Mechanisms of protein misfolding: Novel therapeutic approaches to protein-misfolding diseases

DEFF Research Database (Denmark)

Salahuddin, Parveen; Siddiqi, Mohammad Khursheed; Khan, Sanaullah

2016-01-01

’s disease (PD), Alzheimer’s disease (AD), Prion disease and Amylo lateral Sclerosis (ALS). Furthermore, tau protein shows intrinsically disorder conformation; therefore its interaction with microtubule is impaired and this protein undergoes aggregation. This is also underlying cause of Alzheimers and other......In protein misfolding, protein molecule acquires wrong tertiary structure, thereby induces protein misfolding diseases. Protein misfolding can occur through various mechanisms. For instance, changes in environmental conditions, oxidative stress, dominant negative mutations, error in post......-translational modifications, increase in degradation rate and trafficking error. All of these factors cause protein misfolding thereby leading to diseases conditions. Both in vitro and in vivo observations suggest that partially unfolded or misfolded intermediates are particularly prone to aggregation. These partially...

Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex.

Science.gov (United States)

Jeong, Anna; Wong, Michael

2016-09-01

Epilepsy is one of the most disabling symptoms of tuberous sclerosis complex (TSC) and is a leading cause of morbidity and mortality in affected individuals. The relationship between systemic disease manifestations and the presence of epilepsy has not been thoroughly investigated. This study utilizes a multicenter TSC Natural History Database including 1,816 individuals to test the hypothesis that systemic disease manifestations of TSC are associated with epilepsy. Univariate analysis was used to identify patient characteristics (e.g., age, gender, race, and TSC mutation status) associated with the presence of epilepsy. Individual logistic regression models were built to examine the association between epilepsy and each candidate systemic or neurologic disease variable, controlling for the patient characteristics found to be significant on univariate analysis. Finally, a multivariable logistic regression model was constructed, using the variables found to be significant on the individual analyses as well as the patient characteristics that were significant on univariate analysis. Nearly 88% of our cohort had a history of epilepsy. After adjusting for age, gender, and TSC mutation status, multiple systemic disease manifestations including cardiac rhabdomyomas (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.3-3.9, p = 0.002), retinal hamartomas (OR 2.1, CI 1.0-4.3, p = 0.04), renal cysts (OR 2.1, CI 1.3-3.4, p = 0.002), renal angiomyolipomas (OR 3.0, CI 1.8-5.1, p epilepsy. In the multivariable logistic regression model, cardiac rhabdomyomas (OR 1.9, CI 1.0-3.5, p = 0.04) remained significantly associated with the presence of epilepsy. The identification of systemic disease manifestations such as cardiac rhabdomyomas that confer a higher risk of epilepsy development in TSC could contribute to disease prognostication and assist in the identification of individuals who may receive maximal benefit from potentially novel, targeted, preventative therapies. Wiley

Discovering disease-associated genes in weighted protein-protein interaction networks

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Cui, Ying; Cai, Meng; Stanley, H. Eugene

2018-04-01

Although there have been many network-based attempts to discover disease-associated genes, most of them have not taken edge weight - which quantifies their relative strength - into consideration. We use connection weights in a protein-protein interaction (PPI) network to locate disease-related genes. We analyze the topological properties of both weighted and unweighted PPI networks and design an improved random forest classifier to distinguish disease genes from non-disease genes. We use a cross-validation test to confirm that weighted networks are better able to discover disease-associated genes than unweighted networks, which indicates that including link weight in the analysis of network properties provides a better model of complex genotype-phenotype associations.

Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis

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Mario A. Moscarello

2013-03-01

Multiple sclerosis (MS is the most common CNS-demyelinating disease of humans, showing clinical and pathological heterogeneity and a general resistance to therapy. We first discovered that abnormal myelin hypercitrullination, even in normal-appearing white matter, by peptidylarginine deiminases (PADs correlates strongly with disease severity and might have an important role in MS progression. Hypercitrullination is known to promote focal demyelination through reduced myelin compaction. Here we report that 2-chloroacetamidine (2CA, a small-molecule, PAD active-site inhibitor, dramatically attenuates disease at any stage in independent neurodegenerative as well as autoimmune MS mouse models. 2CA reduced PAD activity and protein citrullination to pre-disease status. In the autoimmune models, disease induction uniformly induced spontaneous hypercitrullination with citrulline+ epitopes targeted frequently. 2CA rapidly suppressed T cell autoreactivity, clearing brain and spinal cord infiltrates, through selective removal of newly activated T cells. 2CA essentially prevented disease when administered before disease onset or before autoimmune induction, making hypercitrullination, and specifically PAD enzymes, a therapeutic target in MS models and thus possibly in MS.

Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants?

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Antony, Joseph M; Deslauriers, Andre M; Bhat, Rakesh K; Ellestad, Kristofer K; Power, Christopher

2011-02-01

Human endogenous retroviruses (HERVs) constitute 5-8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue. Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation. The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders. A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses. HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease. The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions. Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells. Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients. Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases. Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies. 2010 Elsevier B.V. All rights reserved.

Association of autoimmune hepatitis and multiple sclerosis: a coincidence?

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Marta Sofia Mendes Oliveira

2015-09-01

Full Text Available Autoimmune hepatitis is a chronic liver inflammation resulting from deregulation of immune tolerance mechanisms. Multiple sclerosis is also an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. Here we present a case of an 18 year old female with multiple sclerosis was treated with glatiramer acetate and with interferon beta 1a at our hospital. Seven months after initiating treatment, liver dysfunction occurred. Clinical and laboratory findings were suggestive of drug-induced hepatitis, which led to discontinuation of treatment with interferon. Facing a new episode of acute hepatitis one year later, she was subjected to a liver biopsy, and the analysis of autoantibodies was positive for smooth muscle antibodies. Given the diagnosis of autoimmune hepatitis she started therapy with prednisolone and azathioprine, with good clinical and analytical response. Besides, the demyelinating lesions of multiple sclerosis became lower. In conclusion, there are only a few cases that describe the association of autoimmune hepatitis with multiple sclerosis, and there is a chance both diseases have the same autoimmune inflammatory origin.

Magnetic resonance imaging perfusion is associated with disease severity and activity in multiple sclerosis

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Sowa, Piotr [Oslo University Hospital, Department of Radiology and Nuclear Medicine, Oslo (Norway); University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo (Norway); Owren Nygaard, Gro [Oslo University Hospital, Department of Neurology, Oslo (Norway); Bjoernerud, Atle [Intervention Center, Oslo University Hospital, Oslo (Norway); University of Oslo, Department of Physics, Oslo (Norway); Gulowsen Celius, Elisabeth [Oslo University Hospital, Department of Neurology, Oslo (Norway); University of Oslo, Institute of Health and Society, Faculty of Medicine, Oslo (Norway); Flinstad Harbo, Hanne [University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo (Norway); Oslo University Hospital, Department of Neurology, Oslo (Norway); Kristiansen Beyer, Mona [Oslo University Hospital, Department of Radiology and Nuclear Medicine, Oslo (Norway); Oslo and Akershus University College of Applied Sciences, Department of Life Sciences and Health, Oslo (Norway)

2017-07-15

The utility of perfusion-weighted imaging in multiple sclerosis (MS) is not well investigated. The purpose of this study was to compare baseline normalized perfusion measures in subgroups of newly diagnosed MS patients. We wanted to test the hypothesis that this method can differentiate between groups defined according to disease severity and disease activity at 1 year follow-up. Baseline magnetic resonance imaging (MRI) including a dynamic susceptibility contrast perfusion sequence was performed on a 1.5-T scanner in 66 patients newly diagnosed with relapsing-remitting MS. From the baseline MRI, cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were generated. Normalized (n) perfusion values were calculated by dividing each perfusion parameter obtained in white matter lesions by the same parameter obtained in normal-appearing white matter. Neurological examination was performed at baseline and at follow-up approximately 1 year later to establish the multiple sclerosis severity score (MSSS) and evidence of disease activity (EDA). Baseline normalized mean transit time (nMTT) was lower in patients with MSSS >3.79 (p = 0.016), in patients with EDA (p = 0.041), and in patients with both MSSS >3.79 and EDA (p = 0.032) at 1-year follow-up. Baseline normalized cerebral blood flow and normalized cerebral blood volume did not differ between these groups. Lower baseline nMTT was associated with higher disease severity and with presence of disease activity 1 year later in newly diagnosed MS patients. Further longitudinal studies are needed to confirm whether baseline-normalized perfusion measures can differentiate between disease severity and disease activity subgroups over time. (orig.)

Magnetic resonance imaging perfusion is associated with disease severity and activity in multiple sclerosis

International Nuclear Information System (INIS)

Sowa, Piotr; Owren Nygaard, Gro; Bjoernerud, Atle; Gulowsen Celius, Elisabeth; Flinstad Harbo, Hanne; Kristiansen Beyer, Mona

2017-01-01

The utility of perfusion-weighted imaging in multiple sclerosis (MS) is not well investigated. The purpose of this study was to compare baseline normalized perfusion measures in subgroups of newly diagnosed MS patients. We wanted to test the hypothesis that this method can differentiate between groups defined according to disease severity and disease activity at 1 year follow-up. Baseline magnetic resonance imaging (MRI) including a dynamic susceptibility contrast perfusion sequence was performed on a 1.5-T scanner in 66 patients newly diagnosed with relapsing-remitting MS. From the baseline MRI, cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were generated. Normalized (n) perfusion values were calculated by dividing each perfusion parameter obtained in white matter lesions by the same parameter obtained in normal-appearing white matter. Neurological examination was performed at baseline and at follow-up approximately 1 year later to establish the multiple sclerosis severity score (MSSS) and evidence of disease activity (EDA). Baseline normalized mean transit time (nMTT) was lower in patients with MSSS >3.79 (p = 0.016), in patients with EDA (p = 0.041), and in patients with both MSSS >3.79 and EDA (p = 0.032) at 1-year follow-up. Baseline normalized cerebral blood flow and normalized cerebral blood volume did not differ between these groups. Lower baseline nMTT was associated with higher disease severity and with presence of disease activity 1 year later in newly diagnosed MS patients. Further longitudinal studies are needed to confirm whether baseline-normalized perfusion measures can differentiate between disease severity and disease activity subgroups over time. (orig.)

Mechanisms of Neuroprotection by Protein Disulphide Isomerase in Amyotrophic Lateral Sclerosis

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Adam K. Walker

2011-01-01

Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating neurodegenerative disease characterised by the progressive loss of motor neurons, leading to paralysis and death within several years of onset. Although protein misfolding is a key feature of ALS, the upstream triggers of disease remain elusive. Recently, endoplasmic reticulum (ER stress was identified as an early and central feature in ALS disease models as well as in human patient tissues, indicating that ER stress could be an important process in disease pathogenesis. One important chaperone induced by ER stress is protein disulphide isomerase (PDI, which is both upregulated and posttranslationally inhibited by S-nitrosylation in ALS. In this paper, we present evidence from studies of genetics, model organisms, and patient tissues which indicate an active role for PDI and ER stress in ALS disease processes.

Tomography patterns of lung disease in systemic sclerosis

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Bastos, Andrea de Lima; Correa, Ricardo de Amorim; Ferreira, Gilda Aparecida, E-mail: andrealb@ufmg.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Faculdade de Medicina

2016-09-15

Currently, lung impairment is the leading factor responsible for the morbidity and mortality associated with systemic sclerosis. Therefore, the recognition of the various tomography patterns becomes decisive in the clinical management of these patients. In high-resolution computed tomography studies, the most common pattern is that of nonspecific interstitial pneumonia. However, there are other forms of lung involvement that must also be recognized. The aim of this study was to review the literature on the main changes resulting from pulmonary involvement in systemic sclerosis and the corresponding radiological findings, considering the current classification of interstitial diseases. We searched the Medline (PubMed), Lilacs, and SciELO databases in order to select articles related to pulmonary changes in systemic sclerosis and published in English between 2000 and 2015. The pulmonary changes seen on computed tomography in systemic sclerosis are varied and are divided into three main categories: interstitial, alveolar, and vascular. Interstitial changes constitute the most common type of pulmonary involvement in systemic sclerosis. However, alveolar and vascular manifestations must also be recognized and considered in the presence of atypical clinical presentations and inadequate treatment responses. (author)

Tomography patterns of lung disease in systemic sclerosis

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Andréa de Lima Bastos

Full Text Available Abstract Currently, lung impairment is the leading factor responsible for the morbidity and mortality associated with systemic sclerosis. Therefore, the recognition of the various tomography patterns becomes decisive in the clinical management of these patients. In high-resolution computed tomography studies, the most common pattern is that of nonspecific interstitial pneumonia. However, there are other forms of lung involvement that must also be recognized. The aim of this study was to review the literature on the main changes resulting from pulmonary involvement in systemic sclerosis and the corresponding radiological findings, considering the current classification of interstitial diseases. We searched the Medline (PubMed, Lilacs, and SciELO databases in order to select articles related to pulmonary changes in systemic sclerosis and published in English between 2000 and 2015. The pulmonary changes seen on computed tomography in systemic sclerosis are varied and are divided into three main categories: interstitial, alveolar, and vascular. Interstitial changes constitute the most common type of pulmonary involvement in systemic sclerosis. However, alveolar and vascular manifestations must also be recognized and considered in the presence of atypical clinical presentations and inadequate treatment responses.

Tomography patterns of lung disease in systemic sclerosis

International Nuclear Information System (INIS)

Bastos, Andrea de Lima; Correa, Ricardo de Amorim; Ferreira, Gilda Aparecida

2016-01-01

Currently, lung impairment is the leading factor responsible for the morbidity and mortality associated with systemic sclerosis. Therefore, the recognition of the various tomography patterns becomes decisive in the clinical management of these patients. In high-resolution computed tomography studies, the most common pattern is that of nonspecific interstitial pneumonia. However, there are other forms of lung involvement that must also be recognized. The aim of this study was to review the literature on the main changes resulting from pulmonary involvement in systemic sclerosis and the corresponding radiological findings, considering the current classification of interstitial diseases. We searched the Medline (PubMed), Lilacs, and SciELO databases in order to select articles related to pulmonary changes in systemic sclerosis and published in English between 2000 and 2015. The pulmonary changes seen on computed tomography in systemic sclerosis are varied and are divided into three main categories: interstitial, alveolar, and vascular. Interstitial changes constitute the most common type of pulmonary involvement in systemic sclerosis. However, alveolar and vascular manifestations must also be recognized and considered in the presence of atypical clinical presentations and inadequate treatment responses. (author)

Pu-Erh Tea Extract Induces the Degradation of FET Family Proteins Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis

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Yang Yu

2014-01-01

Full Text Available FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS, Ewing's sarcoma (EWS, and TATA-binding protein-associated factor 15 (TAF15. Mutations in the copper/zinc superoxide dismutase (SOD1, TAR DNA-binding protein 43 (TDP-43, and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS, a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.

Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis.

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Jafari, Naghmeh; Broer, Linda; Hoppenbrouwers, Ilse A; van Duijn, Cornelia M; Hintzen, Rogier Q

2010-11-01

Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10( -5)). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 (p = 0.003) for HLA-A. HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

'Multi-epitope-targeted' immune-specific therapy for a multiple sclerosis-like disease via engineered multi-epitope protein is superior to peptides.

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Nathali Kaushansky

Full Text Available Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and "epitope spread", have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such "multi-epitope-targeting" approach in murine experimental autoimmune encephalomyelitis (EAE associated with a single ("classical" or multiple ("complex" anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as "multi-epitope-targeting" agents. Y-MSPc was superior to peptide(s in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells. Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of "classical" or "complex EAE" or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a "multi-epitope-targeting" strategy is required for

Motor neuron disease (amyotrophic lateral sclerosis) arising from longstanding primary lateral sclerosis

NARCIS (Netherlands)

Bruyn, R. P.; Koelman, J. H.; Troost, D.; de Jong, J. M.

1995-01-01

Three men were initially diagnosed as having primary lateral sclerosis (PLS), but eventually developed amyotrophic lateral sclerosis (ALS) after 7.5, 9, and at least 27 years. Non-familial ALS and PLS might be different manifestations of a single disease or constitute completely distinct entities.

TDP-43 Proteinopathies: A New Player in Neurodegenerative Diseases with Defective Protein Folding

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Suna Lahut

2012-03-01

Full Text Available The proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer’s Disease (AD, Parkinson’s Disease (PD, Huntington’s Disease (HD, Amyotrophic Lateral Sclerosis (ALS, cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD, the two best studied examples of TDP-43 proteinopathies

TDP-43 Proteinopathies: A New Player in Neurodegenerative Diseases with Defective Protein Folding

Directory of Open Access Journals (Sweden)

Suna Lahut

2012-03-01

Full Text Available The proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer’s Disease (AD, Parkinson’s Disease (PD, Huntington’s Disease (HD, Amyotrophic Lateral Sclerosis (ALS, cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD, the two best studied examples of TDP-43 proteinopathies.

Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.

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Lee, Joo-Yong; Kawaguchi, Yoshiharu; Li, Ming; Kapur, Meghan; Choi, Su Jin; Kim, Hak-June; Park, Song-Yi; Zhu, Haining; Yao, Tso-Pang

2015-01-01

Aberrant accumulation of protein aggregates is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although a buildup of protein aggregates frequently leads to cell death, whether it is the key pathogenic factor in driving neurodegenerative disease remains controversial. HDAC6, a cytosolic ubiquitin-binding deacetylase, has emerged as an important regulator of ubiquitin-dependent quality control autophagy, a lysosome-dependent degradative system responsible for the disposal of misfolded protein aggregates and damaged organelles. Here, we show that in cell models HDAC6 plays a protective role against multiple disease-associated and aggregation-prone cytosolic proteins by facilitating their degradation. We further show that HDAC6 is required for efficient localization of lysosomes to protein aggregates, indicating that lysosome targeting to autophagic substrates is regulated. Supporting a critical role of HDAC6 in protein aggregate disposal in vivo, genetic ablation of HDAC6 in a transgenic SOD1G93A mouse, a model of ALS, leads to dramatic accumulation of ubiquitinated SOD1G93A protein aggregates. Surprisingly, despite a robust buildup of SOD1G93A aggregates, deletion of HDAC6 only moderately modified the motor phenotypes. These findings indicate that SOD1G93A aggregation is not the only determining factor to drive neurodegeneration in ALS, and that HDAC6 likely modulates neurodegeneration through additional mechanisms beyond protein aggregate clearance. © 2015 S. Karger AG, Basel.

Structure and function of the contactin-associated protein family in myelinated axons and their relationship with nerve diseases

Institute of Scientific and Technical Information of China (English)

Yan Zou; De-en Xu; Wei-feng Zhang; Hai-ying Liu; Xia Li; Xing Zhang; Xiao-fang Ma; Yang Sun; Shi-yi Jiang; Quan-hong Ma

2017-01-01

The contactin-associated protein (Caspr) family participates in nerve excitation and conduction, and neurotransmitter release in myelinated axons. We analyzed the structures and functions of the Caspr family–CNTNAP1 (Caspr1), CNTNAP2 (Caspr2), CNTNAP3 (Caspr3), CNTNAP4 (Caspr4) and CNTNAP5 (Caspr5), Caspr1–5 is not only involved in the formation of myelinated axons, but also participates in maintaining the stability of adjacent connections. Caspr1 participates in the formation, differentiation, and proliferation of neurons and astrocytes, and in motor control and cognitive function. We also analyzed the relationship between the Caspr family and neurodegenerative diseases, multiple sclerosis, and autoimmune encephalitis. However, the effects of Caspr on disease course and prognosis remain poorly understood. The effects of Caspr on disease diagnosis and treatment need further investigation.

Pulmonary dystrophic Calcinosis associated to systemic sclerosis: Report of the first case in Colombia

International Nuclear Information System (INIS)

Mendez Patarroyo, Paul; Rojas, Adriana; Restrepo Suarez, Jose Felix; Iglesias Gamarra, Antonio

2002-01-01

The association of pulmonary calcinosis with systemic sclerosis has not been described in the medical literature. There are two type of lung calcification: dystrophic and metastatic; in the collagen vascular diseases the most frequent is the dystrophic calcinosis, seen mainly in dermatomyositis and scleroderma. We describe the first case of dystrophic calcinosis associated with systemic sclerosis

Associations of Systemic Diseases with Intermediate Uveitis.

Science.gov (United States)

Shoughy, Samir S; Kozak, Igor; Tabbara, Khalid F

2016-01-01

To determine the associations of systemic diseases with intermediate uveitis. The medical records of 50 consecutive cases with intermediate uveitis referred to The Eye Center in Riyadh, Saudi Arabia, were reviewed. Age- and sex-matched patients without uveitis served as controls. Patients had complete ophthalmic and medical examinations. There were 27 male and 23 female patients. Mean age was 29 years with a range of 5-62 years. Overall, 21 cases (42%) had systemic disorders associated with intermediate uveitis and 29 cases (58%) had no associated systemic disease. A total of 11 patients (22%) had asthma, 4 (8%) had multiple sclerosis, 3 (6%) had presumed ocular tuberculosis, 1 (2%) had inflammatory bowel disease, 1 (2%) had non-Hodgkin lymphoma and 1 (2%) had sarcoidosis. Evidence of systemic disease was found in 50 (5%) of the 1,000 control subjects. Bronchial asthma was found in 37 patients (3.7 %), multiple sclerosis in 9 patients (0.9%), inflammatory bowel disease in 3 patients (0.3%), and tuberculosis in 1 patient (0.1%). None of the control patients had sarcoidosis or lymphoma. There were statistically significant associations between intermediate uveitis and bronchial asthma (p = 0.0001), multiple sclerosis (p = 0.003) and tuberculosis (p = 0.0005). Bronchial asthma and multiple sclerosis were the most frequently encountered systemic diseases associated with intermediate uveitis in our patient population. Patients with intermediate uveitis should undergo careful history-taking and investigations to rule out associated systemic illness.

Amyotrophic Lateral Sclerosis and Organ Donation: Is There Risk of Disease Transmission?

OpenAIRE

Holmes, Brandon B.; Diamond, Marc I.

2012-01-01

A new protocol suggests that patients with amyotrophic lateral sclerosis (ALS) are a viable source of tissue for organ transplantation. However, multiple lines of evidence suggest that many neurodegenerative diseases, including ALS, might progress due to transcellular propagation of protein aggregation among neurons. Transmission of the disease state from donor to host thus may be possible under the permissive circumstances of graft transplantation. We argue for careful patient selection and ...

A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis

DEFF Research Database (Denmark)

Jagodic, Maja; Colacios, Celine; Nohra, Rita

2009-01-01

Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome...... region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal......-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher...

Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

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Asako Otomo

2012-01-01

Full Text Available Amyotrophic lateral sclerosis (ALS is a heterogeneous group of incurable motor neuron diseases (MNDs characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

Prioritizing disease candidate proteins in cardiomyopathy-specific protein-protein interaction networks based on "guilt by association" analysis.

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Wan Li

Full Text Available The cardiomyopathies are a group of heart muscle diseases which can be inherited (familial. Identifying potential disease-related proteins is important to understand mechanisms of cardiomyopathies. Experimental identification of cardiomyophthies is costly and labour-intensive. In contrast, bioinformatics approach has a competitive advantage over experimental method. Based on "guilt by association" analysis, we prioritized candidate proteins involving in human cardiomyopathies. We first built weighted human cardiomyopathy-specific protein-protein interaction networks for three subtypes of cardiomyopathies using the known disease proteins from Online Mendelian Inheritance in Man as seeds. We then developed a method in prioritizing disease candidate proteins to rank candidate proteins in the network based on "guilt by association" analysis. It was found that most candidate proteins with high scores shared disease-related pathways with disease seed proteins. These top ranked candidate proteins were related with the corresponding disease subtypes, and were potential disease-related proteins. Cross-validation and comparison with other methods indicated that our approach could be used for the identification of potentially novel disease proteins, which may provide insights into cardiomyopathy-related mechanisms in a more comprehensive and integrated way.

Structure and function of the contactin-associated protein family in myelinated axons and their relationship with nerve diseases

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Yan Zou

2017-01-01

Full Text Available The contactin-associated protein (Caspr family participates in nerve excitation and conduction, and neurotransmitter release in myelinated axons. We analyzed the structures and functions of the Caspr family–CNTNAP1 (Caspr1, CNTNAP2 (Caspr2, CNTNAP3 (Caspr3, CNTNAP4 (Caspr4 and CNTNAP5 (Caspr5, Caspr1–5 is not only involved in the formation of myelinated axons, but also participates in maintaining the stability of adjacent connections. Caspr1 participates in the formation, differentiation, and proliferation of neurons and astrocytes, and in motor control and cognitive function. We also analyzed the relationship between the Caspr family and neurodegenerative diseases, multiple sclerosis, and autoimmune encephalitis. However, the effects of Caspr on disease course and prognosis remain poorly understood. The effects of Caspr on disease diagnosis and treatment need further investigation.

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

Science.gov (United States)

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

Multiple sclerosis susceptibility-associated SNPs do not influence disease severity measures in a cohort of Australian MS patients.

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Cathy J Jensen

Full Text Available Recent association studies in multiple sclerosis (MS have identified and replicated several single nucleotide polymorphism (SNP susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13-14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity.

HDAPD: a web tool for searching the disease-associated protein structures

Science.gov (United States)

2010-01-01

Background The protein structures of the disease-associated proteins are important for proceeding with the structure-based drug design to against a particular disease. Up until now, proteins structures are usually searched through a PDB id or some sequence information. However, in the HDAPD database presented here the protein structure of a disease-associated protein can be directly searched through the associated disease name keyed in. Description The search in HDAPD can be easily initiated by keying some key words of a disease, protein name, protein type, or PDB id. The protein sequence can be presented in FASTA format and directly copied for a BLAST search. HDAPD is also interfaced with Jmol so that users can observe and operate a protein structure with Jmol. The gene ontological data such as cellular components, molecular functions, and biological processes are provided once a hyperlink to Gene Ontology (GO) is clicked. Further, HDAPD provides a link to the KEGG map such that where the protein is placed and its relationship with other proteins in a metabolic pathway can be found from the map. The latest literatures namely titles, journals, authors, and abstracts searched from PubMed for the protein are also presented as a length controllable list. Conclusions Since the HDAPD data content can be routinely updated through a PHP-MySQL web page built, the new database presented is useful for searching the structures for some disease-associated proteins that may play important roles in the disease developing process for performing the structure-based drug design to against the diseases. PMID:20158919

MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.

Science.gov (United States)

MacNair, Laura; Xiao, Shangxi; Miletic, Denise; Ghani, Mahdi; Julien, Jean-Pierre; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Robertson, Janice

2016-01-01

Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare. However, TDP-43 pathology is common to over 95% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 play an active role in disease pathogenesis. It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will lead to changes in RNA processing and expression. Identifying these changes could uncover molecular pathways that underpin motor neuron degeneration. Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP-43(A315T) mice compared to age-matched non-transgenic littermates. No significant changes were found at 5 months (presymptomatic) of age, but at 10 months (symptomatic) the translational profile revealed significant changes in genes involved in RNA metabolic process, immune response and cell cycle regulation. Of 28 differentially expressed genes, seven had a ≥ 2-fold change; four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model

Improved pulmonary function following pirfenidone treatment in a patient with progressive interstitial lung disease associated with systemic sclerosis

Directory of Open Access Journals (Sweden)

Zarir F Udwadia

2015-01-01

Full Text Available Pirfenidone is an anti-fibrotic drug which has been approved for the management of patients with Idiopathic Pulmonary Fibrosis (IPF. However, its role in interstitial lung disease (ILD due to other causes such as systemic sclerosis (SSc is not clear. We present a case of a patient with SSc associated ILD who showed a subjective as well as objective improvement in lung function with pirfenidone.

Association between systemic lupus erythematosus and multiple sclerosis: lupoid sclerosis

International Nuclear Information System (INIS)

Medina, Yimy F; Martinez, Jose B; Fernandez, Andres R; Quintana, Gerardo; Restrepo, Jose Felix; Rondon, Federico; Gamarra, Antonio Iglesias

2010-01-01

Multiple sclerosis (MS) and Systemic Lupus Erythematosus (SLE) with/without antiphospholipid syndrome are autoimmune illnesses. It has been described in many occasions the association of these two illnesses and the clinical picture of MS with characteristics of laboratory of SLE. When they affect to the central nervous system they can make it in a defined form for each illness or they can also make it in interposed or combined form of the two illnesses what has been called lupoid sclerosis; making that in some cases difficult the differentiation of the two illnesses and therefore to address the treatment. We present four cases of lupoid sclerosis, discuss the clinical and laboratory characteristics of this entity and we make a differentiation of the multiple sclerosis with the neurological affectation of SLE especially for images and laboratory results.

Association of systemic sclerosis and psoriatic arthritis: a case report

Directory of Open Access Journals (Sweden)

A. Musio

2011-09-01

Full Text Available The association of Systemic Sclerosis (SSc and Psoriatic Arthritis (PsA is unfrequent; only few cases are reported in literature. We describe a case of a patient with SSc following the onset of PsA. The disease begun with tenosynovitis, polyarthritis in association with psoriasis. After two years, Raynaud’s phenomenon and sclerodactyly appeared, and, later, pulmonary interstizial fibrosis and esophageal dysfunction. The existence of a common pathogenesis of the two diseases, SSc and PsA, is discussed.

Speech and Pause Characteristics Associated with Voluntary Rate Reduction in Parkinson's Disease and Multiple Sclerosis

Science.gov (United States)

Tjaden, Kris; Wilding, Greg

2011-01-01

The primary purpose of this study was to investigate how speakers with Parkinson's disease (PD) and Multiple Sclerosis (MS) accomplish voluntary reductions in speech rate. A group of talkers with no history of neurological disease was included for comparison. This study was motivated by the idea that knowledge of how speakers with dysarthria…

Shared mechanisms among neurodegenerative diseases: from ...

Indian Academy of Sciences (India)

douglas arneson

amyotrophic lateral sclerosis (ALS) are pressing health concerns in modern societies for which ... subsets of diseases, and a systematic review of the most current information ... (vesicle-associated membrane protein)-associated protein B) for ...

CD40: Novel Association with Crohn's Disease and Replication in Multiple Sclerosis Susceptibility

Science.gov (United States)

Alcina, Antonio; Teruel, María; Díaz-Gallo, Lina M.; Gómez-García, María; López-Nevot, Miguel A.; Rodrigo, Luis; Nieto, Antonio; Cardeña, Carlos; Alcain, Guillermo; Díaz-Rubio, Manuel; de la Concha, Emilio G.; Fernandez, Oscar; Arroyo, Rafael

2010-01-01

Background A functional polymorphism located at −1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves' disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn's disease (CD) lesions. Methodology Genotyping of rs1883832C>T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. Principal Findings The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p = 0.025; OR (95% CI) = 1.12 (1.01–1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p = 0.002; OR (95% CI) = 1.19 (1.06–1.33)]. This increased predisposition was not detected in UC patients [p = 0.5; OR (95% CI) = 1.04 (0.93–1.17)]. Conclusion The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions. PMID:20634952

The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis.

Science.gov (United States)

Sako, Wataru; Abe, Takashi; Izumi, Yuishin; Harada, Masafumi; Kaji, Ryuji

2016-05-01

Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N-acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease.

Science.gov (United States)

Stürner, Elisabeth; Behl, Christian

2017-01-01

In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 ( BCL-2-associated athanogene 3 ). Under acute stress and during cellular aging, BAG3 in concert with the molecular chaperones HSP70 and HSPB8 as well as the ubiquitin receptor p62/SQSTM1 specifically targets aggregation-prone proteins to autophagic degradation. Thereby, BAG3-mediated selective macroautophagy represents a pivotal adaptive safeguarding and emergency system of the PQC which is activated under pathophysiological conditions to ensure cellular proteostasis. Interestingly, BAG3-mediated selective macroautophagy is also involved in the clearance of aggregated proteins associated with age-related neurodegenerative disorders, like Alzheimer's disease (tau-protein), Huntington's disease (mutated huntingtin/polyQ proteins), and amyotrophic lateral sclerosis (mutated SOD1). In addition, based on its initial description BAG3 is an anti-apoptotic protein that plays a decisive role in other widespread diseases, including cancer and myopathies. Therefore, in the search for novel therapeutic intervention avenues in neurodegeneration, myopathies and cancer BAG3 is a promising candidate.

Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells.

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Giovanni Nardo

Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC, a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%, and from patients with neurological disorders that may resemble ALS (91%, between two levels of disease severity (90%, and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.

Genetic association of multiple sclerosis with the marker rs391745 near the endogenous retroviral locus HERV-Fc1: analysis of disease subtypes

DEFF Research Database (Denmark)

Hansen, Bettina; Oturai, Annette Bang; Harbo, Hanne F

2011-01-01

We have previously described the occurrence of multiple sclerosis (MS) to be associated with human endogenous retroviruses, specifically the X-linked viral locus HERV-Fc1. The aim of this study was to investigate a possible association of the HERV-Fc1 locus with subtypes of MS. MS patients......-Fc1 locus (p = 0.003), while primary progressive disease was not. The ability to see genetic differences between subtypes of MS near this gene speaks for the involvement of the virus HERV-Fc1 locus in modifying the disease course of MS....

Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis.

Science.gov (United States)

Feucht, Nikolaus; Maier, Mathias; Lepennetier, Gildas; Pettenkofer, Moritz; Wetzlmair, Carmen; Daltrozzo, Tanja; Scherm, Pauline; Zimmer, Claus; Hoshi, Muna-Miriam; Hemmer, Bernhard; Korn, Thomas; Knier, Benjamin

2018-01-01

Patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) may show alterations of retinal layer architecture as measured by optical coherence tomography. Little is known about changes in the retinal vascular network during MS. To characterize retinal vessel structures in patients with MS and CIS and to test for associations with MS disease activity. In all, 42 patients with MS or CIS and 50 healthy controls underwent retinal optical coherence tomography angiography (OCT-A) with analysis of the superficial and deep vascular plexuses and the choriocapillaries. We tested OCT-A parameters for associations with retinal layer volumes, history of optic neuritis (ON), and the retrospective disease activity. Inner retinal layer volumes correlated positively with the density of both the superficial and deep vascular plexuses. Eyes of MS/CIS patients with a history of ON revealed reduced vessel densities of the superficial and deep vascular plexuses as compared to healthy controls. Higher choriocapillary vessel densities were associated with ongoing inflammatory disease activity during 24 months prior to OCT-A examination in MS and CIS patients. Optic neuritis is associated with rarefaction of the superficial and deep retinal vessels. Alterations of the choriocapillaries might be linked to disease activity in MS.

Nervous system disease associated with dominant cellular radiosensitivity

International Nuclear Information System (INIS)

Kidson, C.; Chen, P.; Imray, F.P.; Gipps, E.

1983-01-01

Ionizing radiation sensitivity has been demonstrated in the following neurological diseases: sporadic and familial Alzheimer's disease, familial non-specific dementia, amyotrophic lateral sclerosis and Parkinsonism dementia of Guam, Huntington's disease, multiple sclerosis. Family studies in many cases give data consistent with dominant genetics, as does cell fusion analysis in the one disease so studied. In no case was there an absolute association between radiosensitivity and a given neurological disease. It is proposed that the underlying mutations are in genes controlling facets of nervous or immune system differentiation and development. 15 references, 2 tables

Purification of infectious human herpesvirus 6A virions and association of host cell proteins

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Garoff Henrik

2007-10-01

Full Text Available Abstract Background Viruses that are incorporating host cell proteins might trigger autoimmune diseases. It is therefore of interest to identify possible host proteins associated with viruses, especially for enveloped viruses that have been suggested to play a role in autoimmune diseases, like human herpesvirus 6A (HHV-6A in multiple sclerosis (MS. Results We have established a method for rapid and morphology preserving purification of HHV-6A virions, which in combination with parallel analyses with background control material released from mock-infected cells facilitates qualitative and quantitative investigations of the protein content of HHV-6A virions. In our iodixanol gradient purified preparation, we detected high levels of viral DNA by real-time PCR and viral proteins by metabolic labelling, silver staining and western blots. In contrast, the background level of cellular contamination was low in the purified samples as demonstrated by the silver staining and metabolic labelling analyses. Western blot analyses showed that the cellular complement protein CD46, the receptor for HHV-6A, is associated with the purified and infectious virions. Also, the cellular proteins clathrin, ezrin and Tsg101 are associated with intact HHV-6A virions. Conclusion Cellular proteins are associated with HHV-6A virions. The relevance of the association in disease and especially in autoimmunity will be further investigated.

Axonal loss in the multiple sclerosis spinal cord revisited.

Science.gov (United States)

Petrova, Natalia; Carassiti, Daniele; Altmann, Daniel R; Baker, David; Schmierer, Klaus

2018-05-01

Preventing chronic disease deterioration is an unmet need in people with multiple sclerosis, where axonal loss is considered a key substrate of disability. Clinically, chronic multiple sclerosis often presents as progressive myelopathy. Spinal cord cross-sectional area (CSA) assessed using MRI predicts increasing disability and has, by inference, been proposed as an indirect index of axonal degeneration. However, the association between CSA and axonal loss, and their correlation with demyelination, have never been systematically investigated using human post mortem tissue. We extensively sampled spinal cords of seven women and six men with multiple sclerosis (mean disease duration= 29 years) and five healthy controls to quantify axonal density and its association with demyelination and CSA. 396 tissue blocks were embedded in paraffin and immuno-stained for myelin basic protein and phosphorylated neurofilaments. Measurements included total CSA, areas of (i) lateral cortico-spinal tracts, (ii) gray matter, (iii) white matter, (iv) demyelination, and the number of axons within the lateral cortico-spinal tracts. Linear mixed models were used to analyze relationships. In multiple sclerosis CSA reduction at cervical, thoracic and lumbar levels ranged between 19 and 24% with white (19-24%) and gray (17-21%) matter atrophy contributing equally across levels. Axonal density in multiple sclerosis was lower by 57-62% across all levels and affected all fibers regardless of diameter. Demyelination affected 24-48% of the gray matter, most extensively at the thoracic level, and 11-13% of the white matter, with no significant differences across levels. Disease duration was associated with reduced axonal density, however not with any area index. Significant association was detected between focal demyelination and decreased axonal density. In conclusion, over nearly 30 years multiple sclerosis reduces axonal density by 60% throughout the spinal cord. Spinal cord cross sectional area

Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus.

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Stefano Bonapace

Full Text Available BACKGROUND: Recent epidemiological data suggest that non-alcoholic fatty liver disease (NAFLD is closely associated with aortic valve sclerosis (AVS, an emerging risk factor for adverse cardiovascular outcomes, in nondiabetic and type 2 diabetic individuals. To date, nobody has investigated the association between NAFLD and AVS in people with type 2 diabetes, a group of individuals in which the prevalence of these two diseases is high. METHODS AND RESULTS: We recruited 180 consecutive type 2 diabetic patients without ischemic heart disease, valvular heart disease, hepatic diseases or excessive alcohol consumption. NAFLD was diagnosed by liver ultrasonography whereas AVS was determined by conventional echocardiography in all participants. In the whole sample, 120 (66.7% patients had NAFLD and 53 (29.4% had AVS. No patients had aortic stenosis. NAFLD was strongly associated with an increased risk of prevalent AVS (odds ratio [OR] 2.79, 95% CI 1.3-6.1, p<0.01. Adjustments for age, sex, duration of diabetes, diabetes treatment, body mass index, smoking, alcohol consumption, hypertension, dyslipidemia, hemoglobin A1c and estimated glomerular filtration rate did not attenuate the strong association between NAFLD and risk of prevalent AVS (adjusted-OR 3.04, 95% CI 1.3-7.3, p = 0.01. CONCLUSIONS: Our results provide the first demonstration of a positive and independent association between NAFLD and AVS in patients with type 2 diabetes mellitus.

Amyotrophic lateral sclerosis – a motor neuron disease. Case report

Directory of Open Access Journals (Sweden)

Maja Rubinowicz-Zasada

2015-03-01

Full Text Available Amyotrophic lateral sclerosis, also known as Charcot’s disease and motor neuron disease, is a progressive neurodegenerative disease that causes muscle weakness, paralysis, and ultimately, respiratory failure. The aetiology and the pathogenesis of the syndrome remain unknown. Most people live 2–5 years after their first signs of the disease. There is no cure or effective treatment. We present a case of a female patient affected by progressing Charcot’s disease. On the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R, the patient obtained 21 points. Atrophy and muscle spasm were very extended. Electromyography revealed features of coexisting denervation and reinnervation in the examined muscles. A growing number of Charcot’s disease cases require multidirectional actions to meet patient’s physical, emotional, and nutritional needs. Amyotrophic lateral sclerosis is an incurable disease. However, it is possible to relieve its symptoms by applying systematic physical rehabilitation.

Traces of disease in amyotrophic lateral sclerosis

NARCIS (Netherlands)

Verstraete, E.

2012-01-01

Amyotrophic lateral sclerosis (ALS) is a progressive disease of the motor system involving both upper motor neurons in the brain and lower motor neurons in the spinal cord. Patients suffer from progressive wasting and weakness of limb, bulbar and respiratory muscles. Onset and disease course in ALS

Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

Science.gov (United States)

Fournier, Christina N; Murphy, Alyssa; Loci, Lorena; Mitsumoto, Hiroshi; Lomen-Hoerth, Catherine; Kisanuki, Yasushi; Simmons, Zachary; Maragakis, Nicholas J; McVey, April L; Al-Lahham, Tawfiq; Heiman-Patterson, Terry D; Andrews, Jinsy; McDonnell, Erin; Cudkowicz, Merit; Atassi, Nazem

2016-03-01

The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

Directory of Open Access Journals (Sweden)

Elisabeth Stürner

2017-06-01

Full Text Available In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy. One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3. Under acute stress and during cellular aging, BAG3 in concert with the molecular chaperones HSP70 and HSPB8 as well as the ubiquitin receptor p62/SQSTM1 specifically targets aggregation-prone proteins to autophagic degradation. Thereby, BAG3-mediated selective macroautophagy represents a pivotal adaptive safeguarding and emergency system of the PQC which is activated under pathophysiological conditions to ensure cellular proteostasis. Interestingly, BAG3-mediated selective macroautophagy is also involved in the clearance of aggregated proteins associated with age-related neurodegenerative disorders, like Alzheimer’s disease (tau-protein, Huntington’s disease (mutated huntingtin/polyQ proteins, and amyotrophic lateral sclerosis (mutated SOD1. In addition, based on its initial description BAG3 is an anti-apoptotic protein that plays a decisive role in other widespread diseases, including cancer and myopathies. Therefore, in the search for novel therapeutic intervention avenues in neurodegeneration, myopathies and cancer BAG3 is a promising candidate.

Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution.

Science.gov (United States)

Medina-Carmona, Encarnación; Fuchs, Julian E; Gavira, Jose A; Mesa-Torres, Noel; Neira, Jose L; Salido, Eduardo; Palomino-Morales, Rogelio; Burgos, Miguel; Timson, David J; Pey, Angel L

2017-09-15

Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site-specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine:glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please

CD4 T cell activation and disease activity at onset of multiple sclerosis

DEFF Research Database (Denmark)

Jensen, J; Langkilde, Annika Reynberg; Fenst, C

2004-01-01

We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease...... severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states...

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

DEFF Research Database (Denmark)

Lill, Christina M; Rengmark, Aina; Pihlstrøm, Lasse

2015-01-01

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we......) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10......(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628...

Adie’s Tonic Pupil in Systemic Sclerosis: A Rare Association

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Anusha Venkataraman

2015-01-01

Full Text Available We report a rare association of Adie’s tonic pupil in a patient with systemic sclerosis who was otherwise systemically stable. This paper is an effort to unravel whether the tonic pupil and systemic sclerosis are an association by chance (which may be the case or systemic sclerosis is the source of the tonic pupil.

[Effects of nutritional status on the multiple sclerosis disease: systematic review].

Science.gov (United States)

Ródenas Esteve, Irene; Wanden-Berghe, Carmina; Sanz-Valero, Javier

2018-01-19

To review the available scientific literature about the effects of nutritional status on the multiple sclerosis disease. A systematic review of the scientific literature in the Medline (PubMed), Scopus, Cochrane Library and Web of Science databases through November 2016. Search equation: ("Multiple Sclerosis"[Mesh] OR "Multiple Sclerosis"[Title/Abstract] OR "Disseminated Sclerosis"[Title/Abstract] OR "Multiple Sclerosis Acute Fulminating"[Title/Abstract]) AND ("Nutritional Status"[Mesh] OR "Nutritional Status"[Title/Abstract] OR "Nutrition Status"[Title/Abstract]). The quality of the selected articles was discussed using the STROBE questionnaire. The search was completed through experts inquiry and additional review of the bibliographic references included in the selected papers. The concordance between authors (Kappa index) had to be higher than 80% for inclusion in this review. Of the 160 references recovered, after applying inclusion and exclusion criteria, 29 articles were selected for review. Concordance between evaluators was 100.00%. The most studies established vitamin D levels. Others focused their research on finding out which nutrient deficits might be related to the multiple sclerosis development. Vitamin D may influence multiple sclerosis improvement. Sunlight and physical activity would be important factors, with nutritional status, in the course of this disease. It is necessary to produce new specific works that will delve into the subject to find out more about the relationship between nutritional status and multiple sclerosis.

Mechanisms of protein misfolding: Novel therapeutic approaches to protein-misfolding diseases

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Salahuddin, Parveen; Siddiqi, Mohammad Khursheed; Khan, Sanaullah; Abdelhameed, Ali Saber; Khan, Rizwan Hasan

2016-11-01

In protein misfolding, protein molecule acquires wrong tertiary structure, thereby induces protein misfolding diseases. Protein misfolding can occur through various mechanisms. For instance, changes in environmental conditions, oxidative stress, dominant negative mutations, error in post-translational modifications, increase in degradation rate and trafficking error. All of these factors cause protein misfolding thereby leading to diseases conditions. Both in vitro and in vivo observations suggest that partially unfolded or misfolded intermediates are particularly prone to aggregation. These partially misfolded intermediates aggregate via the interaction with the complementary intermediates and consequently enhance oligomers formation that grows into fibrils and proto-fibrils. The amyloid fibrils for example, accumulate in the brain and central nervous system (CNS) as amyloid deposits in the Parkinson's disease (PD), Alzheimer's disease (AD), Prion disease and Amylo lateral Sclerosis (ALS). Furthermore, tau protein shows intrinsically disorder conformation; therefore its interaction with microtubule is impaired and this protein undergoes aggregation. This is also underlying cause of Alzheimers and other neurodegenerative diseases. Treatment of such misfolding maladies is considered as one of the most important challenges of the 21st century. Currently, several treatments strategies have been and are being discovered. These therapeutic interventions partly reversed or prevented the pathological state. More recently, a new approach was discovered, which employs nanobodies that targets multisteps in fibril formation pathway that may possibly completely cure these misfolding diseases. Keeping the above views in mind in the current review, we have comprehensively discussed the different mechanisms underlying protein misfolding thereby leading to diseases conditions and their therapeutic interventions.

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

Science.gov (United States)

Giovannoni, Gavin

2018-06-01

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

Association study between XRCC1 gene polymorphisms and sporadic amyotrophic lateral sclerosis.

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Coppedè, Fabio; Migheli, Francesca; Lo Gerfo, Annalisa; Fabbrizi, Maria Rita; Carlesi, Cecilia; Mancuso, Michelangelo; Corti, Stefania; Mezzina, Nicoletta; del Bo, Roberto; Comi, Giacomo P; Siciliano, Gabriele; Migliore, Lucia

2010-01-01

The aim of the present study was to investigate the possible contribution of three common functional polymorphisms in the DNA repair protein X-ray repair cross-complementing group 1 (XRCC1), namely Arg194Trp (rs1799782), Arg280His (rs25489) and Arg399Gln (rs25487), to sporadic amyotrophic lateral sclerosis (SALS). We genotyped 206 Italian SALS patients and 203 matched controls for XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms by means of PCR/RFLP technique, searching for association between any of the studied polymorphisms and disease risk, age and site of onset. We observed a statistically significant difference in XRCC1 Gln399 allele frequencies between SALS cases and controls (0.39/0.28; p=0.001). The present study suggests that the XRCC1 Arg399Gln polymorphism might contribute to SALS risk.

Differentially expressed microRNA in multiple sclerosis: A window into pathogenesis?

DEFF Research Database (Denmark)

Martin, Nellie Anne; Illés, Zsolt

2014-01-01

MicroRNA are small non-coding RNA that mediate mRNA translation repression or mRNA degradation, and thereby refine protein expression levels. More than 30–60% of all genes are regulated by microRNA. Exploring disease-related microRNA signatures is an emerging tool in biomarker discovery, and sile......MicroRNA are small non-coding RNA that mediate mRNA translation repression or mRNA degradation, and thereby refine protein expression levels. More than 30–60% of all genes are regulated by microRNA. Exploring disease-related microRNA signatures is an emerging tool in biomarker discovery......RNA related to multiple sclerosis has increased significantly in recent years. Differentially expressed microRNA have been identified in the whole blood, serum, plasma, cerebrospinal fluid, peripheral blood mononuclear cells, blood-derived cell subsets and brain lesions of patients with multiple sclerosis....... Most studies applied a non-candidate approach of screening by microarray and validation by quantitative polymerase chain reaction or next generation sequencing; others used a candidate-driven approach. Despite a relatively high number of multiple sclerosis-associated microRNA, just a few could...

Why are proteins with glutamine- and asparagine-rich regions associated with protein misfolding diseases?

Energy Technology Data Exchange (ETDEWEB)

Cruzeiro, Leonor [CCMAR and FCT, University of Algarve, Campus de Gambelas, 8000 Faro (Portugal)

2005-12-21

The possibility that vibrational excited states (VESs) are the drivers of protein folding and function (the VES hypothesis) is explored to explain the reason why Gln- and Asn-rich proteins are associated with degenerative diseases. The Davydov/Scott model is extended to describe energy transfer from the water solution to the protein and vice versa. Computer simulations show that, on average, Gln and Asn residues lead to an initial larger absorption of energy from the environment to the protein, something that can explain the greater structural instability of prions. The sporadic, inherited and infectious character of prion diseases is discussed in the light of the VES hypothesis. An alternative treatment for prion diseases is suggested.

Association of copeptin and cortisol in newly diagnosed multiple sclerosis patients.

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Baranowska-Bik, Agnieszka; Kochanowski, Jan; Uchman, Dorota; Litwiniuk, Anna; Kalisz, Malgorzata; Martynska, Lidia; Wolinska-Witort, Ewa; Baranowska, Boguslawa; Bik, Wojciech

2015-05-15

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Obesity may increase the risk of developing MS. The aim of this study was to evaluate copeptin and cortisol plasma levels in newly diagnosed untreated MS patients and to determine whether copeptin and cortisol are related to the patients' clinical statuses. We report that copeptin and cortisol were higher in overweight/obese MS patients. Positive correlations were observed between the two parameters. We conclude that alterations of copeptin and cortisol levels in multiple sclerosis patients may be related to adiposity. An increase in cortisol may also be associated with copeptin secretion. Copyright © 2015 Elsevier B.V. All rights reserved.

Gallium-67 uptake by the thyroid associated with progressive systemic sclerosis

International Nuclear Information System (INIS)

Sjoberg, R.J.; Blue, P.W.; Kidd, G.S.

1989-01-01

Although thyroidal uptake of gallium-67 has been described in several thyroid disorders, gallium-67 scanning is not commonly used in the evaluation of thyroid disease. Thyroidal gallium-67 uptake has been reported to occur frequently with subacute thyroiditis, anaplastic thyroid carcinoma, and thyroid lymphoma, and occasionally with Hashimoto's thyroiditis and follicular thyroid carcinoma. A patient is described with progressive systemic sclerosis who, while being scanned for possible active pulmonary involvement, was found incidentally to have abnormal gallium-67 uptake only in the thyroid gland. Fine needle aspiration cytology of the thyroid revealed Hashimoto's thyroiditis. Although Hashimoto's thyroiditis occurs with increased frequency in patients with progressive systemic sclerosis, thyroidal uptake of gallium-67 associated with progressive systemic sclerosis has not, to our knowledge, been previously described. Since aggressive thyroid malignancies frequently are imaged by gallium-67 scintigraphy, fine needle aspiration cytology of the thyroid often is essential in the evaluation of thyroidal gallium-67 uptake

Gallium-67 uptake by the thyroid associated with progressive systemic sclerosis

Energy Technology Data Exchange (ETDEWEB)

Sjoberg, R.J.; Blue, P.W.; Kidd, G.S.

1989-01-01

Although thyroidal uptake of gallium-67 has been described in several thyroid disorders, gallium-67 scanning is not commonly used in the evaluation of thyroid disease. Thyroidal gallium-67 uptake has been reported to occur frequently with subacute thyroiditis, anaplastic thyroid carcinoma, and thyroid lymphoma, and occasionally with Hashimoto's thyroiditis and follicular thyroid carcinoma. A patient is described with progressive systemic sclerosis who, while being scanned for possible active pulmonary involvement, was found incidentally to have abnormal gallium-67 uptake only in the thyroid gland. Fine needle aspiration cytology of the thyroid revealed Hashimoto's thyroiditis. Although Hashimoto's thyroiditis occurs with increased frequency in patients with progressive systemic sclerosis, thyroidal uptake of gallium-67 associated with progressive systemic sclerosis has not, to our knowledge, been previously described. Since aggressive thyroid malignancies frequently are imaged by gallium-67 scintigraphy, fine needle aspiration cytology of the thyroid often is essential in the evaluation of thyroidal gallium-67 uptake.

The Cyanobacteria Derived Toxin Beta-N-Methylamino-L-Alanine and Amyotrophic Lateral Sclerosis

Directory of Open Access Journals (Sweden)

Elijah W. Stommel

2010-12-01

Full Text Available There is mounting evidence to suggest that environmental factors play a major role in the development of neurodegenerative diseases like ALS (Amyotrophic Lateral Sclerosis. The non-protein amino acid beta-N-methylamino-L-alanine (BMAA was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC in Guam, and has been implicated as a potential environmental factor in ALS, Alzheimer’s disease, and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-protein amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. The ramifications of discovering an environmental trigger for ALS are enormous. In this article, we discuss the history, ecology, pharmacology and clinical ramifications of this ubiquitous, cyanobacteria-derived toxin.

The need for a disease-specific prospective pregnancy registry for multiple sclerosis (MS).

Science.gov (United States)

Alwan, Sura; Chambers, Christina D; Armenti, Vincent T; Sadovnick, A Dessa

2015-01-01

Multiple sclerosis (MS) is the most commonly acquired neurological disorder affecting young adults of reproductive age with an approximately 3:1 female to male ratio. Although pregnancy is not contraindicated in MS, data are limited regarding pregnancy outcome among MS patients, and the safety or risk to the fetus associated with most maternal MS treatments, such as disease modifying therapies (DMTs), during pregnancy is unknown. We review available epidemiological and registry data on MS and pregnancy and discuss the need to initiate a North American Multiple Sclerosis Pregnancy Registry that will prospectively identify pregnancies in women with MS, obtain information on the disease, and its treatment during gestation and lactation and follow the children to determine their health status. Copyright © 2014 Elsevier B.V. All rights reserved.

Hippocampal Sclerosis in Older Patients

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Cykowski, Matthew D.; Powell, Suzanne Z.; Schulz, Paul E.; Takei, Hidehiro; Rivera, Andreana L.; Jackson, Robert E.; Roman, Gustavo; Jicha, Gregory A.; Nelson, Peter T.

2018-01-01

Context Autopsy studies of the older population (≥65 years of age), and particularly of the “oldest-old” (≥85 years of age), have identified a significant proportion (~20%) of cognitively impaired patients in which hippocampal sclerosis is the major substrate of an amnestic syndrome. Hippocampal sclerosis may also be comorbid with frontotemporal lobar degeneration, Alzheimer disease, and Lewy body disease. Until recently, the terms hippocampal sclerosis of aging or hippocampal sclerosis dementia were applied in this context. Recent discoveries have prompted a conceptual expansion of hippocampal sclerosis of aging because (1) cellular inclusions of TAR DNA-binding protein 43 kDa (TDP-43) are frequent; (2) TDP-43 pathology may be found outside hippocampus; and (3) brain arteriolosclerosis is a common, possibly pathogenic, component. Objective To aid pathologists with recent recommendations for diagnoses of common neuropathologies in older persons, particularly hippocampal sclerosis, and highlight the recent shift in diagnostic terminology from HS-aging to cerebral age-related TDP-43 with sclerosis (CARTS). Data Sources Peer-reviewed literature and 5 autopsy examples that illustrate common age-related neuropathologies, including CARTS, and emphasize the importance of distinguishing CARTS from late-onset frontotemporal lobar degeneration with TDP-43 pathology and from advanced Alzheimer disease with TDP-43 pathology. Conclusions In advanced old age, the substrates of cognitive impairment are often multifactorial. This article demonstrates common and frequently comorbid neuropathologic substrates of cognitive impairment in the older population, including CARTS, to aid those practicing in this area of pathology. PMID:28467211

CCR5 delta32, matrix metalloproteinase-9 and disease activity in multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, Finn; Madsen, Hans O; Jensen, Claus V

2000-01-01

Chemokines and matrix metalloproteinases (MMPs) appear to be crucial in leukocyte recruitment to the central nervous system in multiple sclerosis (MS). CCR5 delta32, a truncated allele of the CC chemokine receptor CCR5 gene encoding a non-functional receptor, did not confer protection from MS. CCR5...... delta32 was, however, associated with a lower risk of recurrent clinical disease activity. High CSF levels of MMP-9 activity were also associated with recurrent disease activity. These results directly link intrathecal inflammation to disease activity in patients with MS, suggesting that treatments...... targeting CCR5 or treatment with MMP inhibitors may attenuate disease activity in MS...

Lipid and protein composition as driving force for multiple sclerosis

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Beck, Roy; Shaharabani, Rona

Physical models and experiments often reduce the number of components aiming to address the fundamental mechanisms. Nevertheless, the inherent heterogeneity is an essential ingredient in the biological context. We present our recent efforts to model and understand the development of multiple sclerosis (MS) from a biophysical perspective. Myelin sheath is a multilamellar complex of various lipids and proteins that surround axons and acts as an insulating layer for proper nerve conduction. In MS the myelin structure is disrupted impairing its function. Previous studies showed that MS is correlated with small lipid composition variation and reduction in the adhesive myelin basic protein. We found that such alterations result in pathological phase transition from a lamellar to inverted hexagonal that involve enhanced local curvature. Similar curvatures are also found in vivo in diseased myelin sheaths. Since the etiology and recovery pathways of MS are currently unclear, these findings delineate novel functional roles to dominant constituents in cytoplasmic myelin sheaths, shed new light on mechanisms disrupting lipid-protein complexes, and suggest new courses for diagnosis and treatment for MS.

Antibodies against oligodendrocytes in serum and CSF in multiple sclerosis and other neurological diseases: 125I-protein A studies

International Nuclear Information System (INIS)

Steck, A.J.; Link, H.

1984-01-01

Antibodies against oligodendrocytes were determined in pairs of unconcentrated CSF serum from 12 patients with multiple sclerosis (MS) and 25 control patients including 10 with aseptic meningoencephalitis (AM), using a 125 I-protein A microassay. Antibody levels in serum and in CSF did not differ between MS and controls. Calculating the antibody index equal to (CSF/serum antibodies against oligodendrocytes):(CSF/serum albumin) in analogy to the CSF IgG index, thereby compensating for influence of serum antibody concentration as well as altered blood-brain barrier, no evidence was obtained for intrathecal antibody production in the patients with MS. Those with AM had higher antibody index values, probably reflecting intrathecal synthesis. Antibodies against oligodendrocytes seem to be regular component of CSF and serum in neurological diseases; intrathecal antibody production is less frequent in MS than in AM. (author)

PRKCA and multiple sclerosis: association in two independent populations.

Directory of Open Access Journals (Sweden)

Janna Saarela

2006-03-01

Full Text Available Multiple sclerosis (MS is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, both unknown environmental factors and genetic predisposition are required to generate MS. We ascertained a set of 63 Finnish MS families, originating from a high-risk region of the country, to identify a susceptibility gene within the previously established 3.4-Mb region on 17q24. Initial single nucleotide polymorphism (SNP-based association implicated PRKCA (protein kinase C alpha gene, and this association was replicated in an independent set of 148 Finnish MS families (p = 0.0004; remaining significant after correction for multiple testing. Further, a dense set of 211 SNPs evenly covering the PRKCA gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to PRKCA and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of PRKCA, which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07-1.68. A second allelic variant, covering the same region of the PRKCA gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39-1.94. Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of PRKCA showed correlation with the copy number of the Finnish and Canadian "risk" haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d'Etude du Polymorphisme Humain (CEPH individuals of European origin.

Progression of regional grey matter atrophy in multiple sclerosis.

Science.gov (United States)

Eshaghi, Arman; Marinescu, Razvan V; Young, Alexandra L; Firth, Nicholas C; Prados, Ferran; Jorge Cardoso, M; Tur, Carmen; De Angelis, Floriana; Cawley, Niamh; Brownlee, Wallace J; De Stefano, Nicola; Laura Stromillo, M; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A; Rovira, Alex; Sastre-Garriga, Jaume; Geurts, Jeroen J G; Vrenken, Hugo; Wottschel, Viktor; Leurs, Cyra E; Uitdehaag, Bernard; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Gandini Wheeler-Kingshott, Claudia A; Chard, Declan; Thompson, Alan J; Barkhof, Frederik; Alexander, Daniel C; Ciccarelli, Olga

2018-06-01

See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple

Progression of regional grey matter atrophy in multiple sclerosis

Science.gov (United States)

Marinescu, Razvan V; Young, Alexandra L; Firth, Nicholas C; Jorge Cardoso, M; Tur, Carmen; De Angelis, Floriana; Cawley, Niamh; Brownlee, Wallace J; De Stefano, Nicola; Laura Stromillo, M; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A; Rovira, Alex; Sastre-Garriga, Jaume; Geurts, Jeroen J G; Vrenken, Hugo; Wottschel, Viktor; Leurs, Cyra E; Uitdehaag, Bernard; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Gandini Wheeler-Kingshott, Claudia A; Chard, Declan; Thompson, Alan J; Barkhof, Frederik; Alexander, Daniel C; Ciccarelli, Olga

2018-01-01

Abstract See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article. Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse

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

International Nuclear Information System (INIS)

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

1985-01-01

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

Endogenous retroviruses are associated with autoimmune diseases

DEFF Research Database (Denmark)

Nexø, Bjørn A; Bisgaard Jensen, Sara; Hansen, Bettina

2016-01-01

of transmission is called vertical. Viral variants of importance for development of disease must be more frequent among diseased persons than among healthy individuals. Multiple sclerosis, diabetes and rheumatoid arthritis are all associated with sets of endogenouos retroviruses but not the same sets. If a virus...

Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.

Science.gov (United States)

Kauwe, John S K; Bailey, Matthew H; Ridge, Perry G; Perry, Rachel; Wadsworth, Mark E; Hoyt, Kaitlyn L; Staley, Lyndsay A; Karch, Celeste M; Harari, Oscar; Cruchaga, Carlos; Ainscough, Benjamin J; Bales, Kelly; Pickering, Eve H; Bertelsen, Sarah; Fagan, Anne M; Holtzman, David M; Morris, John C; Goate, Alison M

2014-10-01

Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (pprocessing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage.

Science.gov (United States)

Hill, Sarah J; Mordes, Daniel A; Cameron, Lisa A; Neuberg, Donna S; Landini, Serena; Eggan, Kevin; Livingston, David M

2016-11-29

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.

Prediction of disease and phenotype associations from genome-wide association studies.

Directory of Open Access Journals (Sweden)

Stephanie N Lewis

Full Text Available Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases.Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits.The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

Is there an association between glaucoma and capillaroscopy in patients with systemic sclerosis?

Science.gov (United States)

Gomes, Beatriz Fiuza; Souza, Rebeca; Valadão, Thiago; Kara-Junior, Newton; Moraes, Haroldo Vieira; Santhiago, Marcony R

2018-02-01

To evaluate the relationship between glaucoma diagnosis and the nailfold capillaroscopy pattern in patients with systemic sclerosis. An observational study in a cohort of patients with SSc was conducted. Patients with at least one nailfold videocapillaroscopy and one ophthalmology examination at the same year were included. Data collected were: age, sex; type of systemic sclerosis according to the degree of skin impairment, self-reported ethnicity, disease duration, current use and dosage of systemic corticosteroid, current use and dosage of bosentan ® , intraocular pressure, central corneal thickness, diagnosis of glaucoma and capillaroscopy pattern. Thirty-one patients with systemic sclerosis were enrolled, 23% had glaucoma. There was no statistically significant association between glaucoma diagnosis and the capillaroscopic pattern (p = 0.86). There was also no significant difference (p = 0.66) regarding intraocular pressure between patients with mild (13.9 ± 3.8 mmHg) and severe capillaroscopic pattern (14.4 ± 2.8 mmHg). The odds ratio of glaucoma for severe capillaroscopic pattern compared to mild was 1.6 (95% confidence interval: 0.3-9.5). Up to 23% of patients with SSc have glaucoma. The high prevalence of glaucoma in SSc suggests a possible systemic vascular disturbance as the cause. However, there seems to be no significant association between the capillaroscopy pattern and glaucoma in systemic sclerosis. Further research is required to improve the understanding of glaucoma in the context of systemic sclerosis.

A Case of Multiple Sclerosis and Celiac Disease

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H. Z. Batur-Caglayan

2013-01-01

Full Text Available Objectives. Multiple sclerosis (MS is an inflammatory autoimmune disorder of the central nervous system (CNS. Since a correlation between gluten intake and incidence of MS had been reported, the relationship of antigliadin antibodies and MS was debated. Case Report. We report the case of a 45-year-old female MS patient who is under interferon treatment. After seven years of monitoring, during her routine gastroenterological assessment, she was diagnosed with celiac disease. Conclusion. Beside the neurological manifestations that have been demonstrated in about 10% of celiac disease (CD patients, white-matter abnormalities in brain MRI are uncommon and controversial. But in the literature, MS seems to be associated with CD as in our patient. We suggest that MS patients with gastroenterological complaints should undergo an assessment for CD.

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

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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.

The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis.

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Goursaud, Stéphanie; Schäfer, Sabrina; Dumont, Amélie O; Vergouts, Maxime; Gallo, Alessandro; Desmet, Nathalie; Deumens, Ronald; Hermans, Emmanuel

2015-01-01

Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV-treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-α and repressed the production of the pro-inflammatory mediators interleukin-1β, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-α likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis

Multiple sclerosis or neurological manifestations of Celiac disease

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Vahid Shaygannejad

2013-01-01

Full Text Available Multiple sclerosis (MS and celiac disease (CD are considered to be T-cell-mediated autoimmune disease. We discuss about a known case of CD-showed relapsing - remitting neurological symptoms compatible with MS. In this rare co-occurrence subject, MS-CD patient, the interaction between MS - and CD-related inflammatory processes is open to discussion.

Localized Scleroderma, Systemic Sclerosis and Cardiovascular Risk

DEFF Research Database (Denmark)

Hesselvig, Jeanette Halskou; Kofoed, Kristian; Wu, Jashin J

2018-01-01

Recent findings indicate that patients with systemic sclerosis have an increased risk of cardiovascular disease. To determine whether patients with systemic sclerosis or localized scleroderma are at increased risk of cardiovascular disease, a cohort study of the entire Danish population aged ≥ 18...... and ≤ 100 years was conducted, followed from 1997 to 2011 by individual-level linkage of nationwide registries. Multivariable adjusted Cox regression models were used to estimate the hazard ratios (HRs) for a composite cardiovascular disease endpoint. A total of 697 patients with localized scleroderma and 1......,962 patients with systemic sclerosis were identified and compared with 5,428,380 people in the reference population. In systemic sclerosis, the adjusted HR was 2.22 (95% confidence interval 1.99-2.48). No association was seen between patients with localized scleroderma and cardiovascular disease. In conclusion...

The association of illness perceptions with physical and mental health in systemic sclerosis patients: an exploratory study.

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Arat, Seher; Verschueren, Patrick; De Langhe, Ellen; Smith, Vanessa; Vanthuyne, Marie; Diya, Luwis; Van den Heede, Koen; Blockmans, Daniel; De Keyser, Filip; Houssiau, Frédéric A; Westhovens, René

2012-03-01

The aim of the present study was to evaluate the association between illness perceptions and the ability to cope with physical and mental health problems in a large cohort of systemic sclerosis (SSc) patients. This was a cross-sectional study in 217 systemic sclerosis patients from the Belgian Systemic Sclerosis Cohort. Illness perception and coping were measured by the Revised Illness Perception Questionnaire and a coping questionnaire--the Coping Orientation of Problem Experience inventory (COPE). Physical and mental health-related quality of life was measured by the 36-item short-form health survey (SF-36), as were disease activity and several severity parameters. The relationship between illness perceptions and the ability to cope with physical/mental health problems was examined using multiple linear regression analysis. According to LeRoy's classification, 49 patients had limited SSc (lSSc), 129 had limited cutaneous SSc (lcSSc) and 39 had diffuse cutaneous SSc (dcSSc). Median disease duration was five years and the modified Rodnan skin score was 4. Good physical health was significantly associated with the lcSSc subtype and low disease activity (p consequences' and strong 'illness identity' correlated with poor physical health (p mental health was associated with low illness identity scores and low 'emotional response' scores (p mental health compared with the illness perception items. Illness representations contribute more than classical disease characteristics to physical and mental health. Copyright © 2011 John Wiley & Sons, Ltd.

Cytoskeletal proteins in the cerebrospinal fluid as biomarker of multiple sclerosis.

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Madeddu, Roberto; Farace, Cristiano; Tolu, Paola; Solinas, Giuliana; Asara, Yolande; Sotgiu, Maria Alessandra; Delogu, Lucia Gemma; Prados, Jose Carlos; Sotgiu, Stefano; Montella, Andrea

2013-02-01

The axonal cytoskeleton is a finely organized system, essential for maintaining the integrity of the axon. Axonal degeneration is implicated in the pathogenesis of unremitting disability of multiple sclerosis (MS). Purpose of this study is to evaluate levels of cytoskeletal proteins such as neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), and β-tubulin (β-Tub) isoforms II and III in the cerebrospinal fluid (CSF) of MS patients and their correlation with MS clinical indices. CSF levels of cytoskeletal proteins were determined in 51 patients: 33 with MS and 18 with other neurological diseases (OND). NFL, GFAP and β-Tub II proteins were significantly higher (p 0.05) was found between MS and OND with regard to β-Tub III. Interestingly, levels of β-Tub III and NFL were higher in progressive than in remitting MS forms; on the contrary, higher levels of β-Tub II and GFAP were found in remitting MS forms. However, with the exception of β-Tub III, all proteins tend to decrease their CSF levels concomitantly with the increasing disability (EDSS) score. Overall, our results might indicate β-Tub II as a potential candidate for diagnostic and β-Tub III as a possible prognostic biomarker of MS. Therefore, further analyses are legitimated and desirable.

Surgical management of gastroesophageal reflux disease in patients with systemic sclerosis.

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Yan, Jingliang; Strong, Andrew T; Sharma, Gautam; Gabbard, Scott; Thota, Prashanti; Rodriguez, John; Kroh, Matthew

2018-02-12

Systemic sclerosis (scleroderma) is frequently associated with both gastroesophageal reflux disease (GERD) and simultaneous esophageal dysmotility. Anti-reflux procedures in this patient population must account for the existing physiology of each patient and likely disease progression. We aim to compare perioperative and intermediate outcomes of fundoplication versus gastric bypass for the treatment of GERD. After IRB approval, patients with systemic sclerosis undergoing fundoplication or gastric bypass for the treatment of GERD from 2004 to 2016 were identified. Demographics, perioperative data, immediate complications, and symptom improvement were retrieved and analyzed. Fourteen patients with systemic sclerosis underwent surgical treatment of GERD during the defined study period. Average body mass index was 26 kg/m 2 . Seven fundoplications (2 Nissens, 4 Toupets, and 1 Dor) and 7 Roux-en-Y gastric bypasses (RYGB) were performed. No 30-day mortality was observed in either group. Median follow-up was 97 months for the fundoplication group (range 28-204 months), and 19 months for the RYGB group (range 1-164 months). Preoperatively, dysphagia, heartburn, and regurgitation were present in 71% (n = 10), 86% (n = 12), and 64% (n = 9) of patients, respectively. Eleven patients had pH study prior to surgical intervention, and 91% of them had abnormal acid exposure. Esophagitis was evident in 85% (n = 11) of patients during preoperative upper endoscopy, and two patients had Barrett's esophagus. Impaired esophageal motility was present in all RYGB patients and 71% of fundoplication patients. Of the patients who had assessment of their GERD symptoms at follow-up, all five patients in the RYGB group and only 3 (50%) patients in the fundoplication group reported symptom improvement or resolution. Laparoscopic RYGB as an anti-reflux procedure is safe and may provide an alternative to fundoplication in the treatment of GERD for systemic sclerosis patients

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

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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

Multiple sclerosis-associated retrovirus, Epstein-Barr virus, and vitamin D status in patients with relapsing remitting multiple sclerosis.

Science.gov (United States)

Mostafa, Aliehossadat; Jalilvand, Somayeh; Shoja, Zabihollah; Nejati, Ahmad; Shahmahmoodi, Shohreh; Sahraian, Mohammad Ali; Marashi, Sayed Mahdi

2017-07-01

The relationship between infections and autoimmune diseases is complex and there are several reports highlighting the role of human endogenous retroviruses (HERVs) in these patients. The levels of multiple sclerosis-associated retrovirus (MSRV)-type DNA of Env gene was measured in peripheral blood mononuclear cells from 52 patients with relapsing-remitting multiple sclerosis (RRMS) and 40 healthy controls using specific quantitative PCR (qPCR) analysis. Furthermore, we analyzed the status of HERV-W/MSRV in these patients with regards to both EBV (DNA load and anti-EBNA1 IgG antibody) and vitamin D concentration. MSRV DNA copy number were significantly higher in RRMS patients than healthy controls (P < 0.0001). Interestingly, an inverse correlation was found between MSRV DNA copy number and serum vitamin D concentration (P < 0.01), but not for EBV load or anti-EBNA-1 IgG antibody. © 2017 Wiley Periodicals, Inc.

Cutaneous Adverse Events Associated with Interferon-β Treatment of Multiple Sclerosis

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Annette Kolb-Mäurer

2015-07-01

Full Text Available Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS patient treated with interferon-β who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs.

Cavernous angioma associated with ipsilateral hippocampal sclerosis

International Nuclear Information System (INIS)

Okujava, M.; Ebner, A.; Schmitt, J.; Woermann, F.G.

2002-01-01

We report two cases with extratemporal cavernous angioma (CA) and coexisting ipsilateral hippocampal sclerosis. Classically dual pathology is defined as the association of hippocampal sclerosis with an extrahippocampal lesion. Subtle changes in hippocampus might be overlooked in the presence of an unequivocal extrahippocampal abnormality. Seizure outcome after epilepsy surgery in cases with dual pathology is less favourable if only one of the lesions is removed. Dual pathology must always be considered in diagnostic imaging of patients with intractable epilepsy and CA. (orig.)

Cavernous angioma associated with ipsilateral hippocampal sclerosis

Energy Technology Data Exchange (ETDEWEB)

Okujava, M [Institute of Radiology and Interventional Diagnostics, Tbilisi (Georgia); Ebner, A; Schmitt, J; Woermann, F G [Bethel Epilepsy Centre, Mara Hospital, Bielefeld (Germany)

2002-07-01

We report two cases with extratemporal cavernous angioma (CA) and coexisting ipsilateral hippocampal sclerosis. Classically dual pathology is defined as the association of hippocampal sclerosis with an extrahippocampal lesion. Subtle changes in hippocampus might be overlooked in the presence of an unequivocal extrahippocampal abnormality. Seizure outcome after epilepsy surgery in cases with dual pathology is less favourable if only one of the lesions is removed. Dual pathology must always be considered in diagnostic imaging of patients with intractable epilepsy and CA. (orig.)

Translocator Protein-18 kDa (TSPO Positron Emission Tomography (PET Imaging and Its Clinical Impact in Neurodegenerative Diseases

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Anne-Claire Dupont

2017-04-01

Full Text Available In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO. In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease’s stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia’s role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.

Hippocampal Sclerosis in Older Patients: Practical Examples and Guidance With a Focus on Cerebral Age-Related TDP-43 With Sclerosis.

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Cykowski, Matthew D; Powell, Suzanne Z; Schulz, Paul E; Takei, Hidehiro; Rivera, Andreana L; Jackson, Robert E; Roman, Gustavo; Jicha, Gregory A; Nelson, Peter T

2017-08-01

- Autopsy studies of the older population (≥65 years of age), and particularly of the "oldest-old" (≥85 years of age), have identified a significant proportion (∼20%) of cognitively impaired patients in which hippocampal sclerosis is the major substrate of an amnestic syndrome. Hippocampal sclerosis may also be comorbid with frontotemporal lobar degeneration, Alzheimer disease, and Lewy body disease. Until recently, the terms hippocampal sclerosis of aging or hippocampal sclerosis dementia were applied in this context. Recent discoveries have prompted a conceptual expansion of hippocampal sclerosis of aging because (1) cellular inclusions of TAR DNA-binding protein 43 kDa (TDP-43) are frequent; (2) TDP-43 pathology may be found outside hippocampus; and (3) brain arteriolosclerosis is a common, possibly pathogenic, component. - To aid pathologists with recent recommendations for diagnoses of common neuropathologies in older persons, particularly hippocampal sclerosis, and highlight the recent shift in diagnostic terminology from HS-aging to cerebral age-related TDP-43 with sclerosis (CARTS). - Peer-reviewed literature and 5 autopsy examples that illustrate common age-related neuropathologies, including CARTS, and emphasize the importance of distinguishing CARTS from late-onset frontotemporal lobar degeneration with TDP-43 pathology and from advanced Alzheimer disease with TDP-43 pathology. - In advanced old age, the substrates of cognitive impairment are often multifactorial. This article demonstrates common and frequently comorbid neuropathologic substrates of cognitive impairment in the older population, including CARTS, to aid those practicing in this area of pathology.

Transplantation of Human Embryonic Stem Cells in Patients with Multiple Sclerosis and Lyme Disease

OpenAIRE

Shroff, Geeta

2016-01-01

Case series Patient: Male, 42 ? Female, 30 Final Diagnosis: Human embryonic stem cells showed good therapeutic potential for treatment of multiple sclerosis with lyme disease Symptoms: Fatigue ? weakness in limbs Medication: ? Clinical Procedure: Human embryonic stem cells transplantation Specialty: Transplantology Objective: Rare disease Background: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease in which the myelin sheath of nerve cells is damaged. It can cause dela...

Serological prevalence of celiac disease in Brazilian population of multiple sclerosis, neuromyelitis optica and myelitis.

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de Oliveira, Pérola; de Carvalho, Daniel Rocha; Brandi, Ivar Viana; Pratesi, Riccardo

2016-09-01

Comorbidity of celiac disease with demyelinating diseases of the central nervous system has been reported since the 1960s. The objective of this study was to determine the serological prevalence of celiac disease in the largest series of patients diagnosed with multiple sclerosis, neuromyelitis optica, or myelitis. A prevalence study was conducted with patients evaluated at Sarah Network of Rehabilitation Hospitals between March 2012 and September 2013. They were previously diagnosed with multiple sclerosis, neuromyelitis optica, or idiopathic myelitis. The serum levels of antibodies against tissue transglutaminase and endomysium were assessed. Of the 379 patients evaluated, 249 (65.70%) were diagnosed with multiple sclerosis, 37 (9.56%) with neuromyelitis optica, and 96 (24.54%) with idiopathic myelitis. Two patients (0.53%), one with multiple sclerosis and other with myelitis, tested positive for both antibodies. Our study do not confirm the relationship between celiac serological antibodies with multiple sclerosis, neuromyelitis optica and inflammatory myelitis of an unknown etiology. Copyright © 2016 Elsevier B.V. All rights reserved.

Erasmus syndrome: Association of silicosis and systemic sclerosis

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Reena K Sharma

2018-01-01

Full Text Available Silicosis is an inflammatory disease of the lung characterized by irreversible lung fibrosis which develops from prolonged pulmonary inhalation and retention of crystalline silica and immune reaction. It mainly appears as an occupational hazard in persons involved in stone-quarrying, mining, and sand blasting. Crystalline silica is not only known to be responsible for silicosis but also for other autoimmune diseases including systemic lupus erythematosus (SLE, rheumatoid arthritis (RA-Caplan syndrome, systemic sclerosis (SSc, and antineutrophil cytoplasmic antibody (ANCA-related vasculitis. Erasmus syndrome is the association of silica exposure and subsequent development of SSc. The limited numbers of cases reported in the literature were miners and only sporadically involved in other professionals. Here, we report a case of a 52 -year-old stone cutter who developed silicosis and SSc after 25 years of exposure.

Infectious mononucleosis and multiple sclerosis - Updated review on associated risk.

Science.gov (United States)

Sheik-Ali, Sharaf

2017-05-01

There has been substantial evidence accumulating on the role of infectious mononucleosis (IM) and the subsequent risk of obtaining Multiple Sclerosis (MS). Up to date studies not previously explored were reviewed by the author to further clarify the association. Medline and Web of Science were searched with no time constraints for articles exploring an association between Multiple Sclerosis and Infectious Mononucleosis. 24 articles were found, totalling 1063 cases and 13,227 cohort/controls. 23/24 (96%) articles reported a significant association of Infectious Mononucleosis on the risk of subsequent multiple sclerosis. Overall, new literature on IM and risk of MS categorically supports the association. Future work should focus on other risk factors such as age and gender on IM and subsequent risk of MS. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics.

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Bicchi, Ilaria; Emiliani, Carla; Vescovi, Angelo; Martino, Sabata

2015-01-01

Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms. © 2015 S. Karger AG, Basel.

Relationship between disease characteristics and orofacial manifestations in systemic sclerosis: Canadian Systemic Sclerosis Oral Health Study III.

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Baron, Murray; Hudson, Marie; Tatibouet, Solène; Steele, Russell; Lo, Ernest; Gravel, Sabrina; Gyger, Geneviève; El Sayegh, Tarek; Pope, Janet; Fontaine, Audrey; Masetto, Ariel; Matthews, Debora; Sutton, Evelyn; Thie, Norman; Jones, Niall; Copete, Maria; Kolbinson, Dean; Markland, Janet; Nogueira, Getulio; Robinson, David; Fritzler, Marvin; Gornitsky, Mervyn

2015-05-01

Systemic sclerosis (SSc; scleroderma) is associated with decreased saliva production and interincisal distance, more missing teeth, and periodontal disease. We undertook this study to determine the clinical correlates of SSc with these oral abnormalities. Subjects were recruited from the Canadian Scleroderma Research Group cohort. Detailed dental and clinical examinations were performed according to standardized protocols. Associations between dental abnormalities and selected clinical and serologic manifestations of SSc were examined. One hundred sixty-three SSc subjects were included: 90% women, mean ± SD age 56 ± 11 years, mean ± SD disease duration 14 ± 8 years, 72% with limited cutaneous disease, and 28% with diffuse cutaneous disease. Decreased saliva production was associated with Sjögren's syndrome-related autoantibodies (β = -43.32; 95% confidence interval [95% CI] -80.89, -5.75), but not with disease severity (β = -2.51; 95% CI -8.75, 3.73). Decreased interincisal distance was related to disease severity (β = -1.02; 95% CI -1.63, -0.42) and the modified Rodnan skin thickness score (β = -0.38; 95% CI -0.53, -0.23). The number of missing teeth was associated with decreased saliva production (relative risk [RR] 0.97; 95% CI 0.94, 0.99), worse hand function (RR 1.52; 95% CI 1.13, 2.02), and the presence of gastroesophageal reflux disease (GERD; RR 1.68 [95% CI 1.14, 2.46]). No clinical or serologic variables were correlated with periodontal disease. In SSc, diminished interincisal distance is related to overall disease severity. Decreased saliva production is related to concomitant Sjögren's syndrome antibodies. Tooth loss is associated with poor upper extremity function, GERD, and decreased saliva. The etiology of excess periodontal disease is likely multifactorial and remains unclear. © 2015, American College of Rheumatology.

The association between multiple sclerosis and uveitis

DEFF Research Database (Denmark)

Olsen, Tine Gadegaard; Frederiksen, Jette

2016-01-01

The association between multiple sclerosis (MS) and uveitis has been questioned. Nerve tissue and eye tissue develop from the same embryonic cells; thus, MS and uveitis could be etiologically associated. In published studies, the prevalence of MS in patients with uveitis differe from 0.7% to 30...

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

LENUS (Irish Health Repository)

Lonergan, Roisin

2012-02-01

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

CSF glial markers correlate with survival in amyotrophic lateral sclerosis.

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Süssmuth, S D; Sperfeld, A D; Hinz, A; Brettschneider, J; Endruhn, S; Ludolph, A C; Tumani, H

2010-03-23

In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, and understanding of pathophysiologic processes. To identify a biomarker profile of neuronal and glial CSF proteins to discriminate ALS from other motor neuron diseases (MND) and to assess whether baseline levels of CSF measures in ALS are associated with the course of the disease. A total of 122 consecutive subjects with MND were included in this cross-sectional study (ALS, n = 75; lower motor neuron syndrome, n = 39; upper motor neuron diseases, n = 8). Clinical follow-up included 76 patients. We determined baseline levels of protein tau and astroglial S100beta in CSF and microglial sCD14 in CSF and serum in relation to diagnosis, duration of disease, and survival. CSF tau was significantly elevated in ALS and upper motor neuron diseases as compared to lower motor neuron diseases and controls. CSF S100beta levels were significantly lower in lower motor neuron diseases as compared to other MND. CSF concentrations of S100beta and sCD14 correlated with the survival time in patients with ALS. In motor neuron diseases, CSF tau elevation indicates the degeneration of upper motor neurons, while S100 beta and sCD14 may indicate the activation of CNS glial cells. Because S100beta and sCD14 concentrations correlate with survival in amyotrophic lateral sclerosis (ALS), we suppose that the combination of both markers may be useful to obtain prognostic information in patients with ALS.

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

DEFF Research Database (Denmark)

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

2011-01-01

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

Cognitive-Linguistic Deficit and Speech Intelligibility in Chronic Progressive Multiple Sclerosis

Science.gov (United States)

Mackenzie, Catherine; Green, Jan

2009-01-01

Background: Multiple sclerosis is a disabling neurological disease with varied symptoms, including dysarthria and cognitive and linguistic impairments. Association between dysarthria and cognitive-linguistic deficit has not been explored in clinical multiple sclerosis studies. Aims: In patients with chronic progressive multiple sclerosis, the…

Rehabilitation and multiple sclerosis

DEFF Research Database (Denmark)

Dalgas, Ulrik

2011-01-01

In a chronic and disabling disease like multiple sclerosis, rehabilitation becomes of major importance in the preservation of physical, psychological and social functioning. Approximately 80% of patients have multiple sclerosis for more than 35 years and most will develop disability at some point......, a paradigm shift is taking place and it is now increasingly acknowledged that exercise therapy is both safe and beneficial. Robot-assisted training is also attracting attention in multiple sclerosis rehabilitation. Several sophisticated commercial robots exist, but so far the number of scientific studies...... promising. This drug has been shown to improve walking ability in some patients with multiple sclerosis, associated with a reduction of patients' self-reported ambulatory disability. Rehabilitation strategies involving these different approaches, or combinations of them, may be of great use in improving...

Cognitive and behavioural deficits associated with the orbitomedial prefrontal cortex in amyotrophic lateral sclerosis.

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Meier, Sandra L; Charleston, Alison J; Tippett, Lynette J

2010-11-01

Amyotrophic lateral sclerosis, a progressive disease affecting motor neurons, may variably affect cognition and behaviour. We tested the hypothesis that functions associated with orbitomedial prefrontal cortex are affected by evaluating the behavioural and cognitive performance of 18 participants with amyotrophic lateral sclerosis without dementia and 18 healthy, matched controls. We measured Theory of Mind (Faux Pas Task), emotional prosody recognition (Aprosodia Battery), reversal of behaviour in response to changes in reward (Probabilistic Reversal Learning Task), decision making without risk (Holiday Apartment Task) and aberrant behaviour (Neuropsychiatric Inventory). We also assessed dorsolateral prefrontal function, using verbal and written fluency and planning (One-touch Stockings of Cambridge), to determine whether impairments in tasks sensitive to these two prefrontal regions co-occur. The patient group was significantly impaired at identifying social faux pas, recognizing emotions and decision-making, indicating mild, but consistent impairment on most measures sensitive to orbitomedial prefrontal cortex. Significant levels of aberrant behaviour were present in 50% of patients. Patients were also impaired on verbal fluency and planning. Individual subject analyses involved computing classical dissociations between tasks sensitive to different prefrontal regions. These revealed heterogeneous patterns of impaired and spared cognitive abilities: 33% of participants had classical dissociations involving orbitomedial prefrontal tasks, 17% had classical dissociations involving dorsolateral prefrontal tasks, 22% had classical dissociations between tasks of both regions, and 28% had no classical dissociations. These data indicate subtle changes in behaviour, emotional processing, decision-making and altered social awareness, associated with orbitomedial prefrontal cortex, may be present in a significant proportion of individuals with amyotrophic lateral sclerosis

Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis.

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Bakkar, Nadine; Kovalik, Tina; Lorenzini, Ileana; Spangler, Scott; Lacoste, Alix; Sponaugle, Kyle; Ferrante, Philip; Argentinis, Elenee; Sattler, Rita; Bowser, Robert

2018-02-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no effective treatments. Numerous RNA-binding proteins (RBPs) have been shown to be altered in ALS, with mutations in 11 RBPs causing familial forms of the disease, and 6 more RBPs showing abnormal expression/distribution in ALS albeit without any known mutations. RBP dysregulation is widely accepted as a contributing factor in ALS pathobiology. There are at least 1542 RBPs in the human genome; therefore, other unidentified RBPs may also be linked to the pathogenesis of ALS. We used IBM Watson ® to sieve through all RBPs in the genome and identify new RBPs linked to ALS (ALS-RBPs). IBM Watson extracted features from published literature to create semantic similarities and identify new connections between entities of interest. IBM Watson analyzed all published abstracts of previously known ALS-RBPs, and applied that text-based knowledge to all RBPs in the genome, ranking them by semantic similarity to the known set. We then validated the Watson top-ten-ranked RBPs at the protein and RNA levels in tissues from ALS and non-neurological disease controls, as well as in patient-derived induced pluripotent stem cells. 5 RBPs previously unlinked to ALS, hnRNPU, Syncrip, RBMS3, Caprin-1 and NUPL2, showed significant alterations in ALS compared to controls. Overall, we successfully used IBM Watson to help identify additional RBPs altered in ALS, highlighting the use of artificial intelligence tools to accelerate scientific discovery in ALS and possibly other complex neurological disorders.

Selective association of multiple sclerosis with infectious mononucleosis

NARCIS (Netherlands)

Zaadstra, B.M.; Chorus, A.M.J.; Buuren, S. van; Kalsbeek, H.; Noort, J.M. van

2008-01-01

Previous studies have suggested an association between multiple sclerosis (MS) and infectious mononucleosis (IM) but data on the exact strength of this association or its selectivity have been conflicting. In this study we have evaluated the association between MS and a variety of common childhood

Peripapillar retinal hamartoma associated with tuberous sclerosis. Case report.

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Hernández Pardines, F; Núñez Márquez, S; Fernández Montalvo, L; Serra Verdú, M C; Juárez Marroquí, A

2018-03-01

Tuberous sclerosis is a rare multisystemic disease with an autosomal dominant inheritance pattern. There are few documented cases in the literature of retinal hamartomas (astrocytomas) with aggressive progression in the context of this disease. A report is presented on a case of a 31 year-old male with unknown history of ophthalmic or systemic conditions, who referred to a history of 6 months of blurred vision in his right eye. This was caused by a unilateral retinal hamartoma due to an undiagnosed tuberous sclerosis. Multidisciplinary management, with the cooperation of Internal Medicine and the Oncology Department, is needed in these cases, as well as genetic counselling for affected patients. Complications are directly related to increased tumour size. Treatment does not seem to have any influence on the natural history of the disease. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

Type D, anxiety and depression in association with quality of life in patients with Parkinson's disease and patients with multiple sclerosis

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Dubayova, Tatiana; Krokavcova, Martina; Nagyova, Iveta; Rosenberger, Jaroslav; Gdovinova, Zuzana; Middel, Berrie; Groothoff, Johan W.; van Dijk, Jitse P.

The present study examines the role of Type D personality, anxiety and depression in quality of life (QoL) in patients with two chronic neurological diseases-Parkinson's disease (PD) and multiple sclerosis (MS). This cross-sectional study included 142 PD patients (73 % males; mean age 67.6 +/- A 9.2

Mining gene expression data of multiple sclerosis.

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Pi Guo

Full Text Available Microarray produces a large amount of gene expression data, containing various biological implications. The challenge is to detect a panel of discriminative genes associated with disease. This study proposed a robust classification model for gene selection using gene expression data, and performed an analysis to identify disease-related genes using multiple sclerosis as an example.Gene expression profiles based on the transcriptome of peripheral blood mononuclear cells from a total of 44 samples from 26 multiple sclerosis patients and 18 individuals with other neurological diseases (control were analyzed. Feature selection algorithms including Support Vector Machine based on Recursive Feature Elimination, Receiver Operating Characteristic Curve, and Boruta algorithms were jointly performed to select candidate genes associating with multiple sclerosis. Multiple classification models categorized samples into two different groups based on the identified genes. Models' performance was evaluated using cross-validation methods, and an optimal classifier for gene selection was determined.An overlapping feature set was identified consisting of 8 genes that were differentially expressed between the two phenotype groups. The genes were significantly associated with the pathways of apoptosis and cytokine-cytokine receptor interaction. TNFSF10 was significantly associated with multiple sclerosis. A Support Vector Machine model was established based on the featured genes and gave a practical accuracy of ∼86%. This binary classification model also outperformed the other models in terms of Sensitivity, Specificity and F1 score.The combined analytical framework integrating feature ranking algorithms and Support Vector Machine model could be used for selecting genes for other diseases.

Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols

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Vejux, Anne; Namsi, Amira; Nury, Thomas; Moreau, Thibault; Lizard, Gérard

2018-01-01

Amyotrophic lateral sclerosis (ALS) is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases) and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer’s disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25-hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology. PMID:29445325

Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols

Directory of Open Access Journals (Sweden)

Anne Vejux

2018-01-01

Full Text Available Amyotrophic lateral sclerosis (ALS is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer’s disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25-hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology.

HLA DRB5*01 Association Survey with Multiple Sclerosis in Khuzestan Province of Iran

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Tahereh Latifi Pakdehi

2017-08-01

Full Text Available Background Multiple sclerosis is a potentially disabling disease of the brain and spinal cord (central nervous system (CNS. Although the cause of MS is currently unknown, both genetic and environmental factors have been shown to contribute to the pathogenesis of MS. The human leukocyte antigen (HLA class II alleles DRB1*1501, DRB5*0101, DQA1*0102, DQB1*0602 may have an important genetic effect. However, this is controversial in different population studies. Objectives The aim of this study was to investigate the correlation of HLA DRB5*01 with MS in Khuzestan province. Methods The present case-control study focused on HLA DRB5*01 association in 202 MS patients from Khuzestan. Seventy four point two five percent (74.25% of patients classified as relapsing-remitting and other patients were as primary-progressive, secondary progressive and progressive-relapsing MS. One hundred eighty seven persons that have no any inflammatory diseases investigated as control group. Polymerase chain reaction amplification method was performed to determine the type of HLA with sequence-specific primers (PCR-SSP. The frequencies of the mentioned allele were compared between the patients and control group using SPSS 21 statistical software and the chi square test. Results Twenty- seven point seven two percent (27.72% of patients and 21.39% from the control group were positive with this type of HLA. Conclusions This is the first study that investigate HLA DRB5*01 association with multiple sclerosis patients in Khuzestan. We found that there is no association between HLA DRB5*01 with multiple sclerosis in Khuzestan province (P = 0.148.

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.

Science.gov (United States)

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.

Hippocampal Sclerosis of Aging, a Common Alzheimer's Disease 'Mimic': Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe.

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Nho, Kwangsik; Saykin, Andrew J; Nelson, Peter T

2016-01-01

Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults.

Clinical significance of high-sensitivity C- reactive protein in systemic sclerosis

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T. A. Nevskaya

2007-01-01

Full Text Available Objective. To determine diagnostic and prognostic significance of high-sensitivity Creactive protein (hsCRP in systemic sclerosis (SS, to define relationship of this factor with activity of the disease and cardiovascular pathology, to assess role of pro-inflammatory cytokines in induction of acute phase proteins synthesis in SS.Material and methods. Serum levels of hsCRP, interleukin (IL 6, IL 1β, IL1ra, IL 10, sIL2r were evaluated by enzyme immunoassay (EIA in 40 pts with SS and 24 subjects of control group. Relationship with clinical features of the disease, endothelial dysfunction, capillaries structure changes, sub-clinical atherosclerosis, total coronary risk and some traditional cardiovascular risk factors was analyzed. Instrumental assessment included nailfold capillaroscopy, sonographic duplex examination of carotids , brachial arte ry sonographic examination. HsCRP prognostic significance was assessed in 51 pts with SS.Results. Elevated levels of hsCRP were found in 32% of SS pts and correlated with activity and severity of the disease, HAQ and SHAQ. Direct correlation of hsCRP with skin fibrosis distribution, interstitial lung disease, arthritis, laboratory indices of SS activity (ESR, sIL2r and Scl-70 was revealed. HsCRP concentration in SS did not depend on character and intensity of cardiovascular pathology, subclinical atherosclerosis, endothelial dysfunction and proinflammatory cytokines production.Conclusion. HsCRP in SS reflects intensity of immuno-inflammatory process, correlates with T-cell activation markers and can be used as index of the disease activity, severity of skin and lung fibrosis.

Analysis of disease-associated protein expression using quantitative proteomics—fibulin-5 is expressed in association with hepatic fibrosis.

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Bracht, Thilo; Schweinsberg, Vincent; Trippler, Martin; Kohl, Michael; Ahrens, Maike; Padden, Juliet; Naboulsi, Wael; Barkovits, Katalin; Megger, Dominik A; Eisenacher, Martin; Borchers, Christoph H; Schlaak, Jörg F; Hoffmann, Andreas-Claudius; Weber, Frank; Baba, Hideo A; Meyer, Helmut E; Sitek, Barbara

2015-05-01

Hepatic fibrosis and cirrhosis are major health problems worldwide. Until now, highly invasive biopsy remains the diagnostic gold standard despite many disadvantages. To develop noninvasive diagnostic assays for the assessment of liver fibrosis, it is urgently necessary to identify molecules that are robustly expressed in association with the disease. We analyzed biopsied tissue samples from 95 patients with HBV/HCV-associated hepatic fibrosis using three different quantification methods. We performed a label-free proteomics discovery study to identify novel disease-associated proteins using a subset of the cohort (n = 27). Subsequently, gene expression data from all available clinical samples were analyzed (n = 77). Finally, we performed a targeted proteomics approach, multiple reaction monitoring (MRM), to verify the disease-associated expression in samples independent from the discovery approach (n = 68). We identified fibulin-5 (FBLN5) as a novel protein expressed in relation to hepatic fibrosis. Furthermore, we confirmed the altered expression of microfibril-associated glycoprotein 4 (MFAP4), lumican (LUM), and collagen alpha-1(XIV) chain (COL14A1) in association to hepatic fibrosis. To our knowledge, no tissue-based quantitative proteomics study for hepatic fibrosis has been performed using a cohort of comparable size. By this means, we add substantial evidence for the disease-related expression of the proteins examined in this study.

The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span

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Wang, Ji-Wu; Brent, Jonathan R.; Tomlinson, Andrew; Shneider, Neil A.; McCabe, Brian D.

2011-01-01

The fatal adult motor neuron disease amyotrophic lateral sclerosis (ALS) shares some clinical and pathological overlap with frontotemporal dementia (FTD), an early-onset neurodegenerative disorder. The RNA/DNA-binding proteins fused in sarcoma (FUS; also known as TLS) and TAR DNA binding protein-43 (TDP-43) have recently been shown to be genetically and pathologically associated with familial forms of ALS and FTD. It is currently unknown whether perturbation of these proteins results in disease through mechanisms that are independent of normal protein function or via the pathophysiological disruption of molecular processes in which they are both critical. Here, we report that Drosophila mutants in which the homolog of FUS is disrupted exhibit decreased adult viability, diminished locomotor speed, and reduced life span compared with controls. These phenotypes were fully rescued by wild-type human FUS, but not ALS-associated mutant FUS proteins. A mutant of the Drosophila homolog of TDP-43 had similar, but more severe, deficits. Through cross-rescue analysis, we demonstrated that FUS acted together with and downstream of TDP-43 in a common genetic pathway in neurons. Furthermore, we found that these proteins associated with each other in an RNA-dependent complex. Our results establish that FUS and TDP-43 function together in vivo and suggest that molecular pathways requiring the combined activities of both of these proteins may be disrupted in ALS and FTD. PMID:21881207

Absence of Multiple Sclerosis and Demyelinating Diseases among Lacandonians, a Pure Amerindian Ethnic Group in Mexico

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Jose Flores

2012-01-01

Full Text Available Multiple Sclerosis (MS is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and treatment of demyelinating disorders to detect clinical signs compatible with a demyelinating disease. We did not find any clinical signs compatible with multiple sclerosis among study participants.

No evidence of association between optic neuritis and secondary LHON mtDNA mutations in patients with multiple sclerosis

DEFF Research Database (Denmark)

Andalib, Sasan; Talebi, Mahnaz; Sakhinia, Ebrahim

2017-01-01

Leber's Hereditary Optic Neuropathy (LHON) shares features with Multiple Sclerosis (MS). Both diseases develop optic lesions. Frequent secondary LHON mutations in MS patients may explain the optic damage. Here, we tested the hypothesis that secondary LHON mutations are associated with optic...

Visual field impairment captures disease burden in multiple sclerosis.

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Ortiz-Perez, Santiago; Andorra, Magí; Sanchez-Dalmau, Bernardo; Torres-Torres, Rubén; Calbet, David; Lampert, Erika J; Alba-Arbalat, Salut; Guerrero-Zamora, Ana M; Zubizarreta, Irati; Sola-Valls, Nuria; Llufriu, Sara; Sepúlveda, María; Saiz, Albert; Villoslada, Pablo; Martinez-Lapiscina, Elena H

2016-04-01

Monitoring disease burden is an unmeet need in multiple sclerosis (MS). Identifying patients at high risk of disability progression will be useful for improving clinical-therapeutic decisions in clinical routine. To evaluate the role of visual field testing in non-optic neuritis eyes (non-ON eyes) as a biomarker of disability progression in MS. In 109 patients of the MS-VisualPath cohort, we evaluated the association between visual field abnormalities and global and cognitive disability markers and brain and retinal imaging markers of neuroaxonal injury using linear regression models adjusted for sex, age, disease duration and use of disease-modifying therapies. We evaluated the risk of disability progression associated to have baseline impaired visual field after 3 years of follow-up. Sixty-two percent of patients showed visual field defects in non-ON eyes. Visual field mean deviation was statistically associated with global disability; brain (normalized brain parenchymal, gray matter volume and lesion load) and retinal (peripapillary retinal nerve fiber layer thickness and macular ganglion cell complex thickness) markers of neuroaxonal damage. Patients with impaired visual field had statistically significative greater disability, lower normalized brain parenchymal volume and higher lesion volume than patients with normal visual field testing. MS patients with baseline impaired VF tripled the risk of disability progression during follow-up [OR = 3.35; 95 % CI (1.10-10.19); p = 0.033]. The association of visual field impairment with greater disability and neuroaxonal injury and higher risk of disability progression suggest that VF could be used to monitor MS disease burden.

Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis.

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Panas, M; Karadima, G; Kalfakis, N; Psarrou, O; Floroskoufi, P; Kladi, A; Petersen, M B; Vassilopoulos, D

2000-12-01

The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis are not fully understood. Recent studies suggest that apoptosis is involved in the abnormal neural death that occurs in this devastating disease. Presenilin-1, a transmembrane protein, seems to be implicated in apoptosis. To determine whether presenilin-1 intron 8 polymorphism has an influence in the course of amyotrophic lateral sclerosis, we examined this polymorphism genotypes in a large group of patients (n = 72) with amyotrophic lateral sclerosis and in a random sample of 213 healthy individuals. The results showed a significant difference in genotype (P < 0.04) and allele (P < 0.03) distribution between patients controls. These results suggest a possible intervention of presenilin-1 in the pathogenesis of amyotrophic lateral sclerosis.

Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients

KAUST Repository

Conti, Antonio

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS\\'s pathogenesis and to seek diagnostic markers, we analyzed skeletal muscle biopsies with the differential expression proteomic approach. We studied skeletal muscle biopsies from healthy controls (CN), sporadic ALS (sALS), motor neuropathies (MN) and myopathies (M). Pre-eminently among several differentially expressed proteins, Myosin binding protein H (MyBP-H) expression in ALS samples was anomalously high. MyBP-H is a component of the thick filaments of the skeletal muscle and has strong affinity for myosin, but its function is still unclear. High MyBP-H expression level was associated with abnormal expression of Rho kinase 2 (ROCK2), LIM domain kinase 1 (LIMK1) and cofilin2, that might affect the actin-myosin interaction. We propose that MyBP-H expression level serves, as a putative biomarker in the skeletal muscle, to discriminate ALS from motor neuropathies, and that it signals the onset of dysregulation in actin-myosin interaction; this in turn might contribute to the pathogenesis of ALS. © 2013 Elsevier B.V.

Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.

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Ciechanover, Aaron; Kwon, Yong Tae

2015-03-13

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

Localized Scleroderma, Systemic Sclerosis and Cardiovascular Risk: A Danish Nationwide Cohort Study.

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Hesselvig, Jeanette Halskou; Kofoed, Kristian; Wu, Jashin J; Dreyer, Lene; Gislason, Gunnar; Ahlehoff, Ole

2018-03-13

Recent findings indicate that patients with systemic sclerosis have an increased risk of cardiovascular disease. To determine whether patients with systemic sclerosis or localized scleroderma are at increased risk of cardiovascular disease, a cohort study of the entire Danish population aged ≥ 18 and ≤ 100 years was conducted, followed from 1997 to 2011 by individual-level linkage of nationwide registries. Multivariable adjusted Cox regression models were used to estimate the hazard ratios (HRs) for a composite cardiovascular disease endpoint. A total of 697 patients with localized scleroderma and 1,962 patients with systemic sclerosis were identified and compared with 5,428,380 people in the reference population. In systemic sclerosis, the adjusted HR was 2.22 (95% confidence interval 1.99-2.48). No association was seen between patients with localized scleroderma and cardiovascular disease. In conclusion, systemic sclerosis is a significant cardiovascular disease risk factor, while patients with localized scleroderma are not at increased risk of cardiovascular disease.

Multiple sclerosis

International Nuclear Information System (INIS)

Grunwald, I.Q.; Kuehn, A.L.; Backens, M.; Papanagiotou, P.; Shariat, K.; Kostopoulos, P.

2008-01-01

Multiple sclerosis is the most common chronic inflammatory disease of myelin with interspersed lesions in the white matter of the central nervous system. Magnetic resonance imaging (MRI) plays a key role in the diagnosis and monitoring of white matter diseases. This article focuses on key findings in multiple sclerosis as detected by MRI. (orig.) [de

Association between systemic lupus erythematosus and multiple sclerosis: lupoid sclerosis; Asociacion de LES y esclerosis multiple: esclerosis lupoide.

Energy Technology Data Exchange (ETDEWEB)

Medina, Yimy F; Martinez, Jose B; Fernandez, Andres R; Quintana, Gerardo; Restrepo, Jose Felix; Rondon, Federico; Gamarra, Antonio Iglesias

2010-07-01

Multiple sclerosis (MS) and Systemic Lupus Erythematosus (SLE) with/without antiphospholipid syndrome are autoimmune illnesses. It has been described in many occasions the association of these two illnesses and the clinical picture of MS with characteristics of laboratory of SLE. When they affect to the central nervous system they can make it in a defined form for each illness or they can also make it in interposed or combined form of the two illnesses what has been called lupoid sclerosis; making that in some cases difficult the differentiation of the two illnesses and therefore to address the treatment. We present four cases of lupoid sclerosis, discuss the clinical and laboratory characteristics of this entity and we make a differentiation of the multiple sclerosis with the neurological affectation of SLE especially for images and laboratory results.

Evaluation of prevalence of headache in Multiple Sclerosis patients before & after the disease

Directory of Open Access Journals (Sweden)

H. Mozhdehipanah

2017-08-01

Full Text Available Background: Multiple Sclerosis disease is a chronic disease of nervous system which causes different symptoms. Although headache is not a major symptom of this disease, but a lot of patients suffer from it. To specify the prevalence of headache and its’ types has an important role in diagnose, treatment and improvement the quality of patients’ life. Objective: Our goal of this study was to determine the prevalence of headache in multiple sclerosis patients, before and after the diagnosis of this disease. Methods: This cross-sectional descriptive epidemiologic study was performed on 150 multiple sclerosis patients referred to the neurology clinic of Qazvin in 2015. Data were recorded by history taking & physical examination the existence of headache before the MS diagnosis and at the time of study was evaluated by the patients’ data. Findings: Among participants, prevalence of headache before the MS diagnosis was 40%, which increased to 64% after that (P<0.001. The most common type of headache, before and after the affection was tension headache, which formed 58.3% and 70.8% of all headaches, respectively. The average rate of headache in the group with headache, before and after the diagnosis of MS was 5.8 and 5.76 days in month, which calculated 2.32 and 3.68 days in month in all patients, respectively. Conclusion: Prevalence of headache increases in multiple sclerosis patients. Patients suffer from headache almost 13% of their life days.

Endogenous and recombinant type I interferons and disease activity in multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, Finn; Krakauer, Martin; Limborg, Signe

2012-01-01

the percentage of CD4+ T cells expressing CD71 and HLA-DR (activated T cells), and this was associated with an increased risk of clinical disease activity. In contrast, induction of CD71 and HLA-DR was not observed in untreated MS patients with evidence of endogenous type IFN I activity. In conclusion......Although treatment of multiple sclerosis (MS) with the type I interferon (IFN) IFN-ß lowers disease activity, the role of endogenous type I IFN in MS remains controversial. We studied CD4+ T cells and CD4+ T cell subsets, monocytes and dendritic cells by flow cytometry and analysed the relationship...... with endogenous type I IFN-like activity, the effect of IFN-ß therapy, and clinical and magnetic resonance imaging (MRI) disease activity in MS patients. Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells...

Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

Directory of Open Access Journals (Sweden)

Polona Lavtar

Full Text Available Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02 distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001 and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002. The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

DEFF Research Database (Denmark)

Hedegaard, Chris J; Krakauer, Martin; Bendtzen, Klaus

2008-01-01

Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and...

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

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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.

A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.

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Derfuss, Tobias; Curtin, François; Guebelin, Claudia; Bridel, Claire; Rasenack, Maria; Matthey, Alain; Du Pasquier, Renaud; Schluep, Myriam; Desmeules, Jules; Lang, Alois B; Perron, Hervé; Faucard, Raphael; Porchet, Hervé; Hartung, Hans-Peter; Kappos, Ludwig; Lalive, Patrice H

2015-06-01

GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period. © The Author(s) 2014.

Thick Filament Protein Network, Functions, and Disease Association.

Science.gov (United States)

Wang, Li; Geist, Janelle; Grogan, Alyssa; Hu, Li-Yen R; Kontrogianni-Konstantopoulos, Aikaterini

2018-03-13

Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018. Copyright © 2018 American Physiological Society. All rights reserved.

Pulmonary function tests as outcomes for systemic sclerosis interstitial lung disease.

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Caron, Melissa; Hoa, Sabrina; Hudson, Marie; Schwartzman, Kevin; Steele, Russell

2018-06-30

Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc). We performed a systematic review to characterise the use and validation of pulmonary function tests (PFTs) as surrogate markers for systemic sclerosis-associated interstitial lung disease (SSc-ILD) progression.Five electronic databases were searched to identify all relevant studies. Included studies either used at least one PFT measure as a longitudinal outcome for SSc-ILD progression ( i.e. outcome studies) and/or reported at least one classical measure of validity for the PFTs in SSc-ILD ( i.e. validation studies).This systematic review included 169 outcome studies and 50 validation studies. Diffusing capacity of the lung for carbon monoxide ( D LCO ) was cumulatively the most commonly used outcome until 2010 when it was surpassed by forced vital capacity (FVC). FVC (% predicted) was the primary endpoint in 70.4% of studies, compared to 11.3% for % predicted D LCO Only five studies specifically aimed to validate the PFTs: two concluded that D LCO was the best measure of SSc-ILD extent, while the others did not favour any PFT. These studies also showed respectable validity measures for total lung capacity (TLC).Despite the current preference for FVC, available evidence suggests that D LCO and TLC should not yet be discounted as potential surrogate markers for SSc-ILD progression. Copyright ©ERS 2018.

A homologous mapping method for three-dimensional reconstruction of protein networks reveals disease-associated mutations.

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Huang, Sing-Han; Lo, Yu-Shu; Luo, Yong-Chun; Tseng, Yu-Yao; Yang, Jinn-Moon

2018-03-19

One of the crucial steps toward understanding the associations among molecular interactions, pathways, and diseases in a cell is to investigate detailed atomic protein-protein interactions (PPIs) in the structural interactome. Despite the availability of large-scale methods for analyzing PPI networks, these methods often focused on PPI networks using genome-scale data and/or known experimental PPIs. However, these methods are unable to provide structurally resolved interaction residues and their conservations in PPI networks. Here, we reconstructed a human three-dimensional (3D) structural PPI network (hDiSNet) with the detailed atomic binding models and disease-associated mutations by enhancing our PPI families and 3D-domain interologs from 60,618 structural complexes and complete genome database with 6,352,363 protein sequences across 2274 species. hDiSNet is a scale-free network (γ = 2.05), which consists of 5177 proteins and 19,239 PPIs with 5843 mutations. These 19,239 structurally resolved PPIs not only expanded the number of PPIs compared to present structural PPI network, but also achieved higher agreement with gene ontology similarities and higher co-expression correlation than the ones of 181,868 experimental PPIs recorded in public databases. Among 5843 mutations, 1653 and 790 mutations involved in interacting domains and contacting residues, respectively, are highly related to diseases. Our hDiSNet can provide detailed atomic interactions of human disease and their associated proteins with mutations. Our results show that the disease-related mutations are often located at the contacting residues forming the hydrogen bonds or conserved in the PPI family. In addition, hDiSNet provides the insights of the FGFR (EGFR)-MAPK pathway for interpreting the mechanisms of breast cancer and ErbB signaling pathway in brain cancer. Our results demonstrate that hDiSNet can explore structural-based interactions insights for understanding the mechanisms of disease-associated

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

NARCIS (Netherlands)

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

2016-01-01

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

Olfactory bulb and olfactory sulcus depths are associated with disease duration and attack frequency in multiple sclerosis patients.

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Tanik, Nermin; Serin, Halil Ibrahim; Celikbilek, Asuman; Inan, Levent Ertugrul; Gundogdu, Fatma

2015-11-15

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease that progresses to axonal loss and demyelinization. Olfactory dysfunction in patients with MS has been reported frequently. We were interested in the associations of olfactory bulb (OB) and olfactory sulcus depth (OSD) with disease duration and attack frequency. We included 25 patients with MS and 30 age- and sex-matched controls in this study. The Expanded Disability Status Scale, Beck Depression Inventory, and Mini Mental State Examination were applied. OB, OSD, and magnetic resonance imaging plaque numbers were calculated. OB volume and OSD in patients with MS were significantly lower than those in the control group (right and left OB: p<0.001; right OSD: p=0.001; and left OSD: p=0.039). Disease duration was negatively correlated with right and left OB volume (right OB: r=-0.434, p=0.030 and left OB: r=-0.518, p=0.008). Attack frequency was negatively correlated with left OB volume and left OSD (left OB: r=-0.428, p=0.033 and left OSD: r=-0.431, p=0.032). The OB and OSD were atrophied significantly in patients with MS, and this was correlated with disease duration and attack frequency. The left side tended to be dominant. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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

Report of a case of Hodgkin's nodular sclerosis disease

International Nuclear Information System (INIS)

Canizares, Claudio; Araujo, Ivan; Flores, Marlon; Guerrero, Patricia; Sanchez, Mayra

2004-01-01

We report a case of Hodgkin's nodular sclerosis disease that presents moderate anemia and lymph node enlargement with a massive infiltrate to the bone marrow. It is rare for these patients to develop such an infiltrate, which give a bad prognosis. The treatment recommended in stage I is Radiotherapy and chemotherapy. (The author)

Defining active progressive multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, Finn; Börnsen, Lars; Ammitzbøll, Cecilie

2017-01-01

BACKGROUND: It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). OBJECTIVE: To compare CSF biomarkers in active and inactive...

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

Science.gov (United States)

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

2011-01-01

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

New insight on the Xq28 association with systemic sclerosis

Science.gov (United States)

Carmona, F David; Cénit, M Carmen; Diaz-Gallo, Lina-Marcela; Broen, Jasper C A; Simeón, Carmen P; Carreira, Patricia E; Callejas-Rubio, José-Luis; Fonollosa, Vicente; López-Longo, Francisco J; González-Gay, Miguel A; Hunzelmann, Nicolas; Riemekasten, Gabriela; Witte, Torsten; Kreuter, Alexander; Distler, Jörg H W; Madhok, Rajan; Shiels, Paul; van Laar, Jacob M; Schuerwegh, Annemie J; Vonk, Madelon C; Voskuyl, Alexandre E; Fonseca, Carmen; Denton, Christopher P; Herrick, Ariane; Worthington, Jane; Arnett, Frank C; Tan, Filemon K; Assassi, Shervin; Radstake, Timothy R D J; Mayes, Maureen D; Martín, Javier

2013-01-01

Objective To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). Methods We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. Results IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10−3, OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10−4, OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). Conclusions Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease. PMID:23444193

Supportive care needs of patients with amyotrophic lateral sclerosis/motor neuron disease and their caregivers: A scoping review.

Science.gov (United States)

Oh, Juyeon; Kim, Jung A

2017-12-01

To identify the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, categorise and summarise them into a Supportive Care Needs Framework and identify gaps in literature. Little is known about the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, and this subject has not previously been systemically reviewed. Scoping review. We conducted a scoping review from the MEDLINE, EMBASE, CINAHL and Cochrane databases for the period January 2000-July 2016, using the following inclusion criteria: (i) written in English only, (ii) published in peer-reviewed journals, (iii) at least part of the research considered the supportive care needs perspective of amyotrophic lateral sclerosis/motor neuron disease patients or their caregivers and (iv) the population sample included patients of amyotrophic lateral sclerosis/motor neuron disease or their caregivers. Thirty-seven articles were included. Our review shows that amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers' supportive care needs were mentioned across all seven domains of the Supportive Care Needs Framework. Most common were practical needs (n = 24), followed by Informational needs (n = 19), Social needs (n = 18), Psychological needs (n = 16), Physical needs (n = 15), Emotional needs (n = 13) and Spiritual needs (n = 8). From the perspectives of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, there is a significant need for more practical, social, informational, psychological, physical, emotional and spiritual support. The Supportive Care Needs Framework has potential utility in the development of patient-centred support services or healthcare policies and serves as an important base for further studies; especially, specific examples of each supportive care needs domain can guide in clinical settings when healthcare professionals

Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases

Directory of Open Access Journals (Sweden)

G. Natale

2013-03-01

Full Text Available Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-to-cell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs; mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs. The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step.

A proposal of criteria for the classification of systemic sclerosis.

Science.gov (United States)

Nadashkevich, Oleg; Davis, Paul; Fritzler, Marvin J

2004-11-01

Sensitive and specific criteria for the classification of systemic sclerosis are required by clinicians and investigators to achieve higher quality clinical studies and approaches to therapy. A clinical study of systemic sclerosis patients in Europe and Canada led to a set of criteria that achieve high sensitivity and specificity. Both clinical and laboratory investigations of patients with systemic sclerosis, related conditions and diseases with clinical features that can be mistaken as part of the systemic sclerosis spectrum were undertaken. Laboratory investigations included the detection of autoantibodies to centromere proteins, Scl-70 (topoisomerase I), and fibrillarin (U3-RNP). Based on the investigation of 269 systemic sclerosis patients and 720 patients presenting with related and confounding conditions, the following set of criteria for the classification of systemic sclerosis was proposed: 1) autoantibodies to: centromere proteins, Scl-70 (topo I), fibrillarin; 2) bibasilar pulmonary fibrosis; 3) contractures of the digital joints or prayer sign; 4) dermal thickening proximal to the wrists; 5) calcinosis cutis; 6) Raynaud's phenomenon; 7) esophageal distal hypomotility or reflux-esophagitis; 8) sclerodactyly or non-pitting digital edema; 9) teleangiectasias. The classification of definite SSc requires at least three of the above criteria. Criteria for the classification of systemic sclerosis have been proposed. Preliminary testing has defined the sensitivity and specificity of these criteria as high as 99% and 100%, respectively. Testing and validation of the proposed criteria by other clinical centers is required.

Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients.

Science.gov (United States)

Conti, Antonio; Riva, Nilo; Pesca, Mariasabina; Iannaccone, Sandro; Cannistraci, Carlo V; Corbo, Massimo; Previtali, Stefano C; Quattrini, Angelo; Alessio, Massimo

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS's pathogenesis and to seek diagnostic markers, we analyzed skeletal muscle biopsies with the differential expression proteomic approach. We studied skeletal muscle biopsies from healthy controls (CN), sporadic ALS (sALS), motor neuropathies (MN) and myopathies (M). Pre-eminently among several differentially expressed proteins, Myosin binding protein H (MyBP-H) expression in ALS samples was anomalously high. MyBP-H is a component of the thick filaments of the skeletal muscle and has strong affinity for myosin, but its function is still unclear. High MyBP-H expression level was associated with abnormal expression of Rho kinase 2 (ROCK2), LIM domain kinase 1 (LIMK1) and cofilin2, that might affect the actin-myosin interaction. We propose that MyBP-H expression level serves, as a putative biomarker in the skeletal muscle, to discriminate ALS from motor neuropathies, and that it signals the onset of dysregulation in actin-myosin interaction; this in turn might contribute to the pathogenesis of ALS. © 2013 Elsevier B.V. All rights reserved.

Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features.

Science.gov (United States)

Thom, Maria; Eriksson, Sofia; Martinian, Lillian; Caboclo, Luis O; McEvoy, Andrew W; Duncan, John S; Sisodiya, Sanjay M

2009-08-01

Widespread changes involving neocortical and mesial temporal lobe structures can be present in patients with temporal lobe epilepsy and hippocampal sclerosis. The incidence, pathology, and clinical significance of neocortical temporal lobe sclerosis (TLS) are not well characterized. We identified TLS in 30 of 272 surgically treated cases of hippocampal sclerosis. Temporal lobe sclerosis was defined by variable reduction of neurons from cortical layers II/III and laminar gliosis; it was typically accompanied by additional architectural abnormalities of layer II, that is, abnormal neuronal orientation and aggregation. Quantitative analysis including tessellation methods for the distribution of layer II neurons supported these observations. In 40% of cases, there was a gradient of TLS with more severe involvement toward the temporal pole, possibly signifying involvement of hippocampal projection pathways. There was a history of a febrile seizure as an initial precipitating injury in 73% of patients with TLS compared with 36% without TLS; no other clinical differences between TLS and non-TLS cases were identified. Temporal lobe sclerosis was not evident preoperatively by neuroimaging. No obvious effect of TLS on seizure outcome was noted after temporal lobe resection; 73% became seizure-free at 2-year follow-up. In conclusion, approximately 11% of surgically treated hippocampal sclerosis is accompanied by TLS. Temporal lobe sclerosis is likely an acquired process with accompanying reorganizational dysplasia and an extension of mesial temporal sclerosis rather than a separate pathological entity.

Internal tremor in Parkinson's disease, multiple sclerosis, and essential tremor.

Science.gov (United States)

Cochrane, Graham D; Rizvi, Syed; Abrantes, Ana; Crabtree, Brigid; Cahill, Jonathan; Friedman, Joseph H

2015-10-01

Internal tremor (IT) is a poorly recognized symptom that has been described in Parkinson's disease (PD). Described as a feeling of tremor in the extremities or trunk without actual movement, ITs are not debilitating but can be bothersome to patients. The origin of the sensation is unknown., and ITs may be prevalent in other diseases than PD. The present study sought to expand knowledge about IT by confirming their presence in PD, and determining their prevalence in Multiple Sclerosis (MS), and Essential Tremor (ET). A survey was developed in order to determine the prevalence of IT in PD, MS, and ET and to learn what associations with various disease characteristics were present. The survey was administered to 89 consecutive PD, 70 MS, and 11 ET patients. ITs were found to be a prevalent symptom in all three disorders (32.6% of PD, 35.9% of MS, and 54.5% of ET subjects reported experiencing ITs). ITs were found to be associated both with the subjects' perceived levels of anxiety and the presence of visible tremors. ITs appear to be a common symptom in all three disorders studied. These results need to be confirmed and compared to appropriate control populations. Copyright © 2015. Published by Elsevier Ltd.

FET Proteins TAF15 and EWS Are Selective Markers that Distinguish FTLD with FUS Pathology from Amyotrophic Lateral Sclerosis with "FUS" Mutations

Science.gov (United States)

Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A.; Munoz, David G.; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R. A.

2011-01-01

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in "FUS" as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with "FUS" mutations. The mechanisms…

Management of dysphagia in Parkinson's disease and amyotrophic lateral sclerosis.

Science.gov (United States)

Luchesi, Karen Fontes; Kitamura, Satoshi; Mourão, Lucia Figueiredo

2013-01-01

To describe swallowing management in patients with amyotrophic lateral sclerosis (ALS) and Parkinson' disease (PD), to investigate whether physiopathology determines the choice of therapeutic approaches, and to investigate whether the disease duration modifies the therapeutic approaches. This is a long-term study comprising 24 patients with idiopathic PD and 27 patients with ALS. The patients were followed-up in a dysphagia outpatient clinic between 2006 and 2011. The patients underwent clinic evaluation and Fiberoptic Endoscopic Evaluation of Swallowing, Functional Oral Intake Scale, and therapeutic intervention every 3 months. The swallowing management was based on orientation about the adequate food consistency and volume, besides the necessary maneuvers or exercises to improve swallowing functionality. An exploratory analysis of data was used to investigate associations between the groups of disease (PD or ALS) and clinic aspects and to know about the association between the groups of diseases and the application of maneuver or exercises over the follow-up. The most frequent recommended maneuvers in PD were bolus effect (83.3%), bolus consistency (79.2%), and swallowing frequency (79%). To patients with ALS, the bolus consistency (92%) and the bolus effect (74.1%) were more recommended. Strengthening-tongue (p=0.01), tongue control (p=0.05), and vocal exercises (p<0.001) were significantly more recommended in PD than in ALS. Compensatory and sensorial maneuvers are more recommended to rehabilitee program in both diseases. The physiopathology of the diseases determined the choice of therapeutic approaches. The disease duration of the patients did not interfere directly in the therapeutic approaches.

Evaluating the association of allergies with multiple sclerosis susceptibility risk and disease activity in a pediatric population.

Science.gov (United States)

Bourne, Theresa; Waltz, Michael; Casper, T C; Kavak, K; Aaen, G; Belman, A; Benson, L; Candee, M; Chitnis, T; Graves, J; Greenberg, B; Gorman, M; Harris, Y; Krupp, L; Lotze, T; Mar, S; Ness, J; Olsen, C; Roalstad, S; Rodriguez, M; Rose, J; Rubin, J; Schreiner, T; Tillema, J M; Kahn, I; Waldman, A; Barcellos, L; Waubant, E; Weinstock-Guttman, B

2017-04-15

Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies. Copyright © 2017 Elsevier B.V. All rights reserved.

Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis.

Science.gov (United States)

Angelov, D N; Waibel, S; Guntinas-Lichius, O; Lenzen, M; Neiss, W F; Tomov, T L; Yoles, E; Kipnis, J; Schori, H; Reuter, A; Ludolph, A; Schwartz, M

2003-04-15

Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 +/- 7 days (n = 15) to 263 +/- 8 days (n = 14; P sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

A minimal unified model of disease trajectories captures hallmarks of multiple sclerosis

KAUST Repository

Kannan, Venkateshan; Kiani, Narsis A.; Piehl, Fredrik; Tegner, Jesper

2017-01-01

Multiple Sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) causing demyelination and neurodegeneration leading to accumulation of neurological disability. Here we present a minimal, computational model involving

Temporal lobe pathology in amyotrophic lateral sclerosis. Do amyotrophic lateral sclerosis and Alzheimer's disease share a common etiological factor?

NARCIS (Netherlands)

Smitt, P. A.; Troost, D.; Louwerse, E. S.; de Jong, J. M.; van Kessel, D. T.; de Leeuw, M. A.

1993-01-01

An autopsy study was performed on temporal lobe samples from 20 non-demented patients with amyotrophic lateral sclerosis (ALS), 17 age-matched non-demented controls and 4 Alzheimer's disease (AD) patients. Formalin fixed, paraffin embedded sections from the hippocampus with adjacent parahippocampal

Neurotrophin Expression in Lymphocytes: a Powerful Indicator of Degeneration in Parkinson's Disease, Amyotrophic Lateral Sclerosis and Ataxia.

Science.gov (United States)

Sadanand, Anjana; Janardhanan, Anjali; Vanisree, A J; Pavai, Thamil

2018-02-01

Deregulated neurotrophin is an etiological factor in the pathology of neurodegenerative diseases (ND) that are clinically different entities but characterised by similar limb dysfunction. Earlier validation of peripheral biomarkers can provide significant translational benefit to ND patients. We analysed brain-derived neurotrophic factor (BDNF)-tropomyosin possessing tyrosine-related kinase (Trk B) and its key downstream proteins which are implicated in ND such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and ataxia. Blood from ND patients with PD, ALS and Ataxia with movement dysfunctions were obtained to analyse mRNA and protein expressions of the above mentioned factors in lymphocytes. The mRNA and protein expression of BDNF-Trk B and its key downstream molecules showed a significant variation when compared to control and among NDs. The study intends to show that on identifying the variation of these key molecules in the blood samples of patients with ND can serve as early diagnostic candidates. Thus by intervening, the neurotrophins and their pathways can help in early diagnosis and optimising levels of diagnostic certainty.

A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis.

Science.gov (United States)

Colpitts, Sara L; Kasper, Eli J; Keever, Abigail; Liljenberg, Caleb; Kirby, Trevor; Magori, Krisztian; Kasper, Lloyd H; Ochoa-Repáraz, Javier

2017-11-02

The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

Vitamin D levels are associated with gross motor function in amyotrophic lateral sclerosis.

Science.gov (United States)

Paganoni, Sabrina; Macklin, Eric A; Karam, Chafic; Yu, Hong; Gonterman, Fernando; Fetterman, K Ashley; Cudkowicz, Merit; Berry, James; Wills, Anne-Marie

2017-10-01

The objective of this study was to determine whether serum vitamin D [25(OH)D] levels are associated with disease progression in amyotrophic lateral sclerosis (ALS). 25(OH)D was measured in subjects enrolled in a multicenter study for validation of ALS biomarkers. Baseline 25(OH)D levels were correlated with baseline ALSFRS-R scores. Average 25(OH)D levels from baseline and month 6 visits (seasonally asynchronous) were used to predict subsequent rate of change in ALSFRS-R from month 6 to month 18. Most subjects had either insufficient or deficient 25(OH)D levels. Lower 25(OH)D was associated with lower ALSFRS-R gross motor scores, but not lower ALSFRS-R total scores at baseline. Levels of 25(OH)D were not predictive of disease progression over the next 12 months. 25(OH)D was associated with baseline gross motor ALSFRS-R scores but did not predict the rate of disease progression. Vitamin D levels may reflect poor mobility in patients with ALS. Muscle Nerve, 2017 Muscle Nerve 56: 726-731, 2017. © 2017 Wiley Periodicals, Inc.

Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis.

Science.gov (United States)

Vercellino, Marco; Fenoglio, Chiara; Galimberti, Daniela; Mattioda, Alessandra; Chiavazza, Carlotta; Binello, Eleonora; Pinessi, Lorenzo; Giobbe, Dario; Scarpini, Elio; Cavalla, Paola

2016-07-01

Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia. In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers. We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01). GRN genetic polymorphisms likely influence disease course and relapse recovery in MS. © The Author(s), 2015.

IGF binding protein alterations on periplaque oligodendrocytes in multiple sclerosis : Implications for remyelination

NARCIS (Netherlands)

Wilczak, Nadine; Chesik, Daniel; Hoekstra, Dick; De Keyser, Jacques

Why myelin repair greatly fails in multiple sclerosis (MS) is unclear. The insulin-like growth factor (IGF) system plays vital roles in oligodendrocyte development, survival, and myelin synthesis. We used immunohistochemistry to study IGF-I, IGF-I receptors and IGF binding proteins (IGFBPs) 1-6 on

Substantial adverse association of visual and vascular comorbidities on visual disability in multiple sclerosis.

Science.gov (United States)

Marrie, Ruth Ann; Cutter, Gary; Tyry, Tuula

2011-12-01

Visual comorbidities are common in multiple sclerosis (MS) but the impact of visual comorbidities on visual disability is unknown. We assessed the impact of visual and vascular comorbidities on severity of visual disability in MS. In 2006, we queried participants of the North American Research Committee on Multiple Sclerosis (NARCOMS) about cataracts, glaucoma, uveitis, hypertension, hypercholesterolemia, heart disease, diabetes and peripheral vascular disease. We assessed visual disability using the Vision subscale of Performance Scales. Using Cox regression, we investigated whether visual or vascular comorbidities affected the time between MS symptom onset and the development of mild, moderate and severe visual disability. Of 8983 respondents, 1415 (15.9%) reported a visual comorbidity while 4745 (52.8%) reported a vascular comorbidity. The median (interquartile range) visual score was 1 (0-2). In a multivariable Cox model the risk of mild visual disability was higher among participants with vascular (hazard ratio [HR] 1.45; 95% confidence interval [CI]: 1.39-1.51) and visual comorbidities (HR 1.47; 95% CI: 1.37-1.59). Vascular and visual comorbidities were similarly associated with increased risks of moderate and severe visual disability. Visual and vascular comorbidities are associated with progression of visual disability in MS. Clinicians hearing reports of worsening visual symptoms in MS patients should consider visual comorbidities as contributing factors. Further study of these issues using objective, systematic neuro-ophthalmologic evaluations is warranted.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

Science.gov (United States)

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

Linear associations between clinically assessed upper motor neuron disease and diffusion tensor imaging metrics in amyotrophic lateral sclerosis.

Science.gov (United States)

Woo, John H; Wang, Sumei; Melhem, Elias R; Gee, James C; Cucchiara, Andrew; McCluskey, Leo; Elman, Lauren

2014-01-01

To assess the relationship between clinically assessed Upper Motor Neuron (UMN) disease in Amyotrophic Lateral Sclerosis (ALS) and local diffusion alterations measured in the brain corticospinal tract (CST) by a tractography-driven template-space region-of-interest (ROI) analysis of Diffusion Tensor Imaging (DTI). This cross-sectional study included 34 patients with ALS, on whom DTI was performed. Clinical measures were separately obtained including the Penn UMN Score, a summary metric based upon standard clinical methods. After normalizing all DTI data to a population-specific template, tractography was performed to determine a region-of-interest (ROI) outlining the CST, in which average Mean Diffusivity (MD) and Fractional Anisotropy (FA) were estimated. Linear regression analyses were used to investigate associations of DTI metrics (MD, FA) with clinical measures (Penn UMN Score, ALSFRS-R, duration-of-disease), along with age, sex, handedness, and El Escorial category as covariates. For MD, the regression model was significant (p = 0.02), and the only significant predictors were the Penn UMN Score (p = 0.005) and age (p = 0.03). The FA regression model was also significant (p = 0.02); the only significant predictor was the Penn UMN Score (p = 0.003). Measured by the template-space ROI method, both MD and FA were linearly associated with the Penn UMN Score, supporting the hypothesis that DTI alterations reflect UMN pathology as assessed by the clinical examination.

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy

DEFF Research Database (Denmark)

Coles, Alasdair J; Twyman, Cary L; Arnold, Douglas L

2012-01-01

The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment....

Tuberous sclerosis

Directory of Open Access Journals (Sweden)

Krishnan S

1996-01-01

Full Text Available Although tuberous sclerosis has been described with a diagnostic triad, it is not present consistently in all cases. Variety of skin manifestations were reported in tuberous sclerosis. This studay was undertaken to assess the frequency of various skin changes in tuberous sclerosis. Ten consecutive cases of tuberous sclerosis were studied. Angiofibroma was the commonest cutaneous manifestation. Atypical fibroxanthoma, dermatofibroma and neurofibroma were also noticed as interesting associations.

Comorbidity of Bipolar Disorder and Multiple Sclerosis: A Case Report

Directory of Open Access Journals (Sweden)

Necla Keskin

2013-08-01

Full Text Available Multiple sclerosis is a chronic demyelinating disease of a central nervous system. Neuropsychiatric symptoms are common in multiple sclerosis and bipolar disorder is one of the most common psychiatric disorders that coexist with multiple sclerosis. Manic episodes may be the first presenting symptom of multiple sclerosis as comorbid pathology or as an adverse effect of pharmacotherapies used in multiple sclerosis. The comorbidity of bipolar disorder and multiple sclerosis is well-proven but its etiology is not known and investigated accurately. Recent studies support a common genetic susceptibility. Management of bipolar disorder in multiple sclerosis is based on evidence provided by case reports and treatment should be individualized. In this report, the association between bipolar disorder and multiple sclerosis, epidemiology, ethiology and treatment is discussed through a case had diagnosed as multiple sclerosis and had a manic episode with psychotic features. [Cukurova Med J 2013; 38(4.000: 832-836

A rare association of localized gigantism with tuberous sclerosis.

Science.gov (United States)

Reddy, B S; Sheriff, M O; Garg, B R; Ratnakar, C

1992-10-01

An unusual association of localized gigantism with hypertrophy of the long bones and soft tissues in the left lower limb in an 18-year-old male with tuberous sclerosis (TS) is reported. The significance of this association is discussed from the point of view of its common neural crest origin during embryogenesis.

Increased cerebrospinal fluid levels of cytokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) in patients with amyotrophic lateral sclerosis.

Science.gov (United States)

Martínez, H R; Escamilla-Ocañas, C E; Camara-Lemarroy, C R; González-Garza, M T; Moreno-Cuevas, J; García Sarreón, M A

2017-10-10

Neuroinflammation has recently been described in amyotrophic lateral sclerosis (ALS). However, the precise role of such proinflammatory cytokines as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) in ALS has not yet been determined. In this study, we determined cerebrospinal fluid (CSF) MCP-1 and MIP-1β levels and assessed their association with the duration and severity of ALS. Concentrations of MCP-1 and MIP-1β were determined in the CSF of 77 patients diagnosed with ALS and 13 controls. Cytokine levels were analysed in relation to ALS duration (12months) and severity (30points on the ALS Functional Rating Scale administered at hospital admission). Higher CSF MIP-1β (10.68pg/mL vs. 4.69pg/mL, P<.0001) and MCP-1 (234.89pg/mL vs. 160.95pg/mL, P=.011) levels were found in the 77 patients with ALS compared to controls. There were no differences in levels of either cytokine in relation to disease duration or severity. However, we did observe a significant positive correlation between MIP-1β and MCP-1 in patients with ALS. The increase in MIP-1β and MCP-1 levels suggests that these cytokines may have a synergistic effect on ALS pathogenesis. However, in our cohort, no association was found with either the duration or the clinical severity of the disease. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing

Science.gov (United States)

Neltner, Janna H.; Abner, Erin L.; Baker, Steven; Schmitt, Frederick A.; Kryscio, Richard J.; Jicha, Gregory A.; Smith, Charles D.; Hammack, Eleanor; Kukull, Walter A.; Brenowitz, Willa D.; Van Eldik, Linda J.

2014-01-01

Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer’s Disease Centre, Nun Study, and National Alzheimer’s Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case–control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin

Demyelination versus remyelination in progressive multiple sclerosis

DEFF Research Database (Denmark)

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

2010-01-01

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

Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.

Directory of Open Access Journals (Sweden)

Timothy G Lesnick

2008-01-01

Full Text Available We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs within axon guidance pathway genes were highly predictive of Parkinson disease (PD susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD.Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS; and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60, survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74, and age at onset of ALS (R(2 = 0.86, p = 5.96x10(-66. We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

Epstein-Barr virus and disease activity in multiple sclerosis

NARCIS (Netherlands)

D. Buljevac (Dragan); H.Z. Flach (Zwenneke); J. Groen (Jan); P.A. van Doorn (Pieter); F.G.A. van der Meché (Frans); R.Q. Hintzen (Rogier); W.C.J. Hop (Wim); A.D.M.E. Osterhaus (Albert); G.J.J. van Doornum (Gerard)

2005-01-01

textabstractOBJECTIVES: To study in relapsing-remitting (RR) multiple sclerosis (MS) whether exacerbations and brain activity as measured by magnetic resonance imaging (MRI) are associated with plasma levels of anti-Epstein Barr (EBV) antibodies and EBV DNA. METHODS: This was a prospective study

MYO9B polymorphisms in multiple sclerosis

DEFF Research Database (Denmark)

Kemppinen, A.; Suvela, M.; Tienari, P.J.

2009-01-01

Single-nucleotide polymorphisms (SNPs) in the 3' region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First...

Metallothionein expression in the central nervous system of multiple sclerosis patients

DEFF Research Database (Denmark)

Penkowa, M; Espejo, C; Ortega-Aznar, A

2003-01-01

Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS...

Self-esteem is associated with perceived stress in multiple sclerosis patients.

Science.gov (United States)

N Ifantopoulou, Parthena; K Artemiadis, Artemios; Triantafyllou, Nikolaos; Chrousos, George; Papanastasiou, Ioannis; Darviri, Christina

2015-07-01

Previous studies have showed that perceived stress (PS) in patients with multiple sclerosis (MS) constitutes an important factor for disease onset, relapse, symptomatology and psychological adjustment. The aim of this pilot cross-sectional study was to examine the role of self-esteem in PS, after controlling for sociodemographical characteristics, depression and personality in MS patients. Sixty-six relapsing-remitting MS patients (66.67% females, mean age of 40 ± 11.1 years old, mean duration of disease 133.6 ± 128.8 months) were studied. Perceived stress, self-esteem, depression and personality type were assessed using self-administered questionnaires. Hierarchical multivariate regression modelling was used. Higher education and depression and lower self-esteem were independently and significantly associated with increased PS, accounting for 40.5% of its variance. Univariate analyses revealed that low extroversion and openness and higher neurotism were associated with higher PS, although no significant after adjusting for other factors. Although our findings need further confirmation, psychological interventions targetting self-esteem are strongly encouraged.

Interferon Treatment of Multiple Sclerosis

OpenAIRE

Alajbegovic, Azra; Deljo, Dervis; Alajbegovic, Salem; Djelilovic-Vranic, Jasminka; Todorovic, Ljubica; Tiric-Campara, Merita

2012-01-01

Introduction: In the treatment of Multiple Sclerosis (MS) differ: treatment of relapse, treatment slow the progression of the disease (immunomodulators and immunosuppression), and symptomatic treatment. The aim: The aim of this study is to analyze the application of interferon therapy in the treatment of MS-E: Process the disease, patients with multiple sclerosis who have passed the commission for multiple sclerosis at the Neurology Clinic of Clinical Center of Sarajevo University as a refere...

Research advances in association between Golgi protein 73 and liver diseases

Directory of Open Access Journals (Sweden)

WEI Fengxian

2017-08-01

Full Text Available Golgi protein 73 (GP73 has a very low expression level in normal people, while it has a significantly higher expression level in patients with liver diseases and hepatocellular carcinoma (HCC, and therefore, it may become a new marker for HCC. This article introduces the distribution of GP73 in human body and definitions of different subtypes of GP73 and elaborates on its association with benign/malignant liver diseases and surgical operation based on the subtypes of GP73, as well as the application of GP73 in the differentiation of benign/malignant liver diseases. Since GP73 is closely associated with the development, progression, and prognosis of liver diseases, this article summarizes the latest advances in basic research, introduces the structural basis of fucosylated GP73 and proliferation, migration, and invasion of hepatoma cells and known signaling pathways, and lists the factors which affect the expression of GP73.

Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis

DEFF Research Database (Denmark)

Oslejsková, Lucie; Grigorian, Mariam; Hulejová, Hana

2009-01-01

To evaluate the association between metastasis-inducing protein S100A4 and disease activity in patients with RA, and to demonstrate the effect of TNF-alpha blocking therapy on plasma levels of S100A4 in these patients.......To evaluate the association between metastasis-inducing protein S100A4 and disease activity in patients with RA, and to demonstrate the effect of TNF-alpha blocking therapy on plasma levels of S100A4 in these patients....

Pediatric multiple sclerosis: current perspectives on health behaviors

Directory of Open Access Journals (Sweden)

Sikes EM

2018-03-01

Full Text Available Elizabeth Morghen Sikes,1 Robert W Motl,1 Jayne M Ness2 1Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Pediatric Neurology, University of Alabama at Birmingham, Birmingham, AL, USA Purpose: Pediatric-onset multiple sclerosis (POMS accounts for ~5% of all multiple sclerosis cases, and has a prevalence of ~10,000 children in the USA. POMS is associated with a higher relapse rate, and results in irreversible disability on average 10 years earlier than adult-onset multiple sclerosis. Other manifestations of POMS include mental and physical fatigue, cognitive impairment, and depression. We believe that the health behaviors of physical activity, diet, and sleep may have potential benefits in POMS, and present a scoping review of the existing literature. Methods: We identified papers by searching three electronic databases (PubMed, GoogleScholar, and CINAHL. Search terms included: pediatric multiple sclerosis OR pediatric onset multiple sclerosis OR POMS AND health behavior OR physical activity OR sleep OR diet OR nutrition OR obesity. Papers were included in this review if they were published in English, referenced nutrition, diet, obesity, sleep, exercise, or physical activity, and included pediatric-onset multiple sclerosis as a primary population. Results: Twenty papers were identified via the literature search that addressed health-promoting behaviors in POMS, and 11, 8, and 3 papers focused on diet, activity, and sleep, respectively. Health-promoting behaviors were associated with markers of disease burden in POMS. Physical activity participation was associated with reduced relapse rate, disease burden, and sleep/rest fatigue symptoms. Nutritional factors, particularly vitamin D intake, may be associated with relapse rate. Obesity has been associated with increased risk of developing POMS. POMS is associated with better sleep hygiene, and this may benefit fatigue and quality of life

Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing.

Science.gov (United States)

Neltner, Janna H; Abner, Erin L; Baker, Steven; Schmitt, Frederick A; Kryscio, Richard J; Jicha, Gregory A; Smith, Charles D; Hammack, Eleanor; Kukull, Walter A; Brenowitz, Willa D; Van Eldik, Linda J; Nelson, Peter T

2014-01-01

Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer's Disease Centre, Nun Study, and National Alzheimer's Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case-control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0

Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis.

Science.gov (United States)

Collins, Mahlon A; An, Jiyan; Hood, Brian L; Conrads, Thomas P; Bowser, Robert P

2015-11-06

Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.

Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis

DEFF Research Database (Denmark)

Dalbjerg, Sara Maria; Tsakiri, Anna; Fredriksen, Jette Lautrup

2016-01-01

Background Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis...... associated with Interferon-beta treatment. Case presentation We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved...... Interferon-beta-1-alpha therapy in patients with multiple sclerosis....

Somatosensory impairment and its association with balance limitation in people with multiple sclerosis.

Science.gov (United States)

Jamali, Akram; Sadeghi-Demneh, Ebrahim; Fereshtenajad, Niloufar; Hillier, Susan

2017-09-01

Somatosensory impairments are common in multiple sclerosis. However, little data are available to characterize the nature and frequency of these problems in people with multiple sclerosis. To investigate the frequency of somatosensory impairments and identify any association with balance limitations in people with multiple sclerosis. The design was a prospective cross-sectional study, involving 82 people with multiple sclerosis and 30 healthy controls. Tactile and proprioceptive sensory acuity were measured using the Rivermead Assessment of Somatosensory Performance. Vibration duration was assessed using a tuning fork. Duration for the Timed Up and Go Test and reaching distance of the Functional Reach Test were measured to assess balance limitations. The normative range of sensory modalities was defined using cut-off points in the healthy participants. The multivariate linear regression was used to identify the significant predictors of balance in people with multiple sclerosis. Proprioceptive impairments (66.7%) were more common than tactile (60.8%) and vibration impairments (44.9%). Somatosensory impairments were more frequent in the lower limb (78.2%) than the upper limb (64.1%). All sensory modalities were significantly associated with the Timed Up and Go and Functional Reach tests (plimitation. Copyright © 2017 Elsevier B.V. All rights reserved.

Fatigue Perceived by Multiple Sclerosis Patients Is Associated With Muscle Fatigue

NARCIS (Netherlands)

Steens, Anneke; de Vries, Astrid; Hemmen, Jolien; Heersema, Thea; Heerings, Marco; Maurits, Natasha; Zijdewind, Inge

Background. Fatigue is a debilitating symptom in multiple sclerosis (MS). Previous studies showed no association between fatigue as perceived by the patient and physiological measures of fatigability. Objective. The authors investigated associations between perceived fatigue and measures of

Multiple sclerosis: current immunological aspects

Directory of Open Access Journals (Sweden)

Carlos Cuevas-García

2017-02-01

Full Text Available Multiple sclerosis is the most common inflammatory, chronic and degenerative condition of the central nervous system, and represents the first cause of disability in young adults. In Mexico, 11 to 20 out of every 100 000 people suffer from this disease. The causes of multiple sclerosis remain unknown, but several theories have been proposed on its origin: the interaction of environmental factors, viral infectious factors and genetic and immune susceptibility of each individual patient, which induce an autoimmune response and promote neuronal/axonal degeneration. In this review, the immune reaction main components and neurodegeneration present in multiple sclerosis are analyzed, as well as the inflammatory cascade associated with demyelination. Available treatments’ main purpose is to modulate aspects related to the adaptive immune response (B and T cells. The therapeutic challenge will be antigen-specific immune-tolerance induction, for example, with the use of tolerance protocols with peptides or DNA or nanoparticles vaccines. Future therapies should aim to control innate components (microglia, macrophages, astrocytes and to promote remyelination. To optimize the treatment, a combined therapeutic approach targeting the control of inflammatory and neurodegenerative components of the disease and monitoring of biomarkers will be necessary.

Neuroimage in neuroecthodermic diseases Part II: Tuberous Sclerosis

International Nuclear Information System (INIS)

Menor, F.; Marti-Bonmati, L.; Poyatos, C.; Cortina, H.; Esteban, J.M.; Vilar, J.

1993-01-01

A prospective clinicoradiological study has been carried out in 36 patients with tuberous sclerosis. The neuroimaging studies detected some type of disorder in 94% of patients, contributing significantly to the positive diagnosis of the disease. CT was better for viewing periventricular nodules, while MR was more reliable in disclosing the number and location of cortical and white matter lesions. The use of gadolinium-DTPA in MR demonstrated frequent uptake by the periventricular nodules which was exceptional in the cortical and subcortical lesions. The use of contrast, both in CT and in MR, enhanced the images of the 7 presumed giant-cell astrocytomas detected in 6 patients. Uptake by the tumors was always much greater than that observed in the nodules, being and important criterion for the differentiation between nodules and small tumors. The appearance and topography of these CNS lesions can be reasonably well explained by considering the disease to be a disorder of the migration of dysgenic cells. We have found no consistent correlation between the neuroradiological findings and the clinical evolution of the patients. MR and CT are similarly useful in the diagnosis of tuberous sclerosis. Given that MR is more effective in the detection of the set of intracranial lesions, it could be used as the initial technique, resorting to CT in those cases in which the clinical evidence is highly suggestive and the MR study is negative. Periodic MR control is not justified unless there is suspicion of tumor implantation or growth

Tuberous sclerosis complex: Recent advances in manifestations and therapy.

Science.gov (United States)

Wataya-Kaneda, Mari; Uemura, Motohide; Fujita, Kazutoshi; Hirata, Haruhiko; Osuga, Keigo; Kagitani-Shimono, Kuriko; Nonomura, Norio

2017-09-01

Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, "a cross-sectional medical examination system," a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex-associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex. © 2017 The Japanese Urological Association.

Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy

DEFF Research Database (Denmark)

Comabella, M; Balashov, K; Issazadeh-Navikas, Shohreh

1998-01-01

Multiple sclerosis is postulated to be a Th1-type cell-mediated autoimmune disease. We investigated cytokine profiles in patients with progressive multiple sclerosis by using intracytoplasmic staining. We found increased IL-12 production by monocytes and increased IFN-gamma production by T cells...

Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course

DEFF Research Database (Denmark)

Khademi, Mohsen; Kockum, Ingrid; Andersson, Magnus L

2011-01-01

Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments.......Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments....

Characteristics and correlates of coping with multiple sclerosis: a systematic review.

Science.gov (United States)

Keramat Kar, Maryam; Whitehead, Lisa; Smith, Catherine M

2017-10-10

The purpose of this systematic review was to examine coping strategies that people with multiple sclerosis use, and to identify factors that influence their coping pattern. This systematic review followed the Joanna Briggs Institute guidelines for synthesizing descriptive quantitative research. The following databases were searched from the inception of databases until December 2016: Ovid (Medline, Embase, CINAHL, and PsycINFO), Science Direct, Web of Science, and Scopus. Manual search was also conducted from the reference lists of retrieved articles. Findings related to the patterns of coping with multiple sclerosis and factors influencing coping with multiple sclerosis were extracted and synthesized. The search of the database yielded 455 articles. After excluding duplicates (n = 341) and studies that did not meet the inclusion criteria (n = 27), 71 studies were included in the full-text review. Following the full-text, a further 21 studies were excluded. Quality appraisal of 50 studies was completed, and 38 studies were included in the review. Synthesis of findings indicated that people with multiple sclerosis use emotional and avoidance coping strategies more than other types of coping, particularly in the early stages of the disease. In comparison to the general population, people with multiple sclerosis were less likely to use active coping strategies and used more avoidance and emotional coping strategies. The pattern of coping with multiple sclerosis was associated with individual, clinical and psychological factors including gender, educational level, clinical course, mood and mental status, attitude, personality traits, and religious beliefs. The findings of this review suggest that considering individual or disease-related factors could help healthcare professionals in identifying those less likely to adapt to multiple sclerosis. This information could also be used to provide client-centered rehabilitation for people living with multiple

Toll-Like Receptor Pathways in Autoimmune Diseases.

Science.gov (United States)

Chen, Ji-Qing; Szodoray, Peter; Zeher, Margit

2016-02-01

Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location; the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. In particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS, are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathway regulation in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis.

Rehabilitation in multiple sclerosis.

Science.gov (United States)

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.

Development of protein biomarkers in cerebrospinal fluid for secondary progressive multiple sclerosis using selected reaction monitoring mass spectrometry (SRM-MS

Directory of Open Access Journals (Sweden)

Jia Yan

2012-07-01

Full Text Available Abstract Background Multiple sclerosis (MS is a chronic inflammatory disorder of the central nervous system (CNS. It involves damage to the myelin sheath surrounding axons and to the axons themselves. MS most often presents with a series of relapses and remissions but then evolves over a variable period of time into a slowly progressive form of neurological dysfunction termed secondary progressive MS (SPMS. The reasons for this change in clinical presentation are unclear. The absence of a diagnostic marker means that there is a lag time of several years before the diagnosis of SPMS can be established. At the same time, understanding the mechanisms that underlie SPMS is critical to the development of rational therapies for this untreatable stage of the disease. Results Using high performance liquid chromatography-coupled mass spectrometry (HPLC; we have established a highly specific and sensitive selected reaction monitoring (SRM assay. Our multiplexed SRM assay has facilitated the simultaneous detection of surrogate peptides originating from 26 proteins present in cerebrospinal fluid (CSF. Protein levels in CSF were generally ~200-fold lower than that in human sera. A limit of detection (LOD was determined to be as low as one femtomol. We processed and analysed CSF samples from a total of 22 patients with SPMS, 7 patients with SPMS treated with lamotrigine, 12 patients with non-inflammatory neurological disorders (NIND and 10 healthy controls (HC for the levels of these 26 selected potential protein biomarkers. Our SRM data found one protein showing significant difference between SPMS and HC, three proteins differing between SPMS and NIND, two proteins between NIND and HC, and 11 protein biomarkers showing significant difference between a lamotrigine-treated and untreated SPMS group. Principal component analysis (PCA revealed that these 26 proteins were correlated, and could be represented by four principal components. Overall, we established an

Lipid droplet-associated proteins in alcoholic liver disease: a potential linkage with hepatocellular damage

OpenAIRE

Ikura, Yoshihiro; Caldwell, Stephen H

2015-01-01

Steatosis is a characteristic morphological change of alcoholic liver disease, but its pathologic significance is still obscure. Regardless of cell types, intracellular lipid droplets are coated with a phospholipid monolayer, on which many kinds of lipid droplet-associated proteins are present. These proteins, such as the perilipin family of proteins and the cell death inducing DNA fragmentation factor (DFF) 45-like effectors, are recognized to play important roles in lipid metabolism in the ...

The essential role of t cells in multiple sclerosis: A reappraisal

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Cris S Constantinescu

2014-04-01

Full Text Available Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which destruction of myelin and nerve axons has been shown to be mediated by immune mechanisms. Although the focus of research has been traditionally on T cells as key mediators of the immunopathology, more recent efforts at understanding this complex disorder have been directed increasingly at other cellular and humoral elements of the immune response. This review is a reappraisal of the crucial role of T cells, in particular the CD4+ helper T-cell subset, in multiple sclerosis. Recent evidence is discussed underlining the predominant contribution of T-cell-associated genes to the genome-wide association study results of multiple sclerosis susceptibility, the loss of T-cell quiescence in the conversion from clinically isolated syndrome to clinically definite multiple sclerosis, and the fact that T cells represent the main target of effective immunomodulatory and immunosuppressive treatments in multiple sclerosis.

Pure spinal multiple sclerosis: A possible novel entity within the multiple sclerosis disease spectrum.

Science.gov (United States)

Schee, Jie Ping; Viswanathan, Shanthi

2018-05-01

We identified five female patients retrospectively with relapsing short-segment partial myelitis whose clinical and paraclinical features were suggestive of cord involvement of multiple sclerosis (MS)-type albeit not rigidly fulfilling the 2017 McDonald criteria. Notably, these patients had not developed any typical MS-like brain lesions despite repeated neuroimaging assessments over years. Comprehensive work-up for differential diagnoses of MS and other causes of transverse myelitis particularly neuromyelitis optica spectrum disorders had been consistently negative on longitudinal follow-up. Thus, we postulate a possible entity of pure spinal MS which may represent a novel forme fruste within the MS disease spectrum.

Tryptophan 32 potentiates aggregation and cytotoxicity of a copper/zinc superoxide dismutase mutant associated with familial amyotrophic lateral sclerosis.

Science.gov (United States)

Taylor, David M; Gibbs, Bernard F; Kabashi, Edor; Minotti, Sandra; Durham, Heather D; Agar, Jeffrey N

2007-06-01

One familial form of the neurodegenerative disease, amyotrophic lateral sclerosis, is caused by gain-of-function mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1). This study provides in vivo evidence that normally occurring oxidative modification to SOD-1 promotes aggregation and toxicity of mutant proteins. The oxidation of Trp-32 was identified as a normal modification being present in both wild-type enzyme and SOD-1 with the disease-causing mutation, G93A, isolated from erythrocytes. Mutating Trp-32 to a residue with a slower rate of oxidative modification, phenylalanine, decreased both the cytotoxicity of mutant SOD-1 and its propensity to form cytoplasmic inclusions in motor neurons of dissociated mouse spinal cord cultures.

Morphostructural MRI Abnormalities Related to Neuropsychiatric Disorders Associated to Multiple Sclerosis

Directory of Open Access Journals (Sweden)

Simona Bonavita

2013-01-01

Full Text Available Multiple Sclerosis associated neuropsychiatric disorders include major depression (MD, obsessive-compulsive disorder (OCD, bipolar affective disorder, euphoria, pseudobulbar affect, psychosis, and personality change. Magnetic Resonance Imaging (MRI studies focused mainly on identifying morphostructural correlates of MD; only a few anecdotal cases on OCD associated to MS (OCD-MS, euphoria, pseudobulbar affect, psychosis, personality change, and one research article on MRI abnormalities in OCD-MS have been published. Therefore, in the present review we will report mainly on neuroimaging abnormalities found in MS patients with MD and OCD. All together, the studies on MD associated to MS suggest that, in this disease, depression is linked to a damage involving mainly frontotemporal regions either with discrete lesions (with those visible in T1 weighted images playing a more significant role or subtle normal appearing white matter abnormalities. Hippocampal atrophy, as well, seems to be involved in MS related depression. It is conceivable that grey matter pathology (i.e., global and regional atrophy, cortical lesions, which occurs early in the course of disease, may involve several areas including the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex whose disruption is currently thought to explain late-life depression. Further MRI studies are necessary to better elucidate OCD pathogenesis in MS.

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

Directory of Open Access Journals (Sweden)

Botond Penke

2018-01-01

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

Mechanical cough augmentation techniques in amyotrophic lateral sclerosis/motor neuron disease

OpenAIRE

Rafiq, M.K.; Bradburn, M.; Mustfa, N.; Mcdermott, C.J.; Annane, D.

2016-01-01

© 2016 The Cochrane Collaboration.This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of mechanical insufflator/exsufflator (MI-E) and the breath-stacking technique for reducing morbidity and mortality and enhancing quality of life in people with amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

[Future challenges in multiple sclerosis].

Science.gov (United States)

Fernández, Óscar

2014-12-01

Multiple sclerosis occurs in genetically susceptible individuals, in whom an unknown environmental factor triggers an immune response, giving rise to a chronic and disabling autoimmune disease. Currently, significant progress is being made in our knowledge of the frequency and distribution of multiple sclerosis and its risk factors, genetics, pathology, pathogenesis, diagnostic and prognostic markers, and treatment. This has radically changed patients' and clinicians' expectations of multiple sclerosis and has raised hope that there will soon be a way to control the disease. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis.

Science.gov (United States)

Johnson, Janel O; Pioro, Erik P; Boehringer, Ashley; Chia, Ruth; Feit, Howard; Renton, Alan E; Pliner, Hannah A; Abramzon, Yevgeniya; Marangi, Giuseppe; Winborn, Brett J; Gibbs, J Raphael; Nalls, Michael A; Morgan, Sarah; Shoai, Maryam; Hardy, John; Pittman, Alan; Orrell, Richard W; Malaspina, Andrea; Sidle, Katie C; Fratta, Pietro; Harms, Matthew B; Baloh, Robert H; Pestronk, Alan; Weihl, Conrad C; Rogaeva, Ekaterina; Zinman, Lorne; Drory, Vivian E; Borghero, Giuseppe; Mora, Gabriele; Calvo, Andrea; Rothstein, Jeffrey D; Drepper, Carsten; Sendtner, Michael; Singleton, Andrew B; Taylor, J Paul; Cookson, Mark R; Restagno, Gabriella; Sabatelli, Mario; Bowser, Robert; Chiò, Adriano; Traynor, Bryan J

2014-05-01

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

Antecedents of Coping with the Disease in Patients with Multiple Sclerosis: A Qualitative Content Analysis.

Science.gov (United States)

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

2017-01-01

Due to many physical and mental disorders that occur in multiple sclerosis patients, identifying the factors affecting coping based on the experiences of patients using qualitative study is essential to improve their quality of life. This study was conducted to explore the antecedents of coping with the disease in patients with multiple sclerosis. This is a qualitative study conducted on 11 patients with multiple sclerosis in 2015 in Tehran, Iran. These patients were selected based on purposive sampling. Data were collected using semi-structured and in-depth interviews and coded. These data were analyzed using the conventional content analysis. The rigor of qualitative data using the criteria proposed by Guba and Lincoln were assessed. Five main categories were revealed: (1) social support, (2) lenience, (3) reliance on faith, (4) knowledge of multiple sclerosis and modeling, and (5) economic and environmental situation. Each category had several distinct sub-categories. The results of this study showed that coping with multiple sclerosis is a complex, multidimensional and contextual concept that is affected by various factors in relation to the context of Iran. The findings of the study can provide the healthcare professionals with deeper recognition and understanding of these antecedents to improve successful coping in Iranian patients suffering from multiple sclerosis.

Neurogenic bowel dysfunction in patients with spinal cord injury, myelomeningocele, multiple sclerosis and Parkinson's disease

Institute of Scientific and Technical Information of China (English)

Richard A Awad

2011-01-01

Exciting new features have been described concerning neurogenic bowel dysfunction, including interactions between the central nervous system, the enteric nervous system, axonal injury, neuronal loss, neurotransmission of noxious and non-noxious stimuli, and the fields of gastroenterology and neurology. Patients with spinal cord injury, myelomeningocele, multiple sclerosis and Parkinson's disease present with serious upper and lower bowel dysfunctions characterized by constipation, incontinence, gastrointestinal motor dysfunction and altered visceral sensitivity. Spinal cord injury is associated with severe autonomic dysfunction, and bowel dysfunction is a major physical and psychological burden for these patients. An adult myelomeningocele patient commonly has multiple problems reflecting the multisystemic nature of the disease. Multiple sclerosis is a neurodegenerative disorder in which axonal injury, neuronal loss, and atrophy of the central nervous system can lead to permanent neurological damage and clinical disability. Parkinson's disease is a multisystem disorder involving dopaminergic, noradrenergic, serotoninergic and cholinergic systems, characterized by motor and non-motor symptoms. Parkinson's disease affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. Recent reports have shown that the lesions in the enteric nervous system occur in very early stages of the disease, even before the involvement of the central nervous system. This has led to the postulation that the enteric nervous system could be critical in the pathophysiology of Parkinson's disease, as it could represent the point of entry for a putative environmental factor to initiate the pathological process. This review covers the data related to the etiology, epidemiology, clinical expression, pathophysiology, genetic aspects, gastrointestinal motor dysfunction, visceral sensitivity, management, prevention and prognosis of neurogenic bowel

Therapeutic compliance of first line disease-modifying therapies in patients with multiple sclerosis. COMPLIANCE Study.

Science.gov (United States)

Saiz, A; Mora, S; Blanco, J

2015-05-01

Non-adherence to disease-modifying therapies (DMTs) in multiple sclerosis may be associated with reduced efficacy. We assessed compliance, the reasons for non-compliance, treatment satisfaction, and quality of life (QoL) of patients treated with first-line therapies. A cross-sectional, multicenter study was conducted that included relapsing multiple sclerosis patients. Compliance in the past month was assessed using Morisky-Green test. Seasonal compliance and reasons for non-compliance were assessed by an ad-hoc questionnaire. Treatment satisfaction and QoL were evaluated by means of TSQM and PRIMUS questionnaires. A total of 220 patients were evaluated (91% relapsing-remitting); the mean age was 39.1 years, 70% were female, and the average time under treatment was 5.4 years. Subcutaneous interferon (IFN) β-1b was used in 23% of the patients, intramuscular IFN β-1a in 21%, subcutaneous IFN β-1a in 37%, and with glatiramer acetate in 19%. The overall compliance was 75%, with no significant differences related to the therapy, and 81% did not report any seasonal variation. Compliant patients had significantly lower disability scores and time of diagnosis, and greater satisfaction with treatment and its effectiveness. Discomfort and flu-like symptoms were the most frequent reasons for non-compliance. The satisfaction and QoL were associated with less disability and number of therapeutic switches. The rate of compliance, satisfaction and QoL in multiple sclerosis patients under DMTs is high, especially for those newly diagnosed, less disabled, and with fewer therapeutic switches. Discomfort and flu-like symptoms associated with injected therapies significantly affect adherence. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Relationship between contrast sensitivity test and disease severity in multiple sclerosis patients.

Science.gov (United States)

Soler García, A; González Gómez, A; Figueroa-Ortiz, L C; García-Ben, A; García-Campos, J

2014-09-01

To assess the importance of the Pelli-Robson contrast sensitivity test in multiple sclerosis patients according to the Expanded Disability Status Scale (EDSS). A total of 62 patients with multiple sclerosis were included in a retrospective study. Patients were enrolled from the Neurology Department to Neuroophthalmology at Virgen de la Victoria Hospital. Patients were classified into 3 groups according to EDSS: group A) lower than 1.5, group B) between 1.5 and 3.5 and group C) greater than 3.5. Visual acuity and monocular and binocular contrast sensitivity were performed with Snellen and Pelli-Robson tests respectively. Twelve disease-free control participants were also recruited. Correlations between parameter changes were analyzed. The mean duration of the disease was 81.54±35.32 months. Monocular and binocular Pelli-Robson mean values in the control group were 1.82±0.10 and 1.93±0.43 respectively, and 1.61±0.29 and 1.83±0.19 in multiple sclerosis patients. There were statistically significant differences in the monocular analysis for a level of significance P<.05. Mean monocular and binocular Pelli-Robson values in relation to gravity level were, in group A: 1.66±0.24 and 1.90±0.98, group B: 1.64±0.21 and 1.82±0.16, and group C: 1.47±0.45 and 1.73±0.32 respectively. Group differences were statistically significant in both tests: P=.05 and P=.027. Monocular and binocular contrast discrimination analyzed using the Pelli-Robson test was found to be significantly lower when the severity level, according EDSS, increases in multiple sclerosis patients. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis

International Nuclear Information System (INIS)

McMahon, Róisín M.; Friis, Lone; Siebold, Christian; Friese, Manuel A.; Fugger, Lars; Jones, E. Yvonne

2011-01-01

The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease

[User Associations and Multiple Sclerosis: Impact of Neoliberalism in France on the trajectory of life].

Science.gov (United States)

Colinet, Séverine

Multiple sclerosis is a neurological disease that induces limitation of bodily performance. It has a major impact on the work and social life of affected persons because the patient's disability, often in the absence of visible symptoms, is o source of incomprehension in a society marked by the neoliberal dogma of performance. Patient associations often provide support for patients in their trajectory. The aim of this research was to identify how the principles of neoliberalism manifest themselves in the discourse of multiple sclerosis subjects, to understand the effects of neoliberal integration, and to clarify the role played by the association involvement in the trajectories of life. This qualitative study was based on 30 individual interviews and 4 group interviews with patients, as well as 23 observations of patient group meetings and focus groups. Ten people met in interviews also kept a mini-diary, in order to record their daily involvement in a patient association. Data were analysed thematically, initially independently then by cross-linked AtlasTi software. The association constitutes two forms, practical and ideological, an illustration of the resistance to neoliberalism, particularly in the form of individual and collective responsibilities. However, to a certain extent, it also recreates performance spaces. From a practical point of view, this research re-affirms the need to create collective activities to accompany people with chronic illness.

Multiple sclerosis and other white matter diseases

International Nuclear Information System (INIS)

Zimmerman, R.A.

1991-01-01

The diagnosis of multiple sclerosis (MS) by computerized tomography and nuclear magnetic resonance are shown, including the examination of cerebral spinal fluid. Lymphocytic, foamy histiocytic perivascular cuffing, degenerated oligodendrocytes, and microglia proliferation with relative axonal sparing are presented. In the latter stage of the chronic MS plaque there is sclerosis with microcystic formation with complete demyelination and organization. (author)

Treatment Satisfaction in Multiple Sclerosis

OpenAIRE

Glanz, Bonnie I.; Musallam, Alexander; Rintell, David J.; Chitnis, Tanuja; Weiner, Howard L.; Healy, Brian C.

2014-01-01

Background: Disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) are associated with inconvenient methods of administration, significant side effects, and low adherence rates. This study was undertaken to compare treatment satisfaction in MS patients treated with interferon beta-1a intramuscular (IFNβ-1a IM), interferon beta-1a subcutaneous (IFNβ-1a SC), glatiramer acetate (GA), and natalizumab (NTZ), and to examine the associations between treatment satisfaction ra...

Optimizing treatment success in multiple sclerosis

OpenAIRE

Ziemssen, T; Derfuss, T; de Stefano, N; Giovannoni, G; Palavra, F; Tomic, D; Vollmer, T; Schippling, S

2016-01-01

Despite important advances in the treatment of multiple sclerosis (MS) over recent years, the introduction of several disease-modifying therapies (DMTs), the burden of progressive disability and premature mortality associated with the condition remains substantial. This burden, together with the high healthcare and societal costs associated with MS, creates a compelling case for early treatment optimization with highly efficacious therapies. Often, patients receive several first-line therapie...

Redox Regulation in Amyotrophic Lateral Sclerosis

Science.gov (United States)

Parakh, Sonam; Spencer, Damian M.; Halloran, Mark A.; Soo, Kai Y.; Atkin, Julie D.

2013-01-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS. PMID:23533690

Amyotrophic lateral sclerosis associated with pregnancy.

LENUS (Irish Health Repository)

Tyagi, A

2012-02-03

Amyotrophic lateral sclerosis (ALS) is the most common, progressive motor neurone disease but is rare in the obstetric population. Only 4 cases have been described in the English literature since 1975. We describe a 29 year old woman who presented with ataxia, lower limb weakness and dysarthria 4 weeks after the birth of her first child. The symptoms had onset during the pregnancy but had not been considered remarkable. There were clinical features of upper and lower motor neurone involvement without any sensory loss. MRI of brain and spine was normal. CSF analysis was negative. EMG studies confirmed the presence of widespread anterior horn cell dysfunction compatible with ALS. The patient was commenced on Riluzole and has progressed clinically, at 12 months post diagnosis.

The Use of Protein-Protein Interactions for the Analysis of the Associations between PM2.5 and Some Diseases.

Science.gov (United States)

Zhang, Qing; Zhang, Pei-Wei; Cai, Yu-Dong

2016-01-01

Nowadays, pollution levels are rapidly increasing all over the world. One of the most important pollutants is PM2.5. It is known that the pollution environment may cause several problems, such as greenhouse effect and acid rain. Among them, the most important problem is that pollutants can induce a number of serious diseases. Some studies have reported that PM2.5 is an important etiologic factor for lung cancer. In this study, we extensively investigate the associations between PM2.5 and 22 disease classes recommended by Goh et al., such as respiratory diseases, cardiovascular diseases, and gastrointestinal diseases. The protein-protein interactions were used to measure the linkage between disease genes and genes that have been reported to be modulated by PM2.5. The results suggest that some diseases, such as diseases related to ear, nose, and throat and gastrointestinal, nutritional, renal, and cardiovascular diseases, are influenced by PM2.5 and some evidences were provided to confirm our results. For example, a total of 18 genes related to cardiovascular diseases are identified to be closely related to PM2.5, and cardiovascular disease relevant gene DSP is significantly related to PM2.5 gene JUP.

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

Science.gov (United States)

Celius, E G

2017-11-01

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

Comparison between cerebral ischemia disease and multiple sclerosis by using MR diffusion tensor imaging

International Nuclear Information System (INIS)

Lou Xin; Cai Youquan; Ma Lin; Cai Jianming

2007-01-01

Objective: To assess the value of MR diffusion tensor imaging (DTI) in the differentiation between the patients with cerebral ischemia disease and multiple sclerosis. Methods: MR diffusion tensor imaging was performed in thirty-two patients with internal carotid artery stenosis ≥70% and eighteen patients with clinical diagnosed multiple sclerosis. Fractional anisotropy (FA) value of the germ, splenium, body of the corpus callosum, and the white matter of the frontal and occipital lobe were measured respectively, and independent-sample t-test statistical analysis was performed. Results: The FA value was decreased obviously in the anterior and posterior body and splenium of the corpus callosumin the MS patients compared with the ICA severe stenosis patients (0.67 ± 0.12 vs. 0.75 ± 0.05, t=3.443, P 0.05; 0.34 ± 0.08 vs. 0.34 ± 0.05, t=0.137, P> 0.05; 0.29 ± 0.06 vs. 0.40 ± 0.06, t=5.449, P>0.05). Conclusion: DTI can noninvasive detect the potential disorder of corpus callosum in vivo, thus providing useful information to differentiate the cerebral ischemia disease from multiple sclerosis. (authors)

Mining disease genes using integrated protein-protein interaction and gene-gene co-regulation information.

Science.gov (United States)

Li, Jin; Wang, Limei; Guo, Maozu; Zhang, Ruijie; Dai, Qiguo; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Xuan, Ping; Zhang, Mingming

2015-01-01

In humans, despite the rapid increase in disease-associated gene discovery, a large proportion of disease-associated genes are still unknown. Many network-based approaches have been used to prioritize disease genes. Many networks, such as the protein-protein interaction (PPI), KEGG, and gene co-expression networks, have been used. Expression quantitative trait loci (eQTLs) have been successfully applied for the determination of genes associated with several diseases. In this study, we constructed an eQTL-based gene-gene co-regulation network (GGCRN) and used it to mine for disease genes. We adopted the random walk with restart (RWR) algorithm to mine for genes associated with Alzheimer disease. Compared to the Human Protein Reference Database (HPRD) PPI network alone, the integrated HPRD PPI and GGCRN networks provided faster convergence and revealed new disease-related genes. Therefore, using the RWR algorithm for integrated PPI and GGCRN is an effective method for disease-associated gene mining.

Antidepressant Drug Treatment in Association with Multiple Sclerosis Disease-Modifying Therapy: Using Explorys in the MS Population.

Science.gov (United States)

Mirsky, Matthew M; Marrie, Ruth Ann; Rae-Grant, Alexander

2016-01-01

Background: The Explorys Enterprise Performance Management (EPM) database contains de-identified clinical data for 50 million patients. Multiple sclerosis (MS) disease-modifying therapies (DMTs), specifically interferon beta (IFNβ) treatments, may potentiate depression. Conflicting data have emerged, and a large-scale claims-based study by Patten et al. did not support such an association. This study compares the results of Patten et al. with those using the EPM database. Methods: "Power searches" were built to test the relationship between antidepressant drug use and DMT in the MS population. Searches were built to produce a cohort of individuals diagnosed as having MS in the past 3 years taking a specific DMT who were then given any antidepressant drug. The antidepressant drug therapy prevalence was tested in the MS population on the following DMTs: IFNβ-1a, IFNβ-1b, combined IFNβ, glatiramer acetate, natalizumab, fingolimod, and dimethyl fumarate. Results: In patients with MS, the rate of antidepressant drug use in those receiving DMTs was 40.60% to 44.57%. The rate of antidepressant drug use for combined IFNβ DMTs was 41.61% (males: 31.25%-39.62%; females: 43.10%-47.33%). Antidepressant drug use peaked in the group aged 45 to 54 years for five of six DMTs. Conclusions: We found no association between IFNβ treatment and antidepressant drug use in the MS population compared with other DMTs. The EPM database has been validated against the Patten et al. data for future use in the MS population.

Prescriptive Oriented Drug Analysis of Multiple Sclerosis Disease by LC-UV in Whole Human Blood.

Science.gov (United States)

Suneetha, A; Rajeswari, Raja K

2016-02-01

As a polytherapy treatment, multiple sclerosis disease demands prescriptions with more than one drug. Polytherapy is sometimes rational for drug combinations chosen to minimize adverse effects. Estimation of drugs that are concomitantly administered in polytherapy is acceptable as it shortens the analytical timepoints and also the usage of biological matrices. In clinical phase trials, the withdrawal of biofluids is a critical issue for each analysis. Estimating all the coadminsitered drugs in a single shot will be more effective and economical for pharmaceuticals. A single, simple, rapid and sensitive high-performance liquid chromatography assay method has been developed with UV detection and fully validated for the quantification of 14 drugs (at random combinations) used in the treatment of multiple sclerosis disease. The set of combinations was based on prescriptions to patients. Separations were achieved on an X-Terra MS C18 (100 × 3.9 mm, 5 µm) column. The analytes were extracted from 50 µL aliquots of whole human blood with protein precipitation using acetonitrile. All the drugs were sufficiently stable during storage for 24 h at room temperature and for 23 days at 2-8°C. The percentage recoveries of all drugs were between 90 and 115%, with RSD values <10.6%. This method has been shown to be reproducible and sensitive and can be applied to clinical samples from pharmacokinetic studies and also a useful tool in studying the drug interaction studies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Genotype-Property Patient-Phenotype Relations Suggest that Proteome Exhaustion Can Cause Amyotrophic Lateral Sclerosis

DEFF Research Database (Denmark)

Kepp, Kasper Planeta

2015-01-01

Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogen...

Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers.

Science.gov (United States)

Blanc, Paul D; Järvholm, Bengt; Torén, Kjell

2015-10-01

The association between occupational exposure and autoimmune disease is well recognized for silica, and suspected for other inhalants. We used a large cohort to estimate the risks of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and dermatomyositis associated with silica and other occupational exposures. We analyzed data for male Swedish construction industry employees. Exposure was defined by a job-exposure matrix for silica and for other inorganic dusts; those with other job-exposure matrix exposures but not to either of the 2 inorganic dust categories were excluded. National hospital treatment data were linked for International Classification of Diseases, 10(th) Revision-coded diagnoses of rheumatoid arthritis (seronegative and positive), systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. The 2 occupational exposures were tested as independent predictors of prospective hospital-based treatment for these diagnoses using age-adjusted Poisson multivariable regression analyses to calculate relative risk (RR). We analyzed hospital-based treatment data (1997 through 2010) for 240,983 men aged 30 to 84 years. There were 713 incident cases of rheumatoid arthritis (467 seropositive, 195 seronegative, 51 not classified) and 128 cases combined for systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Adjusted for smoking and age, the 2 occupational exposures (silica and other inorganic dusts) were each associated with increased risk of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and dermatomyositis combined: RR 1.39 (95% confidence interval [CI], 1.17-1.64) and RR 1.31 (95% CI, 1.11-1.53), respectively. Among ever smokers, both silica and other inorganic dust exposure were associated with increased risk of rheumatoid arthritis (RRs 1.36; 95% CI, 1.11-1.68 and 1.42; 95% CI, 1.17-1.73, respectively), while among never smokers, neither exposure was associated with statistically

Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab

DEFF Research Database (Denmark)

Laursen, Julie Hejgaard; Søndergaard, Helle Bach; Sørensen, Per Soelberg

2016-01-01

Background Vitamin D insufficiency is common among multiple sclerosis patients, and hypovitaminosis D has been associated with multiple sclerosis (MS) risk and disease activity.  Objective To investigate how recommendations on vitamin D3 supplements affect 25-hydroxyvitamin D (25(OH)D) levels in ...

Disease specific protein corona

Science.gov (United States)

Rahman, M.; Mahmoudi, M.

2015-03-01

It is now well accepted that upon their entrance into the biological environments, the surface of nanomaterials would be covered by various biomacromolecules (e.g., proteins and lipids). The absorption of these biomolecules, so called `protein corona', onto the surface of (nano)biomaterials confers them a new `biological identity'. Although the formation of protein coronas on the surface of nanoparticles has been widely investigated, there are few reports on the effect of various diseases on the biological identity of nanoparticles. As the type of diseases may tremendously changes the composition of the protein source (e.g., human plasma/serum), one can expect that amount and composition of associated proteins in the corona composition may be varied, in disease type manner. Here, we show that corona coated silica and polystyrene nanoparticles (after interaction with in the plasma of the healthy individuals) could induce unfolding of fibrinogen, which promotes release of the inflammatory cytokines. However, no considerable releases of inflammatory cytokines were observed for corona coated graphene sheets. In contrast, the obtained corona coated silica and polystyrene nanoparticles from the hypofibrinogenemia patients could not induce inflammatory cytokine release where graphene sheets do. Therefore, one can expect that disease-specific protein coronas can provide a novel approach for applying nanomedicine to personalized medicine, improving diagnosis and treatment of different diseases tailored to the specific conditions and circumstances.

SMAD family proteins: the current knowledge on their expression and potential role in neoplastic diseases

Directory of Open Access Journals (Sweden)

Magdalena Witkowska

2014-03-01

Full Text Available Transforming growth factor beta (TGF-β plays a crucial role and takes part in many processes in the human body both in physiology and pathology. This cytokine is involved in angiogenesis, regulates apoptosis and stimulates divisions of cells, such as hepatocytes, lymphocytes or hematopoietic cells. SMAD proteins family is a unique group of particles responsible for transducting the signal induced by TGF-β into the nucleus. This molecules, after receiving a signal from activated TGF-β, act on transcription factors in the nucleus, leading directly to the expression of the corresponding genes. According to current knowledge, disturbances in the functioning of SMAD proteins are present in a number of diseases. The reduced expression was observed, for example in cardiovascular diseases such as primary pulmonary hypertension or myocardial infarction, autoimmune diseases for instance systemic lupus erythematosus and multiple sclerosis, Alzheimer’s disease or osteoporosis. The latest clinical data showed the presence of mutations in SMAD proteins in cancerogenesis. Mutation of SMAD-4 protein can be detected in half of the patients with pancreatic cancer, 20% of patients with colorectal cancer and 10% of patients with lung cancer. However, mutation in SMAD-2 protein was observed in 7% of both patients with colorectal cancer and lung cancer. On the basis of numerous works, SMAD protein expression would be valuable prognostic factor in some of neoplastic diseases.

Heterogeneity in Multiple Sclerosis: Scratching the Surface of a Complex Disease

Science.gov (United States)

Disanto, Giulio; Berlanga, Antonio J.; Handel, Adam E.; Para, Andrea E.; Burrell, Amy M.; Fries, Anastasia; Handunnetthi, Lahiru; De Luca, Gabriele C.; Morahan, Julia M.

2011-01-01

Multiple Sclerosis (MS) is the most common demyelinating disease of the central nervous system. Although the etiology and the pathogenesis of MS has been extensively investigated, no single pathway, reliable biomarker, diagnostic test, or specific treatment have yet been identified for all MS patients. One of the reasons behind this failure is likely to be the wide heterogeneity observed within the MS population. The clinical course of MS is highly variable and includes several subcategories and variants. Moreover, apart from the well-established association with the HLA-class II DRB1*15:01 allele, other genetic variants have been shown to vary significantly across different populations and individuals. Finally both pathological and immunological studies suggest that different pathways may be active in different MS patients. We conclude that these “MS subtypes” should still be considered as part of the same disease but hypothesize that spatiotemporal effects of genetic and environmental agents differentially influence MS course. These considerations are extremely relevant, as outcome prediction and personalised medicine represent the central aim of modern research. PMID:21197462

The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis.

Science.gov (United States)

Leveugle, B; Spik, G; Perl, D P; Bouras, C; Fillit, H M; Hof, P R

1994-07-04

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these

Calcium Channel Blockers and Esophageal Sclerosis: Should We Expect Exacerbation of Interstitial Lung Disease

Directory of Open Access Journals (Sweden)

Charalampos Seretis

2012-01-01

Full Text Available Esophageal sclerosis is the most common visceral manifestation of systemic sclerosis, resulting in impaired esophageal clearance and retention of ingested food; in addition, co-existence of lung fibrosis with esophageal scleroderma is not uncommon. Both the progression of generalized connective tissue disorders and the damaging effect of chronic aspiration due to esophageal dysmotility appear to be involved in this procedure of interstitial fibrosis. Nifedipine is a widely prescribed calcium antagonist in a significant percentage of rheumatologic patients suffering from Raynaud syndrome, in order to inhibit peripheral vasospasm. Nevertheless, blocking calcium channels has proven to contribute to exacerbation of gastroesophageal reflux, which consequently can lead to chronic aspiration. We describe the case of severe exacerbation of interstitial lung disease in a 76-year-old female with esophageal sclerosis who was treated with oral nifedipine for Raynaud syndrome.

Genetic Factors Associated with Risk and Disability Progression of Multiple Sclerosis in Slovak Population

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Hanysova Sandra

2017-08-01

Full Text Available Objective: The aim of our study was to determine the relation of particular genetic variants in selected genes (GSTM1, GSTT1 null genotypes; rs1695 GSTP1; rs10735781 EVI5 to the risk of multiple sclerosis (MS development and find out the possible association with disease disability progression rate. Material and methods: Our study included 202 MS patients and 174 healthy control volunteers. MS patients were divided according to disability progression rate to three groups - slowly progressing, mid-rate progressing and rapidly progressing. All DNA samples were isolated from venous blood. Genotyping was performed by PCR-RFLP and multiplex PCR. Results: Our analysis showed that GSTT1 null genotype (OR 0.56; 95%CI 0.33 -0.95; p=0.04 and GSTM1, GSTT1 double null genotype (OR 0.32; 95%CI 0.14 - 0.74; p=0.006 are potentially protective in relation to MS. We observed similar result in GSTT1 null genotype in association with mid-rate progression (OR 0.48; 95%CI 0.24 - 0.97; p=0.05. Frequency of GSTM1 and GSTT1 double null genotype is significantly lower in subgroup of MS patients with progression rate defined as slow (OR 0.22; 95%CI 0.05 - 0.98; p=0.05 and middle (OR 0.33; 95%CI 0.11 - 0.99; p=0.045. We did not show any significant association of genetic changes rs1695 in GSTP1 and rs10735781 in EVI5 with MS or rate of disease progression. Conclusions: Genetic basis of multiple sclerosis is still not fully elucidated. Further research may clarify our results and confirm the value of studied factors for clinical practice.

[Current Perspective on Voltage-gated Potassium Channel Complex Antibody Associated Diseases].

Science.gov (United States)

Watanabe, Osamu

2018-04-01

Voltage-gated potassium channel (VGKC) complex auto-antibodies were initially identified in Isaacs' syndrome (IS), which is characterized by muscle cramps and neuromyotonia. These antibodies were subsequently identified in patients with Morvan's syndrome (MoS), which includes IS in conjunction with psychosis, insomnia, and dysautonomia. The antibodies have also been detected in a patient with limbic encephalopathy (LE) presenting with prominent amnesia and frequent seizures. Typical cases of LE have adult-onset, with frequent, brief dystonic seizures that predominantly affect the arms and ipsilateral face, and has recently been termed faciobrachial dystonic seizures. Autoantibodies against the extracellular domains of VGKC complex proteins, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-2 (Caspr2), occur in patients with IS, MoS, and LE. However, routine testing has detected VGKC complex antibodies without LGI1 or Caspr2 reactivities (double-negative) in patients with other diseases, such as Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis. Furthermore, double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits. Therefore, these antibodies should no longer be classified as neuronal-surface antibodies and lacking pathogenic potential. Novel information has been generated regarding autoantibody disruption of the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, thereby reducing the synaptic AMPA receptors. It may be that the main action is on inhibitory neurons, explaining why the loss of AMPA receptors causes amnesia, neuronal excitability and seizures.

Effect of disease duration on personality type in multiple sclerosis patients and healthy individual

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Sahar Vesal

2016-01-01

Full Text Available Background: Multiple sclerosis may have profound emotional consequences. The relation between psychological and physical factors could lead patients toward unforeseen disease. This study focuses on multiple sclerosis (MS disease duration on personality type A and B in relation to individuals' behaviors. Materials and Methods: This descriptive-analytical study was conducted in Isfahan Alzahra hospital in 2013. Three hundred MS patients and 100 healthy individuals were determined. The distributed questionnaires related to MS patients and considering the descriptive statistics such as demographic variables. Data were analyzed by SPSS software (version 18 based on Chi-square test and independent T-test. Results: Disease duration varied between 1 to 38 years: 30% (1-4 years, 38% (5-10 years, 20% (10-20 years, and 12% (more than 20 years. Significant relationship was observed between disease duration and tendency to type A (higher stress. This relation was positive and significant in Relapsing Remitting MS patients; but negative correlation was seen in Secondary Progressive MS patients. These patients tended to type B (lower stress when disease duration increased. Conclusions: Individuals with disease duration of one year and less than one year tend to type A personality, while patients with increment of disease duration have tendency to type B.

Erythrocyte membrane fatty acids in multiple sclerosis patients and ...

African Journals Online (AJOL)

The risk of developing multiple sclerosis (MS) is associated with increased dietary intake of saturated fatty acids. For many years it has been suspected that this disease might be associated with an imbalance between unsaturated and saturated fatty acids. We determined erythrocyte membrane fatty acids levels in Hot ...

Multiple Sclerosis and Vitamin D

Science.gov (United States)

... Editors David C. Spencer, MD Steven Karceski, MD Multiple sclerosis and vitamin D Andrew J. Solomon, MD WHAT ... caused by improper immune responses (autoimmune diseases), including multiple sclerosis (MS). A recent Patient Page in Neurology provided ...

Oxidative Modification of Blood Serum Proteins in Multiple Sclerosis after Interferon Beta and Melatonin Treatment

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Monika Adamczyk-Sowa

2017-01-01

Full Text Available Multiple sclerosis (MS is a disease involving oxidative stress (OS. This study was aimed at examination of the effect of melatonin supplementation on OS parameters, especially oxidative protein modifications of blood serum proteins, in MS patients. The study included 11 control subjects, 14 de novo diagnosed MS patients with the relapsing-remitting form of MS (RRMS, 36 patients with RRMS receiving interferon beta-1b (250 μg every other day, and 25 RRMS patients receiving interferon beta-1b plus melatonin (5 mg daily. The levels of N′-formylkynurenine, kynurenine, dityrosine, carbonyl groups, advanced glycation products (AGEs, advanced oxidation protein products (AOPP, and malondialdehyde were elevated in nontreated RRSM patients. N′-Formylkynurenine, kynurenine, AGEs, and carbonyl contents were decreased only in the group treated with interferon beta plus melatonin, while dityrosine and AOPP contents were decreased both in the group of patients treated with interferon beta and in the group treated with interferon beta-1b plus melatonin. These results demonstrate that melatonin ameliorates OS in MS patients supporting the view that combined administration of interferon beta-1b and melatonin can be more effective in reducing OS in MS patients than interferon beta-1b alone.

A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs).

Science.gov (United States)

Brütting, Christine; Emmer, Alexander; Kornhuber, Malte; Staege, Martin S

2016-08-01

Although multiple sclerosis (MS) is one of the most common central nervous system diseases in young adults, little is known about its etiology. Several human endogenous retroviruses (ERVs) are considered to play a role in MS. We are interested in which ERVs can be identified in the vicinity of MS associated genetic marker to find potential initiators of MS. We analysed the chromosomal regions surrounding 58 single nucleotide polymorphisms (SNPs) that are associated with MS identified in one of the last major genome wide association studies. We scanned these regions for putative endogenous retrovirus sequences with large open reading frames (ORFs). We observed that more retrovirus-related putative ORFs exist in the relatively close vicinity of SNP marker indices in multiple sclerosis compared to control SNPs. We found very high homologies to HERV-K, HCML-ARV, XMRV, Galidia ERV, HERV-H/env62 and XMRV-like mouse endogenous retrovirus mERV-XL. The associated genes (CYP27B1, CD6, CD58, MPV17L2, IL12RB1, CXCR5, PTGER4, TAGAP, TYK2, ICAM3, CD86, GALC, GPR65 as well as the HLA DRB1*1501) are mainly involved in the immune system, but also in vitamin D regulation. The most frequently detected ERV sequences are related to the multiple sclerosis-associated retrovirus, the human immunodeficiency virus 1, HERV-K, and the Simian foamy virus. Our data shows that there is a relation between MS associated SNPs and the number of retroviral elements compared to control. Our data identifies new ERV sequences that have not been associated with MS, so far.

A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

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Fogh, Isabella; Ratti, Antonia; Gellera, Cinzia; Lin, Kuang; Tiloca, Cinzia; Moskvina, Valentina; Corrado, Lucia; Sorarù, Gianni; Cereda, Cristina; Corti, Stefania; Gentilini, Davide; Calini, Daniela; Castellotti, Barbara; Mazzini, Letizia; Querin, Giorgia; Gagliardi, Stella; Del Bo, Roberto; Conforti, Francesca L.; Siciliano, Gabriele; Inghilleri, Maurizio; Saccà, Francesco; Bongioanni, Paolo; Penco, Silvana; Corbo, Massimo; Sorbi, Sandro; Filosto, Massimiliano; Ferlini, Alessandra; Di Blasio, Anna M.; Signorini, Stefano; Shatunov, Aleksey; Jones, Ashley; Shaw, Pamela J.; Morrison, Karen E.; Farmer, Anne E.; Van Damme, Philip; Robberecht, Wim; Chiò, Adriano; Traynor, Bryan J.; Sendtner, Michael; Melki, Judith; Meininger, Vincent; Hardiman, Orla; Andersen, Peter M.; Leigh, Nigel P.; Glass, Jonathan D.; Overste, Daniel; Diekstra, Frank P.; Veldink, Jan H.; van Es, Michael A.; Shaw, Christopher E.; Weale, Michael E.; Lewis, Cathryn M.; Williams, Julie; Brown, Robert H.; Landers, John E.; Ticozzi, Nicola; Ceroni, Mauro; Pegoraro, Elena; Comi, Giacomo P.; D'Alfonso, Sandra; van den Berg, Leonard H.; Taroni, Franco; Al-Chalabi, Ammar; Powell, John; Silani, Vincenzo; Brescia Morra, Vincenzo; Filla, Alessandro; Massimo, Filosto; Marsili, Angela; Viviana, Pensato; Puorro, Giorgia; La Bella, Vincenzo; Logroscino, Giancarlo; Monsurrò, Maria Rosaria; Quattrone, Aldo; Simone, Isabella Laura; Ahmeti, Kreshnik B.; Ajroud-Driss, Senda; Armstrong, Jennifer; Birve, Anne; Blauw, Hylke M.; Bruijn, Lucie; Chen, Wenjie; Comeau, Mary C.; Cronin, Simon; Soraya, Gkazi Athina; Grab, Josh D.; Groen, Ewout J.; Haines, Jonathan L.; Heller, Scott; Huang, Jie; Hung, Wu-Yen; Jaworski, James M.; Khan, Humaira; Langefeld, Carl D.; Marion, Miranda C.; McLaughlin, Russell L.; Miller, Jack W.; Mora, Gabriele; Pericak-Vance, Margaret A.; Rampersaud, Evadnie; Siddique, Nailah; Siddique, Teepu; Smith, Bradley N.; Sufit, Robert; Topp, Simon; Vance, Caroline; van Vught, Paul; Yang, Yi; Zheng, J.G.

2014-01-01

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10−8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10−9; OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10−9; OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci. PMID:24256812

Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity.

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Sojka, Stephen; Amin, Nirav M; Gibbs, Devin; Christine, Kathleen S; Charpentier, Marta S; Conlon, Frank L

2014-08-01

The identification and characterization of the cellular and molecular pathways involved in the differentiation and morphogenesis of specific cell types of the developing heart are crucial to understanding the process of cardiac development and the pathology associated with human congenital heart disease. Here, we show that the cardiac transcription factor CASTOR (CASZ1) directly interacts with congenital heart disease 5 protein (CHD5), which is also known as tryptophan-rich basic protein (WRB), a gene located on chromosome 21 in the proposed region responsible for congenital heart disease in individuals with Down's syndrome. We demonstrate that loss of CHD5 in Xenopus leads to compromised myocardial integrity, improper deposition of basement membrane, and a resultant failure of hearts to undergo cell movements associated with cardiac formation. We further report that CHD5 is essential for CASZ1 function and that the CHD5-CASZ1 interaction is necessary for cardiac morphogenesis. Collectively, these results establish a role for CHD5 and CASZ1 in the early stages of vertebrate cardiac development. © 2014. Published by The Company of Biologists Ltd.

Multiple Sclerosis: Evaluation of Purine Nucleotide Metabolism in Central Nervous System in Association with Serum Levels of Selected Fat-Soluble Antioxidants

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Kuračka, Ľubomír; Kalnovičová, Terézia; Kucharská, Jarmila; Turčáni, Peter

2014-01-01

In the pathogenesis of demyelinating diseases including multiple sclerosis (MS) an important role is played by oxidative stress. Increased energy requirements during remyelination of axons and mitochondria failure is one of the causes of axonal degeneration and disability in MS. In this context, we analyzed to what extent the increase in purine catabolism is associated with selected blood lipophilic antioxidants and if there is any association with alterations in serum levels of coenzyme Q10....

Vitamin D-Binding Protein Polymorphisms, 25-Hydroxyvitamin D, Sunshine and Multiple Sclerosis

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Annette Langer-Gould

2018-02-01

Full Text Available Blacks have different dominant polymorphisms in the vitamin D-binding protein (DBP gene that result in higher bioavailable vitamin D than whites. This study tested whether the lack of association between 25-hydroxyvitamin D (25OHD and multiple sclerosis (MS risk in blacks and Hispanics is due to differences in these common polymorphisms (rs7041, rs4588. We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267 from Kaiser Permanente Southern California. AA is the dominant rs7041 genotype in blacks (70.0% whereas C is the dominant allele in whites (79.0% AC/CC and Hispanics (77.1%. Higher 25OHD levels were associated with a lower risk of MS in whites who carried at least one copy of the C allele but not AA carriers. No association was found in Hispanics or blacks regardless of genotype. Higher ultraviolet radiation exposure was associated with a lower risk of MS in blacks (OR = 0.06, Hispanics and whites who carried at least one copy of the C allele but not in others. Racial/ethnic variations in bioavailable vitamin D do not explain the lack of association between 25OHD and MS in blacks and Hispanics. These findings further challenge the biological plausibility of vitamin D deficiency as causal for MS.

Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.

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Larroquette, Frédérique; Seto, Lesley; Gaub, Perrine L; Kamal, Brishna; Wallis, Deeann; Larivière, Roxanne; Vallée, Joanne; Robitaille, Richard; Tsuda, Hiroshi

2015-11-15

Missense mutations (P56S) in Vapb are associated with autosomal dominant motor neuron diseases: amyotrophic lateral sclerosis and lower motor neuron disease. Although transgenic mice overexpressing the mutant vesicle-associated membrane protein-associated protein B (VAPB) protein with neuron-specific promoters have provided some insight into the toxic properties of the mutant proteins, their role in pathogenesis remains unclear. To identify pathological defects in animals expressing the P56S mutant VAPB protein at physiological levels in the appropriate tissues, we have generated Vapb knock-in mice replacing wild-type Vapb gene with P56S mutant Vapb gene and analyzed the resulting pathological phenotypes. Heterozygous P56S Vapb knock-in mice show mild age-dependent defects in motor behaviors as characteristic features of the disease. The homozygous P56S Vapb knock-in mice show more severe defects compared with heterozygous mice reflecting the dominant and dose-dependent effects of P56S mutation. Significantly, the knock-in mice demonstrate accumulation of P56S VAPB protein and ubiquitinated proteins in cytoplasmic inclusions, selectively in motor neurons. The mutant mice demonstrate induction of ER stress and autophagic response in motor neurons before obvious onset of behavioral defects, suggesting that these cellular biological defects might contribute to the initiation of the disease. The P56S Vapb knock-in mice could be a valuable tool to gain a better understanding of the mechanisms by which the disease arises. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Spatial Correlation of Pathology and Perfusion Changes within the Cortex and White Matter in Multiple Sclerosis.

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Mulholland, A D; Vitorino, R; Hojjat, S-P; Ma, A Y; Zhang, L; Lee, L; Carroll, T J; Cantrell, C G; Figley, C R; Aviv, R I

2018-01-01

The spatial correlation between WM and cortical GM disease in multiple sclerosis is controversial and has not been previously assessed with perfusion MR imaging. We sought to determine the nature of association between lobar WM, cortical GM, volume and perfusion. Nineteen individuals with secondary-progressive multiple sclerosis, 19 with relapsing-remitting multiple sclerosis, and 19 age-matched healthy controls were recruited. Quantitative MR perfusion imaging was used to derive CBF, CBV, and MTT within cortical GM, WM, and T2-hyperintense lesions. A 2-step multivariate linear regression (corrected for age, disease duration, and Expanded Disability Status Scale) was used to assess correlations between perfusion and volume measures in global and lobar normal-appearing WM, cortical GM, and T2-hyperintense lesions. The Bonferroni adjustment was applied as appropriate. Global cortical GM and WM volume was significantly reduced for each group comparison, except cortical GM volume of those with relapsing-remitting multiple sclerosis versus controls. Global and lobar cortical GM CBF and CBV were reduced in secondary-progressive multiple sclerosis compared with other groups but not for relapsing-remitting multiple sclerosis versus controls. Global and lobar WM CBF and CBV were not significantly different across groups. The distribution of lobar cortical GM and WM volume reduction was disparate, except for the occipital lobes in patients with secondary-progressive multiple sclerosis versus those with relapsing-remitting multiple sclerosis. Moderate associations were identified between lobar cortical GM and lobar normal-appearing WM volume in controls and in the left temporal lobe in relapsing-remitting multiple sclerosis. No significant associations occurred between cortical GM and WM perfusion or volume. Strong correlations were observed between cortical-GM perfusion, normal appearing WM and lesional perfusion, with respect to each global and lobar region within HC, and

The Use of Protein-Protein Interactions for the Analysis of the Associations between PM2.5 and Some Diseases

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Qing Zhang

2016-01-01

Full Text Available Nowadays, pollution levels are rapidly increasing all over the world. One of the most important pollutants is PM2.5. It is known that the pollution environment may cause several problems, such as greenhouse effect and acid rain. Among them, the most important problem is that pollutants can induce a number of serious diseases. Some studies have reported that PM2.5 is an important etiologic factor for lung cancer. In this study, we extensively investigate the associations between PM2.5 and 22 disease classes recommended by Goh et al., such as respiratory diseases, cardiovascular diseases, and gastrointestinal diseases. The protein-protein interactions were used to measure the linkage between disease genes and genes that have been reported to be modulated by PM2.5. The results suggest that some diseases, such as diseases related to ear, nose, and throat and gastrointestinal, nutritional, renal, and cardiovascular diseases, are influenced by PM2.5 and some evidences were provided to confirm our results. For example, a total of 18 genes related to cardiovascular diseases are identified to be closely related to PM2.5, and cardiovascular disease relevant gene DSP is significantly related to PM2.5 gene JUP.

Polymorphic locus rs10492972 of the KIF1B gene association with multiple sclerosis in Russia: case control study.

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Kudryavtseva, Ekaterina A; Rozhdestvenskii, Aleksei S; Kakulya, Anastasia V; Khanokh, Elena V; Delov, Roman A; Malkova, Nadezhda A; Korobko, Denis S; Platonov, Fedor A; Aref Eva, Elena G; Zagorskaya, Natalia N; Aliferova, Valentina M; Titova, Marina A; Babenko, Sergei A; Smagina, Inna V; El Chaninova, Svetlana A; Zolovkina, Anna G; Lifshits, G I; Puzyrev, Valerii P; Filipenko, Maxim L

2011-11-01

Axonal degeneration is responsible for the progression of the irreversible destruction caused by multiple sclerosis (MS) resulting ultimately in permanent disability. The KIF1B protein, a member of the kinesin family, is necessary for axon growth and myelination in vertebrates. In the recent paper, Aulchenko et al. suggested that the rs10492972[C] variant of KIF1B increases susceptibility to MS, but three following replication study didn't confirm this association. We studied the association of the polymorphic locus rs10492972 present in the KIF1B gene with genetic predisposition and its occurrence in clinical presentations of MS patients resident in western Siberia and the Sakha Republic (Yakutia), Russia. rs10492972 has been genotype in 833 samples of MS patient and 689 healthy controls. Distribution of rs10492972 genotypes corresponded with a Hardy-Weinberg distribution in both the MS patient and control groups, with the frequency of the C allele being the same in both groups (33%). Frequencies of occurrence of the genotypes were not shown to be associated with different disease courses or other characteristics of the disease, such as age at onset or duration. A complete meta-analysis of all analogous studies published to date showed that the protective effect of the rs10492972[C] allele is statistically significant (OR=0.95, C.I.95% [0.90-0.99], p=0.02). Copyright © 2011. Published by Elsevier Inc.

Multiple sclerosis: patients’ information sources and needs on disease symptoms and management

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Albert I Matti

2010-06-01

Full Text Available Albert I Matti1, Helen McCarl2, Pamela Klaer2, Miriam C Keane1, Celia S Chen11Department of Ophthalmology, Flinders Medical Centre and Flinders University, Bedford Park, SA, Australia; 2The Multiple Sclerosis Society of South Australia and Northern Territory, Klemzig, SA, AustraliaObjective: To investigate the current information sources of patients with multiple sclerosis (MS in the early stages of their disease and to identify patients’ preferred source of information. The relative amounts of information from the different sources were also compared.Methods: Participants at a newly diagnosed information session organized by the Multiple Sclerosis Society of South Australia were invited to complete a questionnaire. Participants were asked to rate on a visual analog scale how much information they had received about MS and optic neuritis from different information sources and how much information they would like to receive from each of the sources.Results: A close to ideal amount of information is being provided by the MS society and MS specialist nurses. There is a clear deficit between what information patients are currently receiving and the amount of information they actually want from various sources. Patients wish to receive significantly more information from treating general practitioners, eye specialists, neurologists, and education sessions. Patients have identified less than adequate information received on optic neuritis from all sources.Conclusion: This study noted a clear information deficit regarding MS from all sources. This information deficit is more pronounced in relation to optic neuritis and needs to be addressed in the future.Practice implications: More patient information and counselling needs to be provided to MS patients even at early stages of their disease, especially in relation to management of disease relapse.Keywords: information sources, information needs, MS patients, optic neuritis

Depression and anxiety in a case series of amyotrophic lateral sclerosis: frequency and association with clinical features.

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Prado, Laura de Godoy Rousseff; Bicalho, Isabella Carolina Santos; Vidigal-Lopes, Mauro; Prado, Vitor de Godoy Rousseff; Gomez, Rodrigo Santiago; de Souza, Leonardo Cruz; Teixeira, Antônio Lúcio

2017-01-01

To investigate the frequency of anxiety and depression and their association with clinical features of amyotrophic lateral sclerosis. This is a cross-sectional and descriptive study including a consecutive series of patients with sporadic amyotrophic lateral sclerosis according to Awaji's criteria. Patients underwent clinical and psychiatric assessment (anxiety and depression symptoms). We included 76 patients. The men/women ratio was 1.6:1. Participants' mean age at disease onset was 55 years (SD±12.1). Sixty-six patients (86.8%) were able to complete psychiatric evaluation. Clinically significant anxiety was found in 23 patients (34.8%) while clinically significant depression was found in 24 patients (36.4%). When we compared patients with and without depression a significant difference was seen only in the frequency of anxiety symptoms (pescala funcional. Foi encontrada correlação positiva entre os sintomas de ansiedade e depressão (pescala funcional.

Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

NARCIS (Netherlands)

Simpson, Claire L.; Lemmens, Robin; Miskiewicz, Katarzyna; Broom, Wendy J.; Hansen, Valerie K.; van Vught, Paul W. J.; Landers, John E.; Sapp, Peter; Van Den Bosch, Ludo; Knight, Joanne; Neale, Benjamin M.; Turner, Martin R.; Veldink, Jan H.; Ophoff, Roel A.; Tripathi, Vineeta B.; Beleza, Ana; Shah, Meera N.; Proitsi, Petroula; Van Hoecke, Annelies; Carmeliet, Peter; Horvitz, H. Robert; Leigh, P. Nigel; Shaw, Christopher E.; van den Berg, Leonard H.; Sham, Pak C.; Powell, John F.; Verstreken, Patrik; Brown, Robert H.; Robberecht, Wim; Al-Chalabi, Ammar

2009-01-01

Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both

Speech Movement Measures as Markers of Bulbar Disease in Amyotrophic Lateral Sclerosis

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Shellikeri, Sanjana; Green, Jordan R.; Kulkarni, Madhura; Rong, Panying; Martino, Rosemary; Zinman, Lorne; Yunusova, Yana

2016-01-01

Purpose: The goal of this study was to identify the effects of amyotrophic lateral sclerosis (ALS) on tongue and jaw control, both cross-sectionally and longitudinally. The data were examined in the context of their utility as a diagnostic marker of bulbar disease. Method: Tongue and jaw movements were recorded cross-sectionally (n = 33…

Imaging Findings Associated with Cognitive Performance in Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis

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Avner Meoded

2013-08-01

Full Text Available Introduction: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS, but it has not been well studied in primary lateral sclerosis (PLS. The aims of this study were to (1 compare cognitive function in PLS to that in ALS patients, (2 explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI metrics of white matter tracts and gray matter volumes, and (3 compare DTI metrics in patients with and without cognitive and behavioral changes. Methods: The Delis-Kaplan Executive Function System (D-KEFS, the Mattis Dementia Rating Scale (DRS-2, and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model. Results: More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores. Conclusion: The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.

Protein carbonylation, protein aggregation and neuronal cell death in a murine model of multiple sclerosis

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Dasgupta, Anushka

Many studies have suggested that oxidative stress plays an important role in the pathophysiology of both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Yet, the mechanism by which oxidative stress leads to tissue damage in these disorders is unclear. Recent work from our laboratory has revealed that protein carbonylation, a major oxidative modification caused by severe and/or chronic oxidative stress conditions, is elevated in MS and EAE. Furthermore, protein carbonylation has been shown to alter protein structure leading to misfolding/aggregation. These findings prompted me to hypothesize that carbonylated proteins, formed as a consequence of oxidative stress and/or decreased proteasomal activity, promote protein aggregation to mediate neuronal apoptosis in vitro and in EAE. To test this novel hypothesis, I first characterized protein carbonylation, protein aggregation and apoptosis along the spinal cord during the course of myelin-oligodendrocyte glycoprotein (MOG)35-55 peptide-induced EAE in C57BL/6 mice [Chapter 2]. The results show that carbonylated proteins accumulate throughout the course of the disease, albeit by different mechanisms: increased oxidative stress in acute EAE and decreased proteasomal activity in chronic EAE. I discovered not only that there is a temporal correlation between protein carbonylation and apoptosis but also that carbonyl levels are significantly higher in apoptotic cells. A high number of juxta-nuclear and cytoplasmic protein aggregates containing the majority of the oxidized proteins are also present during the course of EAE, which seems to be due to reduced autophagy. In chapter 3, I show that when gluthathione levels are reduced to those in EAE spinal cord, both neuron-like PC12 (nPC12) cells and primary neuronal cultures accumulate carbonylated proteins and undergo cell death (both by necrosis and apoptosis). Immunocytochemical and biochemical studies also revealed a temporal

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

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Morgan, Sarah; Shatunov, Aleksey; Sproviero, William; Jones, Ashley R; Shoai, Maryam; Hughes, Deborah; Al Khleifat, Ahmad; Malaspina, Andrea; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; Sidle, Katie; Orrell, Richard W; Fratta, Pietro; Hardy, John; Pittman, Alan; Al-Chalabi, Ammar

2017-06-01

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Serum homocysteine levels in relation to clinical progression in multiple sclerosis

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Teunissen, C.E.; Killestein, J.; Kragt, J.J.; Polman, C.H.; Dijkstra, C.D.; Blom, H.J.

2008-01-01

Background: Elevated homocysteine levels are associated with various neurodegenerative diseases and have even been identified as a risk factor for some of these. Homocysteine levels may be elevated in patients with multiple sclerosis (MS) but large studies are lacking and the relation with disease

Top 10 Research Questions Related to Physical Activity and Multiple Sclerosis

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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…

Metaphyseal sclerosis in patients with chronic renal failure

Energy Technology Data Exchange (ETDEWEB)

Young, W.; Sevcik, M.; Tallroth, K. (Michigan Univ., Ann Arbor (USA). Dept. of Radiology)

1991-04-01

We reviewed radiographs of the hand and wrists of 33 patients with immature skeletons and chronic renal disease. Various radiographic manifestations of renal osteodystrophy were seen, including osteopenia in 23 patients (70%), subperiosteal resorption in 20 (61%), distal tuft resorption in 14 (42%), sclerosis of vertebral bodies in 2 (6%), and soft-tissue calcification in 1 (3%). We also noted that 13 patients (39%) exhibited metaphyseal sclerosis adjacent to the growth plates. Five of these 13 showed persistent sclerosis years after the growth plates had fused. None of the patients showed other radiographic changes of rickets, and there was no correlation between the serum calcium, phosphorus, or aluminum levels and the presence of metaphyseal sclerosis. Neiter was there any association with the underlying cause of renal failure, method of treatment, presence of a transplant, or type of dialysis. We view this finding as another manifestation of renal osteodystrophy. The importance of distinguishing it from other sclerotic lesions is discussed. (orig.).

Metaphyseal sclerosis in patients with chronic renal failure

International Nuclear Information System (INIS)

Young, W.; Sevcik, M.; Tallroth, K.

1991-01-01

We reviewed radiographs of the hand and wrists of 33 patients with immature skeletons and chronic renal disease. Various radiographic manifestations of renal osteodystrophy were seen, including osteopenia in 23 patients (70%), subperiosteal resorption in 20 (61%), distal tuft resorption in 14 (42%), sclerosis of vertebral bodies in 2 (6%), and soft-tissue calcification in 1 (3%). We also noted that 13 patients (39%) exhibited metaphyseal sclerosis adjacent to the growth plates. Five of these 13 showed persistent sclerosis years after the growth plates had fused. None of the patients showed other radiographic changes of rickets, and there was no correlation between the serum calcium, phosphorus, or aluminum levels and the presence of metaphyseal sclerosis. Neiter was there any association with the underlying cause of renal failure, method of treatment, presence of a transplant, or type of dialysis. We view this finding as another manifestation of renal osteodystrophy. The importance of distinguishing it from other sclerotic lesions is discussed. (orig.)

Implementation of a population-based epidemiological rare disease registry: study protocol of the amyotrophic lateral sclerosis (ALS) - registry Swabia

OpenAIRE

Nagel, Gabriele; ?nal, Hatice; Rosenbohm, Angela; Ludolph, Albert C; Rothenbacher, Dietrich

2013-01-01

Abstract Background The social and medical impact of rare diseases is increasingly recognized. Amyotrophic lateral sclerosis (ALS) is the most prevalent of the motor neuron diseases. It is characterized by rapidly progressive damage to the motor neurons with a survival of 2–5 years for the majority of patients. The objective of this work is to describe the study protocol and the implementation steps of the amyotrophic lateral sclerosis (ALS) registry Swabia, located in the South of Germany. M...

The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis

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Bernstock, Joshua D.; Pluchino, Stefano

2015-01-01

Multiple sclerosis is one of the most common causes of chronic neurological disability beginning in early to middle adult life. Multiple sclerosis is idiopathic in nature, yet increasing correlative evidence supports a strong association between one’s genetic predisposition, the environment and the immune system. Symptoms of multiple sclerosis have primarily been shown to result from a disruption in the integrity of myelinated tracts within the white matter of the central nervous system. However, recent research has also highlighted the hitherto underappreciated involvement of gray matter in multiple sclerosis disease pathophysiology, which may be especially relevant when considering the accumulation of irreversible damage and progressive disability. This review aims at providing a comprehensive overview of the interplay between inflammation, glial/neuronal damage and regeneration throughout the course of multiple sclerosis via the analysis of both white and gray matter lesional pathology. Further, we describe the common pathological mechanisms underlying both relapsing and progressive forms of multiple sclerosis, and analyze how current (as well as future) treatments may interact and/or interfere with its pathology. Understanding the putative mechanisms that drive disease pathogenesis will be key in helping to develop effective therapeutic strategies to prevent, mitigate, and treat the diverse morbidities associated with multiple sclerosis. PMID:25802011

Prevalence of benign tumors among patients with multiple sclerosis

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Aryan Rafiee Zadeh

2015-10-01

Full Text Available Multiple sclerosis (MS, an inflammatory autoimmune disease, affects almost 1% of world’s population in which myelin sheaths of neurons are targeted by immune cells. Association of different factors and diseases with MS provides new insights into possible pathogenesis and treatment for this disease. In this regard, we investigated the association of benign tumors with MS disease by studying total Isfehan multiple sclerosis (TIMS records for MS patients registered in Isfahan Multiple Sclerosis Society (IMSS who had developed any kind of benign tumors whether before MS diagnosis or after it. This study was performed in Isfahan province, third large province of Iran, with 4,815,863 populations located 1590 meters above sea level between latitudes 30 and 34 degrees north of the equator, and longitude 49-55 east. Among 4950 registered patients, 28 patients were discovered to have three types of benign tumors; pituitary adenoma in 22, meningioma in 5 and lipoma in 1 patient. The incidence rate of developing pituitary adenoma and meningioma were higher than in general population (OR 95%CI: 1.110; range: 0.731-1.685 and 1.035; range: 0.431-2.487 respectively but these findings were not statistically significant (p= 0.624 for pituitary adenoma and p= 0.939 for meningioma. But the incidence rate for lipoma was lower among MS patients (OR 95%CI: 0.020; range: 0.003-0.143 which was statistically significant (p <0.001.

Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis.

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Liang, Ya-Ling; Wu, Hua; Shen, Xi; Li, Pei-Qiang; Yang, Xiao-Qing; Liang, Li; Tian, Wei-Hua; Zhang, Li-Feng; Xie, Xiao-Dong

2012-09-01

The association between the signal transducer and activator of transcription 4 (STAT4) gene rs7574865 single nucleotide polymorphism and different autoimmune diseases remains controversial and ambiguous. We conducted this study to investigate whether combined evidence shows the association between STAT4 rs7574865 polymorphism and autoimmune diseases. Comprehensive Medline search and review of the references were used to get the relevant reports published before September 2011. Meta-analysis was conducted for genotype T/T (recessive effect), T/T + G/T (dominant effect) and T allele in random effects models. 40 studies with 90 comparisons including 32 systemic lupus erythematosus (SLE), 19 rheumatoid arthritis (RA), 3 type 1 diabetes (T1D), 11 Systemeric Sclerosis (SSc), 4 inflammatory bowed diseases (IBD), 3 Primary Sjogren's syndrome (pSS), 4 juvenile idiopathic arthritis (JIA), 2 Primary antiphospholipid syndrome (APS), 1 Autoimmune thyroid diseases, 1 multiple sclerosis, 1 Psoriasis, 1 Wegener's granulomatosis, 1 Type 2 diabetes, and 1 giant cell arteritis disease were available for this meta-analysis. The overall odds ratios for rs7574865 T-allele significantly increased in SLE, RA, T1D, SSc, JIA, and APS (OR = 1.56, 1.25, 1.13, 1.34, 1.25, and 2.15, respectively, P rs7574865 T allele confers susceptibility to SLE, RA, T1D, SSc, JIA, APS, IBD-UC, and pSS patients, supporting the hypothesis of association between STAT4 gene polymorphism and subgroup of autoimmune diseases.

Abnormal protein in the cerebrospinal fluid of patients with a submicroscopic X-chromosomal deletion associated with Norrie disease: preliminary report.

Science.gov (United States)

Joy, J E; Poglod, R; Murphy, D L; Sims, K B; de la Chapelle, A; Sankila, E M; Norio, R; Merril, C R

1991-01-01

Norrie disease is an X-linked recessive disorder characterized by congenital blindness and, in many cases, mental retardation. Some Norrie disease cases have been shown to be associated with a submicroscopic deletion in chromosomal region Xp11.3. Cerebrospinal fluid (CSF) was collected from four male patients with an X-chromosomal deletion associated with Norrie disease. CSF proteins were resolved using two-dimensional gel electrophoresis and then analyzed by computer using the Elsie V program. Our analysis revealed a protein that appears to be altered in patients with Norrie disease deletion.

Established and novel disease-modifying treatments in multiple sclerosis.

Science.gov (United States)

Cross, A H; Naismith, R T

2014-04-01

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

Protein misfolding and obstructive lung disease.

LENUS (Irish Health Repository)

Greene, Catherine M

2010-11-01

The endoplasmic reticulum has evolved a number of mechanisms to manage the accumulation of incorrectly folded proteins. This results in loss of function of these proteins, but occasionally, in conditions such as α-1 antitrpysin (A1AT) deficiency, the misfolded protein can acquire a toxic gain of function promoting exaggerated ER stress responses and inflammation. Mutations leading to deficiency in a second serine proteinase inhibitor, α-1 antichymotrpysin (ACT), can induce potentially similar consequences. A1AT and ACT deficiencies are associated with chronic obstructive lung disease. Until recently, it was thought that the lung diseases associated with these conditions were entirely due to loss of antiprotease protection in the lung (i.e., loss of function), whereas gain of function was the major cause of the liver disease associated with A1AT deficiency. This paradigm is being increasingly challenged because ER stress is being recognized in bronchial epithelial cells and inflammatory cells normally resident in the lung, giving rise to an inflammatory phenotype that adds to the proteolytic burden associated with these conditions. In this article, we describe the cellular mechanisms that are activated to cope with an increasing burden of misfolded proteins within the ER in A1AT and ACT deficiency, show how these events are linked to inflammation, and outline the therapeutic strategies that can potentially interfere with production of misfolded proteins.

Reduced Response to Activated Protein C Is Associated with Increased Risk for Cerebrovascular Disease

NARCIS (Netherlands)

Bom, J.G. van der; Bots, M.L.; Haverkate, F.; Slagboom, P.E.; Meijer, P.; Jong, P.T.V.M. de; Hofman, A.; Grobbee, D.E.; Kluft, C.

1996-01-01

Background: Resistance to activated protein C (APC), which results from various factors, including a mutation in the gene for coagulant factor V, has been associated with increased risk for venous thrombosis. However, its relation to arterial disease is still not well defined. Objective: To

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

Science.gov (United States)

Yamamoto, Toshiyuki

2011-11-01

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

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

Science.gov (United States)

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.

Does vagotomy protect against multiple sclerosis?

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Sundbøll, Jens; Horváth-Puhó, Erzsébet; Adelborg, Kasper; Svensson, Elisabeth

2017-07-01

To examine the association between vagotomy and multiple sclerosis. We conducted a matched cohort study of all patients who underwent truncal or super-selective vagotomy and a comparison cohort, by linking Danish population-based medical registries (1977-1995). Hazard ratios (HRs) for multiple sclerosis, adjusting for potential confounders were computed by means of Cox regression analysis. Median age of multiple sclerosis onset corresponded to late onset multiple sclerosis. No association with multiple sclerosis was observed for truncal vagotomy (0-37 year adjusted HR=0.91, 95% confidence interval [CI]: 0.48-1.74) or super-selective vagotomy (0-37 year adjusted HR=1.28, 95% CI: 0.79-2.09) compared with the general population. We found no association between vagotomy and later risk of late onset multiple sclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis

Science.gov (United States)

Beretta, Lorenzo; Simeón, Carmen P.; Carreira, Patricia E.; Callejas, José Luis; Fernández-Castro, Mónica; Sáez-Comet, Luis; Beltrán, Emma; Camps, María Teresa; Egurbide, María Victoria; Airó, Paolo; Scorza, Raffaella; Lunardi, Claudio; Hunzelmann, Nicolas; Riemekasten, Gabriela; Witte, Torsten; Kreuter, Alexander; Distler, Jörg H. W.; Madhok, Rajan; Shiels, Paul; van Laar, Jacob M.; Fonseca, Carmen; Denton, Christopher; Herrick, Ariane; Worthington, Jane; Schuerwegh, Annemie J.; Vonk, Madelon C.; Voskuyl, Alexandre E.; Radstake, Timothy R. D. J.; Martín, Javier

2013-01-01

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10−8, OR  = 1.22, CI 95%  = 1.14–1.30; rs2004640: P  = 4.60×10−7, OR  = 0.84, CI 95%  = 0.78–0.90; rs10488631: P  = 7.53×10−20, OR  = 1.63, CI 95%  = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10−22, OR  = 1.75, CI 95%  = 1.56–1.97) better explained the observed association (likelihood P-value  = 1.48×10−4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that

Growth Hormone and Disease Severity in Early Stage of Multiple Sclerosis

Directory of Open Access Journals (Sweden)

M. Gironi

2013-01-01

Full Text Available Evidence suggests that neurohormones such as GH and IGF-I are involved in the neuroreparative processes in multiple sclerosis (MS. GH and IGF-I blood levels in naïve MS patients with different disease courses were investigated in this study. Serum GH and IGF-I in untreated MS patients (n=64, healthy controls (HC, n=62, and patients affected by other neurological diseases (OND, n=46 were evaluated with a solid-phase-enzyme-labeled-chemiluminescent-immunometric assay. No differences were detected in GH across MS, OND, and HC (MS=0.87±1.32 ng/mL; OND=1.66±3.7; and HC=1.69±3.35; P=0.858 when considering gender, disease duration, and disease course. However, GH was lower (P=0.007 in patients with more severe disease (expanded disability scale score, EDSS≥4.0 compared with milder forms (EDSS<4. IGF-I l did not differ across the 3 groups (P=0.160, as far as concern disease course, disability, and gender were. Lower IGF-I levels were detected in subjects older than 50 years compared to younger ones for all 3 groups. Lower GH was detected in patients with more severe MS, and age was confirmed as the main factor driving IGF-I levels in all subjects. These findings, relying on the natural course of the disease, could help in shedding lights on the mechanisms involved in autoreparative failure associated with poorer prognosis in MS.

Treatment and disease management of multiple sclerosis patients: A review for nurse practitioners.

Science.gov (United States)

Roman, Cortnee; Menning, Kara

2017-10-01

This review discusses the role of the nurse practitioner (NP) in evaluating the clinical effects, potential side effects, and monitoring requirements for treatment options in multiple sclerosis (MS) and provides guidance on how to help patients understand these issues. A literature search was conducted on PubMed to identify publications on monitoring and disease management of MS patients. Additional resources included drug information web sites and package inserts. NPs play an active role in the management of MS patients via effective monitoring and communication throughout the patient's treatment regimen and disease course. In the shared decision-making model of MS treatment, NPs ensure that patients understand the implications of their disease-modifying therapies (DMTs). As patients move through treatments during the course of their disease, the importance of this role increases, and it is critical that NPs follow the guidelines in each medication's product label and take into account any potential lingering effects of prior medications. It is critical for NPs to promote patient adherence, to ensure that patients understand treatment side effects and monitoring requirements, and to take sequencing and reversibility implications of DMTs into account when making clinical decisions. ©2017 American Association of Nurse Practitioners.

Novel Mutation in the TSC2 Gene Associated with Prenatally Diagnosed Cardiac Rhabdomyomas and Cerebral Tuberous Sclerosis

Directory of Open Access Journals (Sweden)

Chih-Ping Chen

2006-01-01

Full Text Available Cardiac rhabdomyomas are prenatal echocardiographic markers for tuberous sclerosis complex (TSC. TSC is caused by mutations in the genes TSC1 and TSC2. We report a 28-year-old, gravida 5, para 2, woman with an uncomplicated pregnancy until prenatal ultrasound at 34 weeks' gestation revealed fetal cardiac tumors. Ultrafast magnetic resonance imaging (MRI at 36 weeks' gestation showed cardiac rhab-domyomas and small subependymal tubers. At 39 weeks' gestation, a 2262 g female infant was delivered uneventfully. Postnatal echocardiography confirmed cardiac rhabdomyomas and MRI verified small cerebral subependymal tubers. Mutational analysis of TSC1 and TSC2 genes using denaturing high-performance liquid chromatography and direct sequencing of the genes was performed and revealed that the parents had wildtype DNA, while the proband was heterozygous for a novel de novo nonsense mutation, c.4830 G > A, in exon 36 of the TSC2 gene, resulting in a change of codon 1610 TGG (tryptophan to TGA (stop codon. The mutation predicted a W1610X premature termination of the tuberin protein. These findings support an association between a TSC2 de novo nonsense mutation and prenatally detected cardiac rhabdomyomas and cerebral tuberous sclerosis. Familial molecular analysis of TSC1 and TSC2 in cases with prenatally diagnosed cardiac rhabdomyomas and cerebral tuberous sclerosis lesions is helpful in prenatal diagnosis and genetic counseling.

Therapeutic neuroprotective agents for amyotrophic lateral sclerosis

Science.gov (United States)

Pandya, Rachna S.; Zhu, Haining; Li, Wei; Bowser, Robert; Friedlander, Robert M.

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient’s life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression. PMID:23864030

Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients

KAUST Repository

Conti, Antonio; Riva, Nilo; Pesca, Mariasabina Sabina; Iannaccone, Sandro; Cannistraci, Carlo; Corbo, Massimo; Previtali, Stefano Carlo; Quattrini, Angelo; Alessio, Massimo

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS's pathogenesis and to seek

Comorbidity in multiple sclerosis is associated with diagnostic delays and increased mortality

DEFF Research Database (Denmark)

Thormann, Anja; Sorensen, Per Soelberg; Koch-Henriksen, Nils

2017-01-01

Objective: To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS. Methods: We conducted a population-based, nationwide cohort study including all incident MS cases in Denmark with first MS symptom between 1980 and 2005. To inve......Objective: To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS. Methods: We conducted a population-based, nationwide cohort study including all incident MS cases in Denmark with first MS symptom between 1980 and 2005.......007). Conclusions: An increased awareness of both the necessity of neurologic evaluation of new neurologic symptoms in persons with preexisting chronic disease and of optimum treatment of comorbidity in MS is critical....

The management of multiple sclerosis in children: a European view

DEFF Research Database (Denmark)

Ghezzi, Angelo; Banwell, Brenda; Boyko, Alexey

2010-01-01

in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce...... in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field.......About 3-5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity...

Occipital neuralgia associates with high cervical spinal cord lesions in idiopathic inflammatory demyelinating disease.

Science.gov (United States)

Kissoon, Narayan R; Watson, James C; Boes, Christopher J; Kantarci, Orhun H

2018-01-01

Background The association of trigeminal neuralgia with pontine lesions has been well documented in multiple sclerosis, and we tested the hypothesis that occipital neuralgia in multiple sclerosis is associated with high cervical spinal cord lesions. Methods We retrospectively reviewed the records of 29 patients diagnosed with both occipital neuralgia and demyelinating disease by a neurologist from January 2001 to December 2014. We collected data on demographics, clinical findings, presence of C2-3 demyelinating lesions, and treatment responses. Results The patients with both occipital neuralgia and multiple sclerosis were typically female (76%) and had a later onset (age > 40) of occipital neuralgia (72%). Eighteen patients (64%) had the presence of C2-3 lesions and the majority had unilateral symptoms (83%) or episodic pain (78%). All patients with documented sensory loss (3/3) had C2-3 lesions. Most patients with progressive multiple sclerosis (6/8) had C2-3 lesions. Of the eight patients with C2-3 lesions and imaging at onset of occipital neuralgia, five (62.5%) had evidence of active demyelination. None of the patients with progressive multiple sclerosis (3/3) responded to occipital nerve blocks or high dose intravenous steroids, whereas all of the other phenotypes with long term follow-up (eight patients) had good responses. Conclusions A cervical spine MRI should be considered in all patients presenting with occipital neuralgia. In patients with multiple sclerosis, clinical features in occipital neuralgia that were predictive of the presence of a C2-3 lesion were unilateral episodic symptoms, sensory loss, later onset of occipital neuralgia, and progressive multiple sclerosis phenotype. Clinical phenotype predicted response to treatment.

Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis.

Science.gov (United States)

Yao, Qingzhou; Song, Rui; Ao, Lihua; Cleveland, Joseph C; Fullerton, David A; Meng, Xianzhong

2017-06-01

Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and overproduction of extracellular matrix (ECM) proteins. However, the mechanism of aortic valve sclerosis remains unclear. Recently, we observed that diseased human aortic valves overexpress growth factor neurotrophin 3 (NT3). In the present study, we tested the hypothesis that NT3 is a profibrogenic factor to human AVICs. AVICs isolated from normal human aortic valves were cultured in M199 growth medium and treated with recombinant human NT3 (0.10 µg/ml). An exposure to NT3 induced AVIC proliferation, upregulated the production of collagen and matrix metalloproteinase (MMP), and augmented collagen deposition. These changes were abolished by inhibition of the Trk receptors. NT3 induced Akt phosphorylation and increased cyclin D1 protein levels in a Trk receptor-dependent fashion. Inhibition of Akt abrogated the effect of NT3 on cyclin D1 production. Furthermore, inhibition of either Akt or cyclin D1 suppressed NT3-induced cellular proliferation and MMP-9 and collagen production, as well as collagen deposition. Thus, NT3 upregulates cellular proliferation, ECM protein production, and collagen deposition in human AVICs. It exerts these effects through the Trk-Akt-cyclin D1 cascade. NT3 is a profibrogenic mediator in human aortic valve, and overproduction of NT3 by aortic valve tissue may contribute to the mechanism of valvular sclerosis. Copyright © 2017 the American Physiological Society.

Heat shock proteins as potential targets for protective strategies in neurodegeneration

NARCIS (Netherlands)

Kampinga, Harm H.; Bergink, Steven

Protein aggregates are hallmarks of nearly all age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several polyglutamine diseases such as Huntington's disease and different forms of spinocerebellar ataxias (SCA; SCA1-3, SCA6,

Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease: Brain protein O-GlcNAcylation in Alzheimer's disease

Energy Technology Data Exchange (ETDEWEB)

Wang, Sheng [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Yang, Feng [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Petyuk, Vladislav A. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Shukla, Anil K. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Monroe, Matthew E. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Gritsenko, Marina A. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Rodland, Karin D. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Smith, Richard D. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Qian, Wei-Jun [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA; Gong, Cheng-Xin [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York USA; Liu, Tao [Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA

2017-07-28

Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer’s disease. Herein we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in post-mortem human brains with and without Alzheimer’s using isobaric tandem mass tags labeling, chemoenzymatic photocleavage enrichment and liquid chromatography coupled to mass spectrometry. A total of 1,850 O-GlcNAc peptides covering 1,094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. 128 O-GlcNAc peptides covering 78 proteins were altered significantly in Alzheimer’s brain as compared to controls (q<0.05). Moreover, alteration of the O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins, and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic Alzheimer’s disease.

Isolated pulmonary veno-occlusive disease and pulmonary arterial thrombosis in systemic sclerosis – a lethal combination

Directory of Open Access Journals (Sweden)

Arun Jeevagan

2010-05-01

Full Text Available Arun JeevaganGeneral Medicine, Ipswich NHS Hospital, UKBackground: Isolated pulmonary hypertension secondary to systemic sclerosis is not uncommon. Our patient with systemic sclerosis presented with a very aggressive form of pulmonary hypertension due to a lethal combination of pulmonary veno-occlusive disease (PVOD and pulmonary arterial thrombosis. This combined presentation has never before been reported in medical literature.Case report: A 75-year-old woman with a 4-month history of atypical chest pains was admitted with a 3-week history of worsening symptoms of shortness of breath, reduced exercise tolerance, and bilateral pitting edema. On examination she had thickened skin in her hands, telangiectasia on her face, maculopapular rash in her legs, raised jugular venous pressure, and bilateral pitting edema. Her autoimmune profile revealed positive anticentromere antibodies, and her echocardiogram showed right ventricular systolic pressure of 91 mmHg. She also had renal impairment secondary to hypoperfusion. A diagnosis of isolated pulmonary hypertension secondary to limited systemic sclerosis was made. As she was clinically improving on slow diuretic infusion and awaiting transfer to a specialist center for management of pulmonary hypertension, our patient died due to cardiopulmonary arrest. Her postmortem revealed that she died of a combination of PVOD and pulmonary arteriopathy due to thrombosis.Conclusion: This is clearly a unique case both in presentation and difficulty of management. Pulmonary vasodilators used in therapy of pulmonary arteriopathy can be detrimental in patients with PVOD. There is no definitive investigation, curative treatment, or management, that exists for a combination of PVOD and pulmonary arteriopathy due to thrombosis secondary to systemic sclerosis.Keywords: pulmonary veno-occlusive disease, pulmonary arterial hypertension, systemic sclerosis, pulmonary arteriopathy with thrombosis

Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

Science.gov (United States)

Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda

2015-01-01

The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. PMID:25142460

Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

Science.gov (United States)

Matthews, Lucy; Kolind, Shannon; Brazier, Alix; Leite, Maria Isabel; Brooks, Jonathan; Traboulsee, Anthony; Jenkinson, Mark; Johansen-Berg, Heidi; Palace, Jacqueline

2015-01-01

Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.

Association of diffuse idiopathic skeletal hyperostosis and aortic valve sclerosis

Directory of Open Access Journals (Sweden)

Alberto O. Orden

2014-06-01

Full Text Available The principal objective of this investigation was to analyze the association between diffuse idiopathic skeletal hyperostosis (DISH and the presence of aortic valve sclerosis (AVS. For this study we used results from 1000 consecutive outpatients (473 males, older than 50 years of age (average 67.6 years, that had been examined with Doppler echocardiogram and anterior and lateral chest radiographs. Overall, 195 patients (19.5% were diagnosed with DISH and 283 (28.3% with AVS. DISH was more prevalent than AVS in males (66.7% vs. 42.6%, p< 0.0001 and in older patients (73.6 ± 9 years vs. 66.1 ± 9 years, p < 0.0001. Furthermore, 55.4% of patients with dorsal DISH presented aortic sclerosis calcification vs. 21.7% of patients free of DISH (OR = 4.47; 95% CI = 3.22-6.21. The adjusted odds ratio (OR was calculated by sex and age resulting in 3.04 (95% CI = 2.12-4.36; p < .0001. A statistically significant association was found between DISH and AVS in accordance to age and sex. The biological plausibility of this association is based on similar risk factors, pathogenic mechanisms and vascular complications.

One-Year Outcomes of an Integrated Multiple Sclerosis Disease Management Program.

Science.gov (United States)

Groeneweg, Marti; Forrester, Sara H; Arnold, Beth; Palazzo, Lorella; Zhu, Weiwei; Yoon, Paul; Scearce, Tim

2018-05-01

Multiple sclerosis (MS) is associated with high total health care cost, the majority of which is attributable to medications. Patients with MS are less likely to experience relapses, emergency department (ED) visits, and hospitalizations when they are adherent to disease-modifying treatments. Disease management programs are hypothesized to improve medication adherence thereby improving clinical and economic outcomes. To evaluate the clinical and economic effects of a specialty pharmacy and chronic disease management program for patients with MS from a health plan perspective. This study was a retrospective analysis using prescription drug claims, medical claims, and electronic medical record information (2013-2015) 1 year before and after enrollment in the disease management program for members with 24 months of continuous health plan coverage. Medication adherence was calculated using proportion of days covered (PDC). Relapse rate was defined as an MS outpatient visit associated with a corticosteroid dispense within 7 days of the visit or an MS hospitalization. Disease progression was assessed using the Modified Expanded Disability Status Scale (mEDSS). Resource use included outpatient visits, ED visits, and hospitalizations. Cost information was collected as health plan-paid amount and was reported in 2013 U.S. dollars. The analysis included 377 patients (mean age 55 years, 76.4% female). After enrollment in the program, 78.7% of the study group had a PDC of ≥ 0.80 compared with 70.0% before enrollment (P management for patients with MS can increase the proportion of patients adherent to medication. The increase in health plan spend on MS medications is not offset by savings in health care resource utilization. This study was funded by Kaiser Permanente Washington Health Research Institute and Kaiser Permanente Washington Pharmacy Administration. The authors have no disclosures to report.

Recurrent myelinoclastic diffuse sclerosis: a case report of a child with Schilder's variant of multiple sclerosis

International Nuclear Information System (INIS)

Fitzgerald, M.J.; Coleman, L.T.

2000-01-01

Myelinoclastic diffuse sclerosis (MDS, Schilder's disease) is a rare CNS demyelinating disorder affecting mainly children and usually presenting as an intracranial mass lesion. We report the first case of recurrent intracranial MDS where the third episode of demyelination involved the cervical spinal cord. This may represent a subset of the disease, which should be considered as Schilder's variant (childhood form) of multiple sclerosis. (orig.)

The etiology of multiple sclerosis: genetic evidence for the involvement of the human endogenous retrovirus HERV-Fc1

DEFF Research Database (Denmark)

Nexø, Bjørn Andersen; Christensen, Tove; Frederiksen, Jette

2011-01-01

or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We...... conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis....

The genetics of multiple sclerosis: review of current and emerging candidates

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Muñoz-Culla M

2013-08-01

Full Text Available Maider Muñoz-Culla,1,2 Haritz Irizar,1,2 David Otaegui1,2 1Multiple Sclerosis Unit, Instituto Biodonostia, San Sebastián, Spain; 2Red Española de Esclerosis Múltiple (REEM, Barcelona, Spain Abstract: Multiple sclerosis (MS is a complex disease in which environmental, genetic, and epigenetic factors determine the risk of developing the disease. The human leukocyte antigen region is the strongest susceptibility locus linked to MS, but it does not explain the whole heritability of the disease. To find other non-human leukocyte antigen loci associated with the disease, high-throughput genotyping, sequencing, and gene-expression studies have been performed, producing a valuable quantity of information. An overview of the genomic and expression studies is provided in this review, as well as microRNA-expression studies, highlighting the importance of combining all the layers of information in order to elucidate the causes or pathological mechanisms occurring in the disease. Genetics in MS is a promising field that is presumably going to be very productive in the next decade understanding the cross talk between all the factors contributing to the development of MS. Keywords: multiple sclerosis, genetics, gene expression, microRNA

Brain magnetic resonance imaging findings in patients with systemic sclerosis.

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Mohamed, Reem H A; Nassef, Amr A

2010-02-01

Systemic sclerosis is a multisystem disease where functional and structural abnormalities of small blood vessels prevail. Recently, transient ischemic attacks, ischemic stroke, and hemorrhages have been reported as primary consequence of vascular central nervous system affection in systemic sclerosis. Magnetic resonance imaging (MRI) is considered to be the most sensitive diagnostic technique for detecting symptomatic and asymptomatic lesions in the brain in cases of multifocal diseases. Evaluate brain changes in patients with systemic sclerosis using MRI. Thirty female patients with systemic sclerosis aged 27-61 years, with disease duration of 1-9 years and with no history of other systemic disease or cerebrovascular accidents, were enrolled. An age-matched female control group of 30 clinically normal subjects, underwent brain MR examination. Central nervous system involvement in the form of white matter hyperintense foci of variable sizes were found in significantly abundant forms in systemic sclerosis patients on MR evaluation than in the age-related control group, signifying a form of central nervous system vasculopathy. Such foci showed no definite correlation with disease duration, yet they showed significant correlation to severity of peripheral vascular disease, headaches, fainting attacks and depression in the group under study. Asymptomatic as well as symptomatic central nervous system ischemic vasculopathy is not uncommon in systemic sclerosis patients and MRI is considered a sensitive noninvasive screening tool for early detection of CNS involvement in patients with systemic sclerosis.

Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia.

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Mishra, Pooja-Shree; Vijayalakshmi, K; Nalini, A; Sathyaprabha, T N; Kramer, B W; Alladi, Phalguni Anand; Raju, T R

2017-12-16

Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory

Validation of patient determined disease steps (PDDS) scale scores in persons with multiple sclerosis.

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Learmonth, Yvonne C; Motl, Robert W; Sandroff, Brian M; Pula, John H; Cadavid, Diego

2013-04-25

The Patient Determined Disease Steps (PDDS) is a promising patient-reported outcome (PRO) of disability in multiple sclerosis (MS). To date, there is limited evidence regarding the validity of PDDS scores, despite its sound conceptual development and broad inclusion in MS research. This study examined the validity of the PDDS based on (1) the association with Expanded Disability Status Scale (EDSS) scores and (2) the pattern of associations between PDDS and EDSS scores with Functional System (FS) scores as well as ambulatory and other outcomes. 96 persons with MS provided demographic/clinical information, completed the PDDS and other PROs including the Multiple Sclerosis Walking Scale-12 (MSWS-12), and underwent a neurological examination for generating FS and EDSS scores. Participants completed assessments of cognition, ambulation including the 6-minute walk (6 MW), and wore an accelerometer during waking hours over seven days. There was a strong correlation between EDSS and PDDS scores (ρ = .783). PDDS and EDSS scores were strongly correlated with Pyramidal (ρ = .578 &ρ = .647, respectively) and Cerebellar (ρ = .501 &ρ = .528, respectively) FS scores as well as 6 MW distance (ρ = .704 &ρ = .805, respectively), MSWS-12 scores (ρ = .801 &ρ = .729, respectively), and accelerometer steps/day (ρ = -.740 &ρ = -.717, respectively). This study provides novel evidence supporting the PDDS as valid PRO of disability in MS.

A gender gap in primary and secondary heart dysfunctions in systemic sclerosis

DEFF Research Database (Denmark)

Elhai, Muriel; Avouac, Jérôme; Walker, Ulrich A

2016-01-01

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed...

Clustering of autoimmune diseases in patients with rosacea

DEFF Research Database (Denmark)

Egeberg, Alexander; Hansen, Peter Riis; Gislason, Gunnar Hilmar

2016-01-01

BACKGROUND: Rosacea is a common inflammatory skin condition that shares genetic risk loci with autoimmune diseases such as type 1 diabetes mellitus (T1DM) and celiac disease. A recent genomewide association study identified 90 genetic regions associated with T1DM, celiac disease, multiple sclerosis......, and/or rheumatoid arthritis, respectively. However, a possible association with rosacea was not investigated. OBJECTIVE: We evaluated the association between rosacea and T1DM, celiac disease, multiple sclerosis, and rheumatoid arthritis, respectively. METHODS: We performed a population-based case...... and socioeconomic status, patients with rosacea had significantly increased ORs for T1DM (OR 2.59, 95% CI 1.41-4.73), celiac disease (OR 2.03, 95% CI 1.35-3.07), multiple sclerosis (OR 1.65, 95% CI 1.20-2.28), and rheumatoid arthritis (OR 2.14, 95% CI 1.82-2.52). The association was mainly observed in women...

Treatment of Cognitive Impairment in Multiple Sclerosis

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Pierson, Susan H.; Griffith, Nathan

2006-01-01

Cognitive impairment in multiple sclerosis is an increasingly recognized entity. This article reviews the cognitive impairment of multiple sclerosis, its prevalence, its relationship to different types of multiple sclerosis, and its contribution to long-term functional prognosis. The discussion also focuses on the key elements of cognitive dysfunction in multiple sclerosis which distinguish it from other forms of cognitive impairment. Therapeutic interventions potentially effective for the cognitive impairment of multiple sclerosis are reviewed including the effects of disease modifying therapies and the use of physical and cognitive interventions. PMID:16720960

Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases.

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Arru, G; Mameli, G; Deiana, G A; Rassu, A L; Piredda, R; Sechi, E; Caggiu, E; Bo, M; Nako, E; Urso, D; Mariotto, S; Ferrari, S; Zanusso, G; Monaco, S; Sechi, G; Sechi, L A

2018-03-31

Human endogenous retroviruses (HERV) K/W seem to play a role in fostering and exacerbation of some neurological diseases, including amyotrophic lateral sclerosis (ALS). Given these findings, the immunity response against HERV-K and HERV-W envelope surface (env-su) glycoprotein antigens in serum and cerebrospinal fluid (CSF) was investigated for ALS, multiple sclerosis (MS) and Alzheimer's disease patients and in healthy controls. Four antigenic peptides derived respectively from HERV-K and HERV-W env-su proteins were studied in 21 definite or probable ALS patients, 26 possible or definite relapsing-remitting MS patients, 18 patients with Alzheimer's disease and 39 healthy controls. An indirect enzyme-linked immunosorbent assay was set up to detect specific antibodies (Abs) against env-su peptides. Amongst the measured levels of Abs against the four different HERV-K peptide fragments, only HERV-K env-su 19-37 was significantly elevated in ALS compared to other groups, both in serum and CSF. Instead, amongst the Abs levels directed against the four different HERV-W peptide fragments, only HERV-W env-su 93-108 and HERV-W env-su 248-262 were significantly elevated, in the serum and CSF of the MS group compared to other groups. In ALS patients, the HERV-K env-su 19-37 Abs levels were significantly correlated with clinical measures of disease severity, both in serum and CSF. Increased circulating levels of Abs directed against the HERV-W env-su 93-108 and HERV-W env-su 248-262 peptide fragments could serve as possible biomarkers in patients with MS. Similarly, increased circulating levels of Abs directed against the HERV-K env-su 19-37 peptide fragment could serve as a possible early novel biomarker in patients with ALS. © 2018 EAN.

Diagnosis and Management of Systemic Sclerosis: A Practical Approach.

Science.gov (United States)

Lee, Jason J; Pope, Janet E

2016-02-01

Systemic sclerosis is a devastating multisystem rheumatologic condition that is characterized by autoimmunity, tissue fibrosis, obliterative vasculopathy and inflammation. Clinical presentation and course of the condition vary greatly, which complicates both diagnosis and corresponding treatment. In this regard, recent advances in disease understanding, both clinically and biochemically, have led to newer classification criteria for systemic sclerosis that are more inclusive than ever before. Still, significant disease modifying therapies do not yet exist for most patients. Therefore, organ-based management strategies are employed and research has been directed within this paradigm focusing on either the most debilitating symptoms, such as Raynaud's phenomenon, digital ulcers and cutaneous sclerosis, or life-threatening organ involvement such as interstitial lung disease and pulmonary arterial hypertension. The current trends in systemic sclerosis diagnosis, evidence-based treatment recommendations and potential future directions in systemic sclerosis treatment are discussed.

Multiple Sclerosis

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Multiple sclerosis (MS) is a nervous system disease that affects your brain and spinal cord. It damages the myelin sheath, the material that surrounds and protects your nerve cells. This damage slows down ...

Targeted assessment of lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis.

Science.gov (United States)

Devine, Matthew S; Ballard, Emma; O'Rourke, Peter; Kiernan, Matthew C; Mccombe, Pamela A; Henderson, Robert D

2016-01-01

Estimating survival in amyotrophic lateral sclerosis (ALS) is challenging due to heterogeneity in clinical features of disease and a lack of suitable markers that predict survival. Our aim was to determine whether scoring of upper or lower motor neuron weakness is associated with survival. With this objective, 161 ALS subjects were recruited from two tertiary referral centres. Scoring of upper (UMN) and lower motor neuron (LMN) signs was performed, in addition to a brief questionnaire. Subjects were then followed until the censorship date. Univariate analysis was performed to identify variables associated with survival to either non-invasive ventilation (NIV) or death, which were then further characterized using Cox regression. Results showed that factors associated with reduced survival included older age, bulbar and respiratory involvement and shorter diagnostic delay (all p NIV or death (p ≤0.001) whereas UMN scores were poorly associated with survival. In conclusion, our results suggest that, early in disease assessment and in the context of other factors (age, bulbar, respiratory status), the burden of LMN weakness provides an accurate estimate of outcome. Such a scoring system could predict prognosis, and thereby aid in selection of patients for clinical trials.

Primary progressive multiple sclerosis in the Polish population

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Waldemar Brola

2017-03-01

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

Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients

KAUST Repository

James, Tojo; Lindé n, Magdalena; Morikawa, Hiromasa; Fernandes, Sunjay Jude; Ruhrmann, Sabrina; Huss, Mikael; Brandi, Maya; Piehl, Fredrik; Jagodic, Maja; Tegner, Jesper; Khademi, Mohsen; Olsson, Tomas; Gomez-Cabrero, David; Kockum, Ingrid

2018-01-01

Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as Multiple Sclerosis (MS

Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder.

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Vladimir Vacic

Full Text Available The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs and regions (IDRs in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study

ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43

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Stoica, Radu; de Vos, Kurt J.; Paillusson, Sébastien; Mueller, Sarah; Sancho, Rosa M.; Lau, Kwok-Fai; Vizcay-Barrena, Gema; Lin, Wen-Lang; Xu, Ya-Fei; Lewis, Jada; Dickson, Dennis W.; Petrucelli, Leonard; Mitchell, Jacqueline C.; Shaw, Christopher E.; Miller, Christopher C. J.

2014-06-01

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

Selective Activation of mTORC1 Signaling Recapitulates Microcephaly, Tuberous Sclerosis, and Neurodegenerative Diseases

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Hidetoshi Kassai

2014-06-01

Full Text Available Mammalian target of rapamycin (mTOR has been implicated in human neurological diseases such as tuberous sclerosis complex (TSC, neurodegeneration, and autism. However, little is known about when and how mTOR is involved in the pathogenesis of these diseases, due to a lack of animal models that directly increase mTOR activity. Here, we generated transgenic mice expressing a gain-of-function mutant of mTOR in the forebrain in a temporally controlled manner. Selective activation of mTORC1 in embryonic stages induced cortical atrophy caused by prominent apoptosis of neuronal progenitors, associated with upregulation of HIF-1α. In striking contrast, activation of the mTORC1 pathway in adulthood resulted in cortical hypertrophy with fatal epileptic seizures, recapitulating human TSC. Activated mTORC1 in the adult cortex also promoted rapid accumulation of cytoplasmic inclusions and activation of microglial cells, indicative of progressive neurodegeneration. Our findings demonstrate that mTORC1 plays different roles in developmental and adult stages and contributes to human neurological diseases.

Clinical pattern of systemic sclerosis in Central Ukraine. Association between clinical manifestations of systemic sclerosis and hypertension.

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Semenov, Viktor; Kuryata, Olexandr; Lysunets, Tatiana

2018-01-01

Systemic sclerosis (SSc) is a rare disease of connective tissue, manifestations of which may vary in different geographical areas. We aimed to describe the clinical portrait of patients with SSc in Dnipropetrovsk region and to investigate how initial clinical and laboratory characteristics are connected with the presence of hypertension in SSc onset. Patients were enrolled to this study from the registry of SSc patients, established in the Rheumatology Department, Mechnikov Dnipropetrovsk Regional Clinic, Dnipro. This registry contains histories of new cases of SSc from 1993 to 2014. Patients are followed-up and receive treatment according to EULAR and local standards. Diagnosis of SSc was based on ACR and EULAR Criteria for systemic Sclerosis. Two patients developed scleroderma renal crisis during follow-up. This report is a cross-sectional study. We analysed only data of the first visit to a rheumatologist. In total 148 patients (median age [IQR] - 47 [40; 52] years) fulfilled the inclusion criteria. Male/female ratio was 1 : 20.1. The most frequent clinical signs were Raynaud's phenomenon and arthritis. The prevalence of skin lesion in dcSSc patients was twice as high as in lcSSc patients. Pulmonary fibrosis occurred significantly more commonly in dcSSc patients. Hypertension occurred in 26-33% in both groups. Patients with hypertension at the SSc onset were seven years older than normotensive patients. More hypertensive patients were classified as lcSSc. Mean GFR was dramatically lower in hypertensive patients. The most common clinical form in our study was diffuse cutaneous subset of SSc. Hypertension in patients with SSc may be associated with local cutaneous subset of SSc and renal impairment. The strongest predictors of clinical form of SSc are signs of fibrosis (skin lesion and pulmonary fibrosis) and inflammation (arthritis and elevated CRP).

Serum uric acid concentrations are directly associated with the presence of benign multiple sclerosis.

Science.gov (United States)

Simental-Mendía, Esteban; Simental-Mendía, Luis E; Guerrero-Romero, Fernando

2017-09-01

It has been reported that patients with multiple sclerosis (MS) exhibit lower serum uric acid levels; however, the association between uric acid concentrations and benign MS (BMS) has not been assessed. Hence, the objective of the present study was to determine whether the serum concentrations of uric acid are associated with the presence of BMS. Men and non-pregnant women over 16 years of age with diagnosis of MS were enrolled in a cross-sectional study. Expanded Disability Status Scale score acid were exclusion criteria. According to subtype of disease, the eligible patients were allocated into groups with BMS and other varieties of MS. A logistic regression analysis was conducted in order to evaluate the association between serum concentrations of uric acid and BMS. A total of 106 patients were included, 39 in the group with BMS and 67 in the group with other varieties of MS. The logistic regression analysis adjusted by age, sex, and disease duration showed that increased concentrations of uric acid, indeed within the physiological levels, are significantly associated with the presence of BMS (OR = 2.60; 95% CI: 1.55-4.38, p uric acid, indeed within the physiological range, are likely linked to the presence of BMS.

Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

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Lucy Matthews

Full Text Available Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.

Dual Functional Small Molecule Probes as Fluorophore and Ligand for Misfolding Proteins

OpenAIRE

Zhang, Xueli; Ran, Chongzhao

2013-01-01

Misfolding of a protein is a destructive process for variety of diseases that include neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington disease, mad cow disease, amyotrophic lateral sclerosis (ALS), and frontal temporal dementia (FTD), and other non-CNS diseases such as diabetes, cystic fibrosis, and lysosomal storage diseases. Formation of various misfunctional large assembles of the misfolded protein is the primary consequence. To detect the formation of ...

Cannabinoids in the management of spasticity associated with multiple sclerosis

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Anna Maria Malfitano

2008-08-01

Full Text Available Anna Maria Malfitano, Maria Chiara Proto, Maurizio BifulcoDipartimento di Scienze Farmaceutiche, Università degli Studi di SalernoAbstract: The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS. In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.Keywords: cannabinoids, multiple sclerosis, spasticity

Tocilizumab for refractory organising pneumonia associated with Sjögren's disease.

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Justet, Aurelien; Ottaviani, Sebastien; Dieudé, Philippe; Taillé, Camille

2015-05-14

Lung involvement in primary Sjögren syndrome occurs in approximately 10-20% of patients. Tocilizumab, an anti-interleukin-6 receptor antibody, has demonstrated efficacy and safety in small series of systemic sclerosis, and systemic lupus erythematosus, but its effect on interstitial lung manifestations of connective tissue diseases is not well known. We report the use of tocilizumab in a refractory organising pneumonia associated with Sjögren's disease. Our observation suggests that tocilizumab could be an alternative therapeutic in refractory organising pneumonia. 2015 BMJ Publishing Group Ltd.

Exploration of machine learning techniques in predicting multiple sclerosis disease course

OpenAIRE

Zhao, Yijun; Healy, Brian C.; Rotstein, Dalia; Guttmann, Charles R. G.; Bakshi, Rohit; Weiner, Howard L.; Brodley, Carla E.; Chitnis, Tanuja

2017-01-01

Objective To explore the value of machine learning methods for predicting multiple sclerosis disease course. Methods 1693 CLIMB study patients were classified as increased EDSS?1.5 (worsening) or not (non-worsening) at up to five years after baseline visit. Support vector machines (SVM) were used to build the classifier, and compared to logistic regression (LR) using demographic, clinical and MRI data obtained at years one and two to predict EDSS at five years follow-up. Results Baseline data...

Role of T cell – glial cell interactions in creating and amplifying Central Nervous System inflammation and Multiple Sclerosis disease symptoms

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Eric S. Huseby

2015-08-01

Full Text Available Multiple Sclerosis (MS is an inflammatory disease of the Central Nervous System (CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought of as a T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified gray matter lesions in MS patients, suggesting that CNS antigens other than myelin proteins may be involved during the MS disease process. We have recently found that T cells targeting astrocyte-specific antigens can drive unique aspects of inflammatory CNS autoimmunity, including the targeting of gray matter and white matter of the brain and inducing heterogeneous clinical disease courses. In addition to being a target of T cells, astrocytes play a critical role in propagating the inflammatory response within the CNS through cytokine induced NF-ΚB signaling. Here, we will discuss the pathophysiology of CNS inflammation mediated by T cell – glial cell interactions and its contributions to CNS autoimmunity.

International Differences in Multiple Sclerosis Health Outcomes and Associated Factors in a Cross-sectional Survey

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Grace D. Reilly

2017-05-01

Full Text Available Multiple sclerosis (MS is a major cause of disability and poor quality of life (QOL. Previous studies have shown differences in MS health outcomes between countries. This study aimed to examine the associations between international regions and health outcomes in people with MS. Self-reported data were taken from the Health Outcomes and Lifestyle In a Sample of people with Multiple Sclerosis online survey collected in 2012. The 2,401 participants from 37 countries were categorized into three regions: Australasia, Europe, and North America. Differences were observed between regions in disability, physical and mental health QOL, fatigue, and depression, but most of these disappeared after adjusting for sociodemographic, disease, and lifestyle factors in multivariable regression models. However, adjusted odds for disability were higher in Europe [odds ratio (OR: 2.17, 95% confidence interval (CI: 1.28 to 3.67] and North America (OR: 1.79, 95% CI: 1.28 to 2.51 compared to Australasia. There may be other unmeasured factors that vary between regions, including differences in access and quality of healthcare services, determining disability in MS. When assessing differences in MS health outcomes, lifestyle factors and medication use should be taken into consideration.

The Impact of Five VDR Polymorphisms on Multiple Sclerosis Risk and Progression: a Case-Control and Genotype-Phenotype Study.

Science.gov (United States)

Křenek, Pavel; Benešová, Yvonne; Bienertová-Vašků, Julie; Vašků, Anna

2018-04-01

Vitamin D receptor polymorphisms have been the target of many studies focusing on multiple sclerosis. However, previously reported results have been inconclusive. The objective of this study was to investigate the association between five vitamin D receptor polymorphisms (EcoRV, FokI, ApaI, TaqI, and BsmI) and multiple sclerosis susceptibility and its course. The study was carried out as a case-control and genotype-phenotype study, consisted of 296 Czech multiple sclerosis patients and 135 healthy controls. Genotyping was carried out using polymerase chain reaction and restriction analysis. In multiple sclerosis men, allele and/or genotype distributions differed in EcoRV, TaqI, BsmI, and ApaI polymorphisms as compared to controls (EcoRV, p a = 0.02; Taq, p g = 0.02, p a = 0.02; BsmI, p g = 0.02, p a = 0.04; ApaI, p g = 0.008, p a = 0.005). In multiple sclerosis women, differences in the frequency of alleles and genotypes were found to be significant in ApaI (controls vs multiple sclerosis women: p g = 0.01, p a = 0.05). Conclusive results were observed between multiple sclerosis women in the case of EcoRV [differences in Expanded Disability Status Scale (p = 0.05); CT genotype was found to increase the risk of primary progressive multiple sclerosis 5.5 times (CT vs CC+TT p corr = 0.01, sensitivity 0.833, specificity 0.525, power test 0.823)] and FokI [borderline difference in Multiple Sclerosis Severity Score (p = 0.05)]. Our results indicate that the distribution of investigated vitamin D receptor polymorphisms is a risk factor for multiple sclerosis susceptibility and progression in the Czech population. The association between disease risk and polymorphisms was found to be stronger in men. The association of disease progression with polymorphisms was observed only in women.

Utilization of dimethyl fumarate and related molecules for treatment of multiple sclerosis, cancer, and other diseases

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Azzam Maghazachi

2016-07-01

Full Text Available Several drugs have been approved for treatment of multiple sclerosis. Dimethyl fumarate (DMF is utilized as an oral drug to treat this disease and is proven to be potent with less side effects than several other drugs. On the other hand, monomethyl fumarate (MMF, a related compound has not been examined in greater details although it has the potential as a therapeutic drug for multiple sclerosis and other diseases. The mechanism of action of DMF or MMF is related to their ability to enhance the antioxidant pathways and to inhibit reactive oxygen species. However, other mechanisms have also been described which include effects on monocytes, dendritic cells, T cells, and natural killer cells. It is also reported that DMF might be useful for treating psoriasis, asthma, aggressive breast cancers, hematopoeitic tumors, inflammatory bowel disease, intracerebral hemorrhage, osteoarthritis, chronic pancreatitis, and retinal ischemia. In this article we will touch on some of these diseases with an emphasis on the effects of DMF and MMF on various immune cells.

Brain-derived neurotrophic factor levels under chronic natalizumab treatment in multiple sclerosis. A preliminary report.

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Văcăraş, Vitalie; Major, Zoltán Zsigmond; Buzoianu, Anca Dana

Our main purpose was to investigate if the chronic treatment with the disease-modifying drug natalizumab shows quantifiable effect on BDNF levels in multiple sclerosis patients. BDNF plasma concentration was evaluated using enzyme-linked immunosorbent assay in healthy individuals, not treated multiple sclerosis patients and patients treated with natalizumab. Multiple sclerosis patients have a significantly lower amount of peripheral BDNF than healthy individuals. Patients treated with natalizumab have significantly higher BDNF levels than not treated patients. Chronic natalizumab treatment is associated with significantly increased plasma BDNF concentration in multiple sclerosis. Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Plasma proteins predict conversion to dementia from prodromal disease.

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Hye, Abdul; Riddoch-Contreras, Joanna; Baird, Alison L; Ashton, Nicholas J; Bazenet, Chantal; Leung, Rufina; Westman, Eric; Simmons, Andrew; Dobson, Richard; Sattlecker, Martina; Lupton, Michelle; Lunnon, Katie; Keohane, Aoife; Ward, Malcolm; Pike, Ian; Zucht, Hans Dieter; Pepin, Danielle; Zheng, Wei; Tunnicliffe, Alan; Richardson, Jill; Gauthier, Serge; Soininen, Hilkka; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon

2014-11-01

The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia. Three multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays. Sixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%). We have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Potential importance of B cells in aging and aging-associated neurodegenerative diseases.

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Biragyn, Arya; Aliseychik, Maria; Rogaev, Evgeny

2017-04-01

Our understanding of B cells as merely antibody producers is slowly changing. Alone or in concert with antibody, they control outcomes of seemingly different diseases such as cancer, rheumatoid arthritis, diabetes, and multiple sclerosis. While their role in activation of effector immune cells is beneficial in cancer but bad in autoimmune diseases, their immunosuppressive and regulatory subsets (Bregs) inhibit autoimmune and anticancer responses. These pathogenic and suppressive functions are not static and appear to be regulated by the nature and strength of inflammation. Although aging increases inflammation and changes the composition and function of B cells, surprisingly, little is known whether the change affects aging-associated neurodegenerative disease, such as Alzheimer's disease (AD). Here, by analyzing B cells in cancer and autoimmune and neuroinflammatory diseases, we elucidate their potential importance in AD and other aging-associated neuroinflammatory diseases.

Association of Periodontal Diseases with Elevation of Serum C-reactive Protein and Body Mass Index.

Science.gov (United States)

Chitsazi, Mohammad Taghi; Pourabbas, Reza; Shirmohammadi, Adileh; Ahmadi Zenouz, Gazaleh; Vatankhah, Amir Hossein

2008-01-01

C-reactive protein (CRP) is a well-known acute-phase reactant produced by the liver in response to inflammation caused by various stimuli. Periodontal disease is a chronic infection of tooth-supporting structures characterized by attachment loss and alveolar bone loss. The aim of this study was to assess the relationship between serum C-reactive protein levels and periodontal diseases. The study was conducted on 166 patients referring to Tabriz Faculty of Dentistry. The age range was between 35 and 59 years. 83 subjects with periodontitis according to NHANES III index as test group and 83 healthy individuals as controls participated in this study. Body mass index (BMI), waist circumference (WC), probing depth, attachment loss and CRP levels were measured in both test and control groups. Data was analyzed with Student's t-test, odds ratio (OR), Chi-square test and Spearman's correlation coefficient, using SPSS 13.0 software. The results revealed a statistically significant difference between all of the analyzed variables in test and control groups (P periodontitis and attachment loss (r = 0.662, P = 0.00). Excluding overweight, the association between all the variables was statistically significant (P periodontal disease is correlated with CRP elevation and dis-eases associated with obesity.

Lack of association between the APEX1 Asp148Glu polymorphism and sporadic amyotrophic lateral sclerosis.

Science.gov (United States)

Coppedè, Fabio; Lo Gerfo, Annalisa; Carlesi, Cecilia; Piazza, Selina; Mancuso, Michelangelo; Pasquali, Livia; Murri, Luigi; Migliore, Lucia; Siciliano, Gabriele

2010-02-01

Impairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1 Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression. We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the Italian population.

Mitochondrial Fusion Proteins and Human Diseases

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Michela Ranieri

2013-01-01

Full Text Available Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1 and 2 (MFN2, located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1, in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

A human phenome-interactome network of protein complexes implicated in genetic disorders

DEFF Research Database (Denmark)

Hansen, Kasper Lage; Karlberg, Erik, Olof, Linnart; Størling, Zenia, Marian

2007-01-01

the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type...

Distribution of Arsenic, Manganese, and Selenium in the Human Brain in Chronic Renal Insufficiency, Parkinsons Disease and Amyotrophic Lateral Sclerosis

DEFF Research Database (Denmark)

Larsen, N. A.; Pakkenberg, H.; Damsgaard, Else

1981-01-01

The concentrations of arsenic, manganese and selenium/g wet tissue weight were determined in samples from 24 areas of the human brain from 3 patients with chronic renal insufficiency, 2 with Parkinson's disease and 1 with amyotrophic lateral sclerosis. The concentrations of the 3 elements were...... determined for each sample by neutron activation analysis with radiochemical separation. Overall arsenic concentrations were about 2.5 times higher in patients with chronic renal failure than in controls, and lower than normal in the patients with Parkinson's disease and amyotrophic lateral sclerosis...

The Danish Multiple Sclerosis Treatment Register

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Magyari M

2016-10-01

Full Text Available Melinda Magyari,1,3 Nils Koch-Henriksen,1,2 Per Soelberg Sørensen3 1Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen, 2Department of Clinical Epidemiology, Clinical Institute, University of Aarhus, Aarhus, 3Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Aim of the database: The Danish Multiple Sclerosis Treatment Register (DMSTR serves as a clinical quality register, enabling the health authorities to monitor the quality of the disease-modifying treatment, and it is an important data source for epidemiological research. Study population: The DMSTR includes all patients with multiple sclerosis who had been treated with disease-modifying drugs since 1996. At present, more than 8,400 patients have been registered in this database. Data are continuously entered online into a central database from all sites in Denmark at start and at regular visits. Main variables: Include age, sex, onset year and year of the diagnosis, basic clinical information, and information about treatment, side effects, and relapses. Descriptive data: Notification is done at treatment start, and thereafter at every scheduled clinical visit 3 months after treatment start, and thereafter every 6 months. The longitudinally collected information about the disease activity and side effects made it possible to investigate the clinical efficacy and adverse events of different disease-modifying therapies. Conclusion: The database contributed to a certain harmonization of treatment procedures in Denmark and will continue to be a major factor in terms of quality in clinical praxis, research and monitoring of adverse events, and plays an important role in research. Keywords: multiple sclerosis, epidemiology, immunomodulatory treatment, neutralizing antibodies, observational studies, registry research, disease modifying therapy

Neuroinflammation and common mechanism in Alzheimer's disease and prion amyloidosis: amyloid-associated proteins, neuroinflammation and neurofibrillary degeneration

NARCIS (Netherlands)

Rozemuller, A.J.M.; Jansen, C.; Carrano, A.; van Haastert, E.S.; Hondius, D.; van der Vies, S.M.; Hoozemans, J.J.M.

2012-01-01

Background: In cases with a long (>1 year) clinical duration of prion disease, the prion protein can form amyloid deposits. These cases do not show accumulation of 4-kDa β-amyloid, which is observed in amyloid deposits in Alzheimer's disease (AD). In AD, amyloid is associated with inflammation and

Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

NARCIS (Netherlands)

López-Isac, Elena; Martín, Jose Ezequiel; Assassi, Shervin; Simeón, Carmen P.; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltrán, Emma; Narváez, Javier; Alegre-Sancho, Juan J.; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Ortiz, Ana M.; González-Gay, Miguel A.; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Witte, Torsten; Hunzelmann, Nicolas; Distler, Jörg H W; Riekemasten, Gabriella; van der Helm-van Mil, Annette H.; de Vries-Bouwstra, Jeska; Magro-Checa, Cesar; Voskuyl, Alexandre E.; Vonk, Madelon C.; Molberg, Øyvind; Merriman, Tony; Hesselstrand, Roger; Nordin, Annika; Padyukov, Leonid; Herrick, Ariane; Eyre, Steve; Koeleman, Bobby P C; Denton, Christopher P.; Fonseca, Carmen; Radstake, Timothy R D J; Worthington, Jane; Mayes, Maureen D.; Martín, Javier; Ríos, Raquel; Callejas, Jose Luis; Hitos, José Antonio Vargas; Portales, Rosa García; Camps, María Teresa; Fernández-Nebro, Antonio; González-Escribano, María F.; García-Hernández, Francisco José; Castillo, Ma Jesús; Ángeles Aguirre, Ma; Gómez-Gracia, Inmaculada; Rodríguez-Rodríguez, Luis; Peña, Paloma García de la; Vicente, Esther; Andreu, José Luis; de Castro, Mónica Fernández; López-Longo, Francisco Javier; Martínez, Lina; Fonollosa, Vicente; Guillén, Alfredo; Castellví, Iván; Espinosa, Gerard; Tolosa, Carlos; Pros, Anna; Carballeira, Mónica Rodríguez; Narváez, Francisco Javier; Rivas, Manel Rubio; Ortiz-Santamaría, Vera; Madroñero, Ana Belén; Díaz, Bernardino; Trapiella, Luis; Sousa, Adrián; Egurbide, María Victoria; Mateo, Patricia Fanlo; Sáez-Comet, Luis; Díaz, Federico; Hernández, Vanesa; Beltrán, Emma; Román-Ivorra, José Andrés; Grau, Elena; Alegre-Sancho, Juan José; Blanco García, Francisco J.; Oreiro, Natividad

2016-01-01

Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new

Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer's disease: Identification as the microtubule-associated protein tau

International Nuclear Information System (INIS)

Goedert, M.; Wischik, C.M.; Crowther, R.A.; Walker, J.E.; Klug, A.

1988-01-01

Screening of cDNA libraries prepared from the frontal cortex of an Alzheimer's disease patient and from fetal human brain has led to isolation of the cDNA for a core protein of the paired helical filament of Alzheimer's disease. The partial amino acid sequence of this core protein was used to design synthetic oligonucleotide probes. The cDNA encodes a protein of 352 amino acids that contains a characteristic amino acid repeat in its carboxyl-terminal half. This protein is highly homologous to the sequence of the mouse microtubule-associated protein tau and thus constitutes the human equivalent of mouse tau. RNA blot analysis indicates the presence of two major transcripts, 6 and 2 kilobases long, with a wide distribution in normal human brain. Tau protein mRNAs were found in normal amounts in the frontal cortex from patients with Alzheimer's disease. The proof that at least part of tau protein forms a component of the paired helical filament core opens the way to understanding the mode of formation of paired helical filaments and thus, ultimately, the pathogenesis of Alzheimer's disease

Safety and Efficacy of Fingolimod in Treatment-Naïve Multiple Sclerosis Patients

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James J. Marriott

2011-01-01

Full Text Available Fingolimod was recently approved for use in the United States after two phase III trials confirmed its effectiveness in reducing disease activity in relapsing-remitting multiple sclerosis. These positive results, coupled with the important fact that this is the first oral disease-modifying therapy, has lead to considerable enthusiasm amongst physicians and patients. However, fingolimod is associated with rare but serious adverse events. In addition, unlike conventional disease-modifying therapies, cardiopulmonary, ophthalmological and dermatological safety monitoring unfamiliar to both neurologists and patients is required before and during treatment. This paper will discuss these issues from the perspective of using fingolimod as a first-line disease-modifying therapy in treatment-Naïve relapsing-remitting multiple sclerosis patients

Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems.

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Mireia Herrando-Grabulosa

Full Text Available Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology, we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis.

Chemokine receptor CCR5 in interferon-treated multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, F; Kristiansen, Thomas Birk; Wittenhagen, P

2007-01-01

OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were...

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

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Rosalia D'Angelo

2011-01-01

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

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

NARCIS (Netherlands)

Jongen, Peter Joseph

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

Src family kinases in chronic kidney disease.

Science.gov (United States)

Wang, Jun; Zhuang, Shougang

2017-09-01

Src family kinases (SFKs) belong to nonreceptor protein tyrosine kinases and have been implicated in the regulation of numerous cellular processes, including cell proliferation, differentiation, migration and invasion, and angiogenesis. The role and mechanisms of SFKs in tumorgenesis have been extensively investigated, and some SFK inhibitors are currently under clinical trials for tumor treatment. Recent studies have also demonstrated the importance of SFKs in regulating the development of various fibrosis-related chronic diseases (e.g., idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, and systemic sclerosis). In this article, we summarize the roles of SFKs in various chronic kidney diseases, including glomerulonephritis, diabetic nephropathy, human immunodeficiency virus-associated nephropathy, autosomal dominant form of polycystic kidney disease, and obesity-associated kidney disease, and discuss the mechanisms involved. Copyright © 2017 the American Physiological Society.

Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis

Science.gov (United States)

Nakazawa, Seshiru; Oikawa, Daisuke; Ishii, Ryohei; Ayaki, Takashi; Takahashi, Hirotaka; Takeda, Hiroyuki; Ishitani, Ryuichiro; Kamei, Kiyoko; Takeyoshi, Izumi; Kawakami, Hideshi; Iwai, Kazuhiro; Hatada, Izuho; Sawasaki, Tatsuya; Ito, Hidefumi; Nureki, Osamu; Tokunaga, Fuminori

2016-01-01

Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS. PMID:27552911

Spinal cord: motor neuron diseases.

Science.gov (United States)

Rezania, Kourosh; Roos, Raymond P

2013-02-01

Spinal cord motor neuron diseases affect lower motor neurons in the ventral horn. This article focuses on the most common spinal cord motor neuron disease, amyotrophic lateral sclerosis, which also affects upper motor neurons. Also discussed are other motor neuron diseases that only affect the lower motor neurons. Despite the identification of several genes associated with familial amyotrophic lateral sclerosis, the pathogenesis of this complex disease remains elusive. Copyright © 2013 Elsevier Inc. All rights reserved.

Multiple Sclerosis Relapses: Epidemiology, Outcomes and Management. A Systematic Review.

Science.gov (United States)

Kalincik, Tomas

2015-01-01

Relapses (episodic exacerbations of neurological signs or symptoms) are a defining feature of relapsing-remitting multiple sclerosis (MS), the most prevalent MS phenotype. While their diagnostic value relates predominantly to the definition of clinically definite MS, their prognostic value is determined by their relatively high associated risk of incomplete remission resulting in residual disability. The mechanisms governing a relapse incidence are unknown, but numerous modifiers of relapse risk have been described, including demographic and clinical characteristics, many of which represent opportunities for improved disease management. Also relapse phenotypes have been associated with patient and disease characteristics and an individual predisposition to certain phenotypic presentations may imply individual neuroanatomical disease patterns. While immunomodulatory therapies and corticosteroids represent the mainstay of relapse prevention and acute management, respectively, their effect has only been partial and further search for more efficient relapse therapies is warranted. Other areas of research include pathophysiology and determinants of relapse incidence, recurrence and phenotypes, including the characteristics of the relapsing and non-relapsing multiple sclerosis variants and their responsiveness to therapies. © 2015 S. Karger AG, Basel.

Correlation between serum E-selectin levels and panoramic nailfold capillaroscopy in systemic sclerosis.

Science.gov (United States)

Valim, V; Assis, L S S; Simões, M F J; Trevisani, V F M; Pucinelli, M L C; Andrade, L E C

2004-09-01

E-selectin is expressed by the activated endothelium and its plasma levels are increased in patients with systemic sclerosis. Eighteen patients fulfilling the American Rheumatism Association criteria for systemic sclerosis, 15 females and 3 males, 42-70 years old, 9 with diffuse and 9 with limited forms, were sequentially recruited for this study. Serum E-selectin levels were determined by commercially available ELISA and their association with nailfold capillaroscopic abnormalities was investigated. Nailfold capillaries were analyzed by 16X magnification wide-field capillaroscopy. Two parameters on capillaroscopy were used to correlate to serum E-selectin: deletion and ectasia. Data were analyzed statistically by the Student t-test and Spearman correlation. Two-tailed P values below 0.05 were considered significant. E-selectin range was 38 to 200 ng/ml (80 +/- 39.94). There was a correlation between serum E-selectin levels and the deletion capillaroscopic score (r = 0.50, P capillaroscopy. The stronger correlation of deletion score in capillaroscopy in early disease suggests that serum E-selectin levels might be a useful biochemical marker of disease activity in systemic sclerosis.

Self-reported levels of education and disability progression in multiple sclerosis

NARCIS (Netherlands)

D'hooghe, M. B.; Haentjens, P.; Van Remoortel, A.; De Keyser, J.; Nagels, G.

2016-01-01

ObjectivesThe purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). Materials and methodsWe performed a

Cognitive Decline in Neuronal Aging and Alzheimer's Disease: Role of NMDA Receptors and Associated Proteins

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Jesús Avila

2017-11-01

Full Text Available Molecular changes associated with neuronal aging lead to a decrease in cognitive capacity. Here we discuss these alterations at the level of brain regions, brain cells, and brain membrane and cytoskeletal proteins with an special focus in NMDA molecular changes through aging and its effect in cognitive decline and Alzheimer disease. Here, we propose that some neurodegenerative disorders, like Alzheimer's disease (AD, are characterized by an increase and acceleration of some of these changes.

Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets.

Science.gov (United States)

Gross, Catharina C; Schulte-Mecklenbeck, Andreas; Hanning, Uta; Posevitz-Fejfár, Anita; Korsukewitz, Catharina; Schwab, Nicholas; Meuth, Sven G; Wiendl, Heinz; Klotz, Luisa

2017-06-01

Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS). To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of distinct circulating T-helper cell subset as well as their innate counterparts. Flow cytometric analysis of lymphocytes derived from the peripheral blood of patients with exclusively cerebral (n = 20) or predominantly spinal (n = 12) disease manifestation. Patients with exclusively cerebral or preferential spinal lesion manifestation were associated with increased proportions of circulating granulocyte-macrophage colony-stimulating factor (GM-CSF) producing T H 1 cells or interleukin (IL)-17-producing T H 17 cells, respectively. In contrast, proportions of peripheral IL-17/IL-22-producing lymphoid tissue inducer (LTi), the innate counterpart of T H 17 cells, were enhanced in RRMS patients with exclusively cerebral lesion topography. Distinct T-helper and T-helper-like innate lymphoid cell (ILC) subsets are associated with different lesion topography in RRMS.

Alemtuzumab in the treatment of multiple sclerosis: patient selection and special considerations

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Dörr J

2016-10-01

Full Text Available Jan Dörr,1,2 Karl Baum1 1Multiple Sclerosis Center, Neurology Department, Klinik Hennigsdorf, Hennigsdorf, 2NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Berlin, Germany Abstract: Multiple sclerosis (MS is among the most common chronic inflammatory diseases of the central nervous system. Although not curable, the constantly increasing armamentarium of disease-modifying drugs now allows control of disease activity in many patients. The humanized monoclonal antibody alemtuzumab is a powerful drug licensed for the treatment of MS. Upon binding to the CD52 surface protein on CD4+ and CD8+ T cells, B cells, and monocytes, circulating CD52+ cells are eliminated via antibody- and complement-mediated lysis, and a less autoreactive adaptive immune system is reconstituted. The efficacy of alemtuzumab in terms of both clinical and magnetic resonance imaging outcomes has been demonstrated in several phase II/III trials including long-term extensions and follow-up studies. Treatment response to alemtuzumab is strongest as long as active inflammation is the predominant pathophysiological feature, and it is becoming less efficacious in neurodegeneration-dominated later stages of the disease. Thus, the optimal placement of alemtuzumab within treatment algorithms of MS is crucial. The impressive efficacy of alemtuzumab is counteracted by a less favorable safety profile. Besides usually manageable infusion-associated side effects, development of secondary autoimmunity in almost half of treated patients is the most disconcerting risk of alemtuzumab. The high frequency, the delayed occurrence, and the potentially severe course of secondary autoimmune diseases require awareness and a close long-term monitoring of patients treated with alemtuzumab. Biomarkers that would allow prediction of treatment response to alemtuzumab on the one hand and identification of patients at risk for the development of secondary autoimmune diseases on

PHAKOMATOSIS : INTRESTING CASES OF TUBEROUS SCLEROSIS WITH RETINAL ASTROCYTOMA

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Srinivasa Rao

2015-05-01

Full Text Available NTRODUCTION: Tuberous sclerosis complex (TSC or Morbus Bourneville - Pringle disease is an autosomal dominant phakomatosis, first described by Desiree - Magloire Bourneville in 1880. Tuberous sclerosis is a genetic disorder characterized by the growth of numerous benign tumours in many parts of the body caused by mutations on either of two genes, TSC1 and TSC2. This rare genetic disorder is usually associated with a triad of seizures, mental retardation and cutaneous lesions. Approximately one half of all patients affected by TS develop at least one retinal astrocytoma in one eye. PRESENTATION OF CASES: In the department of ophthalmology, G.S.L M edical C ollege, Rajahmundry, we came across 3 cases of tuberous sclerosis involving multi organ systems. Out of 3 cases, 2 cases were reported to be familial and 1case is sporadic, with a history of epilepsy with angiofibromatosis lesions over the face, multiple ash - leaf lesions over the abdomen, renal angiomyolipomas, multiple subependymal nodules in brain and retinal astrocytic hamartomas in the retina. CONCLUSION: It is important to be cognizant of the likely presence of systemic and ocular pathology in a child with mental retardation and skin lesions. Identification of retinal phakomatosis during ocular evaluation in any suspected case of Tuberous sclerosis can aid in the establishment of the diagnosis of the disease

Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis

NARCIS (Netherlands)

D'hooghe, M. B.; Haentjens, P.; Nagels, G.; Garmyn, M.; De Keyser, J.

Background: Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS). Objective: We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS. Methods: We conducted a survey among persons with MS, registered by the Flemish MS

Devic's Disease (Neuromyelitis optical)

International Nuclear Information System (INIS)

Pinzon, Alfredo; Echeverry, Tatiana; Rodriguez, Aida Bibiana

2010-01-01

We present a case report about a young woman initially treated as having multiple sclerosis, who relapsed with serious visual impairment. Devic's disease is a demyelinating disorder that presents as transverse myelitis associated with optic neuritis, typically bilateral. Multiple sclerosis is in fact the main differential diagnosis

Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease

Science.gov (United States)

Smith, Charles D.; Abner, Erin L.; Wilfred, Bernard J.; Wang, Wang-Xia; Neltner, Janna H.; Baker, Michael; Fardo, David W.; Kryscio, Richard J.; Scheff, Stephen W.; Jicha, Gregory A.; Jellinger, Kurt A.; Van Eldik, Linda J.; Schmitt, Frederick A.

2013-01-01

Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5–30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available. PMID:23864344

Acute-phase proteins investigation based on lectins affinity capture prior to 2-DE separation: application to serum from multiple sclerosis patients.

Science.gov (United States)

Robotti, Andrea; Natale, Massimo; Albo, Alessandra Giuliano; Lis, Katarzyna; Perga, Simona; Marnetto, Fabiana; Gilli, Francesca; Bertolotto, Antonio

2010-09-01

Plasma acute-phase proteins (APPs) glyco-isoforms are important biomarkers of inflammatory processes such as those occurring in multiple sclerosis (MS). Specific analysis of these proteins is often hampered by sample biochemical complexity. The aim of our study was to set up a method to accurately visualize, identify and quantify APPs glyco-isoforms in human serum. An enrichment strategy based on affinity chromatography using the carbohydrate-binding proteins concanavalin A (ConA) and erythrina cristagalli lectin (ECL) was applied to pooled serum samples from 15 patients and 9 healthy individuals. Image analysis of 2-DE detected 30 spots with a fold change higher than 1.5. A total of 14 were statistically significant (p valuewell known. Performing galectin-3 binding and Western blotting, we were able to demonstrate a correlation between hybrid type glyco-isoforms of β-haptoglobin and MS. In conclusion, although the patho-physiological role of the identified species still remains unclear and further validations are needed, these findings may have a relevant impact on disease-specific marker identification approaches.

Monocyte chemoattractant protein-1 promoter -2518 polymorphism and susceptibility to vasculitis, rheumatoid arthritis, and multiple sclerosis: A meta-analysis.

Science.gov (United States)

Lee, Y H; Bae, S-C

2016-03-20

The purpose of this study was to examine whether the monocyte chemoattractant protein-1 (MCP-1) promoter -2518 A/G polymorphism (rs1024611) is associated with susceptibility to vasculitis, rheumatoid arthritis (RA), or multiple sclerosis (MS). A meta-analysis was conducted on the association between the MCP-1 -2518 A/G polymorphism and vasculitis, RA, and MS. Fourteen studies from 13 articles, including six on vasculitis, five on RA, and three on MS, consisting of 3,038 patients and 3,545 controls were available for the meta-analysis. The meta-analysis revealed no association between the MCP-1 -2518 G allele and vasculitis (odds ratio [OR] = 0.990, 95% confidence interval [CI] = 0.749-1.309, p = 0.943). Stratification by ethnicity indicated no association between the G allele of the MCP-1 -2518 A/G polymorphism and vasculitis in Asians and Caucasians. Meta-analysis by vasculitis type revealed an association between the GG+GA genotype of the MCP-1 -2518 A/G polymorphism and Behçet's disease (BD; OR = 1.349, 95% CI = 1.013-1.796, p = 0.040). However, sensitivity analysis showed that the association was not statistically significant after removing a study that was conducted in China (OR = 1.030, 95% CI = 0.667-1.590, p = 0.895), which indicated that the association was not statistically robust. The meta-analysis revealed no association between the MCP-1 -2518 G allele and RA (OR = 0.986, 95% CI = 0.890-1.093, p = 0.793) or MS (OR = 1.281, 95% CI = 0.802-2.046, p = 0.301). Our meta-analysis demonstrates that the MCP-1 -2518 A/G polymorphism is not associated with susceptibility to vasculitis, RA, or MS.

SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.

Science.gov (United States)

Orlacchio, Antonio; Babalini, Carla; Borreca, Antonella; Patrono, Clarice; Massa, Roberto; Basaran, Sarenur; Munhoz, Renato P; Rogaeva, Ekaterina A; St George-Hyslop, Peter H; Bernardi, Giorgio; Kawarai, Toshitaka

2010-02-01

The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite amyotrophic lateral sclerosis according to the revised El Escorial criteria. The exclusion criterion was a diagnosis of hereditary spastic paraplegia with thin corpus callosum in line with an established protocol. Additional pathological and genetic evaluations were also performed. Surprisingly, 12 sequence alterations in the spatacsin gene (one of which is novel, IVS30 + 1 G > A) were identified in 10 unrelated pedigrees with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival. The countries of origin of these families were Italy, Brazil, Canada, Japan and Turkey. The variants seemed to be pathogenic since they co-segregated with the disease in all pedigrees, were absent in controls and were associated with amyotrophic lateral sclerosis neuropathology in one member of one of these families for whom central nervous system tissue was available. Our study indicates that mutations in the spatascin gene could cause a much wider spectrum of clinical features than previously recognized, including autosomal recessive juvenile amyotrophic lateral sclerosis.

Protein-driven inference of miRNA-disease associations

DEFF Research Database (Denmark)

Mørk, Søren; Pletscher-Frankild, Sune; Palleja, Albert

2014-01-01

MicroRNAs (miRNAs) are a highly abundant class of non-coding RNA genes involved in cellular regulation and thus also diseases. Despite miRNAs being important disease factors, miRNA-disease associations remain low in number and of variable reliability. Furthermore, existing databases and prediction...

Multiple sclerosis research

International Nuclear Information System (INIS)

Battaglia, M.A.

1990-01-01

This volume proceedings contains four contributions which are in INIS scope, dealing with MRI and SPECT in the diagnosis of multiple sclerosis and assessment of disease activity. (H.W.). refs.; figs.; tabs

Exome localization of complex disease association signals

Directory of Open Access Journals (Sweden)

Lewis Cathryn M

2011-02-01

Full Text Available Abstract Background Genome-wide association studies (GWAS of common diseases have had a tremendous impact on genetic research over the last five years; the field is now moving from microarray-based technology towards next-generation sequencing. To evaluate the potential of association studies for complex diseases based on exome sequencing we analysed the distribution of association signal with respect to protein-coding genes based on GWAS data for seven diseases from the Wellcome Trust Case Control Consortium. Results We find significant concentration of association signal in exons and genes for Crohn's Disease, Type 1 Diabetes and Bipolar Disorder, but also observe enrichment from up to 40 kilobases upstream to 40 kilobases downstream of protein-coding genes for Crohn's Disease and Type 1 Diabetes; the exact extent of the distribution is disease dependent. Conclusions Our work suggests that exome sequencing may be a feasible approach to find genetic variation associated with complex disease. Extending the exome sequencing to include flanking regions therefore promises further improvement of covering disease-relevant variants.

SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts.

Science.gov (United States)

Bove, Riley; Chitnis, Tanuja; Cree, Bruce Ac; Tintoré, Mar; Naegelin, Yvonne; Uitdehaag, Bernard Mj; Kappos, Ludwig; Khoury, Samia J; Montalban, Xavier; Hauser, Stephen L; Weiner, Howard L

2017-08-01

There is a pressing need for robust longitudinal cohort studies in the modern treatment era of multiple sclerosis. Build a multiple sclerosis (MS) cohort repository to capture the variability of disability accumulation, as well as provide the depth of characterization (clinical, radiologic, genetic, biospecimens) required to adequately model and ultimately predict a patient's course. Serially Unified Multicenter Multiple Sclerosis Investigation (SUMMIT) is an international multi-center, prospectively enrolled cohort with over a decade of comprehensive follow-up on more than 1000 patients from two large North American academic MS Centers (Brigham and Women's Hospital (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB; BWH)) and University of California, San Francisco (Expression/genomics, Proteomics, Imaging, and Clinical (EPIC))). It is bringing online more than 2500 patients from additional international MS Centers (Basel (Universitätsspital Basel (UHB)), VU University Medical Center MS Center Amsterdam (MSCA), Multiple Sclerosis Center of Catalonia-Vall d'Hebron Hospital (Barcelona clinically isolated syndrome (CIS) cohort), and American University of Beirut Medical Center (AUBMC-Multiple Sclerosis Interdisciplinary Research (AMIR)). We provide evidence for harmonization of two of the initial cohorts in terms of the characterization of demographics, disease, and treatment-related variables; demonstrate several proof-of-principle analyses examining genetic and radiologic predictors of disease progression; and discuss the steps involved in expanding SUMMIT into a repository accessible to the broader scientific community.

Chromosomal radiosensitivity in patients with multiple sclerosis

International Nuclear Information System (INIS)

Milenkova, Maria; Milanov, Ivan; Kmetska, Ksenia; Deleva, Sofia; Popova, Ljubomira; Hadjidekova, Valeria; Groudeva, Violeta; Hadjidekova, Savina; Domínguez, Inmaculada

2013-01-01

Highlights: • We studied radiosensitivity to in vitro γ-irradiated lymphocytes from MS patients. • Immunotherapy in RRMS patients reduced the yield of radiation induced MN. • The group of treated RRMS accounts for the low radiosensitivity in MS patients. • Spontaneous yield of MN was similar in treated and untreated RRMS patients. - Abstract: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing–remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyze the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing–remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing–remitting multiple

Chromosomal radiosensitivity in patients with multiple sclerosis

Energy Technology Data Exchange (ETDEWEB)

Milenkova, Maria; Milanov, Ivan; Kmetska, Ksenia [III Neurological Clinic, University Hospital Saint Naum, Sofia (Bulgaria); Deleva, Sofia; Popova, Ljubomira; Hadjidekova, Valeria [Laboratory of Radiation Genetics, NCRRP, Sofia (Bulgaria); Groudeva, Violeta [Department of Diagnostic Imaging, University Hospital St. Ekaterina, Sofia (Bulgaria); Hadjidekova, Savina [Department of Medical Genetics, Medical University, Sofia (Bulgaria); Domínguez, Inmaculada, E-mail: idomin@us.es [Department of Cell Biology, Faculty of Biology, University of Seville, Avda. Reina Mercedes 6, 41012 (Spain)

2013-09-15

Highlights: • We studied radiosensitivity to in vitro γ-irradiated lymphocytes from MS patients. • Immunotherapy in RRMS patients reduced the yield of radiation induced MN. • The group of treated RRMS accounts for the low radiosensitivity in MS patients. • Spontaneous yield of MN was similar in treated and untreated RRMS patients. - Abstract: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing–remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyze the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing–remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing–remitting multiple

Influence of TYK2 in systemic sclerosis susceptibility : a new locus in the IL-12 pathway

NARCIS (Netherlands)

López-Isac, Elena; Campillo-Davo, Diana; Bossini-Castillo, Lara; Guerra, Sandra G; Assassi, Shervin; Simeón, Carmen Pilar; Carreira, Patricia; Ortego-Centeno, Norberto; García de la Peña, Paloma; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Riemekasten, Gabriela; Witte, Torsten; Hunzelmann, Nicolas; Kreuter, Alexander; Distler, Jörg Hw; Voskuyl, Alexandre E; de Vries-Bouwstra, Jeska; Herrick, Ariane; Worthington, Jane; Denton, Christopher P; Fonseca, Carmen; Radstake, Timothy Rdj; Mayes, Maureen D; Martín, Javier

OBJECTIVES: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus

Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms.

Science.gov (United States)

Martin, Lee J; Wong, Margaret

2013-10-01

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS

Associations of alcohol consumption with clinical and MRI measures in multiple sclerosis

NARCIS (Netherlands)

D'hooghe, Marie B.; De Keyser, Jacques

Evaluation of: Foster M, Zivadinov R, Weinstock-Guttman B et al. Associations of alcohol consumption with clinical and MRI measures in multiple sclerosis. J. Neuroimmunol. 243(1-2), 61-68 (2012). While the harmful effects of alcohol abuse are well documented, experimental and clinical data support a

Exploring the role of microglia in mood disorders associated with experimental multiple sclerosis

Directory of Open Access Journals (Sweden)

Antonietta eGentile

2015-06-01

Full Text Available Microglia is increasingly recognized to play a crucial role in the pathogenesis of psychiatric diseases. In particular, microglia may be the cellular link between inflammation and behavioural alterations: by releasing a number of soluble factors, among which pro-inflammatory cytokines, they can regulate synaptic activity, thereby leading to perturbation of behaviour.In multiple sclerosis (MS, the most common neuroinflammatory disorder affecting young adults, microglia activation and dysfunction may account for mood symptoms, like depression and anxiety, that are often diagnosed in patients even in the absence of motor disability. Behavioural studies in experimental autoimmune encephalomyelitis (EAE, the animal model of MS, have shown that emotional changes occur early in the disease and in correlation to inflammatory mediator and neurotransmitter level alterations. However, such studies lack a full and comprehensive analysis of the role played by microglia in EAE-behavioural syndrome. We review the experimental studies addressing behavioural symptoms in EAE, and propose the study of neuron-glia interaction as a powerful but still poorly explored tool to investigate the burden of microglia in mood alterations associated to MS.

Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference.

Science.gov (United States)

Krueger, Darcy A; Northrup, Hope

2013-10-01

Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices. The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly. The updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established. The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

The ubiquitin proteasome system in glia and its role in neurodegenerative diseases

NARCIS (Netherlands)

Jansen, Anne H. P.; Reits, Eric A. J.; Hol, Elly M.

2014-01-01

The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's,

Systemic sclerosis with normal or nonspecific nailfold capillaroscopy.

Science.gov (United States)

Fichel, Fanny; Baudot, Nathalie; Gaitz, Jean-Pierre; Trad, Salim; Barbe, Coralie; Francès, Camille; Senet, Patricia

2014-01-01

In systemic sclerosis (SSc), a specific nailfold videocapillaroscopy (NVC) pattern is observed in 90% of cases and seems to be associated with severity and progression of the disease. To describe the characteristics of SSc patients with normal or nonspecific (normal/nonspecific) NVC. In a retrospective cohort study, clinical features and visceral involvements of 25 SSc cases with normal/nonspecific NVC were compared to 63 SSc controls with the SSc-specific NVC pattern. Normal/nonspecific NVC versus SSc-specific NVC pattern was significantly associated with absence of skin sclerosis (32 vs. 6.3%, p = 0.004), absence of telangiectasia (47.8 vs. 17.3%, p = 0.006) and absence of sclerodactyly (60 vs. 25.4%, p = 0.002), and less frequent severe pulmonary involvement (26.3 vs. 58.2%, p = 0.017). Normal/nonspecific NVC in SSc patients appears to be associated with less severe skin involvement and less frequent severe pulmonary involvement. © 2014 S. Karger AG, Basel.

Multiple Sclerosis After Infectious Mononucleosis

DEFF Research Database (Denmark)

Nielsen, Trine Rasmussen; Rostgaard, Klaus; Nielsen, Nete Munk

2007-01-01

BACKGROUND: Infectious mononucleosis caused by the Epstein-Barr virus has been associated with increased risk of multiple sclerosis. However, little is known about the characteristics of this association. OBJECTIVE: To assess the significance of sex, age at and time since infectious mononucleosis......, and attained age to the risk of developing multiple sclerosis after infectious mononucleosis. DESIGN: Cohort study using persons tested serologically for infectious mononucleosis at Statens Serum Institut, the Danish Civil Registration System, the Danish National Hospital Discharge Register, and the Danish...... Multiple Sclerosis Registry. SETTING: Statens Serum Institut. PATIENTS: A cohort of 25 234 Danish patients with mononucleosis was followed up for the occurrence of multiple sclerosis beginning on April 1, 1968, or January 1 of the year after the diagnosis of mononucleosis or after a negative Paul...

Association of plasma protein C levels and coronary artery disease ...

African Journals Online (AJOL)

Several studies have shown the risk factor causes of coronary heart disease. In this study we tested the hypothesis that plasma protein C level might be used as a biomarker for coronary heart disease and myocardial infarction. The study included 60 men that were classified into 3 groups according to clinical examination; ...

[Current description of multiple sclerosis].

Science.gov (United States)

Río, Jordi; Montalbán, Xavier

2014-12-01

Multiple sclerosis is a multifocal demyelinating disease leading to progressive neurodegeneration caused by an autoimmune response in genetically predisposed individuals. In the last few years, the knowledge and management of this disease has been revolutionized by a series of findings. The present article reviews pathological features of the disease, in which cortical involvement is increasingly implicated, and aspects related to novel pathogenic mechanisms, such as the role of the microbiota in the genesis of multiple sclerosis, as well as recent contributions from the fields of epidemiology and genetics. Also reviewed are the latest diagnostic criteria, which currently allow a much earlier diagnosis, with clear therapeutic implications. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis.

Science.gov (United States)

Tibshirani, Michael; Zhao, Beibei; Gentil, Benoit J; Minotti, Sandra; Marques, Christine; Keith, Julia; Rogaeva, Ekaterina; Zinman, Lorne; Rouaux, Caroline; Robertson, Janice; Durham, Heather D

2017-11-01

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS. © The Author 2017. Published by Oxford University Press. All rights reserved

131I albumin of patients carrying progressive systemic sclerosis study

International Nuclear Information System (INIS)

Cossermelli, W.; Carvalho, N.; Papaleo Netto, M.

1974-01-01

131 I albumin metabolic changes were studied in 14 female patients with progressive systemic sclerosis. A statistical study of the gathered data disclosed increased distribution and turnover half-life and diminished turnover rate of radioactive substance. Since T/2 of turnover and turnover rate are the result produced by the albumin synthesis and degradation, they are probably lowered during active disease causing hypoalbuminemia. The aminoacids also are probably absorbed by other protein like the gammaglobuline synthesis [pt

Systemic sclerosis in a patient with pityriasis rubra pilaris | Frikha ...

African Journals Online (AJOL)

Pityriasis rubra pilaris (PRP) is a rare, chronic erythematous squamous disorder of unknown etiology. It has been found in association with several autoimmune diseases, including thyroiditis, myositis, myasthenia gravis and vitiligo. Herein we report a case of systemic sclerosis in a patient with classic adult pityriasis rubra ...

Gait Characteristics in Adolescents With Multiple Sclerosis.

Science.gov (United States)

Kalron, Alon; Frid, Lior; Menascu, Shay

2017-03-01

Multiple sclerosis is a progressive autoimmune disease of the central nervous system. A presentation of multiple sclerosis before age18 years has traditionally been thought to be rare. However, during the past decade, more cases have been reported. We examined gait characteristics in 24 adolescents with multiple sclerosis (12 girls, 12 boys). Mean disease duration was 20.4 (S.D. = 24.9) months and mean age was 15.5 (S.D. = 1.1) years. The mean expanded disability status scale score was 1.7 (S.D. = 0.7) indicating minimal disability. Outcomes were compared with gait and the gait variability index value of healthy age-matched adolescents. Adolescents with multiple sclerosis walked slower with a wider base of support compared with age-matched healthy control subjects. Moreover, the gait variability index was lower in the multiple sclerosis group compared with the values in the healthy adolescents: 85.4 (S.D. = 8.1) versus 96.5 (S.D. = 7.4). We present gait parameters of adolescents with multiple sclerosis. From a clinical standpoint, our data could improve management of walking dysfunction in this relatively young population. Copyright © 2016 Elsevier Inc. All rights reserved.

Semantics based approach for analyzing disease-target associations.

Science.gov (United States)

Kaalia, Rama; Ghosh, Indira

2016-08-01

A complex disease is caused by heterogeneous biological interactions between genes and their products along with the influence of environmental factors. There have been many attempts for understanding the cause of these diseases using experimental, statistical and computational methods. In the present work the objective is to address the challenge of representation and integration of information from heterogeneous biomedical aspects of a complex disease using semantics based approach. Semantic web technology is used to design Disease Association Ontology (DAO-db) for representation and integration of disease associated information with diabetes as the case study. The functional associations of disease genes are integrated using RDF graphs of DAO-db. Three semantic web based scoring algorithms (PageRank, HITS (Hyperlink Induced Topic Search) and HITS with semantic weights) are used to score the gene nodes on the basis of their functional interactions in the graph. Disease Association Ontology for Diabetes (DAO-db) provides a standard ontology-driven platform for describing genes, proteins, pathways involved in diabetes and for integrating functional associations from various interaction levels (gene-disease, gene-pathway, gene-function, gene-cellular component and protein-protein interactions). An automatic instance loader module is also developed in present work that helps in adding instances to DAO-db on a large scale. Our ontology provides a framework for querying and analyzing the disease associated information in the form of RDF graphs. The above developed methodology is used to predict novel potential targets involved in diabetes disease from the long list of loose (statistically associated) gene-disease associations. Copyright © 2016 Elsevier Inc. All rights reserved.

Mutations of Profilin-1 Associated with Amyotrophic Lateral Sclerosis Promote Aggregation Due to Structural Changes of Its Native State.

Science.gov (United States)

Del Poggetto, Edoardo; Bemporad, Francesco; Tatini, Francesca; Chiti, Fabrizio

2015-11-20

The PFN1 gene, coding for profilin-1, has recently been associated with familial amyotrophic lateral sclerosis (fALS), as three mutations, namely C71G, M114T, and G118V, have been found in patients with familial forms of the disease and another, E117G, has been proposed to be a moderate risk factor for disease onset. In this work, we have purified the four profilin-1 variants along with the wild-type protein. The resulting aggregates appear to be fibrillar, to have a weak binding to ThT, and to possess a significant amount of intermolecular β-sheet structure. Using ThT fluorescence assays, far-UV circular dichroism, and dynamic light scattering, we found that all four variants have an aggregation propensity higher than that of the wild-type counterpart. In particular, the C71G mutation was found to induce the most dramatic change in aggregation, followed by the G118V and M114T substitutions and then the E117G mutation. Such a propensity was found not to strictly correlate with the conformational stability in this group of profilin-1 variants, determined using both urea-induced denaturation at equilibrium and folding/unfolding kinetics. However, it correlated with structural changes of the folded states, as monitored with far-UV circular dichroism, intrinsic fluorescence spectroscopy, ANS binding, acrylamide quenching, and dynamic light scattering. Overall, the results suggest that all four mutations increase the tendency of profilin-1 to aggregate and that such aggregation behavior is largely determined by the mutation-induced structural changes occurring in the folded state of the protein.

Chemokine receptor CCR5 in interferon-treated multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, F; Kristiansen, T B; Wittenhagen, P

2007-01-01

To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta).......To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta)....

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Science.gov (United States)

Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-Scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-Guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; McCombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-Tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Luis Sanchez-Menoyo, Jose; Laura Saladino, Maria; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut

2017-09-01

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of

Gab Docking Proteins in Cardiovascular Disease, Cancer, and Inflammation

Directory of Open Access Journals (Sweden)

Yoshikazu Nakaoka