An assessment of the factors related to neurological treatment that cause alterations in metabolic and nutritional status was performed: side effects of anti-Parkinson drugs, antiepileptic drugs, and multiple sclerosis drugs; drug-nutrient interactions; and nutrient-drug interactions.

Learned helplessness in the multiple sclerosis population.

PubMed

McGuinness, S

1996-06-01

The purpose of this cross-sectional, descriptive study was to describe the relationships between learned helplessness and disease status, functional and social disability, and disease activity in the multiple sclerosis population. Additionally, the relationships between learned helplessness and age, disease duration, education and marital and employment status were evaluated. Self-report instruments with established validity and reliability in the multiple sclerosis population were used to collect the data. Learned helplessness was significantly positively correlated with social and functional disability. Although not significant at the .05 level, disease status and disease activity were also positively correlated with learned helplessness. Additionally, unemployed individuals were more likely to be helpless than employed individuals. Overall, the results suggest that learned helplessness is related to negative health indicators in the multiple sclerosis population. Nursing interventions to decrease or prevent learned helplessness may be appropriate in this population.

Methodology for quantitative rapid multi-tracer PET tumor characterizations.

PubMed

Kadrmas, Dan J; Hoffman, John M

2013-10-04

Positron emission tomography (PET) can image a wide variety of functional and physiological parameters in vivo using different radiotracers. As more is learned about the molecular basis for disease and treatment, the potential value of molecular imaging for characterizing and monitoring disease status has increased. Characterizing multiple aspects of tumor physiology by imaging multiple PET tracers in a single patient provides additional complementary information, and there is a significant body of literature supporting the potential value of multi-tracer PET imaging in oncology. However, imaging multiple PET tracers in a single patient presents a number of challenges. A number of techniques are under development for rapidly imaging multiple PET tracers in a single scan, where signal-recovery processing algorithms are employed to recover various imaging endpoints for each tracer. Dynamic imaging is generally used with tracer injections staggered in time, and kinetic constraints are utilized to estimate each tracers' contribution to the multi-tracer imaging signal. This article summarizes past and ongoing work in multi-tracer PET tumor imaging, and then organizes and describes the main algorithmic approaches for achieving multi-tracer PET signal-recovery. While significant advances have been made, the complexity of the approach necessitates protocol design, optimization, and testing for each particular tracer combination and application. Rapid multi-tracer PET techniques have great potential for both research and clinical cancer imaging applications, and continued research in this area is warranted.

Methodology for Quantitative Rapid Multi-Tracer PET Tumor Characterizations

PubMed Central

Kadrmas, Dan J.; Hoffman, John M.

2013-01-01

Positron emission tomography (PET) can image a wide variety of functional and physiological parameters in vivo using different radiotracers. As more is learned about the molecular basis for disease and treatment, the potential value of molecular imaging for characterizing and monitoring disease status has increased. Characterizing multiple aspects of tumor physiology by imaging multiple PET tracers in a single patient provides additional complementary information, and there is a significant body of literature supporting the potential value of multi-tracer PET imaging in oncology. However, imaging multiple PET tracers in a single patient presents a number of challenges. A number of techniques are under development for rapidly imaging multiple PET tracers in a single scan, where signal-recovery processing algorithms are employed to recover various imaging endpoints for each tracer. Dynamic imaging is generally used with tracer injections staggered in time, and kinetic constraints are utilized to estimate each tracers' contribution to the multi-tracer imaging signal. This article summarizes past and ongoing work in multi-tracer PET tumor imaging, and then organizes and describes the main algorithmic approaches for achieving multi-tracer PET signal-recovery. While significant advances have been made, the complexity of the approach necessitates protocol design, optimization, and testing for each particular tracer combination and application. Rapid multi-tracer PET techniques have great potential for both research and clinical cancer imaging applications, and continued research in this area is warranted. PMID:24312149

Multiple Targets of Salicylic Acid and Its Derivatives in Plants and Animals

PubMed Central

Klessig, Daniel F.; Tian, Miaoying; Choi, Hyong Woo

2016-01-01

Salicylic acid (SA) is a critical plant hormone that is involved in many processes, including seed germination, root initiation, stomatal closure, floral induction, thermogenesis, and response to abiotic and biotic stresses. Its central role in plant immunity, although extensively studied, is still only partially understood. Classical biochemical approaches and, more recently, genome-wide high-throughput screens have identified more than two dozen plant SA-binding proteins (SABPs), as well as multiple candidates that have yet to be characterized. Some of these proteins bind SA with high affinity, while the affinity of others exhibit is low. Given that SA levels vary greatly even within a particular plant species depending on subcellular location, tissue type, developmental stage, and with respect to both time and location after an environmental stimulus such as infection, the presence of SABPs exhibiting a wide range of affinities for SA may provide great flexibility and multiple mechanisms through which SA can act. SA and its derivatives, both natural and synthetic, also have multiple targets in animals/humans. Interestingly, many of these proteins, like their plant counterparts, are associated with immunity or disease development. Two recently identified SABPs, high mobility group box protein and glyceraldehyde 3-phosphate dehydrogenase, are critical proteins that not only serve key structural or metabolic functions but also play prominent roles in disease responses in both kingdoms. PMID:27303403

Network-Assisted Investigation of Combined Causal Signals from Genome-Wide Association Studies in Schizophrenia

PubMed Central

Jia, Peilin; Wang, Lily; Fanous, Ayman H.; Pato, Carlos N.; Edwards, Todd L.; Zhao, Zhongming

2012-01-01

With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had P meta<1×10−4, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available. PMID:22792057

Autophagy of Mitochondria: A Promising Therapeutic Target for Neurodegenerative Disease

PubMed Central

Kamat, Pradip K.; Kalani, Anuradha; Kyles, Philip; Tyagi, Suresh C.; Tyagi, Neetu

2014-01-01

The autophagic process is the only known mechanism for mitochondrial turnover and it has been speculated that dysfunction of autophagy may result in mitochondrial error and cellular stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is associated with cellular oxidative stress and its impact on neuro-degeneration. This impaired autophagic function may be considered as a possible mechanism in the pathogenesis of several neurodegenerative disorders including: Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington disease (HD). It can be suggested that autophagy dysfunction along with oxidative stress are considered main events in neurodegenerative disorders. New therapeutic approaches have now begun to target mitochondria as a potential drug target. This review discusses evidence supporting the notion that oxidative stress and autophagy are intimately associated with neurodegenerative disease pathogenesis. This review also explores new approaches that can prevent mitochondrial dysfunction, improve neurodegenerative etiology, and also offer possible cures to the aforementioned neurodegenerative diseases. PMID:24807843

Biological pathways involved in the development of inflammatory bowel disease.

PubMed

Zemljic, Mateja; Pejkovic, Bozena; Krajnc, Ivan; Lipovsek, Saska

2014-10-01

Apoptosis, autophagy and necrosis are three distinct functional types of the mammalian cell death network. All of them are characterized by a number of cell's morphological changes. The inappropriate induction of cell death is involved in the pathogenesis of a number of diseases.Pathogenesis of inflammatory bowel diseases (ulcerative colitis, Crohn's disease) includes an abnormal immunological response to disturbed intestinal microflora. One of the most important reason in pathogenesis of chronic inflammatory disease and subsequent multiple organ pathology is a barrier function of the gut, regulating cellular viability. Recent findings have begun to explain the mechanisms by which intestinal epithelial cells are able to survive in such an environment and how loss of normal regulatory processes may lead to inflammatory bowel disease (IBD).This review focuses on the regulation of biological pathways in development and homeostasis in IBD. Better understanding of the physiological functions of biological pathways and their influence on inflammation, immunity, and barrier function will simplify our expertice of homeostasis in the gastrointestinal tract and in upgrading diagnosis and treatment.

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

PubMed

Marrie, Ruth Ann

2011-05-01

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

Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases.

PubMed

Ackers, Ian; Malgor, Ramiro

2018-01-01

Chronic diseases account for approximately 45% of all deaths in developed countries and are particularly prevalent in countries with the most sophisticated and robust public health systems. Chronic metabolic diseases, specifically lifestyle-related diseases pertaining to diet and exercise, continue to be difficult to treat clinically. The most prevalent of these chronic metabolic diseases include obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiovascular disease and will be the focus of this review. Wnt proteins are highly conserved glycoproteins best known for their role in development and homeostasis of tissues. Given the importance of Wnt signalling in homeostasis, aberrant Wnt signalling likely regulates metabolic processes and may contribute to the development of chronic metabolic diseases. Expression of Wnt proteins and dysfunctional Wnt signalling has been reported in multiple chronic diseases. It is interesting to speculate about an interrelationship between the Wnt signalling pathways as a potential pathological mechanism in chronic metabolic diseases. The aim of this review is to summarize reported findings on the contrasting roles of Wnt signalling in lifestyle-related chronic metabolic diseases; specifically, the contribution of Wnt signalling to lipid accumulation, fibrosis and chronic low-grade inflammation.

@neurIST: infrastructure for advanced disease management through integration of heterogeneous data, computing, and complex processing services.

PubMed

Benkner, Siegfried; Arbona, Antonio; Berti, Guntram; Chiarini, Alessandro; Dunlop, Robert; Engelbrecht, Gerhard; Frangi, Alejandro F; Friedrich, Christoph M; Hanser, Susanne; Hasselmeyer, Peer; Hose, Rod D; Iavindrasana, Jimison; Köhler, Martin; Iacono, Luigi Lo; Lonsdale, Guy; Meyer, Rodolphe; Moore, Bob; Rajasekaran, Hariharan; Summers, Paul E; Wöhrer, Alexander; Wood, Steven

2010-11-01

The increasing volume of data describing human disease processes and the growing complexity of understanding, managing, and sharing such data presents a huge challenge for clinicians and medical researchers. This paper presents the @neurIST system, which provides an infrastructure for biomedical research while aiding clinical care, by bringing together heterogeneous data and complex processing and computing services. Although @neurIST targets the investigation and treatment of cerebral aneurysms, the system's architecture is generic enough that it could be adapted to the treatment of other diseases. Innovations in @neurIST include confining the patient data pertaining to aneurysms inside a single environment that offers clinicians the tools to analyze and interpret patient data and make use of knowledge-based guidance in planning their treatment. Medical researchers gain access to a critical mass of aneurysm related data due to the system's ability to federate distributed information sources. A semantically mediated grid infrastructure ensures that both clinicians and researchers are able to seamlessly access and work on data that is distributed across multiple sites in a secure way in addition to providing computing resources on demand for performing computationally intensive simulations for treatment planning and research.

Importance of Apolipoprotein A-I in Multiple Sclerosis.

PubMed

Gardner, Lidia A; Levin, Michael C

2015-01-01

Jean-Martin Charcot has first described multiple sclerosis (MS) as a disease of the central nervous system (CNS) over a century ago. MS remains incurable today, and treatment options are limited to disease modifying drugs. Over the years, significant advances in understanding disease pathology have been made in autoimmune and neurodegenerative components. Despite the fact that brain is the most lipid rich organ in human body, the importance of lipid metabolism has not been extensively studied in this disorder. In MS, the CNS is under attack by a person's own immune system. Autoantigens and autoantibodies are known to cause devastation of myelin through up regulation of T-cells and cytokines, which penetrate through the blood-brain barrier to cause inflammation and myelin destruction. The anti-inflammatory role of high-density lipoproteins (HDLs) has been implicated in a plethora of biological processes: vasodilation, immunity to infection, oxidation, inflammation, and apoptosis. However, it is not known what role HDL plays in neurological function and myelin repair in MS. Understanding of lipid metabolism in the CNS and in the periphery might unveil new therapeutic targets and explain the partial success of some existing MS therapies.

Disease Modifying Therapy in Multiple Sclerosis

PubMed Central

Williams, U. E.; Oparah, S. K.; Philip-Ephraim, E. E.

2014-01-01

Multiple sclerosis is an autoimmune disease of the central nervous system characterized by inflammatory demyelination and axonal degeneration. It is the commonest cause of permanent disability in young adults. Environmental and genetic factors have been suggested in its etiology. Currently available disease modifying drugs are only effective in controlling inflammation but not prevention of neurodegeneration or accumulation of disability. Search for an effective neuroprotective therapy is at the forefront of multiple sclerosis research. PMID:27355035

The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain

PubMed Central

Haider, Lukas; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang

2016-01-01

Abstract Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. PMID:26912645

Measuring health care process quality with software quality measures.

PubMed

Yildiz, Ozkan; Demirörs, Onur

2012-01-01

Existing quality models focus on some specific diseases, clinics or clinical areas. Although they contain structure, process, or output type measures, there is no model which measures quality of health care processes comprehensively. In addition, due to the not measured overall process quality, hospitals cannot compare quality of processes internally and externally. To bring a solution to above problems, a new model is developed from software quality measures. We have adopted the ISO/IEC 9126 software quality standard for health care processes. Then, JCIAS (Joint Commission International Accreditation Standards for Hospitals) measurable elements were added to model scope for unifying functional requirements. Assessment (diagnosing) process measurement results are provided in this paper. After the application, it was concluded that the model determines weak and strong aspects of the processes, gives a more detailed picture for the process quality, and provides quantifiable information to hospitals to compare their processes with multiple organizations.

MUSIDH, multiple use of simulated demographic histories, a novel method to reduce computation time in microsimulation models of infectious diseases.

PubMed

Fischer, E A J; De Vlas, S J; Richardus, J H; Habbema, J D F

2008-09-01

Microsimulation of infectious diseases requires simulation of many life histories of interacting individuals. In particular, relatively rare infections such as leprosy need to be studied in very large populations. Computation time increases disproportionally with the size of the simulated population. We present a novel method, MUSIDH, an acronym for multiple use of simulated demographic histories, to reduce computation time. Demographic history refers to the processes of birth, death and all other demographic events that should be unrelated to the natural course of an infection, thus non-fatal infections. MUSIDH attaches a fixed number of infection histories to each demographic history, and these infection histories interact as if being the infection history of separate individuals. With two examples, mumps and leprosy, we show that the method can give a factor 50 reduction in computation time at the cost of a small loss in precision. The largest reductions are obtained for rare infections with complex demographic histories.

Conflicting Role of Mycobacterium Species in Multiple Sclerosis

PubMed Central

Cossu, Davide; Yokoyama, Kazumasa; Hattori, Nobutaka

2017-01-01

Mycobacterium is a genus of aerobic and acid-fast bacteria, which include several pathogenic organisms that cause serious diseases in mammals. Previous studies have associated the immune response against mycobacteria with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system with unknown etiology. The role of mycobacteria in the pathological process has been controversial and often conflicting. We provide a detailed review of the mycobacteria that have been linked to MS over the last three decades, with a focus on Mycobacterium bovis bacille Calmette–Guérin vaccine for human and oral exposure to Mycobacterium avium subsp. paratuberculosis. We will also discuss the exposure and genetic susceptibility to mycobacterial infection, the protective role of vaccination, as well as the possible mechanisms involved in initiating or worsening MS symptoms, with particular emphasis on the molecular mimicry between mycobacterial and human proteins. Finally, we will introduce topics such as heat shock proteins and recognition by innate immunity, and toll-like receptor signaling-mediated responses to Mycobacterium exposure. PMID:28579973

A review of instruments to measure interprofessional collaboration for chronic disease management for community-living older adults.

PubMed

Bookey-Bassett, Sue; Markle-Reid, Maureen; McKey, Colleen; Akhtar-Danesh, Noori

2016-01-01

It is acknowledged internationally that chronic disease management (CDM) for community-living older adults (CLOA) is an increasingly complex process. CDM for older adults, who are often living with multiple chronic conditions, requires coordination of various health and social services. Coordination is enabled through interprofessional collaboration (IPC) among individual providers, community organizations, and health sectors. Measuring IPC is complicated given there are multiple conceptualisations and measures of IPC. A literature review of several healthcare, psychological, and social science electronic databases was conducted to locate instruments that measure IPC at the team level and have published evidence of their reliability and validity. Five instruments met the criteria and were critically reviewed to determine their strengths and limitations as they relate to CDM for CLOA. A comparison of the characteristics, psychometric properties, and overall concordance of each instrument with salient attributes of IPC found the Collaborative Practice Assessment Tool to be the most appropriate instrument for measuring IPC for CDM in CLOA.

Teriflunomide for the treatment of relapsing-remitting multiple sclerosis: patient preference and adherence.

PubMed

Bayas, Antonios; Mäurer, Mathias

2015-01-01

Multiple sclerosis (MS), a chronic demyelinating neuroinflammatory disease of the central nervous system, is the most common neurological disorder leading to disability in young adulthood. In the last 2 decades, numerous treatments for relapsing-remitting MS have been approved with eleven treatment options available worldwide. One of the determinants in treatment selection is disease activity in the individual patient. However, patient preferences play an increasingly major role in treatment decision making. With teriflunomide, a reversible inhibitor of the enzyme dihydroorotate dehydrogenase, a new oral therapeutic option, given once daily, has been approved within the last 2 years by the regulatory agencies. The current review focuses on characteristics of the drug relevant for patients' preferences in the treatment decision process in the light of the available medications. Perceiving and considering patients' preferences will have an effect on treatment adherence, which is known to be often low in MS patients. Teriflunomide-related adherence issues will also be discussed regarding mode of application, dosing, and potential side effects.

Prospective memory impairment in multiple sclerosis: a review.

PubMed

Rouleau, Isabelle; Dagenais, Emmanuelle; Tremblay, Alexandra; Demers, Mélanie; Roger, Élaine; Jobin, Céline; Duquette, Pierre

2017-08-04

Multiple sclerosis (MS) is a progressive disease of the central nervous system affecting information processing speed, episodic memory, attention, and executive functions. MS patients also often report prospective memory (PM) failures that directly impact their functional autonomy, including professional and social life. The purpose of this paper was to review the literature concerning the assessment and remediation of PM deficits in MS. The literature pertaining to PM impairment in MS was carefully reviewed using PubMed, PsyINFO, and Google Scholar, as well as cross-references from the articles published on this topic. Since PM rehabilitation in MS patients is still in its infancy, this review mainly focuses on studies that have directly assessed PM through various measures including questionnaires, standardized clinical tests, and experimental procedures. This literature review confirms the presence of PM deficits in MS patients, even in the early stages of the disease. A further need for controlled studies on PM assessment and PM interventions in patients with MS is stressed.

Resistive Efficacy and Multiple Sexual Partners among American Indian Young Adults: A Parallel-Process Latent Growth Curve Model

ERIC Educational Resources Information Center

Mitchell, Christina M.; Kaufman, Carol E.; Beals, Janette

2005-01-01

Contracting a sexually transmitted disease (STD) is one of the most serious public health issues for adolescents and young adults; rates of STDs among American Indian youth are among the highest of any racial or ethnic group in the United States. Although it is one of the key risk factors for spreading STDs, little is known about individual…

The US Network of Pediatric Multiple Sclerosis Centers: Development, Progress, and Next Steps.

PubMed

Casper, T Charles; Rose, John W; Roalstad, Shelly; Waubant, Emmanuelle; Aaen, Gregory; Belman, Anita; Chitnis, Tanuja; Gorman, Mark; Krupp, Lauren; Lotze, Timothy E; Ness, Jayne; Patterson, Marc; Rodriguez, Moses; Weinstock-Guttman, Bianca; Browning, Brittan; Graves, Jennifer; Tillema, Jan-Mendelt; Benson, Leslie; Harris, Yolanda

2015-09-01

Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network. © The Author(s) 2014.

The US Network of Pediatric Multiple Sclerosis Centers: Development, Progress, and Next Steps

PubMed Central

Casper, T. Charles; Rose, John W.; Roalstad, Shelly; Waubant, Emmanuelle; Aaen, Gregory; Belman, Anita; Chitnis, Tanuja; Gorman, Mark; Krupp, Lauren; Lotze, Timothy E.; Ness, Jayne; Patterson, Marc; Rodriguez, Moses; Weinstock-Guttman, Bianca; Browning, Brittan; Graves, Jennifer; Tillema, Jan-Mendelt; Benson, Leslie; Harris, Yolanda

2014-01-01

Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network. PMID:25270659

A Specific Reduction in Aβ1-42 vs. a Universal Loss of Aβ Peptides in CSF Differentiates Alzheimer's Disease From Meningitis and Multiple Sclerosis.

PubMed

Spitzer, Philipp; Lang, Roland; Oberstein, Timo J; Lewczuk, Piotr; Ermann, Natalia; Huttner, Hagen B; Masouris, Ilias; Kornhuber, Johannes; Ködel, Uwe; Maler, Juan M

2018-01-01

A reduced concentration of Aβ 1-42 in CSF is one of the established biomarkers of Alzheimer's disease. Reduced CSF concentrations of Aβ 1-42 have also been shown in multiple sclerosis, viral encephalitis and bacterial meningitis. As neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease, an infectious origin of the disease has been proposed. According to this hypothesis, amyloid pathology is a consequence of a microbial infection and the resulting immune defense. Accordingly, changes in CSF levels of amyloid-β peptides should be similar in AD and inflammatory brain diseases. Aβ 1-42 and Aβ 1-40 levels were measured in cerebrospinal fluid by ELISA and Western blotting in 34 patients with bacterial meningitis ( n = 9), multiple sclerosis ( n = 5) or Alzheimer's disease ( n = 9) and in suitable controls ( n = 11). Reduced concentrations of Aβ 1-42 were detected in patients with bacterial meningitis, multiple sclerosis and Alzheimer's disease. However, due to a concurrent reduction in Aβ 1-40 in multiple sclerosis and meningitis patients, the ratio of Aβ 1-42 /Aβ 1-40 was reduced only in the CSF of Alzheimer's disease patients. Urea-SDS-PAGE followed by Western blotting revealed that all Aβ peptide variants are reduced in bacterial meningitis, whereas in Alzheimer's disease, only Aβ 1-42 is reduced. These results have two implications. First, they confirm the discriminatory diagnostic power of the Aβ 1-42 /Aβ 1-40 ratio. Second, the differential pattern of Aβ peptide reductions suggests that the amyloid pathology in meningitis and multiple sclerosis differs from that in AD and does not support the notion of AD as an infection-triggered immunopathology.

Classifying Patients with Chronic Pelvic Pain into Levels of Biopsychosocial Dysfunction Using Latent Class Modeling of Patient Reported Outcome Measures

PubMed Central

Fenton, Bradford W.; Grey, Scott F.; Tossone, Krystel; McCarroll, Michele; Von Gruenigen, Vivian E.

2015-01-01

Chronic pelvic pain affects multiple aspects of a patient's physical, social, and emotional functioning. Latent class analysis (LCA) of Patient Reported Outcome Measures Information System (PROMIS) domains has the potential to improve clinical insight into these patients' pain. Based on the 11 PROMIS domains applied to n=613 patients referred for evaluation in a chronic pelvic pain specialty center, exploratory factor analysis (EFA) was used to identify unidimensional superdomains. Latent profile analysis (LPA) was performed to identify the number of homogeneous classes present and to further define the pain classification system. The EFA combined the 11 PROMIS domains into four unidimensional superdomains of biopsychosocial dysfunction: Pain, Negative Affect, Fatigue, and Social Function. Based on multiple fit criteria, a latent class model revealed four distinct classes of CPP: No dysfunction (3.2%); Low Dysfunction (17.8%); Moderate Dysfunction (53.2%); and High Dysfunction (25.8%). This study is the first description of a novel approach to the complex disease process such as chronic pelvic pain and was validated by demographic, medical, and psychosocial variables. In addition to an essentially normal class, three classes of increasing biopsychosocial dysfunction were identified. The LCA approach has the potential for application to other complex multifactorial disease processes. PMID:26355825

Spatial and Temporal Coordination of Bone Marrow-Derived Cell Activity During Arteriogenesis: Regulation of the Endogenous Response and Therapeutic Implications

PubMed Central

Meisner, Joshua K.; Price, Richard J.

2010-01-01

Arterial occlusive disease (AOD) is the leading cause of morbidity and mortality through the developed world, which creates a significant need for effective therapies to halt disease progression. Despite success of animal and small-scale human therapeutic arteriogenesis studies, this promising concept for treating AOD has yielded largely disappointing results in large-scale clinical trials. One reason for this lack of successful translation is that endogenous arteriogenesis is highly dependent on a poorly understood sequence of events and interactions between bone marrow derived cells (BMCs) and vascular cells, which makes designing effective therapies difficult. We contend that the process follows a complex, ordered sequence of events with multiple, specific BMC populations recruited at specific times and locations. Here we present the evidence suggesting roles for multiple BMC populations from neutrophils and mast cells to progenitor cells and propose how and where these cell populations fit within the sequence of events during arteriogenesis. Disruptions in these various BMC populations can impair the arteriogenesis process in patterns that characterize specific patient populations. We propose that an improved understanding of how arteriogenesis functions as a system can reveal individual BMC populations and functions that can be targeted for overcoming particular impairments in collateral vessel development. PMID:21044213

Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers.

PubMed

Novakova, Lenka; Axelsson, Markus; Malmeström, Clas; Imberg, Henrik; Elias, Olle; Zetterberg, Henrik; Nerman, Olle; Lycke, Jan

2018-01-01

Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization. This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course. This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction. Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration. In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.

Intervention strategies for carcass disposal: pareto analysis of exposures for exotic disease outbreaks.

PubMed

Delgado, João; Longhurst, Phil; Hickman, Gordon A W; Gauntlett, Daniel M; Howson, Simon F; Irving, Phil; Hart, Alwyn; Pollard, Simon J T

2010-06-15

An enhanced methodology for the policy-level prioritization of intervention options during carcass disposal is presented. Pareto charts provide a semiquantitative analysis of opportunities for multiple exposures to human health, animal health, and the wider environment during carcass disposal; they identify critical control points for risk management and assist in waste technology assessment. Eighty percent of the total availability of more than 1300 potential exposures to human, animal, or environmental receptors is represented by 16 processes, these being dominated by on-farm collection and carcass processing, reinforcing the criticality of effective controls during early stages of animal culling and waste processing. Exposures during mass burials are dominated by ground- and surface-water exposures with noise and odor nuisance prevalent for mass pyres, consistent with U.K. experience. Pareto charts are discussed in the context of other visualization formats for policy officials and promoted as a communication tool for informing the site-specific risk assessments required during the operational phases of exotic disease outbreaks.

State and Local Perspective on Implementation of the Centers for Disease Control and Prevention Dog Confinement Agreement.

PubMed

Zaganjor, I; Sinclair, J R; Coleman, M S

2015-12-01

The Centers for Disease Control and Prevention (CDC) works in conjunction with state, territorial, local and tribal agencies (STLTAs) to prevent the transmission of infectious agents. Issuance of confinement agreements using CDC Form 75.37 'Notice to Owners and Importers of Dogs' to importers of dogs that are not vaccinated or incompletely vaccinated against rabies is part of the agency's regulatory programme to prevent the entry of dogs infected with rabies. Although this is a regulatory programme that depends heavily on partnerships between CDC and STLTAs, CDC had never formally evaluated the acceptability of the confinement agreement process with these partners. Thus, a short survey of nine STLTAs was conducted to evaluate whether these partners have enough personnel and resources to implement the regulation and their general opinions of the confinement agreement process. The results illustrate that CDC partners are dissatisfied to some extent with the process, and there are multiple issues limiting their success in enforcing the regulation. © 2015 Blackwell Verlag GmbH.

Engineering Digestion: Multiscale Processes of Food Digestion.

PubMed

Bornhorst, Gail M; Gouseti, Ourania; Wickham, Martin S J; Bakalis, Serafim

2016-03-01

Food digestion is a complex, multiscale process that has recently become of interest to the food industry due to the developing links between food and health or disease. Food digestion can be studied by using either in vitro or in vivo models, each having certain advantages or disadvantages. The recent interest in food digestion has resulted in a large number of studies in this area, yet few have provided an in-depth, quantitative description of digestion processes. To provide a framework to develop these quantitative comparisons, a summary is given here between digestion processes and parallel unit operations in the food and chemical industry. Characterization parameters and phenomena are suggested for each step of digestion. In addition to the quantitative characterization of digestion processes, the multiscale aspect of digestion must also be considered. In both food systems and the gastrointestinal tract, multiple length scales are involved in food breakdown, mixing, absorption. These different length scales influence digestion processes independently as well as through interrelated mechanisms. To facilitate optimized development of functional food products, a multiscale, engineering approach may be taken to describe food digestion processes. A framework for this approach is described in this review, as well as examples that demonstrate the importance of process characterization as well as the multiple, interrelated length scales in the digestion process. © 2016 Institute of Food Technologists®

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

PubMed

Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-Ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan

2011-03-02

No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. ClinicalTrials.gov (NCT00395200).

The High Prevalence of the Varicella Zoster Virus in Patients With Relapsing-Remitting Multiple Sclerosis: A Case-Control Study in the North of Iran

PubMed Central

Najafi, Saeideh; Ghane, Masood; Yousefzadeh-Chabok, Shahrokh; Amiri, Mehdi

2016-01-01

Background Multiple sclerosis (MS) is the most common neurological autoimmune disease, characterized by multifocal areas of inflammatory demyelination within the central nervous system. It has been hypothesized that the stimulation of the immune system by viral infections is the leading cause of MS among susceptible individuals. Objectives The aim of this study was to investigate the prevalence of the varicella zoster virus (VZV) in patients with relapsing-remitting multiple sclerosis. Patients and Methods Plasma and peripheral blood mononuclear cells (PBMCs) collected from MS patients (n = 82) and controls (n = 89) were screened for the presence of anti-VZV antibodies and VZV DNA by the ELISA and PCR methods. DNA was extracted from all samples, and VZV infection was examined by the PCR technique. Statistical analysis was used to investigate the frequency of the virus in MS patients and a healthy control group. Results Of all the MS patients, 78 (95.1%) and 21 (25.6%) were positive for anti-VZV and VZV DNA, respectively. Statistical analysis of the PCR results showed a significant correlation between the abundance of VZV and MS disease (P < 0.001). However, there was no significant correlation between the abundance of anti-VZV antibodies and MS disease by the ELISA method. Conclusions These results support the hypothesis that VZV may contribute to MS in establishing a systemic infection process and inducing an immune response. PMID:27226879

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

PubMed Central

2011-01-01

Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). PMID:21366911

Antibody-enhanced dengue disease generates a marked CNS inflammatory response in the black-tufted marmoset Callithrix penicillata.

PubMed

Vasconcelos, Barbara Cristina Baldez; Vieira, Juliana Almeida; Silva, Geane Oliveira; Fernandes, Taiany Nogueira; Rocha, Luciano Chaves; Viana, André Pereira; Serique, Cássio Diego Sá; Filho, Carlos Santos; Bringel, Raissa Aires Ribeiro; Teixeira, Francisco Fernando Dacier Lobato; Ferreira, Milene Silveira; Casseb, Samir Mansour Moraes; Carvalho, Valéria Lima; de Melo, Karla Fabiane Lopes; de Castro, Paulo Henrique Gomes; Araújo, Sanderson Corrêa; Diniz, José Antonio Picanço; Demachki, Samia; Anaissi, Ana Karyssa Mendes; Sosthenes, Marcia Consentino Kronka; Vasconcelos, Pedro Fernando da Costa; Anthony, Daniel Clive; Diniz, Cristovam Wanderley Picanço; Diniz, Daniel Guerreiro

2016-02-01

Severe dengue disease is often associated with long-term neurological impairments, but it is unclear what mechanisms are associated with neurological sequelae. Previously, we demonstrated antibody-enhanced dengue disease (ADE) dengue in an immunocompetent mouse model with a dengue virus 2 (DENV2) antibody injection followed by DENV3 virus infection. Here we migrated this ADE model to Callithrix penicillata. To mimic human multiple infections of endemic zones where abundant vectors and multiple serotypes co-exist, three animals received weekly subcutaneous injections of DENV3 (genotype III)-infected supernatant of C6/36 cell cultures, followed 24 h later by anti-DENV2 antibody for 12 weeks. There were six control animals, two of which received weekly anti-DENV2 antibodies, and four further animals received no injections. After multiple infections, brain, liver, and spleen samples were collected and tissue was immunolabeled for DENV3 antigens, ionized calcium binding adapter molecule 1, Ki-67, TNFα. There were marked morphological changes in the microglial population of ADE monkeys characterized by more highly ramified microglial processes, higher numbers of trees and larger surface areas. These changes were associated with intense TNFα-positive immunolabeling. It is unclear why ADE should generate such microglial activation given that IgG does not cross the blood-brain barrier, but this study reveals that in ADE dengue therapy targeting the CNS host response is likely to be important. © 2015 Japanese Society of Neuropathology.

Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy.

PubMed

Puska, Gina; Lutz, Mirjam I; Molnar, Kinga; Regelsberger, Günther; Ricken, Gerda; Pirker, Walter; Laszlo, Lajos; Kovacs, Gabor G

2018-06-01

Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of α-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/α-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated α-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of α-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with α-synuclein pre-aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated α-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated α-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of α-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous α-synuclein in MSA. Copyright © 2018 Elsevier Inc. All rights reserved.

Multiple Testing in the Context of Gene Discovery in Sickle Cell Disease Using Genome-Wide Association Studies.

PubMed

Kuo, Kevin H M

2017-01-01

The issue of multiple testing, also termed multiplicity, is ubiquitous in studies where multiple hypotheses are tested simultaneously. Genome-wide association study (GWAS), a type of genetic association study that has gained popularity in the past decade, is most susceptible to the issue of multiple testing. Different methodologies have been employed to address the issue of multiple testing in GWAS. The purpose of the review is to examine the methodologies employed in dealing with multiple testing in the context of gene discovery using GWAS in sickle cell disease complications.

Public health interventions for epidemics: implications for multiple infection waves.

PubMed

Wessel, Lindsay; Hua, Yi; Wu, Jianhong; Moghadas, Seyed M

2011-02-25

Epidemics with multiple infection waves have been documented for some human diseases, most notably during past influenza pandemics. While pathogen evolution, co-infection, and behavioural changes have been proposed as possible mechanisms for the occurrence of subsequent outbreaks, the effect of public health interventions remains undetermined. We develop mean-field and stochastic epidemiological models for disease transmission, and perform simulations to show how control measures, such as drug treatment and isolation of ill individuals, can influence the epidemic profile and generate sequences of infection waves with different characteristics. We demonstrate the impact of parameters representing the effectiveness and adverse consequences of intervention measures, such as treatment and emergence of drug resistance, on the spread of a pathogen in the population. If pathogen resistant strains evolve under drug pressure, multiple outbreaks are possible with variability in their characteristics, magnitude, and timing. In this context, the level of drug use and isolation capacity play an important role in the occurrence of subsequent outbreaks. Our simulations for influenza infection as a case study indicate that the intensive use of these interventions during the early stages of the epidemic could delay the spread of disease, but it may also result in later infection waves with possibly larger magnitudes. The findings highlight the importance of intervention parameters in the process of public health decision-making, and in evaluating control measures when facing substantial uncertainty regarding the epidemiological characteristics of an emerging infectious pathogen. Critical factors that influence population health including evolutionary responses of the pathogen under the pressure of different intervention measures during an epidemic should be considered for the design of effective strategies that address short-term targets compatible with long-term disease outcomes.

Molecular Approach to Targeted Therapy for Multiple Sclerosis.

PubMed

Sherbet, Gajanan V

2016-01-01

The development and evolution of targeted therapy to any disease require the identification of targets amenable to treatment of patients. Here the pathogenetic signalling systems involved in multiple sclerosis are scrutinised to locate nodes of deregulation and dysfunction in order to devise strategies of drug development for targeted intervention. Oliogoclonal bands (OCB) are isoelectric focusing profiles of immunoglobulins synthesised in the central nervous system. OCBs enable the diagnosis of multiple sclerosis with high sensitivity and specificity and are related to the course of the disease and progression. The OCB patterns can be linked with the expression of angiogenic molecular species. Angiogenic signalling which has also been implicated in demyelination provides the option of using angiogenesis inhibitors in disease control. The PI3K (phosphoinositide 3-kinase)/Akt axis has emerged with a key role in myelination with its demonstrable links with mTOR mediated transcription of downstream target genes. Inflammatory signals and innate and acquired immunity from the activation of NF-κB (nuclear factor κB) responsive genes are considered. NF-κB signalling could be implicated in myelination. The transcription factor STAT (signal transducers and activators of transcription) and the EBV (Epstein- Barr virus) transcription factor BZLF1 contributing significantly to the disease process are a major environmental factor linked to MS. EBV can activate TGF (transforming growth factor) and VEGF (vascular endothelial growth factor) signalling. EBV microRNAs are reviewed as signalling mediators of pathogenesis. Stem cell transplantation therapy has lately gained much credence, so the current status of mesenchymal and hematopoietic stem cell therapy is reviewed with emphasis on the differential expression immune-related genes and operation of signalling systems.

Iron oxide magnetic nanoparticles highlight early involvement of the choroid plexus in central nervous system inflammation

PubMed Central

Millward, Jason M.; Schnorr, Jörg; Taupitz, Matthias; Wagner, Susanne; Wuerfel, Jens T.; Infante-Duarte, Carmen

2013-01-01

Neuroinflammation during multiple sclerosis involves immune cell infiltration and disruption of the BBB (blood–brain barrier). Both processes can be visualized by MRI (magnetic resonance imaging), in multiple sclerosis patients and in the animal model EAE (experimental autoimmune encephalomyelitis). We previously showed that VSOPs (very small superparamagnetic iron oxide particles) reveal CNS (central nervous system) lesions in EAE which are not detectable by conventional contrast agents in MRI. We hypothesized that VSOP may help detect early, subtle inflammatory events that would otherwise remain imperceptible. To investigate the capacity of VSOP to reveal early events in CNS inflammation, we induced EAE in SJL mice using encephalitogenic T-cells, and administered VSOP prior to onset of clinical symptoms. In parallel, we administered VSOP to mice at peak disease, and to unmanipulated controls. We examined the distribution of VSOP in the CNS by MRI and histology. Prior to disease onset, in asymptomatic mice, VSOP accumulated in the choroid plexus and in spinal cord meninges in the absence of overt inflammation. However, VSOP was undetectable in the CNS of non-immunized control mice. At peak disease, VSOP was broadly distributed; we observed particles in perivascular inflammatory lesions with apparently preserved glia limitans. Moreover, at peak disease, VSOP was prominent in the choroid plexus and was seen in elongated endothelial structures, co-localized with phagocytes, and diffusely disseminated in the parenchyma, suggesting multiple entry mechanisms of VSOP into the CNS. Thus, using VSOP we were able to discriminate between inflammatory events occurring in established EAE and, importantly, we identified CNS alterations that appear to precede immune cell infiltration and clinical onset. PMID:23452162

Brain Diseases - Multiple Languages

MedlinePlus

... FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Brain Diseases URL of this page: https://medlineplus.gov/ ...

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

PubMed

Giovannoni, Gavin

2018-06-01

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

Incentives for Starting Small Companies Focused on Rare and Neglected Diseases.

PubMed

Ekins, Sean; Wood, Jill

2016-04-01

Starting biotech or pharmaceutical companies is traditionally thought to be based around a scientist, their technology platform or a clinical candidate spun out from another company. Between us we have taken a different approach and formed two small early stage companies after initially leveraging the perspective of a parent with a child with a life-threatening rare disease. Phoenix Nest ( http://www.phoenixnestbiotech.com/ ) was co-founded to work on treatments for Sanfilippo syndrome a devastating neurodegenerative lysosomal storage disorder. In the space of just over 3 years we have built up collaborations with leading scientists in academia and industry and been awarded multiple NIH small business grants. The second company, Collaborations Pharmaceuticals Inc. ( http://www.collaborationspharma.com/ ) was founded to address some of the other 7000 or so rare diseases as well as neglected infectious diseases. The Rare Pediatric Disease Priority Review Voucher is likely the most important incentive for companies working on rare diseases with very small populations. This may also be partially responsible for the recent acquisitions of rare disease companies with late stage candidates. Lessons learned in the process of starting our companies are that rare disease parents or patients can readily partner with a scientist and fund research through NIH grants rather than venture capital or angel investors initially. This process may be slow so patience and perseverance is key. We would encourage other pharmaceutical scientists to meet rare disease parents, patients or advocates and work with them to further the science on their diseases and create a source of future drugs.

Incentives for Starting Small Companies Focused on Rare and Neglected Diseases

PubMed Central

Ekins, Sean; Wood, Jill

2015-01-01

Starting biotech or pharmaceutical companies is traditionally thought to be based around a scientist, their technology platform or a clinical candidate spun out from another company. Between us we have taken a different approach and formed two small early stage companies after initially leveraging the perspective of a parent with a child with a life-threatening rare disease. Phoenix Nest (http://www.phoenixnestbiotech.com/) was co-founded to work on treatments for Sanfilippo syndrome a devastating neurodegenerative lysosomal storage disorder. In the space of just over 3 years we have built up collaborations with leading scientists in academia and industry and been awarded multiple NIH small business grants. The second company, Collaborations Pharmaceuticals Inc. (http://www.collaborationspharma.com/) was founded to address some of the other 7000 or so rare diseases as well as neglected infectious diseases. The Rare Pediatric Disease Priority Review Voucher is likely the most important incentive for companies working on rare diseases with very small populations. This may also be partially responsible for the recent acquisitions of rare disease companies with late stage candidates. Lessons learned in the process of starting our companies are that rare disease parents or patients can readily partner with a scientist and fund research through NIH grants rather than venture capital or angel investors initially. This process may be slow so patience and perseverance is key. We would encourage other pharmaceutical scientists to meet rare disease parents, patients or advocates and work with them to further the science on their diseases and create a source of future drugs. PMID:26666772

Multiple Export Mechanisms for mRNAs

PubMed Central

Delaleau, Mildred; Borden, Katherine L. B.

2015-01-01

Nuclear mRNA export plays an important role in gene expression. We describe the mechanisms of mRNA export including the importance of mRNP assembly, docking with the nuclear basket of the nuclear pore complex (NPC), transit through the central channel of the NPC and cytoplasmic release. We describe multiple mechanisms of mRNA export including NXF1 and CRM1 mediated pathways. Selective groups of mRNAs can be preferentially transported in order to respond to cellular stimuli. RNAs can be selected based on the presence of specific cis-acting RNA elements and binding of specific adaptor proteins. The role that dysregulation of this process plays in human disease is also discussed. PMID:26343730

How does the multifaceted plant hormone salicylic acid combat disease in plants and are similar mechanisms utilized in humans?

PubMed

Dempsey, D'Maris Amick; Klessig, Daniel F

2017-03-23

Salicylic acid (SA) is an important plant hormone that regulates many aspects of plant growth and development, as well as resistance to (a)biotic stress. Efforts to identify SA effector proteins have revealed that SA binds to and alters the activity of multiple plant proteins-this represents a shift from the paradigm that hormones mediate their functions via one or a few receptors. SA and its derivatives also have multiple targets in animals; some of these proteins, like their plant counterparts, are associated with pathological processes. Together, these findings suggest that SA exerts its defense-associated effects in both kingdoms via a large number of targets.

Genetic insights into the mechanisms of Fgf signaling

PubMed Central

Brewer, J. Richard; Mazot, Pierre; Soriano, Philippe

2016-01-01

The fibroblast growth factor (Fgf) family of ligands and receptor tyrosine kinases is required throughout embryonic and postnatal development and also regulates multiple homeostatic functions in the adult. Aberrant Fgf signaling causes many congenital disorders and underlies multiple forms of cancer. Understanding the mechanisms that govern Fgf signaling is therefore important to appreciate many aspects of Fgf biology and disease. Here we review the mechanisms of Fgf signaling by focusing on genetic strategies that enable in vivo analysis. These studies support an important role for Erk1/2 as a mediator of Fgf signaling in many biological processes but have also provided strong evidence for additional signaling pathways in transmitting Fgf signaling in vivo. PMID:27036966

Cells, Biomarkers, and Posttraumatic Stress Disorder: Evidence for Peripheral Involvement in a Central Disease

DTIC Science & Technology

2012-01-01

including; Alzheimer’s disease (Mac- cioni et al. 2009), Parkinson’s disease (Hirsch and Hunot 2009), spinal cord injury (Chan 2008), multiple sclerosis ...states such as multiple sclerosis (Kraus et al. 2000), human immunodeficiency virus dementia (Fischer- Smith et al. 2001), and meningitis (Cauwels et al...Immunologic mechanisms of multiple sclerosis . Neuroi- maging Clin. N. Am. 18, 577–588. Gaylord K. M. (2006) The psychosocial effects of combat: the frequently

Features of Coping with Disease in Iranian Multiple Sclerosis Patients: a Qualitative Study.

PubMed

Dehghani, Ali; Dehghan Nayeri, Nahid; Ebadi, Abbas

2018-03-01

Introduction: Coping with disease is of the main components improving the quality of life in multiple sclerosis patients. Identifying the characteristics of this concept is based on the experiences of patients. Using qualitative research is essential to improve the quality of life. This study was conducted to explore the features of coping with the disease in patients with multiple sclerosis. Method: In this conventional content analysis study, eleven multiple sclerosis patients from Iran MS Society in Tehran (Iran) participated. Purposive sampling was used to select participants. Data were gathered using semi structured interviews. To analyze data, a conventional content analysis approach was used to identify meaning units and to make codes and categories. Results: Results showed that features of coping with disease in multiple sclerosis patients consists of (a) accepting the current situation, (b) maintenance and development of human interactions, (c) self-regulation and (d) self-efficacy. Each of these categories is composed of sub-categories and codes that showed the perception and experience of patients about the coping with disease. Conclusion: Accordingly, a unique set of features regarding features of coping with the disease were identified among the patients with multiple sclerosis. Therefore, working to ensure the emergence of, and subsequent reinforcement of these features in MS patients can be an important step in improving the adjustment and quality of their lives.

Regression-based pediatric norms for the brief visuospatial memory test: revised and the symbol digit modalities test.

PubMed

Smerbeck, A M; Parrish, J; Yeh, E A; Hoogs, M; Krupp, Lauren B; Weinstock-Guttman, B; Benedict, R H B

2011-04-01

The Brief Visuospatial Memory Test - Revised (BVMTR) and the Symbol Digit Modalities Test (SDMT) oral-only administration are known to be sensitive to cerebral disease in adult samples, but pediatric norms are not available. A demographically balanced sample of healthy control children (N = 92) ages 6-17 was tested with the BVMTR and SDMT. Multiple regression analysis (MRA) was used to develop demographically controlled normative equations. This analysis provided equations that were then used to construct demographically adjusted z-scores for the BVMTR Trial 1, Trial 2, Trial 3, Total Learning, and Delayed Recall indices, as well as the SDMT total correct score. To demonstrate the utility of this approach, a comparison group of children with acute disseminated encephalomyelitis (ADEM) or multiple sclerosis (MS) were also assessed. We find that these visual processing tests discriminate neurological patients from controls. As the tests are validated in adult multiple sclerosis, they are likely to be useful in monitoring pediatric onset multiple sclerosis patients as they transition into adulthood.

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

PubMed

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

2016-09-01

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

Is there a genetic solution to bovine respiratory disease complex?

USDA-ARS?s Scientific Manuscript database

Bovine respiratory disease complex (BRDC) is a complex multi-factor disease, which increases costs and reduces revenue from feedlot cattle. Multiple stressors and pathogens (viral and bacterial) have been implicated in the etiology of BRDC, therefore multiple approaches will be needed to evaluate a...

Working with Climate Projections to Estimate Disease Burden: Perspectives from Public Health.

PubMed

Conlon, Kathryn C; Kintziger, Kristina W; Jagger, Meredith; Stefanova, Lydia; Uejio, Christopher K; Konrad, Charles

2016-08-09

There is interest among agencies and public health practitioners in the United States (USA) to estimate the future burden of climate-related health outcomes. Calculating disease burden projections can be especially daunting, given the complexities of climate modeling and the multiple pathways by which climate influences public health. Interdisciplinary coordination between public health practitioners and climate scientists is necessary for scientifically derived estimates. We describe a unique partnership of state and regional climate scientists and public health practitioners assembled by the Florida Building Resilience Against Climate Effects (BRACE) program. We provide a background on climate modeling and projections that has been developed specifically for public health practitioners, describe methodologies for combining climate and health data to project disease burden, and demonstrate three examples of this process used in Florida.

Working with Climate Projections to Estimate Disease Burden: Perspectives from Public Health

PubMed Central

Conlon, Kathryn C.; Kintziger, Kristina W.; Jagger, Meredith; Stefanova, Lydia; Uejio, Christopher K.; Konrad, Charles

2016-01-01

There is interest among agencies and public health practitioners in the United States (USA) to estimate the future burden of climate-related health outcomes. Calculating disease burden projections can be especially daunting, given the complexities of climate modeling and the multiple pathways by which climate influences public health. Interdisciplinary coordination between public health practitioners and climate scientists is necessary for scientifically derived estimates. We describe a unique partnership of state and regional climate scientists and public health practitioners assembled by the Florida Building Resilience Against Climate Effects (BRACE) program. We provide a background on climate modeling and projections that has been developed specifically for public health practitioners, describe methodologies for combining climate and health data to project disease burden, and demonstrate three examples of this process used in Florida. PMID:27517942

[Chronic pancreatitis: new definition and perspectives.

PubMed

Conti Bellocchi, Maria Cristina; De Pretis, Nicolò; Amodio, Antonio; Zerbi, Alessandro; Frulloni, Luca

2018-01-01

Chronic pancreatitis has been considered over the past years as a single disease, alcohol-induced and different from acute pancreatitis, in terms of etiology and prognosis. Actually, the introduction of a new concept of chronic pancreatitis, now considered as a fibroinflammatory process caused by multiple factors (toxic-metabolic, genetic, immunologic, obstructive), allow to better understand the pathogenesis of this complex disease. Furthermore, the discover of peculiar forms of chronic pancreatitis (autoimmune, paraduodenal, associated to gene mutations), different in term of clinical aspects, findings at imaging, prognosis and therapy, radically changed the concept of the disease. In this brief review, we described the impact of this new concept in the comprehension of pathogenesis, in the definition of peculiar forms of chronic pancreatitis, and in the clinical and therapeutic approach of chronic pancreatitis.

Linking genes to diseases with a SNPedia-Gene Wiki mashup

PubMed Central

2012-01-01

Background A variety of topic-focused wikis are used in the biomedical sciences to enable the mass-collaborative synthesis and distribution of diverse bodies of knowledge. To address complex problems such as defining the relationships between genes and disease, it is important to bring the knowledge from many different domains together. Here we show how advances in wiki technology and natural language processing can be used to automatically assemble ‘meta-wikis’ that present integrated views over the data collaboratively created in multiple source wikis. Results We produced a semantic meta-wiki called the Gene Wiki+ that automatically mirrors and integrates data from the Gene Wiki and SNPedia. The Gene Wiki+, available at (http://genewikiplus.org/), captures 8,047 distinct gene-disease relationships. SNPedia accounts for 4,149 of the gene-disease pairs, the Gene Wiki provides 4,377 and only 479 appear independently in both sources. All of this content is available to query and browse and is provided as linked open data. Conclusions Wikis contain increasing amounts of diverse, biological information useful for elucidating the connections between genes and disease. The Gene Wiki+ shows how wiki technology can be used in concert with natural language processing to provide integrated views over diverse underlying data sources. PMID:22541597

Caring for children with special healthcare needs in the managed care environment.

PubMed

Hawkins, Michelle R; Diehl-Svrjcek, Beth; Dunbar, Linda J

2006-01-01

Dramatic medical and technological advances over the past 15 years have resulted in the survival into adulthood of children with chronic health conditions. As this population subset has increased, the demand of caring for these children in the managed care arena has become challenging from a clinical, fiscal, and member satisfaction perspective. A disease management program was designed for children, ages birth through age 18, identified as having special needs at the time of birth or at any point throughout childhood related to disease processes such as diabetes, sickle cell disease, genetic aberrations, or the multiple complications of extreme prematurity. Components of the program included identification of the population, coordinated risk assessment, and ongoing case management interventions. Most important, outcome indicators were tracked to demonstrate program effectiveness. The formulation and function of a dedicated disease management database is also discussed.

Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases

PubMed Central

Vegeto, Elisabetta; Benedusi, Valeria; Maggi, Adriana

2008-01-01

Recent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer’s and Parkinson’s Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia. PMID:18522863

Traumatic brain injury: a risk factor for neurodegenerative diseases.

PubMed

Gupta, Rajaneesh; Sen, Nilkantha

2016-01-01

Traumatic brain injury (TBI), a major global health and socioeconomic problem, is now established as a chronic disease process with a broad spectrum of pathophysiological symptoms followed by long-term disabilities. It triggers multiple and multidirectional biochemical events that lead to neurodegeneration and cognitive impairment. Recent studies have presented strong evidence that patients with TBI history have a tendency to develop proteinopathy, which is the pathophysiological feature of neurodegenerative disorders such as Alzheimer disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). This review mainly focuses on mechanisms related to AD, CTE, and ALS that are induced after TBI and their relevance to the advancement of these neurodegenerative diseases. This review encompasses acute effects and chronic neurodegenerative consequences after TBI for a better understanding of TBI-induced neuronal death and to design therapies that will effectively treat patients in the primary or secondary progressive stages.

Mitochondria-Associated Membranes (MAMs): Overview and Its Role in Parkinson's Disease.

PubMed

Rodríguez-Arribas, M; Yakhine-Diop, S M S; Pedro, J M Bravo-San; Gómez-Suaga, P; Gómez-Sánchez, R; Martínez-Chacón, G; Fuentes, J M; González-Polo, R A; Niso-Santano, M

2017-10-01

Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD) and contributes to the appearance of the pathogenesis features, i.e., autophagy dysregulation, mitochondrial dysfunction, oxidative stress, and lately, neuronal death. Moreover,, ER stress and/or damaged mitochondria can be the cause of these disruptions. Therefore, ER-mitochondria contact structure and function are crucial to multiple cellular processes. This review is focused on the molecular interaction between ER and mitochondria indispensable to MAM formation and on MAM alteration-induced etiology of neurodegenerative diseases.

Dissociative semantic breakdown in Alzheimer's disease: evidence from multiple category fluency test.

PubMed

Ting, Simon Kang Seng; Hameed, Shahul; Earnest, Arul; Tan, Eng-King

2013-07-01

Category-specific semantic dissociation particularly in terms of biological and non-biological dichotomy has been described in Alzheimer's disease (AD). We re-examine above finding by performing multiple superordinate category verbal fluency test in AD patients. We analyze the baseline neuropsychological assessment performance of food and animal fluency test of AD patients from a tertiary hospital that collected prospectively over 5 years period and correlation was calculated by Kappa test. The analysis is stratified according to literacy level (primary: 0-6 years education and secondary: >6 years education) and disease severity (MMSE score: mild 19-24, moderate 13-18 and severe <13). A total of 296 AD patients were analyzed and only fair to moderate agreement between food and animal category fluency test was found especially in the mild AD cases (primary: kappa 0.42; secondary: kappa 0.40). Kappa agreement level increases when disease progress especially in the secondary education group. Food category, which is a more relevant semantic knowledge to Singapore population, is generally more affected. Higher educated subjects appeared to have less semantic dissociation effect when disease progress. Despite less primed in daily life, biological category of semantic knowledge appears to be affected less during AD process in highly urbanized Singapore society. Brain appears to have special protective mechanism towards living things. However, education level seems have a modulation effect towards the biological protective mechanism. Copyright © 2012 Elsevier B.V. All rights reserved.

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

PubMed Central

Gajofatto, Alberto; Benedetti, Maria Donata

2015-01-01

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

Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

PubMed Central

Ontaneda, Daniel; Fox, Robert J.; Chataway, Jeremy

2015-01-01

Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs. PMID:25772899

Design Thinking for mHealth Application Co-Design to Support Heart Failure Self-Management.

PubMed

Woods, Leanna; Cummings, Elizabeth; Duff, Jed; Walker, Kim

2017-01-01

Heart failure is a prevalent, progressive chronic disease costing in excess of $1billion per year in Australia alone. Disease self-management has positive implications for the patient and decreases healthcare usage. However, adherence to recommended guidelines is challenging and existing literature reports sub-optimal adherence. mHealth applications in chronic disease education have the potential to facilitate patient enablement for disease self-management. To the best of our knowledge no heart failure self-management application is available for safe use by our patients. In this paper, we present the process established to co-design a mHealth application in support of heart-failure self-management. For this development, an interdisciplinary team systematically proceeds through the phases of Stanford University's Design Thinking process; empathise, define, ideate, prototype and test with a user-centred philosophy. Using this clinician-led heart failure app research as a case study, we describe a sequence of procedures to engage with local patients, carers, software developers, eHealth experts and clinical colleagues to foster rigorously developed and locally relevant patient-facing mHealth solutions. Importantly, patients are engaged in each stage with ethnographic interviews, a series of workshops and multiple re-design iterations.

The Role of Ephs and Ephrins in Memory Formation.

PubMed

Dines, Monica; Lamprecht, Raphael

2016-04-01

The ability to efficiently store memories in the brain is a fundamental process and its impairment is associated with multiple human mental disorders. Evidence indicates that long-term memory formation involves alterations of synaptic efficacy produced by modifications in neural transmission and morphology. The Eph receptors and their cognate ephrin ligands have been shown to be involved in these key neuronal processes by regulating events such as presynaptic transmitter release, postsynaptic glutamate receptor conductance and trafficking, synaptic glutamate reuptake, and dendritic spine morphogenesis. Recent findings show that Ephs and ephrins are needed for memory formation in different organisms. These proteins participate in the formation of various types of memories that are subserved by different neurons and brain regions. Ephs and ephrins are involved in brain disorders and diseases with memory impairment symptoms, including Alzheimer's disease and anxiety. Drugs that agonize or antagonize Ephs/ephrins signaling have been developed and could serve as therapeutic agents to treat such diseases. Ephs and ephrins may therefore induce cellular alterations mandatory for memory formation and serve as a target for pharmacological intervention for treatment of memory-related brain diseases. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Information processing characteristics in subtypes of multiple sclerosis.

PubMed

De Sonneville, L M J; Boringa, J B; Reuling, I E W; Lazeron, R H C; Adèr, H J; Polman, C H

2002-01-01

The purpose of this study was to evaluate information processing characteristics in patients with multiple sclerosis (MS). We selected 53 patients with MS and 58 matched healthy controls. Using computerized tests, we investigated focused, divided, sustained attention, and executive function, and attempted to pinpoint deficits in attentional control to peripheral or central processing stages. The results substantiate the hypothesis that the slowing of attention-demanding (controlled) information processing underlying more complex cognitive skills is general, i.e. irrespective of type of controlled processing, with MS patients being 40% slower than controls. MS patients may suffer from focused, and divided and sustained attention deficits, as well as from compromised central processing stages, with secondary progressive (SP) patients showing the most extensive range of deficits, closely followed by primary progressive (PP) patients, while relapsing-remitting (RR) patients appear to be much less affected. General slowing appears to be highest in PP and SP type MS patients (50% slower) versus relapsing-remitting MS (24% slower). In contrast to most previous results, (complex) processing speed appeared to be robustly correlated with severity of MS as measured by the expanded disability status scale and with disease duration. Patients did much less differ in accuracy of processing from controls, suggesting the importance of using time strategies in planning everyday life and job activities to compensate for or alleviate MS-related speed handicaps. Copyright 2002 Elsevier Science Ltd.

The measurement of Protein Synthesis for Assessing Proteostasis in Studies of Slowed Aging

PubMed Central

Miller, Benjamin F.; Drake, Joshua C.; Naylor, Bradley; Price, John C.; Hamilton, Karyn L.

2014-01-01

Slowing the aging process can reduce the risk for multiple chronic diseases simultaneously. It is increasingly recognized that maintaining protein homeostasis (or proteostasis) is important for slowing the aging process. Since proteostasis is a dynamic process, monitoring it is not a simple task and requires use of appropriate methods. This review will introduce methods to assess protein and DNA synthesis using deuterium oxide (D2O), and how protein and DNA synthesis outcomes provide insight into proteostatic mechanisms. Finally, we provide a discussion on how these assessments of protein and DNA synthesis are “mechanistic” investigations and provide an appropriate framework for the further development of slowed aging treatments. PMID:25283966

Cytokines in Alzheimer's disease and multiple sclerosis.

PubMed

Patterson, P H

1995-10-01

Cytokines are well known as mediators of inflammation, and recent work has highlighted the role of these agents and inflammatory events in Alzheimer's disease and multiple sclerosis. The discovery of subclasses of T-helper cells has provided a critical framework to aid in understanding how the cytokine network regulates these diseases.

Multiple disease resistance to fungal and oomycete pathogens using a recombinant inbred line population in pepper

USDA-ARS?s Scientific Manuscript database

Incorporating disease resistance into cultivars is a primary focus of modern breeding programs. Resistance to pathogens is often introgressed from landrace or wild individuals with poor fruit quality into commercial-quality cultivars. Sites of multiple disease resistance (MDR) are regions or “hotspo...

Review of Amyotrophic Lateral Sclerosis, Parkinson's and Alzheimer's diseases helps further define pathology of the novel paradigm for Alzheimer's with heavy metals as primary disease cause.

PubMed

Cavaleri, Franco

2015-12-01

Pathologies of neurological diseases are increasingly recognized to have common structural and molecular events that can fit, sometimes loosely, into a central pathological theme. A better understanding of the genetic, proteomic and metabolic similarities between three common neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) - and how these similarities relate to their unique pathological features may shed more light on the underlying pathology of each. These are complex multigenic neuroinflammatory diseases caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease decoding and treatment difficult. One case of ALS, for example, can manifest from a very different pool of genetic mutations than another. In the case of ALS multiple genes in addition to SOD1 are implicated in the pathogenesis of both sporadic and familial variants of the disease. These genes play different roles in the processing and trafficking of signalling, metabolic and structural proteins. However, many of these genetic mutations or the cellular machinery they regulate can play a role in one form or another in PD and AD as well. In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies. This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease hallmarks that we often classify as absolute signatures of one disease. These new perspectives will be discussed in the context of a new paradigm for Alzheimer's disease that implicates heavy metals as a primary cause. Plausible links between these distinctly different pathologies are presented showing intersections of their distinct pathologies that hinge on metal interactions.

Neurotoxicity

MedlinePlus

... disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Also being studied are the mechanisms ... disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Also being studied are the mechanisms ...

[Oral multiple carcinomatosis in a patient from an area with endemic regional chronic hydroarsenicism (ERCH)].

PubMed

Carrica, Victoriano

2006-01-01

Arsenic (As) and its compounds may cause multiple harmful effects on the human organism, interfering with biological processes of vital importance. It is known that the inhabitants of vast areas of the Argentine Republic drink well water contaminated with AS, which results in a disease known as Endemic Regional Chronic Hydroarsenicism (ERCH). It has been observed that these patients present a clinical picture characterized by multiple carcinomatous skin lesions which occur concurrently or successively along long periods of time. To present the clinical case of a female patient from the arsenical area of Cordoba Province, who had multiple carcinomatous oral lesions. The patient's history was written and iconographies, surgical excision of the lip lesions, pathological studies of the samples, and evolution observations were done. Based on both the patient's history and follow-up studies, it was possible to prove the presence of multiple successive carcinomatous lesions in the oral mucosa. It is concluded that drinking water containing more AS than the quantity accepted by the WHO (0.0 5 ppm) can cause multiple carcinomatous lesions on the oral mucosa as well as on the skin.

Symptomatic therapy in multiple sclerosis

PubMed Central

Frohman, Teresa C.; Castro, Wanda; Shah, Anjali; Courtney, Ardith; Ortstadt, Jeffrey; Davis, Scott L.; Logan, Diana; Abraham, Thomas; Abraham, Jaspreet; Remington, Gina; Treadaway, Katherine; Graves, Donna; Hart, John; Stuve, Olaf; Lemack, Gary; Greenberg, Benjamin; Frohman, Elliot M.

2011-01-01

Multiple sclerosis is the most common disabling neurological disease of young adults. The ability to impact the quality of life of patients with multiple sclerosis should not only incorporate therapies that are disease modifying, but should also include a course of action for the global multidisciplinary management focused on quality of life and functional capabilities. PMID:21694806

The effect of electronic package on satisfaction in multiple sclerosis patients

PubMed Central

Mohamadirizi, Shahla; Shaygannejad, Vahid; Mohamadirizi, Soheila; Khosrawi, Saeid

2016-01-01

Background: Traditional teaching methods used in medical education cannot wholly respond to the rapid changes and growth of information as well as continuous changes in the educational needs of society, especially patients with chronic diseases such as multiple sclerosis (MS). Therefore, this study was designed with the aim of examining the effect of electronic package on satisfaction in MS patients. Materials and Methods: The research was a quasi-experimental study. It was carried out at the MS Kashani Center affiliated to the Isfahan University of Medical Sciences, in 2013. One hundred twenty-eight patients with MS were allocated randomly into two equal groups of 64 each for education by booklet (control) and education by multimedia software (experimental) for 2 weeks. Data were collected by processing questionnaires, which consisted of questions about satisfaction (17 items) and questions about demographic and disease characteristics (9 items), answered by both groups before and 2 weeks after education. SPSS version 14 (DARYA software, Iran) was used to conduct statistical tests such as the independent t-test and the paired t-test for analyzing the data. The statistical significance level was less than 0.05. Results: The results show that there was not any significant difference between the satisfaction scores of the electronic package and control groups before intervention, but that there was a significant difference after 2 weeks’ intervention (P = 0.010). Conclusion: The electronic programs comprised an attractive education method. So this technology can increase motivation in MS patients to study more about the disease process. PMID:27308261

STRIPAK complexes: structure, biological function, and involvement in human diseases.

PubMed

Hwang, Juyeon; Pallas, David C

2014-02-01

The mammalian striatin family consists of three proteins, striatin, S/G2 nuclear autoantigen, and zinedin. Striatin family members have no intrinsic catalytic activity, but rather function as scaffolding proteins. Remarkably, they organize multiple diverse, large signaling complexes that participate in a variety of cellular processes. Moreover, they appear to be regulatory/targeting subunits for the major eukaryotic serine/threonine protein phosphatase 2A. In addition, striatin family members associate with germinal center kinase III kinases as well as other novel components, earning these assemblies the name striatin-interacting phosphatase and kinase (STRIPAK) complexes. Recently, there has been a great increase in functional and mechanistic studies aimed at identifying and understanding the roles of STRIPAK and STRIPAK-like complexes in cellular processes of multiple organisms. These studies have identified novel STRIPAK and STRIPAK-like complexes and have explored their roles in specific signaling pathways. Together, the results of these studies have sparked increased interest in striatin family complexes because they have revealed roles in signaling, cell cycle control, apoptosis, vesicular trafficking, Golgi assembly, cell polarity, cell migration, neural and vascular development, and cardiac function. Moreover, STRIPAK complexes have been connected to clinical conditions, including cardiac disease, diabetes, autism, and cerebral cavernous malformation. In this review, we discuss the expression, localization, and protein domain structure of striatin family members. Then we consider the diverse complexes these proteins and their homologs form in various organisms, emphasizing what is known regarding function and regulation. Finally, we explore possible roles of striatin family complexes in disease, especially cerebral cavernous malformation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Stent-Graft Placement for Femoral Artery Pseudoaneurysm in a Patient with Idiopathic Multiple Arterial Aneurysmal Disease

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

Koo, Bon Kwon; Choi, Donghoon; Kwon, Kihwan

2002-12-15

A 34-year-old man presenting with a left inguinal mass was diagnosed as having idiopathic multiple aneurysmal disease and pseudoaneurysm of a left superficial femoral artery. A stent-graft was successfully deployed percutaneously at the left superficial femoral artery pseudoaneurysm. Less invasive treatment should be used to avoid vascular complications in patients with idiopathic multiple aneurysmal disease, especially in those who have a progressive course or a history of prior complications after surgical repair.

Photodynamic Therapy Treatment to Enhance Fracture Healing

DTIC Science & Technology

2013-06-01

applied to treat multiple types  of cancer, skin diseases and  age   related   macular   degeneration . This treatment involves the local  or systemic...treatment, which has been successfully applied to treat multiple types of cancer, skin diseases and age related macular degeneration . This treatment...minimally invasive local treatment, which has been successfully applied to treat multiple types of cancer, skin diseases and age related macular

Interconnected network motifs control podocyte morphology and kidney function.

PubMed

Azeloglu, Evren U; Hardy, Simon V; Eungdamrong, Narat John; Chen, Yibang; Jayaraman, Gomathi; Chuang, Peter Y; Fang, Wei; Xiong, Huabao; Neves, Susana R; Jain, Mohit R; Li, Hong; Ma'ayan, Avi; Gordon, Ronald E; He, John Cijiang; Iyengar, Ravi

2014-02-04

Podocytes are kidney cells with specialized morphology that is required for glomerular filtration. Diseases, such as diabetes, or drug exposure that causes disruption of the podocyte foot process morphology results in kidney pathophysiology. Proteomic analysis of glomeruli isolated from rats with puromycin-induced kidney disease and control rats indicated that protein kinase A (PKA), which is activated by adenosine 3',5'-monophosphate (cAMP), is a key regulator of podocyte morphology and function. In podocytes, cAMP signaling activates cAMP response element-binding protein (CREB) to enhance expression of the gene encoding a differentiation marker, synaptopodin, a protein that associates with actin and promotes its bundling. We constructed and experimentally verified a β-adrenergic receptor-driven network with multiple feedback and feedforward motifs that controls CREB activity. To determine how the motifs interacted to regulate gene expression, we mapped multicompartment dynamical models, including information about protein subcellular localization, onto the network topology using Petri net formalisms. These computational analyses indicated that the juxtaposition of multiple feedback and feedforward motifs enabled the prolonged CREB activation necessary for synaptopodin expression and actin bundling. Drug-induced modulation of these motifs in diseased rats led to recovery of normal morphology and physiological function in vivo. Thus, analysis of regulatory motifs using network dynamics can provide insights into pathophysiology that enable predictions for drug intervention strategies to treat kidney disease.

Interconnected Network Motifs Control Podocyte Morphology and Kidney Function

PubMed Central

Azeloglu, Evren U.; Hardy, Simon V.; Eungdamrong, Narat John; Chen, Yibang; Jayaraman, Gomathi; Chuang, Peter Y.; Fang, Wei; Xiong, Huabao; Neves, Susana R.; Jain, Mohit R.; Li, Hong; Ma’ayan, Avi; Gordon, Ronald E.; He, John Cijiang; Iyengar, Ravi

2014-01-01

Podocytes are kidney cells with specialized morphology that is required for glomerular filtration. Diseases, such as diabetes, or drug exposure that causes disruption of the podocyte foot process morphology results in kidney pathophysiology. Proteomic analysis of glomeruli isolated from rats with puromycin-induced kidney disease and control rats indicated that protein kinase A (PKA), which is activated by adenosine 3′,5′-monophosphate (cAMP), is a key regulator of podocyte morphology and function. In podocytes, cAMP signaling activates cAMP response element–binding protein (CREB) to enhance expression of the gene encoding a differentiation marker, synaptopodin, a protein that associates with actin and promotes its bundling. We constructed and experimentally verified a β-adrenergic receptor–driven network with multiple feedback and feedforward motifs that controls CREB activity. To determine how the motifs interacted to regulate gene expression, we mapped multicompartment dynamical models, including information about protein subcellular localization, onto the network topology using Petri net formalisms. These computational analyses indicated that the juxtaposition of multiple feedback and feedforward motifs enabled the prolonged CREB activation necessary for synaptopodin expression and actin bundling. Drug-induced modulation of these motifs in diseased rats led to recovery of normal morphology and physiological function in vivo. Thus, analysis of regulatory motifs using network dynamics can provide insights into pathophysiology that enable predictions for drug intervention strategies to treat kidney disease. PMID:24497609

Multifunctional Curcumin Mediate Multitherapeutic Effects.

PubMed

Shehzad, Adeeb; Qureshi, Munibah; Anwar, Muhammad Nabeel; Lee, Young Sup

2017-09-01

Inflammation can promote the development of arthritis, obesity, cardiovascular, type II diabetes, pancreatitis, metabolic and neurodegenerative diseases, and certain types of cancer. Compounds isolated from plants have been practiced since ancient times for curing various ailments including inflammatory disorders and to support normal physiological functions. Curcumin (diferuloylmethane) is a yellow coloring agent, extracted from turmeric that has been used for the prevention and treatment of various inflammatory diseases. Numerous studies have shown that curcumin modulate multiple molecular targets and can be translated to the clinics for multiple therapeutic processes. There is compelling evidence that curcumin can block cell proliferation, invasion, and angiogenesis as well as reduced the prolonged survival of cancer cells. Curcumin mediates anti-inflammatory effect through downregulation of inflammatory cytokines, transcription factors, protein kinases, and enzymes that promote inflammation and development of chronic diseases. In addition, curcumin induces apoptosis through mitochondrial and receptor-mediated pathways by activating caspase cascades. Curcumin is a safe and nontoxic drug that has been reported to be well tolerated. Available clinical trials support the potential role of curcumin for treatment of various inflammatory disorders. However, curcumin's efficacy is hindered by poor absorption and low bioavailability, which limit its translation into clinics. This review outlines the potential pharmacological and clinical role of curcumin, which provide a gateway for the beneficial role of plant isolated compounds in treatment of various inflammatory diseases and cancer. © 2017 Institute of Food Technologists®.

Super-enhancer-mediated RNA processing revealed by integrative microRNA network analysis

PubMed Central

Suzuki, Hiroshi I.; Young, Richard A; Sharp, Phillip A

2017-01-01

Summary Super-enhancers are an emerging sub-class of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and a unrecognized higher-order property of super-enhancers in RNA processing beyond transcription. PMID:28283057

Modeling Disease Severity in Multiple Sclerosis Using Electronic Health Records

PubMed Central

Xia, Zongqi; Secor, Elizabeth; Chibnik, Lori B.; Bove, Riley M.; Cheng, Suchun; Chitnis, Tanuja; Cagan, Andrew; Gainer, Vivian S.; Chen, Pei J.; Liao, Katherine P.; Shaw, Stanley Y.; Ananthakrishnan, Ashwin N.; Szolovits, Peter; Weiner, Howard L.; Karlson, Elizabeth W.; Murphy, Shawn N.; Savova, Guergana K.; Cai, Tianxi; Churchill, Susanne E.; Plenge, Robert M.; Kohane, Isaac S.; De Jager, Philip L.

2013-01-01

Objective To optimally leverage the scalability and unique features of the electronic health records (EHR) for research that would ultimately improve patient care, we need to accurately identify patients and extract clinically meaningful measures. Using multiple sclerosis (MS) as a proof of principle, we showcased how to leverage routinely collected EHR data to identify patients with a complex neurological disorder and derive an important surrogate measure of disease severity heretofore only available in research settings. Methods In a cross-sectional observational study, 5,495 MS patients were identified from the EHR systems of two major referral hospitals using an algorithm that includes codified and narrative information extracted using natural language processing. In the subset of patients who receive neurological care at a MS Center where disease measures have been collected, we used routinely collected EHR data to extract two aggregate indicators of MS severity of clinical relevance multiple sclerosis severity score (MSSS) and brain parenchymal fraction (BPF, a measure of whole brain volume). Results The EHR algorithm that identifies MS patients has an area under the curve of 0.958, 83% sensitivity, 92% positive predictive value, and 89% negative predictive value when a 95% specificity threshold is used. The correlation between EHR-derived and true MSSS has a mean R2 = 0.38±0.05, and that between EHR-derived and true BPF has a mean R2 = 0.22±0.08. To illustrate its clinical relevance, derived MSSS captures the expected difference in disease severity between relapsing-remitting and progressive MS patients after adjusting for sex, age of symptom onset and disease duration (p = 1.56×10−12). Conclusion Incorporation of sophisticated codified and narrative EHR data accurately identifies MS patients and provides estimation of a well-accepted indicator of MS severity that is widely used in research settings but not part of the routine medical records. Similar approaches could be applied to other complex neurological disorders. PMID:24244385

Breaking immunological tolerance through OX40 (CD134).

PubMed

Bansal-Pakala, P; Croft, M

2001-11-06

Immunological tolerance represents a mechanism by which cells of the host remain protected from the immune system. Breaking of immunological tolerance can result in a variety of autoimmune diseases such as rheumatoid arthritis, diabetes, and multiple sclerosis. The reasons for tolerance breaking down and autoimmune processes arising are largely unknown but of obvious interest for therapeutic intervention of these diseases. Although reversal of the tolerant state is generally unwanted, there are instances where this may be of benefit to the host. In particular, one way a cancerous cell escapes being targeted by the immune system is through tolerance mechanisms that in effect turn off the reactivity of T lymphocytes that can respond to tumor-associated peptides. Thus tolerance represents a major obstacle in developing effective immunotherapy against tumors. The molecules that are involved in regulating immunological tolerance are then of interest as they may be great targets for positively or negatively manipulating the tolerance process.

Care management role in end-of-life discussions.

PubMed

Meyer, Star

2012-01-01

How do we prepare our patients for decisions that will need to be made for end-of-life care? End-of-life care discussions should occur early on in the patient's disease process and often requires a great deal of coordination between multiple caregivers. There are also ethical, cultural social and spiritual considerations during this very important time in the disease process. Research suggests that we are not doing an adequate job of addressing end-of-life care with our patients and that a great deal of money and resources are being spent in the last days of life when there may be no clinical indication to do so. Registered nurse case managers have a unique knowledge base to serve in the role of coordinating care and leading the multidisciplinary care team in an effort to use resources responsibly while providing patients and families with options for end-of-life care.

Dissociating Normal Aging from Alzheimer’s Disease: A View from Cognitive Neuroscience

PubMed Central

Toepper, Max

2017-01-01

Both normal aging and Alzheimer’s disease (AD) are associated with changes in cognition, grey and white matter volume, white matter integrity, neural activation, functional connectivity, and neurotransmission. Obviously, all of these changes are more pronounced in AD and proceed faster providing the basis for an AD diagnosis. Since these differences are quantitative, however, it was hypothesized that AD might simply reflect an accelerated aging process. The present article highlights the different neurocognitive changes associated with normal aging and AD and shows that, next to quantitative differences, there are multiple qualitative differences as well. These differences comprise different neurocognitive dissociations as different cognitive deficit profiles, different weights of grey and white matter atrophy, and different gradients of structural decline. These qualitative differences clearly indicate that AD cannot be simply described as accelerated aging process but on the contrary represents a solid entity. PMID:28269778

Endoscopic laser treatment of subglottic and tracheal stenosis

NASA Astrophysics Data System (ADS)

Correa, Alex J.; Garrett, C. Gaelyn; Reinisch, Lou

1999-06-01

The ideal laser produces discrete wounds in a reproducible manner. The CO2 laser with its 10.6 micron wavelength is highly absorbed by water, its energy concentrated at the point of impact and the longer wavelength creates less scatter in tissue. The development of binocular endoscopic delivery system for use with binocular microlaryngoscopes have aided in using CO2 laser to treat patients with subglottic and tracheal stenosis. Often, patients with these disease processes require multiple endoscopic or open reconstructive procedures and my ultimately become tracheotomy dependent. The canine model of subglottic stenosis that has been develop allows testing of new agents as adjuncts to laser treatment. Mitomycin-C is an antibiotic with antitumor activity used in chemotherapy and also in ophthalmologic surgery due to its known inhibition of fibroblast proliferation. Current studies indicate this drug to have significant potential for improving our current management of this disease process.

Development of an Integrated Metabolomic Profiling Approach for Infectious Diseases Research

PubMed Central

Lv, Haitao; Hung, Chia S.; Chaturvedi, Kaveri S.; Hooton, Thomas M.; Henderson, Jeffrey P.

2013-01-01

Metabolomic profiling offers direct insights into the chemical environment and metabolic pathway activities at sites of human disease. During infection, this environment may receive important contributions from both host and pathogen. Here we apply untargeted metabolomics approach to identify compounds associated with an E. coli urinary tract infection population. Correlative and structural data from minimally processed samples were obtained using an optimized LC-MS platform capable of resolving ∼2300 molecular features. Principal components analysis readily distinguished patient groups and multiple supervised chemometric analyses resolved robust metabolomic shifts between groups. These analyses revealed nine compounds whose provisional structures suggest candidate infection-associated endocrine, catabolic, and lipid pathways. Several of these metabolite signatures may derive from microbial processing of host metabolites. Overall, this study highlights the ability of metabolomic approaches to directly identify compounds encountered by, and produced from, bacterial pathogens within human hosts. PMID:21922104

A Chemical Engineer's Perspective on Health and Disease

PubMed Central

Androulakis, Ioannis P.

2014-01-01

Chemical process systems engineering considers complex supply chains which are coupled networks of dynamically interacting systems. The quest to optimize the supply chain while meeting robustness and flexibility constraints in the face of ever changing environments necessitated the development of theoretical and computational tools for the analysis, synthesis and design of such complex engineered architectures. However, it was realized early on that optimality is a complex characteristic required to achieve proper balance between multiple, often competing, objectives. As we begin to unravel life's intricate complexities, we realize that that living systems share similar structural and dynamic characteristics; hence much can be learned about biological complexity from engineered systems. In this article, we draw analogies between concepts in process systems engineering and conceptual models of health and disease; establish connections between these concepts and physiologic modeling; and describe how these mirror onto the physiological counterparts of engineered systems. PMID:25506103

Modeling and processing of laser Doppler reactive hyperaemia signals

NASA Astrophysics Data System (ADS)

Humeau, Anne; Saumet, Jean-Louis; L'Huiller, Jean-Pierre

2003-07-01

Laser Doppler flowmetry is a non-invasive method used in the medical domain to monitor the microvascular blood cell perfusion through tissue. Most commercial laser Doppler flowmeters use an algorithm calculating the first moment of the power spectral density to give the perfusion value. Many clinical applications measure the perfusion after a vascular provocation such as a vascular occlusion. The response obtained is then called reactive hyperaemia. Target pathologies include diabetes, hypertension and peripheral arterial occlusive diseases. In order to have a deeper knowledge on reactive hyperaemia acquired by the laser Doppler technique, the present work first proposes two models (one analytical and one numerical) of the observed phenomenon. Then, a study on the multiple scattering between photons and red blood cells occurring during reactive hyperaemia is carried out. Finally, a signal processing that improves the diagnosis of peripheral arterial occlusive diseases is presented.

Development of Carbocyanine Dyes for PRMT Inhibition and Imaging

PubMed Central

Sinha, Sarmistha Halder; Owens, Eric A.; Feng, You; Yang, Yutao; Xie, Yan; Tu, Yaping; Henary, Maged; Zheng, Yujun George

2014-01-01

Summary Protein arginine methylation regulates multiple biological processes. Deregulation of protein arginine methyltransferase (PRMT) activities has been observed in many disease phenotypes. Small molecule probes that target PRMTs with strong affinity and selectivity can be used as valuable tools to dissect biological mechanisms of arginine methylation and establish the role of PRMT proteins in a disease process. In this work, we report synthesis and evaluation of a class of carbocyanine compounds containing indolium, benz[e]indolium or benz[c,d]indolium heterocyclic moieties that bind to the predominant arginine methyltransferase PRMT1 and inhibit its methyltransferase activity at low micromolar potencies. In particular, the developed molecules have long wavelength colorimetric and fluorometric photoactivities, which can be used for optical and near-infrared fluorescence imaging in cells or biological tissues. Together, these new chemical probes have potential application in PRMT studies both as enzyme inhibitors and as fluorescent dyes for microscope imaging. PMID:22749641

Protein fibrillation and nanoparticle interactions: opportunities and challenges

NASA Astrophysics Data System (ADS)

Mahmoudi, Morteza; Kalhor, Hamid R.; Laurent, Sophie; Lynch, Iseult

2013-03-01

Due to their ultra-small size, nanoparticles (NPs) have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technology. NPs are recognized as promising and powerful tools to fight against the human brain diseases such as multiple sclerosis or Alzheimer's disease. In this review, after an introductory part on the nature of protein fibrillation and the existing approaches for its investigations, the effects of NPs on the fibrillation process have been considered. More specifically, the role of biophysicochemical properties of NPs, which define their affinity for protein monomers, unfolded monomers, oligomers, critical nuclei, and other prefibrillar states, together with their influence on protein fibrillation kinetics has been described in detail. In addition, current and possible-future strategies for controlling the desired effect of NPs and their corresponding effects on the conformational changes of the proteins, which have significant roles in the fibrillation process, have been presented.

Automatic detection and recognition of multiple macular lesions in retinal optical coherence tomography images with multi-instance multilabel learning

NASA Astrophysics Data System (ADS)

Fang, Leyuan; Yang, Liumao; Li, Shutao; Rabbani, Hossein; Liu, Zhimin; Peng, Qinghua; Chen, Xiangdong

2017-06-01

Detection and recognition of macular lesions in optical coherence tomography (OCT) are very important for retinal diseases diagnosis and treatment. As one kind of retinal disease (e.g., diabetic retinopathy) may contain multiple lesions (e.g., edema, exudates, and microaneurysms) and eye patients may suffer from multiple retinal diseases, multiple lesions often coexist within one retinal image. Therefore, one single-lesion-based detector may not support the diagnosis of clinical eye diseases. To address this issue, we propose a multi-instance multilabel-based lesions recognition (MIML-LR) method for the simultaneous detection and recognition of multiple lesions. The proposed MIML-LR method consists of the following steps: (1) segment the regions of interest (ROIs) for different lesions, (2) compute descriptive instances (features) for each lesion region, (3) construct multilabel detectors, and (4) recognize each ROI with the detectors. The proposed MIML-LR method was tested on 823 clinically labeled OCT images with normal macular and macular with three common lesions: epiretinal membrane, edema, and drusen. For each input OCT image, our MIML-LR method can automatically identify the number of lesions and assign the class labels, achieving the average accuracy of 88.72% for the cases with multiple lesions, which better assists macular disease diagnosis and treatment.

The development of a disease oriented eFolder for multiple sclerosis decision support

NASA Astrophysics Data System (ADS)

Ma, Kevin; Jacobs, Colin; Fernandez, James; Amezcua, Lilyana; Liu, Brent

2010-03-01

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. The chronic nature of MS necessitates multiple MRI studies to track disease progression. Currently, MRI assessment of multiple sclerosis requires manual lesion measurement and yields an estimate of lesion volume and change that is highly variable and user-dependent. In the setting of a longitudinal study, disease trends and changes become difficult to extrapolate from the lesions. In addition, it is difficult to establish a correlation between these imaged lesions and clinical factors such as treatment course. To address these clinical needs, an MS specific e-Folder for decision support in the evaluation and assessment of MS has been developed. An e-Folder is a disease-centric electronic medical record in contrast to a patient-centric electronic health record. Along with an MS lesion computer aided detection (CAD) package for lesion load, location, and volume, clinical parameters such as patient demographics, disease history, clinical course, and treatment history are incorporated to make the e-Folder comprehensive. With the integration of MRI studies together with related clinical data and informatics tools designed for monitoring multiple sclerosis, it provides a platform to improve the detection of treatment response in patients with MS. The design and deployment of MS e-Folder aims to standardize MS lesion data and disease progression to aid in decision making and MS-related research.

Drug Target Prediction and Repositioning Using an Integrated Network-Based Approach

PubMed Central

Emig, Dorothea; Ivliev, Alexander; Pustovalova, Olga; Lancashire, Lee; Bureeva, Svetlana; Nikolsky, Yuri; Bessarabova, Marina

2013-01-01

The discovery of novel drug targets is a significant challenge in drug development. Although the human genome comprises approximately 30,000 genes, proteins encoded by fewer than 400 are used as drug targets in the treatment of diseases. Therefore, novel drug targets are extremely valuable as the source for first in class drugs. On the other hand, many of the currently known drug targets are functionally pleiotropic and involved in multiple pathologies. Several of them are exploited for treating multiple diseases, which highlights the need for methods to reliably reposition drug targets to new indications. Network-based methods have been successfully applied to prioritize novel disease-associated genes. In recent years, several such algorithms have been developed, some focusing on local network properties only, and others taking the complete network topology into account. Common to all approaches is the understanding that novel disease-associated candidates are in close overall proximity to known disease genes. However, the relevance of these methods to the prediction of novel drug targets has not yet been assessed. Here, we present a network-based approach for the prediction of drug targets for a given disease. The method allows both repositioning drug targets known for other diseases to the given disease and the prediction of unexploited drug targets which are not used for treatment of any disease. Our approach takes as input a disease gene expression signature and a high-quality interaction network and outputs a prioritized list of drug targets. We demonstrate the high performance of our method and highlight the usefulness of the predictions in three case studies. We present novel drug targets for scleroderma and different types of cancer with their underlying biological processes. Furthermore, we demonstrate the ability of our method to identify non-suspected repositioning candidates using diabetes type 1 as an example. PMID:23593264

The role of basic leucine zipper transcription factor E4BP4 in the immune system and immune-mediated diseases.

PubMed

Yin, Jinghua; Zhang, Jian; Lu, Qianjin

2017-07-01

Basic leucine zipper transcription factor E4BP4 (also known as NFIL3) has been implicated in the molecular and cellular mechanisms of functions and activities in mammals. The interactions between E4BP4 and major regulators of cellular processes have triggered significant interest in the roles of E4BP4 in the pathogenesis of certain chronic diseases. Indeed, novel discoveries have been emerging to illustrate the involvement of E4BP4 in multiple disorders. It is recognized that E4BP4 is extensively involved in some immune-mediated diseases, but the mechanisms of E4BP4 involvement in these complex diseases remain poorly defined. Here we review the regulatory mechanisms of E4BP4 engaging in not only the biological function but also the development of immune-mediated diseases, paving the way for future therapies. Copyright © 2017. Published by Elsevier Inc.

Placebo effects in neurological diseases.

PubMed

Dumitriu, Alina; Popescu, Bogdan O

2010-01-01

There is an imperious need of redefining placebo effect in contemporary times. The effects of sham medical intervention, combined with a careful observation of the natural evolution of a disease, could reveal the true efficiency and impact of active drugs. This interest is not driven only by a scientific curiosity, but also by the pragmatic fact that the standard process of approving new medicines through supportive clinical trials requires a comparison against placebo. A complete understanding of the placebo effect should include both its psychological mechanisms and the underlying neurobiology. In contrast to other type of conditions, neurological disorders could provide specific clues in understanding the placebo effect, since the pathogenic mechanisms of different diseases might interfere with neuronal circuitry involved in the perception of disease symptoms. However, there are ethical considerations dictating the limits of using placebo. This paper reviews recent articles about placebo effect, with an emphasis on its importance in several neurological conditions (Parkinson's disease, neuropathic pain, headache, multiple sclerosis, epilepsy), and intends to offer new insights on this major topic.

Drug-disease association and drug-repositioning predictions in complex diseases using causal inference-probabilistic matrix factorization.

PubMed

Yang, Jihong; Li, Zheng; Fan, Xiaohui; Cheng, Yiyu

2014-09-22

The high incidence of complex diseases has become a worldwide threat to human health. Multiple targets and pathways are perturbed during the pathological process of complex diseases. Systematic investigation of complex relationship between drugs and diseases is necessary for new association discovery and drug repurposing. For this purpose, three causal networks were constructed herein for cardiovascular diseases, diabetes mellitus, and neoplasms, respectively. A causal inference-probabilistic matrix factorization (CI-PMF) approach was proposed to predict and classify drug-disease associations, and further used for drug-repositioning predictions. First, multilevel systematic relations between drugs and diseases were integrated from heterogeneous databases to construct causal networks connecting drug-target-pathway-gene-disease. Then, the association scores between drugs and diseases were assessed by evaluating a drug's effects on multiple targets and pathways. Furthermore, PMF models were learned based on known interactions, and associations were then classified into three types by trained models. Finally, therapeutic associations were predicted based upon the ranking of association scores and predicted association types. In terms of drug-disease association prediction, modified causal inference included in CI-PMF outperformed existing causal inference with a higher AUC (area under receiver operating characteristic curve) score and greater precision. Moreover, CI-PMF performed better than single modified causal inference in predicting therapeutic drug-disease associations. In the top 30% of predicted associations, 58.6% (136/232), 50.8% (31/61), and 39.8% (140/352) hit known therapeutic associations, while precisions obtained by the latter were only 10.2% (231/2264), 8.8% (36/411), and 9.7% (189/1948). Clinical verifications were further conducted for the top 100 newly predicted therapeutic associations. As a result, 21, 12, and 32 associations have been studied and many treatment effects of drugs on diseases were investigated for cardiovascular diseases, diabetes mellitus, and neoplasms, respectively. Related chains in causal networks were extracted for these 65 clinical-verified associations, and we further illustrated the therapeutic role of etodolac in breast cancer by inferred chains. Overall, CI-PMF is a useful approach for associating drugs with complex diseases and provides potential values for drug repositioning.

Multiple sclerosis lesion segmentation using dictionary learning and sparse coding.

PubMed

Weiss, Nick; Rueckert, Daniel; Rao, Anil

2013-01-01

The segmentation of lesions in the brain during the development of Multiple Sclerosis is part of the diagnostic assessment for this disease and gives information on its current severity. This laborious process is still carried out in a manual or semiautomatic fashion by clinicians because published automatic approaches have not been universal enough to be widely employed in clinical practice. Thus Multiple Sclerosis lesion segmentation remains an open problem. In this paper we present a new unsupervised approach addressing this problem with dictionary learning and sparse coding methods. We show its general applicability to the problem of lesion segmentation by evaluating our approach on synthetic and clinical image data and comparing it to state-of-the-art methods. Furthermore the potential of using dictionary learning and sparse coding for such segmentation tasks is investigated and various possibilities for further experiments are discussed.

Exploring lipids with nonlinear optical microscopy in multiple biological systems

NASA Astrophysics Data System (ADS)

Alfonso-Garcia, Alba

Lipids are crucial biomolecules for the well being of humans. Altered lipid metabolism may give rise to a variety of diseases that affect organs from the cardiovascular to the central nervous system. A deeper understanding of lipid metabolic processes would spur medical research towards developing precise diagnostic tools, treatment methods, and preventive strategies for reducing the impact of lipid diseases. Lipid visualization remains a complex task because of the perturbative effect exerted by traditional biochemical assays and most fluorescence markers. Coherent Raman scattering (CRS) microscopy enables interrogation of biological samples with minimum disturbance, and is particularly well suited for label-free visualization of lipids, providing chemical specificity without compromising on spatial resolution. Hyperspectral imaging yields large datasets that benefit from tailored multivariate analysis. In this thesis, CRS microscopy was combined with Raman spectroscopy and other label-free nonlinear optical techniques to analyze lipid metabolism in multiple biological systems. We used nonlinear Raman techniques to characterize Meibum secretions in the progression of dry eye disease, where the lipid and protein contributions change in ratio and phase segregation. We employed similar tools to examine lipid droplets in mice livers aboard a spaceflight mission, which lose their retinol content contributing to the onset of nonalcoholic fatty-liver disease. We also focused on atherosclerosis, a disease that revolves around lipid-rich plaques in arterial walls. We examined the lipid content of macrophages, whose variable phenotype gives rise to contrasting healing and inflammatory activities. We also proposed new label-free markers, based on lifetime imaging, for macrophage phenotype, and to detect products of lipid oxidation. Cholesterol was also detected in hepatitis C virus infected cells, and in specific strains of age-related macular degeneration diseased cells by spontaneous Raman spectroscopy. We used synthesized highly-deuterated cholesterol to track its compartmentalization in adrenal cells, revealing heterogeneous lipid droplet content. These examples illustrate the potential of label-free nonlinear optical microscopy for unveiling complex physiological processes by direct visualization of lipids. Detailed image analysis and combined microscopy modalities will continue to reveal and quantify fundamental biology that will support the advance of biomedicine.

Pain management: a review of organisation models with integrated processes for the management of pain in adult cancer patients.

PubMed

Brink-Huis, Anita; van Achterberg, Theo; Schoonhoven, Lisette

2008-08-01

This paper reports a review of the literature conducted to identify organisation models in cancer pain management that contain integrated care processes and describe their effectiveness. Pain is experienced by 30-50% of cancer patients receiving treatment and by 70-90% of those with advanced disease. Efforts to improve pain management have been made through the development and dissemination of clinical guidelines. Early improvements in pain management were focussed on just one or two single processes such as pain assessment and patient education. Little is known about organisational models with multiple integrated processes throughout the course of the disease trajectory and concerning all stages of the care process. Systematic review. The review involved a systematic search of the literature, published between 1986-2006. Subject-specific keywords used to describe patients, disease, pain management interventions and integrated care processes, relevant for this review were selected using the thesaurus of the databases. Institutional models, clinical pathways and consultation services are three alternative models for the integration of care processes in cancer pain management. A clinical pathway is a comprehensive institutionalisation model, whereas a pain consultation service is a 'stand-alone' model that can be integrated in a clinical pathway. Positive patient and process outcomes have been described for all three models, although the level of evidence is generally low. Evaluation of the quality of pain management must involve standardised measurements of both patient and process outcomes. We recommend the development of policies for referrals to a pain consultation service. These policies can be integrated within a clinical pathway. To evaluate the effectiveness of pain management models standardised outcome measures are needed.

Treatment of progressive multiple sclerosis: what works, what does not, and what is needed.

PubMed

Feinstein, Anthony; Freeman, Jenny; Lo, Albert C

2015-02-01

Disease-modifying drugs have mostly failed as treatments for progressive multiple sclerosis. Management of the disease therefore solely aims to minimise symptoms and, if possible, improve function. The degree to which this approach is based on empirical data derived from studies of progressive disease or whether treatment decisions are based on what is known about relapsing-remitting disease remains unclear. Symptoms rated as important by patients with multiple sclerosis include balance and mobility impairments, weakness, reduced cardiovascular fitness, ataxia, fatigue, bladder dysfunction, spasticity, pain, cognitive deficits, depression, and pseudobulbar affect; a comprehensive literature search shows a notable paucity of studies devoted solely to these symptoms in progressive multiple sclerosis, which translates to few proven therapeutic options in the clinic. A new strategy that can be used in future rehabilitation trials is therefore needed, with the adoption of approaches that look beyond single interventions to concurrent, potentially synergistic, treatments that maximise what remains of neural plasticity in patients with progressive multiple sclerosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Population genetics suggest that multiple invasion processes need to be addressed in the management plan of a plant disease vector.

PubMed

Anderson, Kylie L; Congdon, Bradley C

2013-06-01

The use of a multidisciplinary approach is becoming increasingly important when developing management strategies that mitigate the economic and biological costs associated with invasive pests. A framework of simulated dispersal is combined with life-history information and analyses of population genetic structure to investigate the invasion dynamics of a plant disease vector, the island sugarcane planthopper (Eumetopina flavipes), through an archipelago of significant Australian quarantine concern. Analysis of eight microsatellite loci from 648 individuals suggests that frequent, wind-assisted immigration from multiple sources in Papua New Guinea contributes significantly to repeated colonization of far northern islands. However, intermittent wind-assisted immigration better explains patterns of genetic diversity and structure in the southern islands and on the tip of mainland Australia. Significant population structuring associated with the presence of clusters of highly related individuals results from breeding in-situ following colonization, with little postestablishment movement. Results also suggest that less important secondary movements occur between islands; these appear to be human mediated and restricted by quarantine zones. Control of the planthopper may be very difficult on islands close to Papua New Guinea given the apparent propensity for multiple invasion, but may be achievable further south where local populations appear highly independent and isolated.

A three-dimensional point process model for the spatial distribution of disease occurrence in relation to an exposure source.

PubMed

Grell, Kathrine; Diggle, Peter J; Frederiksen, Kirsten; Schüz, Joachim; Cardis, Elisabeth; Andersen, Per K

2015-10-15

We study methods for how to include the spatial distribution of tumours when investigating the relation between brain tumours and the exposure from radio frequency electromagnetic fields caused by mobile phone use. Our suggested point process model is adapted from studies investigating spatial aggregation of a disease around a source of potential hazard in environmental epidemiology, where now the source is the preferred ear of each phone user. In this context, the spatial distribution is a distribution over a sample of patients rather than over multiple disease cases within one geographical area. We show how the distance relation between tumour and phone can be modelled nonparametrically and, with various parametric functions, how covariates can be included in the model and how to test for the effect of distance. To illustrate the models, we apply them to a subset of the data from the Interphone Study, a large multinational case-control study on the association between brain tumours and mobile phone use. Copyright © 2015 John Wiley & Sons, Ltd.

Multiple Roles of Pitx2 in Cardiac Development and Disease

PubMed Central

2017-01-01

Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases. PMID:29367545

Radiation injury to the temporal bone

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

Guida, R.A.; Finn, D.G.; Buchalter, I.H.

1990-01-01

Osteoradionecrosis of the temporal bone is an unusual sequela of radiation therapy to the head and neck. Symptoms occur many years after the radiation is administered, and progression of the disease is insidious. Hearing loss (sensorineural, conductive, or mixed), otalgia, otorrhea, and even gross tissue extrusion herald this condition. Later, intracranial complications such as meningitis, temporal lobe or cerebellar abscess, and cranial neuropathies may occur. Reported here are five cases of this rare malady representing varying degrees of the disease process. They include a case of radiation-induced necrosis of the tympanic ring with persistent squamous debris in the external auditorymore » canal and middle ear. Another case demonstrates the progression of radiation otitis media to mastoiditis with bony sequestration. Further progression of the disease process is seen in a third case that evolved into multiple cranial neuropathies from skull base destruction. Treatment includes systemic antibiotics, local wound care, and debridement in cases of localized tissue involvement. More extensive debridement with removal of sequestrations, abscess drainage, reconstruction with vascularized tissue from regional flaps, and mastoid obliteration may be warranted for severe cases. Hyperbaric oxygen therapy has provided limited benefit.« less

Allostatic load and comorbidities: A mitochondrial, epigenetic, and evolutionary perspective.

PubMed

Juster, Robert-Paul; Russell, Jennifer J; Almeida, Daniel; Picard, Martin

2016-11-01

Stress-related pathophysiology drives comorbid trajectories that elude precise prediction. Allostatic load algorithms that quantify biological "wear and tear" represent a comprehensive approach to detect multisystemic disease processes of the mind and body. However, the multiple morbidities directly or indirectly related to stress physiology remain enigmatic. Our aim in this article is to propose that biological comorbidities represent discrete pathophysiological processes captured by measuring allostatic load. This has applications in research and clinical settings to predict physical and psychiatric comorbidities alike. The reader will be introduced to the concepts of allostasis, allostasic states, allostatic load, and allostatic overload as they relate to stress-related diseases and the proposed prediction of biological comorbidities that extend rather to understanding psychopathologies. In our transdisciplinary discussion, we will integrate perspectives related to (a) mitochondrial biology as a key player in the allostatic load time course toward diseases that "get under the skin and skull"; (b) epigenetics related to child maltreatment and biological embedding that shapes stress perception throughout lifespan development; and (c) evolutionary drivers of distinct personality profiles and biobehavioral patterns that are linked to dimensions of psychopathology.

Improving a full-text search engine: the importance of negation detection and family history context to identify cases in a biomedical data warehouse.

PubMed

Garcelon, Nicolas; Neuraz, Antoine; Benoit, Vincent; Salomon, Rémi; Burgun, Anita

2017-05-01

The repurposing of electronic health records (EHRs) can improve clinical and genetic research for rare diseases. However, significant information in rare disease EHRs is embedded in the narrative reports, which contain many negated clinical signs and family medical history. This paper presents a method to detect family history and negation in narrative reports and evaluates its impact on selecting populations from a clinical data warehouse (CDW). We developed a pipeline to process 1.6 million reports from multiple sources. This pipeline is part of the load process of the Necker Hospital CDW. We identified patients with "Lupus and diarrhea," "Crohn's and diabetes," and "NPHP1" from the CDW. The overall precision, recall, specificity, and F-measure were 0.85, 0.98, 0.93, and 0.91, respectively. The proposed method generates a highly accurate identification of cases from a CDW of rare disease EHRs. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Stiff-Person Syndrome

MedlinePlus

... The disorder is often misdiagnosed as Parkinson’s disease, multiple sclerosis, fibromyalgia, psychosomatic illness, or anxiety and phobia. A ... The disorder is often misdiagnosed as Parkinson’s disease, multiple sclerosis, fibromyalgia, psychosomatic illness, or anxiety and phobia. A ...

Brown-Sequard Syndrome

MedlinePlus

... infectious or inflammatory diseases such as tuberculosis, or multiple sclerosis. × Definition Brown-Sequard syndrome (BSS) is a rare ... infectious or inflammatory diseases such as tuberculosis, or multiple sclerosis. View Full Definition Treatment Generally treatment for individuals ...

Human genetics of infectious diseases: a unified theory

PubMed Central

Casanova, Jean-Laurent; Abel, Laurent

2007-01-01

Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans. PMID:17255931

Epstein Barr Virus and Blood Brain Barrier in Multiple Sclerosis

DTIC Science & Technology

2013-07-01

Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple sclerosis (MS) is a chronic, autoimmune neurodegenerative disease . Epstein - Barr ...of EBV in MS disease . 15. SUBJECT TERMS Blood-brain-barrier, Epstein - Barr virus ; EBV; BBB; MS, Multiple sclerosis 16. SECURITY CLASSIFICATION OF...AD_________________ Award Number: W81XWH-12-1-0225 TITLE: Epstein Barr virus and blood brain

Pervasive sharing of genetic effects in autoimmune disease.

PubMed

Cotsapas, Chris; Voight, Benjamin F; Rossin, Elizabeth; Lage, Kasper; Neale, Benjamin M; Wallace, Chris; Abecasis, Gonçalo R; Barrett, Jeffrey C; Behrens, Timothy; Cho, Judy; De Jager, Philip L; Elder, James T; Graham, Robert R; Gregersen, Peter; Klareskog, Lars; Siminovitch, Katherine A; van Heel, David A; Wijmenga, Cisca; Worthington, Jane; Todd, John A; Hafler, David A; Rich, Stephen S; Daly, Mark J

2011-08-01

Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

PubMed Central

Lidster, Katie; Jackson, Samuel J.; Ahmed, Zubair; Munro, Peter; Coffey, Pete; Giovannoni, Gavin; Baker, Mark D.; Baker, David

2013-01-01

Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine) or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment. PMID:24223903

Multiple sclerosis: individualized disease susceptibility and therapy response.

PubMed

Pravica, Vera; Markovic, Milos; Cupic, Maja; Savic, Emina; Popadic, Dusan; Drulovic, Jelena; Mostarica-Stojkovic, Marija

2013-02-01

Multiple sclerosis (MS) is a heterogeneous disease in which diverse genetic, pathological and clinical backgrounds lead to variable therapy response. Accordingly, MS care should be tailored to address disease traits unique to each person. At the core of personalized management is the emergence of new knowledge, enabling optimized treatment and disease-modifying therapies. This overview analyzes the promise of genetic and nongenetic biomarkers in advancing decision-making algorithms to assist diagnosis or in predicting the disease course and therapy response in any given MS patient.

Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery

PubMed Central

Valdés, Pablo A.; Kim, Anthony; Leblond, Frederic; Conde, Olga M.; Harris, Brent T.; Paulsen, Keith D.; Wilson, Brian C.; Roberts, David W.

2011-01-01

Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin concentration, oxygen saturation, and optical scattering parameters. We developed a diagnostic algorithm for intra-operative tissue delineation that accounts for the combined tumor-specific predictive capabilities of these quantitative biomarkers. Tumor tissue delineation achieved accuracies of up to 94% (specificity = 94%, sensitivity = 94%) across a range of glioma histologies beyond current state-of-the-art optical approaches, including state-of-the-art fluorescence image guidance. This multiple biomarker strategy opens the door to optical methods for surgical guidance that use quantification of well-established neoplastic processes. Future work would seek to validate the predictive power of this proof-of-concept study in a separate larger cohort of patients. PMID:22112112

Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery

NASA Astrophysics Data System (ADS)

Valdés, Pablo A.; Kim, Anthony; Leblond, Frederic; Conde, Olga M.; Harris, Brent T.; Paulsen, Keith D.; Wilson, Brian C.; Roberts, David W.

2011-11-01

Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin concentration, oxygen saturation, and optical scattering parameters. We developed a diagnostic algorithm for intra-operative tissue delineation that accounts for the combined tumor-specific predictive capabilities of these quantitative biomarkers. Tumor tissue delineation achieved accuracies of up to 94% (specificity = 94%, sensitivity = 94%) across a range of glioma histologies beyond current state-of-the-art optical approaches, including state-of-the-art fluorescence image guidance. This multiple biomarker strategy opens the door to optical methods for surgical guidance that use quantification of well-established neoplastic processes. Future work would seek to validate the predictive power of this proof-of-concept study in a separate larger cohort of patients.

Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins.

PubMed

Guerrero-Muñoz, Marcos J; Castillo-Carranza, Diana L; Kayed, Rakez

2014-04-15

Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions. Copyright © 2014 Elsevier Inc. All rights reserved.

[Coactivators in energy metabolism: peroxisome proliferator-activated receptor-gamma coactivator 1 family].

PubMed

Wang, Rui; Chang, Yong-sheng; Fang, Fu-de

2009-12-01

Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) family is highly expressed in tissues with high energy metabolism. They coactivate transcription factors in regulating genes engaged in processes such as gluconeogenesis, adipose beta-oxydation, lipoprotein synthesis and secretion, mitochondrial biogenesis, and oxidative metabolism. Protein conformation studies demonstrated that they lack DNA binding domains and act as coactivators through physical interaction with transcription factors. PGC1 activity is regulated at transcription level or by multiple covalent chemical modifications such as phosphorylation, methylation and acetylation/deacetylation. Abnormal expression of PGC1 coactivators usually is closely correlated with diseases such as diabetes, obesity, hyperglycemia, hyperlipemia, and arterial and brain neuron necrosis diseases.

Prospects for discovery by epigenome comparison

PubMed Central

Milosavljevic, Aleksandar

2010-01-01

Epigenomic analysis efforts have so far focused on the multiple layers of epigenomic information within individual cell types. With the rapidly increasing diversity of epigenomically mapped cell types, unprecedented opportunities for comparative analysis of epigenomes are opening up. One such opportunity is to map the bifurcating tree of cellular differentiation. Another is to understand the epigenomically mediated effects of mutations, environmental influences, and disease processes. Comparative analysis of epigenomes therefore has the potential to provide wide-ranging fresh insights into basic biology and human disease. The realization of this potential will critically depend on availability of a cyberinfrastructure that will scale with the volume of data and diversity of applications and a number of other computational challenges. PMID:20944597

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

NASA Astrophysics Data System (ADS)

Bürli, Roland W.; Thomas, Elizabeth; Beaumont, Vahri

Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

Discovering New Diseases to Accelerate Precision Medicine.

PubMed

Macrae, Calum A

2017-01-01

A rate-limiting step in multiple areas of medicine is the limited number of discrete disorders that current technologies are able to identify. Most clinical disease entities are aggregates of large numbers of discrete biological processes that simply happen to share one or two common features. We have begun to translate a wide range of new technologies to the clinic in an effort to improve the resolution and the efficiency of bedside diagnostics with a view to improving drug trials, genetic studies, and the effectiveness of the clinician in a digital environment. The general trajectory for change that new technologies will bring is outlined with some specific examples of areas where such change has already begun to occur.

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis

PubMed Central

Fletcher, Phillip D.; Downey, Laura E.; Golden, Hannah L.; Clark, Camilla N.; Slattery, Catherine F.; Paterson, Ross W.; Rohrer, Jonathan D.; Schott, Jonathan M.; Rossor, Martin N.

2015-01-01

Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52–84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer’s disease (n = 20, eight female, aged 53–74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients’ brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer’s disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer’s disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases. PMID:26463677

Collective Phenomena Emerging from the Interactions between Dynamical Processes in Multiplex Networks

NASA Astrophysics Data System (ADS)

Nicosia, Vincenzo; Skardal, Per Sebastian; Arenas, Alex; Latora, Vito

2017-03-01

We introduce a framework to intertwine dynamical processes of different nature, each with its own distinct network topology, using a multilayer network approach. As an example of collective phenomena emerging from the interactions of multiple dynamical processes, we study a model where neural dynamics and nutrient transport are bidirectionally coupled in such a way that the allocation of the transport process at one layer depends on the degree of synchronization at the other layer, and vice versa. We show numerically, and we prove analytically, that the multilayer coupling induces a spontaneous explosive synchronization and a heterogeneous distribution of allocations, otherwise not present in the two systems considered separately. Our framework can find application to other cases where two or more dynamical processes such as synchronization, opinion formation, information diffusion, or disease spreading, are interacting with each other.

Development of Partial Ontogenic Resistance to Powdery Mildew in Hop Cones and Its Management Implications

PubMed Central

Twomey, Megan C.; Wolfenbarger, Sierra N.; Woods, Joanna L.; Gent, David H.

2015-01-01

Knowledge of processes leading to crop damage is central to devising rational approaches to disease management. Multiple experiments established that infection of hop cones by Podosphaera macularis was most severe if inoculation occurred within 15 to 21 days after bloom. This period of infection was associated with the most pronounced reductions in alpha acids, cone color, and accelerated maturation of cones. Susceptibility of cones to powdery mildew decreased progressively after the transition from bloom to cone development, although complete immunity to the disease failed to develop. Maturation of cone tissues was associated with multiple significant affects on the pathogen manifested as reduced germination of conidia, diminished frequency of penetration of bracts, lengthening of the latent period, and decreased sporulation. Cones challenged with P. macularis in juvenile developmental stages also led to greater frequency of colonization by a complex of saprophytic, secondary fungi. Since no developmental stage of cones was immune to powdery mildew, the incidence of powdery mildew continued to increase over time and exceeded 86% by late summer. In field experiments with a moderately susceptible cultivar, the incidence of cones with powdery mildew was statistically similar when fungicide applications were made season-long or targeted only to the juvenile stages of cone development. These studies establish that partial ontogenic resistance develops in hop cones and may influence multiple phases of the infection process and pathogen reproduction. The results further reinforce the concept that the efficacy of a fungicide program may depend largely on timing of a small number of sprays during a relatively brief period of cone development. However in practice, targeting fungicide and other management tactics to periods of enhanced juvenile susceptibility may be complicated by a high degree of asynchrony in cone development and other factors that are situation-dependent. PMID:25811173

The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain.

PubMed

Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang; Lassmann, Hans

2016-03-01

Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Computerized clinical decision support systems for chronic disease management: a decision-maker-researcher partnership systematic review.

PubMed

Roshanov, Pavel S; Misra, Shikha; Gerstein, Hertzel C; Garg, Amit X; Sebaldt, Rolf J; Mackay, Jean A; Weise-Kelly, Lorraine; Navarro, Tamara; Wilczynski, Nancy L; Haynes, R Brian

2011-08-03

The use of computerized clinical decision support systems (CCDSSs) may improve chronic disease management, which requires recurrent visits to multiple health professionals, ongoing disease and treatment monitoring, and patient behavior modification. The objective of this review was to determine if CCDSSs improve the processes of chronic care (such as diagnosis, treatment, and monitoring of disease) and associated patient outcomes (such as effects on biomarkers and clinical exacerbations). We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for potentially eligible articles published up to January 2010. We included randomized controlled trials that compared the use of CCDSSs to usual practice or non-CCDSS controls. Trials were eligible if at least one component of the CCDSS was designed to support chronic disease management. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of relevant outcomes. Of 55 included trials, 87% (n = 48) measured system impact on the process of care and 52% (n = 25) of those demonstrated statistically significant improvements. Sixty-five percent (36/55) of trials measured impact on, typically, non-major (surrogate) patient outcomes, and 31% (n = 11) of those demonstrated benefits. Factors of interest to decision makers, such as cost, user satisfaction, system interface and feature sets, unique design and deployment characteristics, and effects on user workflow were rarely investigated or reported. A small majority (just over half) of CCDSSs improved care processes in chronic disease management and some improved patient health. Policy makers, healthcare administrators, and practitioners should be aware that the evidence of CCDSS effectiveness is limited, especially with respect to the small number and size of studies measuring patient outcomes.

The central role of AMP-kinase and energy homeostasis impairment in Alzheimer's disease: a multifactor network analysis.

PubMed

Caberlotto, Laura; Lauria, Mario; Nguyen, Thanh-Phuong; Scotti, Marco

2013-01-01

Alzheimer's disease is the most common cause of dementia worldwide, affecting the elderly population. It is characterized by the hallmark pathology of amyloid-β deposition, neurofibrillary tangle formation, and extensive neuronal degeneration in the brain. Wealth of data related to Alzheimer's disease has been generated to date, nevertheless, the molecular mechanism underlying the etiology and pathophysiology of the disease is still unknown. Here we described a method for the combined analysis of multiple types of genome-wide data aimed at revealing convergent evidence interest that would not be captured by a standard molecular approach. Lists of Alzheimer-related genes (seed genes) were obtained from different sets of data on gene expression, SNPs, and molecular targets of drugs. Network analysis was applied for identifying the regions of the human protein-protein interaction network showing a significant enrichment in seed genes, and ultimately, in genes associated to Alzheimer's disease, due to the cumulative effect of different combinations of the starting data sets. The functional properties of these enriched modules were characterized, effectively considering the role of both Alzheimer-related seed genes and genes that closely interact with them. This approach allowed us to present evidence in favor of one of the competing theories about AD underlying processes, specifically evidence supporting a predominant role of metabolism-associated biological process terms, including autophagy, insulin and fatty acid metabolic processes in Alzheimer, with a focus on AMP-activated protein kinase. This central regulator of cellular energy homeostasis regulates a series of brain functions altered in Alzheimer's disease and could link genetic perturbation with neuronal transmission and energy regulation, representing a potential candidate to be targeted by therapy.

Computerized clinical decision support systems for chronic disease management: A decision-maker-researcher partnership systematic review

PubMed Central

2011-01-01

Background The use of computerized clinical decision support systems (CCDSSs) may improve chronic disease management, which requires recurrent visits to multiple health professionals, ongoing disease and treatment monitoring, and patient behavior modification. The objective of this review was to determine if CCDSSs improve the processes of chronic care (such as diagnosis, treatment, and monitoring of disease) and associated patient outcomes (such as effects on biomarkers and clinical exacerbations). Methods We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for potentially eligible articles published up to January 2010. We included randomized controlled trials that compared the use of CCDSSs to usual practice or non-CCDSS controls. Trials were eligible if at least one component of the CCDSS was designed to support chronic disease management. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of relevant outcomes. Results Of 55 included trials, 87% (n = 48) measured system impact on the process of care and 52% (n = 25) of those demonstrated statistically significant improvements. Sixty-five percent (36/55) of trials measured impact on, typically, non-major (surrogate) patient outcomes, and 31% (n = 11) of those demonstrated benefits. Factors of interest to decision makers, such as cost, user satisfaction, system interface and feature sets, unique design and deployment characteristics, and effects on user workflow were rarely investigated or reported. Conclusions A small majority (just over half) of CCDSSs improved care processes in chronic disease management and some improved patient health. Policy makers, healthcare administrators, and practitioners should be aware that the evidence of CCDSS effectiveness is limited, especially with respect to the small number and size of studies measuring patient outcomes. PMID:21824386

Trophic factors in neurologic disease.

PubMed

Stewart, S S; Appel, S H

1988-01-01

Recent studies suggest that diffusible factors released by neural targets enhance the survival, growth, and differentiation of neurons both peripherally and in the central nervous system. Evidence for such trophic factors exists for many of the neural systems involved in the degenerative neurologic diseases Alzheimer's disease, parkinsonism, and amyotrophic lateral sclerosis. It is our hypothesis that for each of these disorders there is both a primary insult and a secondary effect. The primary insult may have multiple etiologies, but the secondary effect is the result of retrograde degeneration. Such retrograde degeneration occurs because of an impairment of trophic factor function or an inadequacy of trophic effects to keep pace with the primary destructive process. Accordingly, it may be possible to exploit such trophic mechanisms to define further the pathobiology of neural degeneration and to develop specific treatments for currently incurable illnesses.

Autophagy and kidney inflammation

PubMed Central

Kimura, Tomonori; Isaka, Yoshitaka; Yoshimori, Tamotsu

2017-01-01

ABSTRACT Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. It is noteworthy that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy. In this mode, autophagy suppresses inflammation to protect the kidney. Systemic inflammation also affects the kidney via pro-inflammatory cytokines and infiltration of inflammatory cells, and autophagy also has a regulatory role in systemic inflammation. This review focuses on the roles of autophagy in kidney diseases and aging through inflammation, and discusses the potential usage of autophagy as an inflammatory modulator for the treatment of kidney diseases. PMID:28441075

Mechanisms of protein-folding diseases at a glance.

PubMed

Valastyan, Julie S; Lindquist, Susan

2014-01-01

For a protein to function appropriately, it must first achieve its proper conformation and location within the crowded environment inside the cell. Multiple chaperone systems are required to fold proteins correctly. In addition, degradation pathways participate by destroying improperly folded proteins. The intricacy of this multisystem process provides many opportunities for error. Furthermore, mutations cause misfolded, nonfunctional forms of proteins to accumulate. As a result, many pathological conditions are fundamentally rooted in the protein-folding problem that all cells must solve to maintain their function and integrity. Here, to illustrate the breadth of this phenomenon, we describe five examples of protein-misfolding events that can lead to disease: improper degradation, mislocalization, dominant-negative mutations, structural alterations that establish novel toxic functions, and amyloid accumulation. In each case, we will highlight current therapeutic options for battling such diseases.

Molecular brain imaging in the multimodality era

PubMed Central

Price, Julie C

2012-01-01

Multimodality molecular brain imaging encompasses in vivo visualization, evaluation, and measurement of cellular/molecular processes. Instrumentation and software developments over the past 30 years have fueled advancements in multimodality imaging platforms that enable acquisition of multiple complementary imaging outcomes by either combined sequential or simultaneous acquisition. This article provides a general overview of multimodality neuroimaging in the context of positron emission tomography as a molecular imaging tool and magnetic resonance imaging as a structural and functional imaging tool. Several image examples are provided and general challenges are discussed to exemplify complementary features of the modalities, as well as important strengths and weaknesses of combined assessments. Alzheimer's disease is highlighted, as this clinical area has been strongly impacted by multimodality neuroimaging findings that have improved understanding of the natural history of disease progression, early disease detection, and informed therapy evaluation. PMID:22434068

Glycosyltransferases and non-alcoholic fatty liver disease

PubMed Central

Zhan, Yu-Tao; Su, Hai-Ying; An, Wei

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases (GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized. PMID:26937136

Strain-related effects of fenbendazole treatment on murine experimental autoimmune encephalomyelitis.

PubMed

Ramp, A A; Hall, C; Orian, J M

2010-07-01

Parasitic infections are a concern in animal facilities, in view of their influence on physiological processes and the immune status of animals. Pinworms are effectively controlled with the anthelminthic fenbendazole (FBZ, [5-(phenylthio)-1H-benzamidazol-2-yl]carbamic acid methyl ester; C(15)H(13)N(3)O(2)S); however, questions remain as to whether prolonged FBZ exposure alters the disease course in specific experimental models, such as those pertaining to the immune system. We report that a three-month regimen of FBZ-medicated feed severely affected the onset and disease severity of murine experimental autoimmune encephalomyelitis (EAE), a disease that mimics multiple sclerosis. Differences were recorded between mouse strains used. Our data suggest that where the use of FBZ is mandatory, its full effect should be verified on the particular EAE variant adopted by the laboratory.

Autophagy and kidney inflammation.

PubMed

Kimura, Tomonori; Isaka, Yoshitaka; Yoshimori, Tamotsu

2017-06-03

Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. It is noteworthy that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy. In this mode, autophagy suppresses inflammation to protect the kidney. Systemic inflammation also affects the kidney via pro-inflammatory cytokines and infiltration of inflammatory cells, and autophagy also has a regulatory role in systemic inflammation. This review focuses on the roles of autophagy in kidney diseases and aging through inflammation, and discusses the potential usage of autophagy as an inflammatory modulator for the treatment of kidney diseases.

Comparative biology of the neuronal ceroid-lipofuscinoses (NCL): an overview.

PubMed

Jolly, R D

1995-06-05

Multiple forms of ceroid-lipofuscinosis occur in human beings and animals. They are characterized by brain and retinal atrophy associated with selective necrosis of neurons. This neurodegenerative disease appears associated with the disease process rather than storage of fluorescent lipopigment per se, and there is now growing evidence that pathogenesis may involve mitochondria rather than a primary defect of lysosomal catabolism. Of the forms of ceroid-lipofuscinosis studied, most but not all reflect accumulation of subunit c of mitochondrial ATP synthase. If there is a common denominator between all forms other than the presence of fluorescent lipopigment, then it may be the accumulation of hydrophobic protein. Analogous diseases in animals can be expected to reflect the same spectrum of biochemical changes, and they warrant in-depth study to help understand the pathogenesis and heterogeneity of the group.

Multiple Sclerosis in Malaysia: Demographics, Clinical Features, and Neuroimaging Characteristics

PubMed Central

Viswanathan, S.; Rose, N.; Masita, A.; Dhaliwal, J. S.; Puvanarajah, S. D.; Rafia, M. H.; Muda, S.

2013-01-01

Background. Multiple sclerosis (MS) is an uncommon disease in multiracial Malaysia. Diagnosing patients with idiopathic inflammatory demyelinating diseases has been greatly aided by the evolution in diagnostic criterion, the identification of new biomarkers, and improved accessibility to neuroimaging in the country. Objectives. To investigate the spectrum of multiple sclerosis in Malaysia. Methods. Retrospective analysis with longitudinal follow-up of patients referred to a single tertiary medical center with neurology services in Malaysia. Results. Out of 245 patients with idiopathic inflammatory demyelinating disease, 104 patients had multiple sclerosis. Female to male ratio was 5 : 1. Mean age at onset was 28.6 ± 9.9 years. The Malays were the predominant racial group affected followed by the Chinese, Indians, and other indigenous groups. Subgroup analysis revealed more Chinese having neuromyelitis optica and its spectrum disorders rather than multiple sclerosis. Positive family history was reported in 5%. Optic neuritis and myelitis were the commonest presentations at onset of disease, and relapsing remitting course was the commonest disease pattern observed. Oligoclonal band positivity was 57.6%. At disease onset, 61.5% and 66.4% fulfilled the 2005 and 2010 McDonald's criteria for dissemination in space. Mean cord lesion length was 1.86 ± 1.65 vertebral segments in the relapsing remitting group as opposed to 6.25 ± 5.18 vertebral segments in patients with neuromyelitis optica and its spectrum disorders. Conclusion. The spectrum of multiple sclerosis in Malaysia has changed over the years. Further advancement in diagnostic criteria will no doubt continue to contribute to the evolution of this disease here. PMID:24455266

Bioinformatics Knowledge Map for Analysis of Beta-Catenin Function in Cancer

PubMed Central

Arighi, Cecilia N.; Wu, Cathy H.

2015-01-01

Given the wealth of bioinformatics resources and the growing complexity of biological information, it is valuable to integrate data from disparate sources to gain insight into the role of genes/proteins in health and disease. We have developed a bioinformatics framework that combines literature mining with information from biomedical ontologies and curated databases to create knowledge “maps” of genes/proteins of interest. We applied this approach to the study of beta-catenin, a cell adhesion molecule and transcriptional regulator implicated in cancer. The knowledge map includes post-translational modifications (PTMs), protein-protein interactions, disease-associated mutations, and transcription factors co-activated by beta-catenin and their targets and captures the major processes in which beta-catenin is known to participate. Using the map, we generated testable hypotheses about beta-catenin biology in normal and cancer cells. By focusing on proteins participating in multiple relation types, we identified proteins that may participate in feedback loops regulating beta-catenin transcriptional activity. By combining multiple network relations with PTM proteoform-specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity. Finally, by overlaying cancer-associated mutation data with sequence features, we observed mutation patterns in several beta-catenin PTM sites and PTM enzyme binding sites that varied by tissue type, suggesting multiple mechanisms by which beta-catenin mutations can contribute to cancer. The approach described, which captures rich information for molecular species from genes and proteins to PTM proteoforms, is extensible to other proteins and their involvement in disease. PMID:26509276

Epigenetic polypharmacology: from combination therapy to multitargeted drugs.

PubMed

de Lera, Angel R; Ganesan, A

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed.

Medication-taking behaviours in chronic kidney disease with multiple chronic conditions: a meta-ethnographic synthesis of qualitative studies.

PubMed

Bartlett Ellis, Rebecca J; Welch, Janet L

2017-03-01

To identify behaviours associated with taking medications and medication adherence reported in qualitative studies of adults with chronic kidney disease and coexisting multiple chronic conditions. To inform medication adherence interventions, information is needed to clarify the nature of the relationships between behaviours that support medication-taking and medication adherence in multiple chronic conditions. Meta-ethnographic review and synthesis. CINAHL Complete, MEDLINE and PsycINFO databases were searched. Five qualitative studies met the inclusion criteria. A meta-ethnographic approach was used for synthesis. Medication-taking behaviours were abstracted from study findings and synthesised according to the contexts in which they occur and interpreted within a new developing framework named the Medication-taking Across the Care Continuum and Adherence-related Outcomes. Twenty categories of medication-taking behaviours occurred in three main contexts: (1) patient-provider clinical encounters, (2) pharmacy encounters and (3) day-to-day management. These behaviours are distinctly different, multilevel and interrelated. Together they represent a process occurring across a continuum. Future medication adherence research should consider using a multilevel ecological view of medication management. Clinical practice and policy development can benefit from further understanding socio-contextual behaviours that occur across the continuum. Nurses should have greater presence in chronic disease management and be positioned to support the day-to-day home management of patients' medications. Healthcare professionals can partner with patients to elucidate how these behaviours are enacted across the care continuum and in day-to-day management to identify opportunities to intervene on specific behaviours and promote medication adherence. © 2016 John Wiley & Sons Ltd.

Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration

PubMed Central

van Dijk, Gertjan; van Heijningen, Steffen; Reijne, Aaffien C.; Nyakas, Csaba; van der Zee, Eddy A.; Eisel, Ulrich L. M.

2015-01-01

Alzheimer's disease (AD) is a complex, multifactorial disease with a number of leading mechanisms, including neuroinflammation, processing of amyloid precursor protein (APP) to amyloid β peptide, tau protein hyperphosphorylation, relocalization, and deposition. These mechanisms are propagated by obesity, the metabolic syndrome and type-2 diabetes mellitus. Stress, sedentariness, dietary overconsumption of saturated fat and refined sugars, and circadian derangements/disturbed sleep contribute to obesity and related metabolic diseases, but also accelerate age-related damage and senescence that all feed the risk of developing AD too. The complex and interacting mechanisms are not yet completely understood and will require further analysis. Instead of investigating AD as a mono- or oligocausal disease we should address the disease by understanding the multiple underlying mechanisms and how these interact. Future research therefore might concentrate on integrating these by “systems biology” approaches, but also to regard them from an evolutionary medicine point of view. The current review addresses several of these interacting mechanisms in animal models and compares them with clinical data giving an overview about our current knowledge and puts them into an integrated framework. PMID:26041981

[Clinical and therapeutical considerations regarding the diagnosis and treatment in meconial disease].

PubMed

Sabetay, C; Ciobanu, O; Zavate, A; Ciucă, M; Malos, A; Marin-Diu, B

2010-01-01

The meconium disease represents a problem of great impact over the vital prognosis of the newborn, the mortality of this disease being rated in various studies between 30 and 50%. The meconial disease that reunites the meconial ileus and the meconial peritonitis is often associated with cystic fibrosis a disease of general impact over the entire organism increasing the gravity and influencing the vital prognosis of these patients. The authors' purpose is to evaluate the results obtained after the treatment of the meconial disease in the Pediatric Surgery Clinic of the Emergency Hospital of Craiova over a period of 10 years. The study has been made on a number of 16 cases of meconial ileus, plug and peritonitis analising the difficulty of the diagnostic process, the preoperative care as well as the possibilities of surgical treatment. The surgical treatment is composed of multiple procedures including simple suture of the bowel defect and segmentary bowel resections with primary anastomosis and/or secondary anastomosis after ileostoma. The mortality on the studied cases was of 37.5% despite recent progresses achieved in postoperative care of these type of patients.

CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease?

PubMed

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

2009-12-01

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as "immune privilege," it is now clear that immune responses do occur in the CNS-giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.

Autophagy and Mis-targeting of Therapeutic Enzyme in Skeletal Muscle in Pompe Disease

PubMed Central

Fukuda, Tokiko; Ahearn, Meghan; Roberts, Ashley; Mattaliano, Robert J.; Zaal, Kristien; Ralston, Evelyn; Plotz, Paul H.; Raben, Nina

2009-01-01

Enzyme replacement therapy (ERT) became a reality for patients with Pompe disease, a fatal cardiomyopathy and skeletal muscle myopathy caused by a deficiency of glycogen-degrading lysosomal enzyme acid alpha-glucosidase (GAA). The therapy, which relies on receptor-mediated endocytosis of recombinant human GAA (rhGAA), appears to be effective in cardiac muscle, but less so in skeletal muscle. We have previously shown a profound disturbance of the lysosomal degradative pathway (autophagy) in therapy-resistant muscle of GAA knockout mice (KO). Our findings here demonstrate a progressive age-dependent autophagic build-up in addition to enlargement of glycogen-filled lysosomes in multiple muscle groups in the KO. Trafficking and processing of the therapeutic enzyme along the endocytic pathway appear to be affected by the autophagy. Confocal microscopy of live single muscle fibers exposed to fluorescently labeled rhGAA indicates that a significant portion of the endocytosed enzyme in the KO was trapped as a partially processed form in the autophagic areas instead of reaching its target – the lysosomes. A fluid-phase endocytic marker was similarly mis-targeted and accumulated in vesicular structures within the autophagic areas. These findings may explain why ERT often falls short of reversing the disease process, and point to new avenues for the development of pharmacological intervention. PMID:17008131

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis.

PubMed

Loeffler, Jean-Philippe; Picchiarelli, Gina; Dupuis, Luc; Gonzalez De Aguilar, Jose-Luis

2016-03-01

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets. © 2016 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Top 10 Research Questions Related to Physical Activity and Multiple Sclerosis

ERIC Educational Resources Information Center

Motl, Robert W.; Learmonth, Yvonne C.; Pilutti, Lara A.; Gappmaier, Eduard; Coote, Susan

2015-01-01

An estimated 2.5 million people worldwide are living with multiple sclerosis (MS), and this disease may be increasing in prevalence. MS is a disease of the central nervous system that is associated with heterogeneous symptoms and functional consequences, and the current first-line disease-modifying therapies often become ineffective later in the…

The Certainty of Uncertainty: Potential Sources of Bias and Imprecision in Disease Ecology Studies.

PubMed

Lachish, Shelly; Murray, Kris A

2018-01-01

Wildlife diseases have important implications for wildlife and human health, the preservation of biodiversity and the resilience of ecosystems. However, understanding disease dynamics and the impacts of pathogens in wild populations is challenging because these complex systems can rarely, if ever, be observed without error. Uncertainty in disease ecology studies is commonly defined in terms of either heterogeneity in detectability (due to variation in the probability of encountering, capturing, or detecting individuals in their natural habitat) or uncertainty in disease state assignment (due to misclassification errors or incomplete information). In reality, however, uncertainty in disease ecology studies extends beyond these components of observation error and can arise from multiple varied processes, each of which can lead to bias and a lack of precision in parameter estimates. Here, we present an inventory of the sources of potential uncertainty in studies that attempt to quantify disease-relevant parameters from wild populations (e.g., prevalence, incidence, transmission rates, force of infection, risk of infection, persistence times, and disease-induced impacts). We show that uncertainty can arise via processes pertaining to aspects of the disease system, the study design, the methods used to study the system, and the state of knowledge of the system, and that uncertainties generated via one process can propagate through to others because of interactions between the numerous biological, methodological and environmental factors at play. We show that many of these sources of uncertainty may not be immediately apparent to researchers (for example, unidentified crypticity among vectors, hosts or pathogens, a mismatch between the temporal scale of sampling and disease dynamics, demographic or social misclassification), and thus have received comparatively little consideration in the literature to date. Finally, we discuss the type of bias or imprecision introduced by these varied sources of uncertainty and briefly present appropriate sampling and analytical methods to account for, or minimise, their influence on estimates of disease-relevant parameters. This review should assist researchers and practitioners to navigate the pitfalls of uncertainty in wildlife disease ecology studies.

Discovering disease associations by integrating electronic clinical data and medical literature.

PubMed

Holmes, Antony B; Hawson, Alexander; Liu, Feng; Friedman, Carol; Khiabanian, Hossein; Rabadan, Raul

2011-01-01

Electronic health record (EHR) systems offer an exceptional opportunity for studying many diseases and their associated medical conditions within a population. The increasing number of clinical record entries that have become available electronically provides access to rich, large sets of patients' longitudinal medical information. By integrating and comparing relations found in the EHRs with those already reported in the literature, we are able to verify existing and to identify rare or novel associations. Of particular interest is the identification of rare disease co-morbidities, where the small numbers of diagnosed patients make robust statistical analysis difficult. Here, we introduce ADAMS, an Application for Discovering Disease Associations using Multiple Sources, which contains various statistical and language processing operations. We apply ADAMS to the New York-Presbyterian Hospital's EHR to combine the information from the relational diagnosis tables and textual discharge summaries with those from PubMed and Wikipedia in order to investigate the co-morbidities of the rare diseases Kaposi sarcoma, toxoplasmosis, and Kawasaki disease. In addition to finding well-known characteristics of diseases, ADAMS can identify rare or previously unreported associations. In particular, we report a statistically significant association between Kawasaki disease and diagnosis of autistic disorder.

Discovering Disease Associations by Integrating Electronic Clinical Data and Medical Literature

PubMed Central

Holmes, Antony B.; Hawson, Alexander; Liu, Feng; Friedman, Carol; Khiabanian, Hossein; Rabadan, Raul

2011-01-01

Electronic health record (EHR) systems offer an exceptional opportunity for studying many diseases and their associated medical conditions within a population. The increasing number of clinical record entries that have become available electronically provides access to rich, large sets of patients' longitudinal medical information. By integrating and comparing relations found in the EHRs with those already reported in the literature, we are able to verify existing and to identify rare or novel associations. Of particular interest is the identification of rare disease co-morbidities, where the small numbers of diagnosed patients make robust statistical analysis difficult. Here, we introduce ADAMS, an Application for Discovering Disease Associations using Multiple Sources, which contains various statistical and language processing operations. We apply ADAMS to the New York-Presbyterian Hospital's EHR to combine the information from the relational diagnosis tables and textual discharge summaries with those from PubMed and Wikipedia in order to investigate the co-morbidities of the rare diseases Kaposi sarcoma, toxoplasmosis, and Kawasaki disease. In addition to finding well-known characteristics of diseases, ADAMS can identify rare or previously unreported associations. In particular, we report a statistically significant association between Kawasaki disease and diagnosis of autistic disorder. PMID:21731656

Engineering tolerance using biomaterials to target and control antigen presenting cells.

PubMed

Tostanoski, Lisa H; Gosselin, Emily A; Jewell, Christopher M

2016-05-01

Autoimmune diseases occur when cells of the adaptive immune system incorrectly recognize and attack "self" tissues. Importantly, the proliferation and differentiation of these cells is triggered and controlled by interactions with antigen presenting cells (APCs), such as dendritic cells. Thus, modulating the signals transduced by APCs (e.g., cytokines, costimulatory surface proteins) has emerged as a promising strategy to promote tolerance for diseases such as multiple sclerosis, type 1 diabetes, and lupus. However, many approaches have been hindered by non-specific activity of immunosuppressive or immunoregulatory cues, following systemic administration of soluble factors via traditional injections routes (e.g., subcutaneous, intravenous). Biomaterials offer a unique opportunity to control the delivery of tolerogenic signals in vivo via properties such as controlled particle size, tunable release kinetics, and co-delivery of multiple classes of cargo. In this review, we highlight recent reports that exploit these properties of biomaterials to target APCs and promote tolerance via three strategies, i) passive or active targeting of particulate carriers to APCs, ii) biomaterial-mediated control over antigen localization and processing, and iii) targeted delivery of encapsulated or adsorbed immunomodulatory signals. These reports represent exciting advances toward the goal of more effective therapies for autoimmune diseases, without the broad suppressive effects associated with current clinically-approved therapies.

Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease

PubMed Central

McKee, Timothy D.; Loureiro, Robyn M. B.; Dumin, Jo Ann; Xia, Weiming; Pojasek, Kevin; Austin, Wesley F.; Fuller, Nathan O.; Hubbs, Jed L.; Shen, Ruichao; Jonker, Jeff; Ives, Jeff; Bronk, Brian S.

2012-01-01

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aβ 42. Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aβ 42 and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity. PMID:23320246

Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis.

PubMed

McKenzie, Brienne A; Mamik, Manmeet K; Saito, Leina B; Boghozian, Roobina; Monaco, Maria Chiara; Major, Eugene O; Lu, Jian-Qiang; Branton, William G; Power, Christopher

2018-06-12

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS of unknown cause that remains incurable. Inflammasome-associated caspases mediate the maturation and release of the proinflammatory cytokines IL-1β and IL-18 and activate the pore-forming protein gasdermin D (GSDMD). Inflammatory programmed cell death, pyroptosis, was recently shown to be mediated by GSDMD. Here, we report molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both myeloid cells (macrophages/microglia) and, unexpectedly, in myelin-forming oligodendrocytes (ODCs) in the CNS of patients with MS and in the MS animal model, experimental autoimmune encephalomyelitis (EAE). We observed inflammasome activation and pyroptosis in human microglia and ODCs in vitro after exposure to inflammatory stimuli and demonstrate caspase-1 inhibition by the small-molecule inhibitor VX-765 in both cell types. GSDMD inhibition by siRNA transduction suppressed pyroptosis in human microglia. VX-765 treatment of EAE animals reduced the expression of inflammasome- and pyroptosis-associated proteins in the CNS, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in select glia cells is a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating the disease process in MS and other CNS inflammatory diseases.

Robust detection of multiple sclerosis lesions from intensity-normalized multi-channel MRI

NASA Astrophysics Data System (ADS)

Karpate, Yogesh; Commowick, Olivier; Barillot, Christian

2015-03-01

Multiple sclerosis (MS) is a disease with heterogeneous evolution among the patients. Quantitative analysis of longitudinal Magnetic Resonance Images (MRI) provides a spatial analysis of the brain tissues which may lead to the discovery of biomarkers of disease evolution. Better understanding of the disease will lead to a better discovery of pathogenic mechanisms, allowing for patient-adapted therapeutic strategies. To characterize MS lesions, we propose a novel paradigm to detect white matter lesions based on a statistical framework. It aims at studying the benefits of using multi-channel MRI to detect statistically significant differences between each individual MS patient and a database of control subjects. This framework consists in two components. First, intensity standardization is conducted to minimize the inter-subject intensity difference arising from variability of the acquisition process and different scanners. The intensity normalization maps parameters obtained using a robust Gaussian Mixture Model (GMM) estimation not affected by the presence of MS lesions. The second part studies the comparison of multi-channel MRI of MS patients with respect to an atlas built from the control subjects, thereby allowing us to look for differences in normal appearing white matter, in and around the lesions of each patient. Experimental results demonstrate that our technique accurately detects significant differences in lesions consequently improving the results of MS lesion detection.

Behavioural change models for infectious disease transmission: a systematic review (2010–2015)

PubMed Central

2016-01-01

We review behavioural change models (BCMs) for infectious disease transmission in humans. Following the Cochrane collaboration guidelines and the PRISMA statement, our systematic search and selection yielded 178 papers covering the period 2010–2015. We observe an increasing trend in published BCMs, frequently coupled to (re)emergence events, and propose a categorization by distinguishing how information translates into preventive actions. Behaviour is usually captured by introducing information as a dynamic parameter (76/178) or by introducing an economic objective function, either with (26/178) or without (37/178) imitation. Approaches using information thresholds (29/178) and exogenous behaviour formation (16/178) are also popular. We further classify according to disease, prevention measure, transmission model (with 81/178 population, 6/178 metapopulation and 91/178 individual-level models) and the way prevention impacts transmission. We highlight the minority (15%) of studies that use any real-life data for parametrization or validation and note that BCMs increasingly use social media data and generally incorporate multiple sources of information (16/178), multiple types of information (17/178) or both (9/178). We conclude that individual-level models are increasingly used and useful to model behaviour changes. Despite recent advancements, we remain concerned that most models are purely theoretical and lack representative data and a validation process. PMID:28003528

SEA: a super-enhancer archive.

PubMed

Wei, Yanjun; Zhang, Shumei; Shang, Shipeng; Zhang, Bin; Li, Song; Wang, Xinyu; Wang, Fang; Su, Jianzhong; Wu, Qiong; Liu, Hongbo; Zhang, Yan

2016-01-04

Super-enhancers are large clusters of transcriptional enhancers regarded as having essential roles in driving the expression of genes that control cell identity during development and tumorigenesis. The construction of a genome-wide super-enhancer database is urgently needed to better understand super-enhancer-directed gene expression regulation for a given biology process. Here, we present a specifically designed web-accessible database, Super-Enhancer Archive (SEA, http://sea.edbc.org). SEA focuses on integrating super-enhancers in multiple species and annotating their potential roles in the regulation of cell identity gene expression. The current release of SEA incorporates 83 996 super-enhancers computationally or experimentally identified in 134 cell types/tissues/diseases, including human (75 439, three of which were experimentally identified), mouse (5879, five of which were experimentally identified), Drosophila melanogaster (1774) and Caenorhabditis elegans (904). To facilitate data extraction, SEA supports multiple search options, including species, genome location, gene name, cell type/tissue and super-enhancer name. The response provides detailed (epi)genetic information, incorporating cell type specificity, nearby genes, transcriptional factor binding sites, CRISPR/Cas9 target sites, evolutionary conservation, SNPs, H3K27ac, DNA methylation, gene expression and TF ChIP-seq data. Moreover, analytical tools and a genome browser were developed for users to explore super-enhancers and their roles in defining cell identity and disease processes in depth. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Enhancing the Ability of Experimental Autoimmune Encephalomyelitis to Serve as a More Rigorous Model of Multiple Sclerosis through Refinement of the Experimental Design

PubMed Central

Emerson, Mitchell R; Gallagher, Ryan J; Marquis, Janet G; LeVine, Steven M

2009-01-01

Advancing the understanding of the mechanisms involved in the pathogenesis of multiple sclerosis (MS) likely will lead to new and better therapeutics. Although important information about the disease process has been obtained from research on pathologic specimens, peripheral blood lymphocytes and MRI studies, the elucidation of detailed mechanisms has progressed largely through investigations using animal models of MS. In addition, animal models serve as an important tool for the testing of putative interventions. The most commonly studied model of MS is experimental autoimmune encephalomyelitis (EAE). This model can be induced in a variety of species and by various means, but there has been concern that the model may not accurately reflect the disease process, and more importantly, it may give rise to erroneous findings when it is used to test possible therapeutics. Several reasons have been given to explain the shortcomings of this model as a useful testing platform, but one idea provides a framework for improving the value of this model, and thus, it deserves careful consideration. In particular, the idea asserts that EAE studies are inadequately designed to enable appropriate evaluation of putative therapeutics. Here we discuss problem areas within EAE study designs and provide suggestions for their improvement. This paper is principally directed at investigators new to the field of EAE, although experienced investigators may find useful suggestions herein. PMID:19389303

Lesion registration for longitudinal disease tracking in an imaging informatics-based multiple sclerosis eFolder

NASA Astrophysics Data System (ADS)

Ma, Kevin; Liu, Joseph; Zhang, Xuejun; Lerner, Alex; Shiroishi, Mark; Amezcua, Lilyana; Liu, Brent

2016-03-01

We have designed and developed a multiple sclerosis eFolder system for patient data storage, image viewing, and automatic lesion quantification results stored in DICOM-SR format. The web-based system aims to be integrated in DICOM-compliant clinical and research environments to aid clinicians in patient treatments and data analysis. The system needs to quantify lesion volumes, identify and register lesion locations to track shifts in volume and quantity of lesions in a longitudinal study. In order to perform lesion registration, we have developed a brain warping and normalizing methodology using Statistical Parametric Mapping (SPM) MATLAB toolkit for brain MRI. Patients' brain MR images are processed via SPM's normalization processes, and the brain images are analyzed and warped according to the tissue probability map. Lesion identification and contouring are completed by neuroradiologists, and lesion volume quantification is completed by the eFolder's CAD program. Lesion comparison results in longitudinal studies show key growth and active regions. The results display successful lesion registration and tracking over a longitudinal study. Lesion change results are graphically represented in the web-based user interface, and users are able to correlate patient progress and changes in the MRI images. The completed lesion and disease tracking tool would enable the eFolder to provide complete patient profiles, improve the efficiency of patient care, and perform comprehensive data analysis through an integrated imaging informatics system.

Differential diagnosis of suspected multiple sclerosis: a consensus approach

PubMed Central

Miller, DH; Weinshenker, BG; Filippi, M; Banwell, BL; Cohen, JA; Freedman, MS; Galetta, SL; Hutchinson, M; Johnson, RT; Kappos, L; Kira, J; Lublin, FD; McFarland, HF; Montalban, X; Panitch, H; Richert, JR; Reingold, SC; Polman, CH

2008-01-01

Background and objectives Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. Methods Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. Results We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. Conclusions Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision. PMID:18805839

Implementation of cardiovascular disease prevention in primary health care: enhancing understanding using normalisation process theory.

PubMed

Volker, Nerida; Williams, Lauren T; Davey, Rachel C; Cochrane, Thomas; Clancy, Tanya

2017-02-24

The reorientation of primary health care towards prevention is fundamental to addressing the rising burden of chronic disease. However, in Australia, cardiovascular disease prevention practice in primary health care is not generally consistent with existing guidelines. The Model for Prevention study was a whole-of-system cardiovascular disease prevention intervention, with one component being enhanced lifestyle modification support and addition of a health coaching service in the general practice setting. To determine the feasibility of translating intervention outcomes into real world practice, implementation work done by stakeholders was examined using Normalisation Process Theory as a framework. Data was collected through interviews with 40 intervention participants and included general practitioners, practice nurses, practice managers, lifestyle advisors and participants. Data analysis was informed by normalisation process theory constructs. Stakeholders were in agreement that, while prevention is a key function of general practice, it was not their usual work. There were varying levels of engagement with the intervention by practice staff due to staff interest, capacity and turnover, but most staff reconfigured their work for required activities. The Lifestyle Advisors believed staff had varied levels of interest in and understanding of, their service, but most staff felt their role was useful. Patients expanded their existing relationships with their general practice, and most achieved their lifestyle modification goals. While the study highlighted the complex nature of the change required, many of the new or enhanced processes implemented as part of the intervention could be scaled up to improve the systems approach to prevention. Overcoming the barriers to change, such as the perception of CVD prevention as a 'hard sell', is going to rely on improving the value proposition for all stakeholders. The study provided a detailed understanding of the work required to implement a complex cardiovascular disease prevention intervention within general practice. The findings highlighted the need for multiple strategies that engage all stakeholders. Normalisation process theory was a useful framework for guiding change implementation.

A Chemoenzymatic Histology Method for O-GlcNAc Detection.

PubMed

Aguilar, Aime Lopez; Hou, Xiaomeng; Wen, Liuqing; Wang, Peng G; Wu, Peng

2017-12-14

Modification of nuclear and cytoplasmic proteins by the addition or removal of O-GlcNAc dynamically impacts multiple biological processes. Here, we present the development of a chemoenzymatic histology method for the detection of O-GlcNAc in tissue specimens. We applied this method to screen murine organs, uncovering specific O-GlcNAc distribution patterns in different tissue structures. We then utilized our histology method for O-GlcNAc detection in human brain specimens from healthy donors and donors with Alzheimer's disease and found higher levels of O-GlcNAc in specimens from healthy donors. We also performed an analysis using a multiple cancer tissue array, uncovering different O-GlcNAc levels between healthy and cancerous tissues, as well as different O-GlcNAc cellular distributions within certain tissue specimens. This chemoenzymatic histology method therefore holds great potential for revealing the biology of O-GlcNAc in physiopathological processes. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Disease diagnosis in primary care in Uganda.

PubMed

Mbonye, Martin Kayitale; Burnett, Sarah M; Colebunders, Robert; Naikoba, Sarah; Van Geertruyden, Jean-Pierre; Weaver, Marcia R; Ronald, Allan

2014-10-08

The overall burden of disease (BOD) especially for infectious diseases is higher in Sub-Saharan Africa than other regions of the world. Existing data collected through the Health Management Information System (HMIS) may not be optimal to measure BOD. The Infectious Diseases Capacity Building Evaluation (IDCAP) cooperated with the Ugandan Ministry of Health to improve the quality of HMIS data. We describe diagnoses with associated clinical assessments and laboratory investigations of outpatients attending primary care in Uganda. IDCAP supported HMIS data collection at 36 health center IVs in Uganda for five months (November 2009 to March 2010) prior to implementation of the IDCAP interventions. Descriptive analyses were performed on a cross-sectional dataset of 209,734 outpatient visits during this period. Over 500 illnesses were diagnosed. Infectious diseases accounted for 76.3% of these and over 30% of visits resulted in multiple diagnoses. Malaria (48.3%), cough/cold (19.4%), and intestinal worms (6.6%) were the most frequently diagnosed illnesses. Body weight was recorded for 36.8% of patients and less than 10% had other clinical assessments recorded. Malaria smears (64.2%) and HIV tests (12.2%) accounted for the majority of 84,638 laboratory tests ordered. Fewer than 30% of patients for whom a laboratory investigation was available to confirm the clinical impression had the specific test performed. We observed a broad range of diagnoses, a high percentage of multiple diagnoses including true co-morbidities, and underutilization of laboratory support. This emphasizes the complexity of illnesses to be addressed by primary healthcare workers. An improved HMIS collecting timely, quality data is needed. This would adequately describe the burden of disease and processes of care at primary care level, enable appropriate national guidelines, programs and policies and improve accountability for the quality of care.

Multiple biological pathways link cognitive lifestyle to protection from dementia.

PubMed

Valenzuela, Michael J; Matthews, Fiona E; Brayne, Carol; Ince, Paul; Halliday, Glenda; Kril, Jillian J; Dalton, Marshall A; Richardson, Kathryn; Forster, Gill; Sachdev, Perminder S

2012-05-01

An active cognitive lifestyle is linked to diminished dementia risk, but the underlying mechanisms are poorly understood. Potential mechanisms include disease modification, neuroprotection, and compensation. Prospective, population-based brain series provide the rare opportunity to test the plausibility of these mechanisms in humans. Participants came from the United Kingdom Medical Research Council Cognitive Function and Ageing Study, comprising 13,004 individuals aged over 65 years and followed for 14 years. In study 1, a Cognitive Lifestyle Score (CLS) was computed on all Cognitive Function and Ageing Study subjects to define low, middle, and high groups. By August 2004, 329 individuals with CLS data had come to autopsy and underwent Consortium to Establish a Registry of Alzheimer's Disease assessment. Study 2 involved more detailed quantitative histology in the hippocampus and Brodmann area 9 in 72 clinically matched individuals with high and low CLS. CLS groups did not differ on several Alzheimer disease neuropathologic measures; however, high CLS men had less cerebrovascular disease after accounting for vascular risk factors, and women had greater brain weight. No group differences were evident in hippocampal neuronal density. In Brodmann area 9, cognitively active individuals had significantly greater neuronal density, as well as correlated increases in cortical thickness. An active cognitive lifestyle was associated with protection from cerebrovascular disease in men, but there was no evidence for Alzheimer disease modification or hippocampal neuroprotection. Men and women both exhibited neurotrophic changes in the prefrontal lobe linked to cognitive lifestyle, consistent with a compensatory process. Lifespan complex cognitive activity may therefore protect against dementia through multiple biological pathways. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Linking the Primary Cilium to Cell Migration in Tissue Repair and Brain Development

PubMed Central

Veland, Iben Rønn; Lindbæk, Louise; Christensen, Søren Tvorup

2014-01-01

Primary cilia are unique sensory organelles that coordinate cellular signaling networks in vertebrates. Inevitably, defects in the formation or function of primary cilia lead to imbalanced regulation of cellular processes that causes multisystemic disorders and diseases, commonly known as ciliopathies. Mounting evidence has demonstrated that primary cilia coordinate multiple activities that are required for cell migration, which, when they are aberrantly regulated, lead to defects in organogenesis and tissue repair, as well as metastasis of tumors. Here, we present an overview on how primary cilia may contribute to the regulation of the cellular signaling pathways that control cyclic processes in directional cell migration. PMID:26955067

Addiction stigma and the biopolitics of liberal modernity: A qualitative analysis.

PubMed

Fraser, Suzanne; Pienaar, Kiran; Dilkes-Frayne, Ella; Moore, David; Kokanovic, Renata; Treloar, Carla; Dunlop, Adrian

2017-06-01

Definitions of addiction have never been more hotly contested. The advance of neuroscientific accounts has not only placed into public awareness a highly controversial explanatory approach, it has also shed new light on the absence of agreement among the many experts who contest it. Proponents argue that calling addiction a 'brain disease' is important because it is destigmatising. Many critics of the neuroscientific approach also agree on this point. Considered from the point of view of the sociology of health and illness, the idea that labelling something a disease will alleviate stigma is a surprising one. Disease, as demonstrated in that field of research, is routinely stigmatised. In this article we take up the issue of stigma as it plays out in relation to addiction, seeking to clarify and challenge the claims made about the progress associated with disease models. To do so, we draw on Erving Goffman's classic work on stigma, reconsidering it in light of more recent, process oriented, theoretical resources, and posing stigmatisation as a performative biopolitical process. Analysing recently collected interviews conducted with 60 people in Australia who consider themselves to have an alcohol or other drug addiction, dependence or habit, we explore their accounts of stigma, finding experiences of stigma to be common, multiple and strikingly diverse. We argue that by treating stigma as politically productive - as a contingent biopolitically performative process rather than as a stable marker of some kind of anterior difference - we can better understand what it achieves. This allows us to consider not simply how the 'disease' of addiction can be destigmatised, or even whether the 'diseasing' of addiction is itself stigmatising (although this would seem a key question), but whether the very problematisation of 'addiction' in the first place constitutes a stigma process. Copyright © 2017 Elsevier B.V. All rights reserved.

[Application of R-based multiple seasonal ARIMA model, in predicting the incidence of hand, foot and mouth disease in Shaanxi province].

PubMed

Liu, F; Zhu, N; Qiu, L; Wang, J J; Wang, W H

2016-08-10

To apply the ' auto-regressive integrated moving average product seasonal model' in predicting the number of hand, foot and mouth disease in Shaanxi province. In Shaanxi province, the trend of hand, foot and mouth disease was analyzed and tested, under the use of R software, between January 2009 and June 2015. Multiple seasonal ARIMA model was then fitted under time series to predict the number of hand, foot and mouth disease in 2016 and 2017. Seasonal effect was seen in hand, foot and mouth disease in Shaanxi province. A multiple seasonal ARIMA (2,1,0)×(1,1,0)12 was established, with the equation as (1 -B)(1 -B12)Ln (Xt) =((1-1.000B)/(1-0.532B-0.363B(2))*(1-0.644B12-0.454B12(2)))*Epsilont. The mean of absolute error and the relative error were 531.535 and 0.114, respectively when compared to the simulated number of patients from Jun to Dec in 2015. RESULTS under the prediction of multiple seasonal ARIMA model showed that the numbers of patients in both 2016 and 2017 were similar to that of 2015 in Shaanxi province. Multiple seasonal ARIMA (2,1,0)×(1,1,0)12 model could be used to successfully predict the incidence of hand, foot and mouth disease in Shaanxi province.

Therapeutic Nanodevices

NASA Astrophysics Data System (ADS)

Lee, Stephen C.; Ruegsegger, Mark; Barnes, Philip D.; Smith, Bryan R.; Ferrari, Mauro

Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'etre of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multi-step work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

Therapeutic Nanodevices

NASA Astrophysics Data System (ADS)

Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

Rationale and methods of discovering hormetins as drugs for healthy ageing.

PubMed

Rattan, Suresh I S

2012-05-01

Mild stress-induced hormesis is becoming increasingly attractive as an ageing interventional strategy and is leading to the discovery of hormesis-inducing compounds called hormetins. Almost 50 years of modern biogerontolgical research has established a clear framework regarding the biological basis of ageing and longevity, and it is now generally accepted that ageing occurs in spite of the presence of complex pathways of maintenance, repair and defense, and there is no 'enemy within.' This viewpoint makes modulation of ageing different from the treatment of one or more age-related diseases. A promising strategy to slow down ageing and prevent or delay the onset of age-related diseases is that of mild stress-induced hormesis by using hormetins. The article presents the rationale and a strategy for discovering novel hormetins as potential drugs for ageing intervention by elucidating multiple stress responses of normal human cells. Furthermore, it discusses the first steps in identifying prospective hormetin drugs and provides a recent example of successful product development, based on the ideas of hormesis and by following the strategy described here. As a biomedical issue, the biological process of ageing underlies several major diseases, and although the optimal treatment of every disease, irrespective of age, is a social and moral necessity, preventing the onset of age-related diseases by intervening in the basic process of ageing is the best approach for achieving healthy ageing and for extending the healthspan.

Contribution of Bordetella bronchiseptica Filamentous Hemagglutinin and Pertactin to Respiratory Disease in Swine▿ †

PubMed Central

Nicholson, Tracy L.; Brockmeier, Susan L.; Loving, Crystal L.

2009-01-01

Bordetella bronchiseptica is pervasive in swine populations and plays multiple roles in respiratory disease. Most studies addressing virulence factors of B. bronchiseptica are based on isolates derived from hosts other than pigs. Two well-studied virulence factors implicated in the adhesion process are filamentous hemagglutinin (FHA) and pertactin (PRN). We hypothesized that both FHA and PRN would serve critical roles in the adhesion process and be necessary for colonization of the swine respiratory tract. To investigate the role of FHA and PRN in Bordetella pathogenesis in swine, we constructed mutants containing an in-frame deletion of the FHA or the PRN structural gene in a virulent B. bronchiseptica swine isolate. Both mutants were compared to the wild-type swine isolate for their ability to colonize and cause disease in swine. Colonization of the FHA mutant was lower than that of the wild type at all respiratory tract sites and time points examined and caused limited to no disease. In contrast, the PRN mutant caused similar disease severity relative to the wild type; however, colonization of the PRN mutant was reduced relative to the wild type during early and late infection and induced higher anti-Bordetella antibody titers. Together, our results indicate that despite inducing different pathologies and antibody responses, both FHA and PRN are necessary for optimal colonization of the swine respiratory tract. PMID:19237531

The multiple life of nerve growth factor: tribute to rita levi-montalcini (1909-2012).

PubMed

Aloe, Luigi; Chaldakov, George N

2013-03-01

At the end of the 19(th) century, it was envisaged by Santiago Ramon y Cajal, but not, proven, that life at the neuronal level requires trophic support. The proof was obtained in the early 1950's by work initiated by Rita Levi-Montalcini (RLM) discovering the nerve growth factor (NGF). Today, NGF and its relatives, collectively designated neurotrophins, are well recognized as mediators of multiple biological phenomena in health and disease, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other neurotrophins are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, from Alzheimer's and other neurodegenerative diseases to atherosclerosis and other cardiometabolic diseases. Recent studies demonstrated the therapeutic potentials of NGF in these diseases, including ocular and cutaneous diseases. Furthermore, NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma, and urinary bladder syndromes. Altogether, NGF's multiple potential in health and disease is briefly described here.

Optical Coherence Tomography in Alzheimer’s Disease and Other Neurodegenerative Diseases

PubMed Central

Doustar, Jonah; Torbati, Tania; Black, Keith L.; Koronyo, Yosef; Koronyo-Hamaoui, Maya

2017-01-01

Over the past decade, a surge of evidence has documented various pathological processes in the retina of patients suffering from mild cognitive impairment, Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative diseases. Numerous studies have shown that the retina, a central nervous system tissue formed as a developmental outgrowth of the brain, is profoundly affected by AD. Harboring the earliest detectable disease-specific signs, amyloid β-protein (Aβ) plaques, the retina of AD patients undergoes substantial ganglion cell degeneration, thinning of the retinal nerve fiber layer, and loss of axonal projections in the optic nerve, among other abnormalities. More recent investigations described Aβ plaques in the retina located within sites of neuronal degeneration and occurring in clusters in the mid- and far-periphery of the superior and inferior quadrants, regions that had been previously overlooked. Diverse structural and/or disease-specific changes were also identified in the retina of PD, Huntington’s disease, and multiple sclerosis patients. The pathological relationship between the retina and brain prompted the development of imaging tools designed to noninvasively detect and monitor these signs in living patients. One such tool is optical coherence tomography (OCT), uniquely providing high-resolution two-dimensional cross-sectional imaging and three-dimensional volumetric measurements. As such, OCT emerged as a prominent approach for assessing retinal abnormalities in vivo, and indeed provided multiple parameters that allowed for the distinction between normal aged individuals and patients with neurodegenerative diseases. Beyond the use of retinal optical fundus imaging, which recently allowed for the detection and quantification of amyloid plaques in living AD patients via a wide-field view of the peripheral retina, a major advantage of OCT has been the ability to measure the volumetric changes in specified retinal layers. OCT has proven to be particularly useful in analyzing retinal structural abnormalities consistent with disease pathogenesis. In this review, we provide a summary of OCT findings in the retina of patients with AD and other neurodegenerative diseases. Future studies should explore the combination of imaging early hallmark signs together with structural–functional biomarkers in the accessible retina as a practical means of assessing risk, disease progression, and therapeutic efficacy in these patients. PMID:29312125

Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain.

PubMed

Tran, Elise H; Azuma, Yasu-Taka; Chen, Manchuan; Weston, Claire; Davis, Roger J; Flavell, Richard A

2006-09-05

Environmental insults such as microbial pathogens can contribute to the activation of autoreactive T cells, leading to inflammation of target organs and, ultimately, autoimmune disease. Various infections have been linked to multiple sclerosis and its animal counterpart, autoimmune encephalomyelitis. The molecular process by which innate immunity triggers autoreactivity is not currently understood. By using a mouse model of multiple sclerosis, we found that the genetic loss of the MAPK, c-Jun N-terminal kinase 1 (JNK1), enhances IL-10 production, rendering innate myeloid cells unresponsive to certain microbes and less capable of generating IL-17-producing, encephalitogenic T cells. Moreover, JNK1-deficient central nervous system myeloid cells are unable to respond to effector T cell inflammatory cytokines, preventing further progression to neuroinflammation. Thus, we have identified the JNK1 signal transduction pathway in myeloid cells to be a critical component of a regulatory circuit mediating inflammatory responses in autoimmune disease. Our findings provide further insights into the pivotal MAPK-regulated network of innate and adaptive cytokines in the progression to autoimmunity.

Evaluation of Cross-Protocol Stability of a Fully Automated Brain Multi-Atlas Parcellation Tool.

PubMed

Liang, Zifei; He, Xiaohai; Ceritoglu, Can; Tang, Xiaoying; Li, Yue; Kutten, Kwame S; Oishi, Kenichi; Miller, Michael I; Mori, Susumu; Faria, Andreia V

2015-01-01

Brain parcellation tools based on multiple-atlas algorithms have recently emerged as a promising method with which to accurately define brain structures. When dealing with data from various sources, it is crucial that these tools are robust for many different imaging protocols. In this study, we tested the robustness of a multiple-atlas, likelihood fusion algorithm using Alzheimer's Disease Neuroimaging Initiative (ADNI) data with six different protocols, comprising three manufacturers and two magnetic field strengths. The entire brain was parceled into five different levels of granularity. In each level, which defines a set of brain structures, ranging from eight to 286 regions, we evaluated the variability of brain volumes related to the protocol, age, and diagnosis (healthy or Alzheimer's disease). Our results indicated that, with proper pre-processing steps, the impact of different protocols is minor compared to biological effects, such as age and pathology. A precise knowledge of the sources of data variation enables sufficient statistical power and ensures the reliability of an anatomical analysis when using this automated brain parcellation tool on datasets from various imaging protocols, such as clinical databases.

Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease

PubMed Central

Berchtold, Nicole C.; Coleman, Paul D.; Cribbs, David H.; Rogers, Joseph; Gillen, Daniel L.; Cotman, Carl W.

2014-01-01

Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer’s disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20–99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD. PMID:23273601

Intracellular Protein Shuttling: A Mechanism Relevant for Myelin Repair in Multiple Sclerosis?

PubMed Central

Göttle, Peter; Küry, Patrick

2015-01-01

A prominent feature of demyelinating diseases such as multiple sclerosis (MS) is the degeneration and loss of previously established functional myelin sheaths, which results in impaired signal propagation and axonal damage. However, at least in early disease stages, partial replacement of lost oligodendrocytes and thus remyelination occur as a result of resident oligodendroglial precursor cell (OPC) activation. These cells represent a widespread cell population within the adult central nervous system (CNS) that can differentiate into functional myelinating glial cells to restore axonal functions. Nevertheless, the spontaneous remyelination capacity in the adult CNS is inefficient because OPCs often fail to generate new oligodendrocytes due to the lack of stimulatory cues and the presence of inhibitory factors. Recent studies have provided evidence that regulated intracellular protein shuttling is functionally involved in oligodendroglial differentiation and remyelination activities. In this review we shed light on the role of the subcellular localization of differentiation-associated factors within oligodendroglial cells and show that regulation of intracellular localization of regulatory factors represents a crucial process to modulate oligodendroglial maturation and myelin repair in the CNS. PMID:26151843

Linked Clinical Trials – The Development of New Clinical Learning Studies in Parkinson’s Disease Using Screening of Multiple Prospective New Treatments

PubMed Central

Brundin, Patrik; Barker, Roger A.; Conn, P. Jeffrey; Dawson, Ted M.; Kieburtz, Karl; Lees, Andrew J.; Schwarzschild, Michael A.; Tanner, Caroline M.; Isaacs, Tom; Duffen, Joy; Matthews, Helen; Wyse, Richard K.H.

2015-01-01

Finding new therapies for Parkinson’s disease (PD) is a slow process. We assembled an international committee of experts to examine drugs potentially suitable for repurposing to modify PD progression. This committee evaluated multiple drugs currently used, or being developed, in other therapeutic areas, as well as considering several natural, non-pharmaceutical compounds. The committee prioritized which of these putative treatments were most suited to move immediately into pilot clinical trials. Aspects considered included known modes of action, safety, blood-brain-barrier penetration, preclinical data in animal models of PD and the possibility to monitor target engagement in the brain. Of the 26 potential interventions, 10 were considered worth moving forward into small, parallel ‘learning’ clinical trials in PD patients. These trials could be funded in a multitude of ways through support from industry, research grants and directed philanthropic donations. The committee-based approach to select the candidate compounds might help rapidly identify new potential PD treatment strategies for use in clinical trials. PMID:24018336

Construction of EGFP-labeling system for visualizing the infection process of Xanthomonas axonopodis pv. citri in planta.

PubMed

Liu, Li-Ping; Deng, Zi-Niu; Qu, Jin-Wang; Yan, Jia-Wen; Catara, Vittoria; Li, Da-Zhi; Long, Gui-You; Li, Na

2012-09-01

Xanthomonas axonopodis pv. citri (Xac) is the causal agent of citrus bacterial canker, an economically important disease to world citrus industry. To monitor the infection process of Xac in different citrus plants, the enhanced green florescent protein (EGFP) visualizing system was constructed to visualize the propagation and localization in planta. First, the wild-type Xac was isolated from the diseased leaves of susceptible 'Bingtang' sweet orange, and then the isolated Xac was labeled with EGFP by triparental mating. After PCR identification, the growth kinetics and pathogenicity of the transformants were analyzed in comparison with the wild-type Xac. The EGFP-labeled bacteria were inoculated by spraying on the surface and infiltration in the mesophyll of 'Bingtang' sweet orange leaves. The bacterial cell multiplication and diffusion processes were observed directly under confocal laser scanning microscope at different intervals after inoculation. The results indicated that the EGFP-labeled Xac releasing clear green fluorescence light under fluorescent microscope showed the infection process and had the same pathogenicity as the wild type to citrus. Consequently, the labeled Xac demonstrated the ability as an efficient tool to monitor the pathogen infection.

Helminths as governors of immune-mediated inflammation.

PubMed

Elliott, David E; Summers, Robert W; Weinstock, Joel V

2007-04-01

Immune-mediated diseases (e.g. inflammatory bowel disease, asthma, multiple sclerosis and autoimmune diabetes) are increasing in prevalence and emerge as populations adopt meticulously hygienic lifestyles. This change in lifestyles precludes exposure to helminths (parasitic worms). Loss of natural helminth exposure removes a previously universal Th2 and regulatory immune biasing imparted by these organisms. Helminths protect animals from developing immune-mediated diseases (colitis, reactive airway disease, encephalitis and diabetes). Clinical trials show that exposure to helminths can reduce disease activity in patients with ulcerative colitis or Crohn's disease. This paper summarises work by multiple groups demonstrating that colonization with helminths alters immune reactivity and protects against disease from dysregulated inflammation.

Commercial processed soy-based food product contains glycated and glycoxidated lunasin proteoforms.

PubMed

Serra, Aida; Gallart-Palau, Xavier; See-Toh, Rachel Su-En; Hemu, Xinya; Tam, James P; Sze, Siu Kwan

2016-05-18

Nutraceuticals have been proposed to exert positive effects on human health and confer protection against many chronic diseases. A major bioactive component of soy-based foods is lunasin peptide, which has potential to exert a major impact on the health of human consumers worldwide, but the biochemical features of dietary lunasin still remain poorly characterized. In this study, lunasin was purified from a soy-based food product via strong anion exchange solid phase extraction and then subjected to top-down mass spectrometry analysis that revealed in detail the molecular diversity of lunasin in processed soybean foods. We detected multiple glycated proteoforms together with potentially toxic advanced glycation end products (AGEs) derived from lunasin. In both cases, modification sites were Lys24 and Lys29 located at the helical region that shows structural homology with a conserved region of chromatin-binding proteins. The identified post-translational modifications may have an important repercussion on lunasin epigenetic regulatory capacity. Taking together, our results demonstrate the importance of proper chemical characterization of commercial processed food products to assess their impact on consumer's health and risk of chronic diseases.

Mad dogs, vampires, and zombie ants: a multidisciplinary approach to teaching neuroscience, behavior, and microbiology.

PubMed

Esteban, David J; Holloway, Kevin S

2015-01-01

Viruses, parasites, and some bacteria use host organisms to complete their lifecycle. These infectious agents are able to hijack host processes to replicate and transmit to the next host. While we tend to think of infections as just making us sick, they are also capable of changing host behavior. In fact, many infectious agents are able to mediate host behavior in ways that can enhance transmission of the disease. In this course we explore the process of host behavior mediation by infectious agents, combining aspects of multiple fields including neurobiology, animal behavior, infectious disease microbiology, and epidemiology. The goals for this course are: 1) To explore the neurological and behavioral effects of infectious organisms on their hosts, in particular pathogen mediation of host behavior to the benefit of the pathogen, 2) to introduce students to primary literature in a multidisciplinary field, and 3) when applicable, to address cultural/historical/mythological perspectives that might alter societal norms and pressures and influence the impact of the biological processes of behavior modification by infections.

Mad Dogs, Vampires, and Zombie Ants: A Multidisciplinary Approach to Teaching Neuroscience, Behavior, and Microbiology

PubMed Central

Esteban, David J.; Holloway, Kevin S.

2015-01-01

Viruses, parasites, and some bacteria use host organisms to complete their lifecycle. These infectious agents are able to hijack host processes to replicate and transmit to the next host. While we tend to think of infections as just making us sick, they are also capable of changing host behavior. In fact, many infectious agents are able to mediate host behavior in ways that can enhance transmission of the disease. In this course we explore the process of host behavior mediation by infectious agents, combining aspects of multiple fields including neurobiology, animal behavior, infectious disease microbiology, and epidemiology. The goals for this course are: 1) To explore the neurological and behavioral effects of infectious organisms on their hosts, in particular pathogen mediation of host behavior to the benefit of the pathogen, 2) to introduce students to primary literature in a multidisciplinary field, and 3) when applicable, to address cultural/historical/mythological perspectives that might alter societal norms and pressures and influence the impact of the biological processes of behavior modification by infections. PMID:25838806

Developmental mechanisms underlying variation in craniofacial disease and evolution.

PubMed

Fish, Jennifer L

2016-07-15

Craniofacial disease phenotypes exhibit significant variation in penetrance and severity. Although many genetic contributions to phenotypic variation have been identified, genotype-phenotype correlations remain imprecise. Recent work in evolutionary developmental biology has exposed intriguing developmental mechanisms that potentially explain incongruities in genotype-phenotype relationships. This review focuses on two observations from work in comparative and experimental animal model systems that highlight how development structures variation. First, multiple genetic inputs converge on relatively few developmental processes. Investigation of when and how variation in developmental processes occurs may therefore help predict potential genetic interactions and phenotypic outcomes. Second, genetic mutation is typically associated with an increase in phenotypic variance. Several models outlining developmental mechanisms underlying mutational increases in phenotypic variance are discussed using Satb2-mediated variation in jaw size as an example. These data highlight development as a critical mediator of genotype-phenotype correlations. Future research in evolutionary developmental biology focusing on tissue-level processes may help elucidate the "black box" between genotype and phenotype, potentially leading to novel treatment, earlier diagnoses, and better clinical consultations for individuals affected by craniofacial anomalies. Copyright © 2015 Elsevier Inc. All rights reserved.