WorldWideScience

Sample records for human disease multiple

  1. Regulation of human glia by multiple sclerosis disease modifying therapies.

    Science.gov (United States)

    Healy, Luke M; Michell-Robinson, Mackenzie A; Antel, Jack P

    2015-11-01

    This review focuses on the effects of the agents currently approved (or in late clinical trials) as therapies for multiple sclerosis (MS) on the glial cell populations of the central nervous system (CNS). These are comprised of astrocytes, microglia, and oligodendrocytes (OLs), and their progenitors (OPCs). Although the efficacy of these agents is to date established only for the relapsing component of the disease and linked to effects on the systemic immune system, each has been examined with regard to effects on the CNS compartment. The impact of therapies on glia would include modulating these cells immune reactivity, which is considered to underlie the tissue injury process in MS and to any subsequent repair process. As reviewed, these agents can exert their effects either indirectly by modulating the constituents of the systemic immune system or directly depending on their capacity to traverse the blood brain barrier (BBB). Most available data has been derived from administration of these agents in animal models or application to glial cells in vitro. The challenge remains of translating these observations into effective means to impact on the progressive course of disease and reverse existent disabilities.

  2. 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 drug interaction studies.

  3. Multiple cystic lung disease

    Directory of Open Access Journals (Sweden)

    Flavia Angélica Ferreira Francisco

    2015-12-01

    Full Text Available Multiple cystic lung disease represents a diverse group of uncommon disorders that can present a diagnostic challenge due to the increasing number of diseases associated with this presentation. High-resolution computed tomography of the chest helps to define the morphological aspects and distribution of lung cysts, as well as associated findings. The combination of appearance upon imaging and clinical features, together with extrapulmonary manifestations, when present, permits confident and accurate diagnosis of the majority of these diseases without recourse to open-lung biopsy. The main diseases in this group that are discussed in this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and folliculin gene-associated syndrome (Birt–Hogg–Dubé; other rare causes of cystic lung disease, including cystic metastasis of sarcoma, are also discussed. Disease progression is unpredictable, and understanding of the complications of cystic lung disease and their appearance during evolution of the disease are essential for management. Correlation of disease evolution and clinical context with chest imaging findings provides important clues for defining the underlying nature of cystic lung disease, and guides diagnostic evaluation and management.

  4. Complement 3 and factor h in human cerebrospinal fluid in Parkinson's disease, Alzheimer's disease, and multiple-system atrophy.

    Science.gov (United States)

    Wang, Yu; Hancock, Aneeka M; Bradner, Joshua; Chung, Kathryn A; Quinn, Joseph F; Peskind, Elaine R; Galasko, Douglas; Jankovic, Joseph; Zabetian, Cyrus P; Kim, Hojoong M; Leverenz, James B; Montine, Thomas J; Ginghina, Carmen; Edwards, Karen L; Snapinn, Katherine W; Goldstein, David S; Shi, Min; Zhang, Jing

    2011-04-01

    Complement activation, a key component of neuroinflammation, has been reported in both Parkinson's disease (PD) and Alzheimer's disease (AD). However, it is unclear whether complement activation and neuroinflammation in general are distinctly different from each another in major neurodegenerative disorders. In the present study, cerebrospinal fluid complement 3 (C3) and factor H (FH) were measured and evaluated together with amyloid-β(42) (Aβ(42)), which in recent investigations was decreased in patients with PD, in particular those with cognitive impairment. The study included 345 participants: 126 patients with PD at various stages with or without cognitive impairment, 50 with AD, and 32 with multiple-system atrophy, and 137 healthy control individuals. In addition to changes in Aβ(42) concentrations, there were clear differences in the patterns of complement profiles among neurodegenerative disorders. The C3/FH ratio demonstrated high sensitivity and specificity in differentiating patients with multiple-system atrophy from those with AD or PD and control individuals. In addition, the C3/Aβ(42) and FH/Aβ(42) ratios not only correlated with PD severity approximated using the Unified Parkinson's Disease Rating Scale but also with the presence of cognitive impairment or dementia in PD. Both C3 and FH correlated with the severity of impairment in AD as indicated using Mini-Mental State Examination scores.

  5. Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease.

    Science.gov (United States)

    Berchtold, Nicole C; Coleman, Paul D; Cribbs, David H; Rogers, Joseph; Gillen, Daniel L; Cotman, Carl W

    2013-06-01

    Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer's disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20-99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD.

  6. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation.

    Science.gov (United States)

    Perron, Hervé; Lang, Alois

    2010-08-01

    Endogenous retroviruses represent about 8% of the human genome and belong to the superfamily of transposable and retrotransposable genetic elements. Altogether, these mobile genetic elements and their numerous inactivated "junk" sequences represent nearly one half of the human DNA. Nonetheless, a significant part of this "non-conventional" genome has retained potential activity. Epigenetic control is notably involved in silencing most of these genetic elements but certain environmental factors such as viruses are known to dysregulate their expression in susceptible cells. More particularly, embryonal cells with limited gene methylation are most susceptible to uncontrolled activation of these mobile genetic elements by, e.g., viral infections. In particular, certain viruses transactivate promoters from endogenous retroviral family type W (HERV-W). HERV-W RNA was first isolated in circulating viral particles (Multiple Sclerosis-associated RetroViral element, MSRV) that have been associated with the evolution and prognosis of multiple sclerosis. HERV-W elements encode a powerful immunopathogenic envelope protein (ENV) that activates a pro-inflammatory and autoimmune cascade through interaction with Toll-like receptor 4 on immune cells. This ENV protein has repeatedly been detected in MS brain lesions and may be involved in other diseases. Epigenetic factors controlling HERV-W ENV protein expression then reveal critical. This review addresses the gene-environment epigenetic interface of such HERV-W elements and its potential involvement in disease.

  7. Statistical applications in nutrigenomics : analyzing multiple genes and proteins in relation to complex diseases in humans

    NARCIS (Netherlands)

    Heidema, A.G.

    2008-01-01

    Background The recent advances in technology provide the possibility to obtain large genomic datasets that contain information on large numbers of variables, while the sample sizes are moderate to small. This has lead to statistical challenges in the analysis of multiple genes and proteins in relat

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jackalina M Van Kampen

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

  10. The multiple sclerosis-associated retrovirus and its HERV-W endogenous family: a biological interface between virology, genetics, and immunology in human physiology and disease.

    Science.gov (United States)

    Dolei, Antonina; Perron, Hervé

    2009-01-01

    This mini-review summarizes current knowledge of MSRV (multiple sclerosis-associated retrovirus), founder member of the type W family of human endogenous retroviruses (HERVs), its pathogenic potential and association with diseases. As retrotransposable elements, HERVs behave differently from stable genes, and cannot be studied with "Mendelian genetics" concepts only. They also display complex interactions with other HERV families, and with classical viruses. These concepts may contribute to unravelling the etiopathogenesis of complex diseases such as multiple sclerosis, schizophrenia, and other chronic multifactorial diseases.

  11. Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

    OpenAIRE

    Mead, Simon; Uphill, James; Beck, John; Poulter, Mark; Campbell, Tracy; Lowe, Jessica; Adamson, Gary; Hummerich, Holger; Klopp, Norman; Rückert, Ina-Maria; Wichmann, H-Erich; Azazi, Dhoyazan; Plagnol, Vincent; Pako, Wandagi H.; Whitfield, Jerome

    2011-01-01

    Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt–Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru...

  12. Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

    Science.gov (United States)

    Mead, Simon; Uphill, James; Beck, John; Poulter, Mark; Campbell, Tracy; Lowe, Jessica; Adamson, Gary; Hummerich, Holger; Klopp, Norman; Rückert, Ina-Maria; Wichmann, H-Erich; Azazi, Dhoyazan; Plagnol, Vincent; Pako, Wandagi H.; Whitfield, Jerome; Alpers, Michael P.; Whittaker, John; Balding, David J.; Zerr, Inga; Kretzschmar, Hans; Collinge, John

    2012-01-01

    Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt–Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38–RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10−8; OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10−7; odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10−5; two at PRNP, three at ZBTB38–RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only

  13. Humanizing Outgroups Through Multiple Categorization

    Science.gov (United States)

    Prati, Francesca; Crisp, Richard J.; Meleady, Rose; Rubini, Monica

    2016-01-01

    In three studies, we examined the impact of multiple categorization on intergroup dehumanization. Study 1 showed that perceiving members of a rival university along multiple versus simple categorical dimensions enhanced the tendency to attribute human traits to this group. Study 2 showed that multiple versus simple categorization of immigrants increased the attribution of uniquely human emotions to them. This effect was explained by the sequential mediation of increased individuation of the outgroup and reduced outgroup threat. Study 3 replicated this sequential mediation model and introduced a novel way of measuring humanization in which participants generated attributes corresponding to the outgroup in a free response format. Participants generated more uniquely human traits in the multiple versus simple categorization conditions. We discuss the theoretical implications of these findings and consider their role in informing and improving efforts to ameliorate contemporary forms of intergroup discrimination. PMID:26984016

  14. Kidney Disease and Multiple Myeloma

    Science.gov (United States)

    Rennke, Helmut G.; Laubach, Jacob P.; Richardson, Paul G.

    2013-01-01

    Summary Kidney injury is a common complication of multiple myeloma and other plasma cell dyscrasias, and it is associated with increased mortality. Multiple pathogenic mechanisms can contribute to kidney injury in the patient with myeloma, some of which are the result of nephrotoxic monoclonal Ig and some of which are independent of paraprotein deposition. The pathogenic mechanisms that underlie paraprotein-related kidney disease are increasingly well understood. A novel assay allowing the quantification of free light chains in the serum has aided the diagnosis of new onset disease and allowed for the earlier detection of relapse. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes. Stem cell transplantation remains a mainstay of management for younger patients with myeloma who are suitable candidates for intensive therapy, whereas the role of new drugs, plasma exchange, and kidney transplantation continues to evolve. PMID:23868898

  15. Multiple sclerosis, a treatable disease.

    Science.gov (United States)

    Doshi, Anisha; Chataway, Jeremy

    2016-12-01

    This article reviews our current understanding and modern treatment of multiple sclerosis (MS). MS is a disabling condition resulting in devastating social and economic impacts. As MS can affect any part of the central nervous system, the presentation is often diverse; however, there are key features that can be useful in the clinic. We comment on the diagnostic criteria and review the main subtypes of MS, including clinically isolated syndrome, relapsing remitting MS, secondary progressive MS and primary progressive MS. Although the underlying aetiology of MS is still not known, we summarise those with most evidence of association. Finally, we aim to present treatment strategies for managing the acute relapse, disease-modifying therapies and MS symptoms. This review highlights that progressive MS is an area where there is currently a paucity of available disease-modifying treatments and this will be a major focus for future development.

  16. Parasitic Diseases - Multiple Languages: MedlinePlus

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Parasitic Diseases URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Parasitic Diseases - Multiple Languages To use the sharing features on ...

  17. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Goldsteins Gundars

    2010-12-01

    Full Text Available Abstract Background Purified intravenous immunoglobulin (IVIG obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs against β-amyloid (Aβ peptides accumulating in the brains of Alzheimer's disease (AD patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. Methods We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of Aβ burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD in vivo. Results IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits ex vivo. IVIG enhanced microglia-mediated Aβ clearance ex vivo, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ clearance we observed have potential relevance in vivo since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest

  18. Human Environmental Disease Network

    DEFF Research Database (Denmark)

    Taboureau, Olivier; Audouze, Karine

    2017-01-01

    During the past decades, many epidemiological, toxicological and biological studies have been performed to assess the role of environmental chemicals as potential toxicants for diverse human disorders. However, the relationships between diseases based on chemical exposure have been rarely studied...... by computational biology. We developed a human environmental disease network (EDN) to explore and suggest novel disease-disease and chemical-disease relationships. The presented scored EDN model is built upon the integration on systems biology and chemical toxicology using chemical contaminants information...

  19. Brain Diseases - Multiple Languages: MedlinePlus

    Science.gov (United States)

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Brain Diseases URL of this page: https://medlineplus.gov/ ... V W XYZ List of All Topics All Brain Diseases - Multiple Languages To use the sharing features on this page, ...

  20. miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease.

    Science.gov (United States)

    Rossi, Marco; Pitari, Maria Rita; Amodio, Nicola; Di Martino, Maria Teresa; Conforti, Francesco; Leone, Emanuela; Botta, Cirino; Paolino, Francesco Maria; Del Giudice, Teresa; Iuliano, Eleonora; Caraglia, Michele; Ferrarini, Manlio; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2013-07-01

    Skeletal homeostasis relies upon a fine tuning of osteoclast (OCL)-mediated bone resorption and osteoblast (OBL)-dependent bone formation. This balance is unsettled by multiple myeloma (MM) cells, which impair OBL function and stimulate OCLs to generate lytic lesions. Emerging experimental evidence is disclosing a key regulatory role of microRNAs (miRNAs) in the regulation of bone homeostasis suggesting the miRNA network as potential novel target for the treatment of MM-related bone disease (BD). Here, we report that miR-29b expression decreases progressively during human OCL differentiation in vitro. We found that lentiviral transduction of miR-29b into OCLs, even in the presence of MM cells, significantly impairs tartrate acid phosphatase (TRAcP) expression, lacunae generation, and collagen degradation, which are relevant hallmarks of OCL activity. Accordingly, expression of cathepsin K and metalloproteinase 9 (MMP9) as well as actin ring rearrangement were impaired in the presence of miR-29b. Moreover, we found that canonical targets C-FOS and metalloproteinase 2 are suppressed by constitutive miR-29b expression which also downregulated the master OCL transcription factor, NAFTc-1. Overall, these data indicate that enforced expression of miR-29b impairs OCL differentiation and overcomes OCL activation triggered by MM cells, providing a rationale for miR-29b-based treatment of MM-related BD.

  1. Retroviruses and human disease.

    OpenAIRE

    1987-01-01

    Over the past 25 years animal retroviruses have been favoured subjects of research by virologists, oncologists, and molecular biologists. Retroviruses have given us reverse transcriptase, oncogenes, and cloning vectors that may one day be exploited for human gene therapy. They have also given us leukaemia and the acquired immune deficiency syndrome (AIDS). Kawasaki disease and tropical spastic paraparesis are thought to be associated with retrovirus infection, and other diseases such as de Qu...

  2. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

    Directory of Open Access Journals (Sweden)

    Soo-Kyung Choi

    Full Text Available Multiple endocrine neoplasia type 2B (MEN2B is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.

  3. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

    Science.gov (United States)

    Choi, Soo-Kyung; Yoon, Song-Ro; Calabrese, Peter; Arnheim, Norman

    2012-01-01

    Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.

  4. [Cowden's disease or the multiple hamartoma syndrome].

    Science.gov (United States)

    Crickx, B; Sigal, M; Pastel, A; Vissuzaine, C; Grossin, M; Maurer, F; Morinière, B; Belaich, S

    1984-06-01

    Cowden's disease, also called multiple hamartoma syndrome, is a clinical entity characterized by hamartomatous tumours of endodermal, mesodermal and ectodermal origin. Although extremely rare, the disease must be known to all internists. A case of Cowden's disease in a 36-year old male patient is reported. The authors insist on the high incidence of digestive disorders and the risk of malignant degeneration of mammary and thyroid tumours. They also describe the cutaneous and mucosal lesions characteristic of the disease.

  5. Multiple factors interact to produce responses resembling spectrum of human disease in Campylobacter jejuni infected C57BL/6 IL-10-/- mice

    Directory of Open Access Journals (Sweden)

    Wolf John E

    2009-03-01

    Full Text Available Abstract Background Campylobacter jejuni infection produces a spectrum of clinical presentations in humans – including asymptomatic carriage, watery diarrhea, and bloody diarrhea – and has been epidemiologically associated with subsequent autoimmune neuropathies. This microorganism is genetically variable and possesses genetic mechanisms that may contribute to variability in nature. However, relationships between genetic variation in the pathogen and variation in disease manifestation in the host are not understood. We took a comparative experimental approach to explore differences among different C. jejuni strains and studied the effect of diet on disease manifestation in an interleukin-10 deficient mouse model. Results In the comparative study, C57BL/6 interleukin-10-/- mice were infected with seven genetically distinct C. jejuni strains. Four strains colonized the mice and caused disease; one colonized with no disease; two did not colonize. A DNA:DNA microarray comparison of the strain that colonized mice without disease to C. jejuni 11168 that caused disease revealed that putative virulence determinants, including loci encoding surface structures known to be involved in C. jejuni pathogenesis, differed from or were absent in the strain that did not cause disease. In the experimental study, the five colonizing strains were passaged four times in mice. For three strains, serial passage produced increased incidence and degree of pathology and decreased time to develop pathology; disease shifted from watery to bloody diarrhea. Mice kept on an ~6% fat diet or switched from an ~12% fat diet to an ~6% fat diet just before infection with a non-adapted strain also exhibited increased incidence and severity of disease and decreased time to develop disease, although the effects of diet were only statistically significant in one experiment. Conclusion C. jejuni strain genetic background and adaptation of the strain to the host by serial passage

  6. Multiple autoimmune syndrome with celiac disease.

    Science.gov (United States)

    Harpreet, Singh; Deepak, Jain; Kiran, B

    2016-01-01

    Multiple autoimmune syndrome (MAS) is a condition characterised by three or more autoimmune disorders in a same individual. Familial, immunologic and infectious factors are implicated in the development of MAS. Here we report a case of a 32-year-old woman with co-existence of four auto-immune diseases, namely autoimmune hypothyroidism, Sjögren's syndrome, systemic lupus erythematosus (SLE) and celiac disease which leads to the final diagnosis of multiple autoimmune syndrome type 3 with celiac disease. Patients with single autoimmune disorder are at 25% risk of developing other autoimmune disorders. The present case emphasises to clinicians that there is a need for continued surveillance for the development of new autoimmune disease in predisposed patients.

  7. Human Cytomegalovirus and Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    Anne Halenius

    2014-01-01

    Full Text Available Human cytomegalovirus (HCMV represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE, systemic sclerosis (SSc, diabetes mellitus type 1, and rheumatoid arthritis (RA is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention.

  8. Genetic Mapping in Human Disease

    OpenAIRE

    Altshuler, David; Daly, Mark J; Lander, Eric S.

    2008-01-01

    Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases. We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead.

  9. Disease-modifying agents in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Coyle P

    2009-01-01

    Full Text Available Since 1993, six disease-modifying therapies for multiple sclerosis (MS have been proven to be of benefit in rigorous phase III clinical trials. Other agents are also available and are used to treat MS, but definitive data on their efficacy is lacking. Currently, disease-modifying therapy is used for relapsing forms of MS. This includes clinically isolated syndrome/first-attack high-risk patients, relapsing patients, secondary progressive patients who are still experiencing relapses, and progressive relapsing patients. The choice of agent depends upon drug factors (including affordability, availability, convenience, efficacy, and side effects, disease factors (including clinical and neuroimaging prognostic indicators, and patient factors (including comorbidities, lifestyle, and personal preference. This review will discuss the disease-modifying agents used currently in MS, as well as available alternative agents.

  10. Mechanisms of multiple myeloma bone disease

    Science.gov (United States)

    Galson, Deborah L; Silbermann, Rebecca; Roodman, G David

    2012-01-01

    Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies. PMID:23951515

  11. Disease modifying therapies for relapsing multiple sclerosis.

    Science.gov (United States)

    Wingerchuk, Dean M; Weinshenker, Brian G

    2016-08-22

    Multiple sclerosis (MS) is a common, disabling, putatively autoimmune neurological disease with worldwide distribution. It typically begins as a relapsing disorder that later evolves to a secondary progressive phase. Inflammatory and neurodegenerative mechanisms seem to operate in both phases, but their relative contributions and interactions are incompletely understood. Disease modifying therapies (DMTs) approved for relapsing multiple sclerosis interfere with a variety of immunological mechanisms to reduce rates of relapse, accumulation of disease burden measured by magnetic resonance imaging (MRI), and decline in neurological function over the two to three year duration of typical randomized controlled trials. Benefits of longer duration of therapy on disability are less clear, as data beyond three years are largely limited to observational studies. However, current DMTs do not slow accrual of disability once progressive multiple sclerosis is established. This review summarizes the evidence about the use of approved DMTs and examines how to individualize treatment despite the absence of validated biomarkers to guide drug selection. Methods such as stratifying patients on the basis of estimated risk for future disability, weighing patient specific factors and preferences, and using objective outcomes to adjudicate treatment success are discussed. Emerging drug therapies and strategies are also reviewed.

  12. Multiple parapelvic cysts in Fabry disease.

    Science.gov (United States)

    Azancot, María A; Vila, Josefa; Domínguez, Carmen; Serres, Xavier; Espinel, Eugenia

    2016-01-01

    Fabry disease is an inherited, X-linked lysosomal storage disorder caused by deficiency of the enzyme alpha galactosidase A (alpha-GLA A), which leads to glycosphingolipid accumulation, mainly globotriaosylceramide, in tissues. Disease prevalence and the index of suspicion are both low, which tends to result in delayed diagnosis and treatment. We present the case of a male Fabry disease patient who manifested no angiokeratoma lesions but presented multiple parapelvic cysts and renal failure. The genetic study revealed an alpha-GLA A gene mutation that had not been recorded in the mutations registry. The de novo mutation was not found in his relatives and it was not transmitted to his offspring. The large number and peculiar appearance of the parapelvic cysts led to the diagnosis. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  13. Intravenous polyclonal human immunoglobulins in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Per Soelberg

    2008-01-01

    Intravenous immunoglobulin (IVIG) is an established therapy for demyelinating diseases of the peripheral nervous system. IVIG exerts a number of effects that may be beneficial in multiple sclerosis (MS). Four double-blind IVIG trials have been performed in relapsing-remitting MS. A meta...

  14. Multiple myeloma: the disease and its treatment

    Directory of Open Access Journals (Sweden)

    Meenakshi Gupta

    2013-04-01

    Full Text Available Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The tumor, its products and the host response to it result in a number of organ dysfunctions and symptoms of bone pain, fracture, anemia, hypercalcemia, susceptibility to infection, neurologic symptoms, clotting abnormalities and manifestations of hyperviscosity. The cause of myeloma remains unexplained but it is associated with few occupations, inflammatory conditions, autoimmune illnesses, viral infections and genetic heterogeneity. Direct interaction between multiple myeloma cells and bone marrow cells activates pleiotropic signalling pathways that mediate growth, survival, migration of multiple myeloma cells and also resistance to chemotherapy. Although myeloma remains incurable, but the use of novel drugs like thalidomide, lenalidomide and bortezomib have resulted in a paradigm change in the therapy of myeloma. Their inclusion in current multiple myeloma treatment regimens have extended median overall survival especially in younger patient population. Recent advances in the molecular genetics have provided opportunities to design highly specific inhibitors of signal transduction pathways that may enhance the efficacy of standard chemotherapy drugs by reducing or altering the pathways associated with cell survival. Despite therapeutic advances, multiple myeloma ultimately relapses and remains an incurable disease. Current research goals are to further increase our knowledge, to identify additional targeted therapies, and to reduce adverse effects and improve response rate. This review focuses on recent clinical advancement in ant myeloma strategies with additional discussion dedicated to emerging drugs that may prove beneficial to patients with this disease. [Int J Basic Clin Pharmacol 2013; 2(2.000: 103-121

  15. The DNA copy number of human endogenous retrovirus-W (MSRV-type is increased in multiple sclerosis patients and is influenced by gender and disease severity.

    Directory of Open Access Journals (Sweden)

    Marta Garcia-Montojo

    Full Text Available BACKGROUND: Multiple sclerosis is an autoimmune disease more prevalent in women than in men. Multiple Sclerosis Associated Retrovirus element (MSRV is a member of type-W endogenous retrovirus family (HERV-W, known to be associated to MS. Most HERVs are unable to replicate but MSRV expression associated with reverse-transcriptase activity in MS would explain reported DNA copy number increase in MS patients. A potential link between HERV-W copies on chromosome X and gender differential prevalence has been suggested. The present study addresses MSRV-type DNA load in relation with the gender differences and clinical status in MS and healthy controls. RESULTS: 178 MS patients (62.9% women and 124 controls (56.5% women were included. MSRV env load (copies/pg of DNA was analyzed by real time qPCR with specific primers and probe for its env gene, in DNA from peripheral blood mononuclear cells (PBMCs. MSRV load was more elevated in MS patients than in controls (p = 4.15e-7. MS women presented higher MSRV load than control women (p = 0.009 and MS men also had higher load than control men (p = 2.77e-6. Besides, women had higher levels than men, both among patients (p = 0.007 and controls (p = 1.24e-6. Concordantly, EDSS and MSSS scores were higher among female patients with an elevated MSRV load (p = 0.03 and p = 0.04, respectively. CONCLUSIONS: MSRV increases its copy number in PBMC of MS patients and particularly in women with high clinical scores. This may explain causes underlying the higher prevalence of MS in women. The association with the clinical severity calls for further investigations on MSRV load in PBMCs as a biomarker for MS.

  16. Connective tissue diseases mimicking multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Maryam Moghaddassi-Jahromi

    2011-11-01

    Full Text Available Background: Connective tissue diseases (CTD can involve nervous system. Diagnosis and differentiation from multiple sclerosis (MS can be difficult especially when the disease presented by symptoms and signs related to demyelinating process. The aim of this article is to review the variant forms of central nervous system involvement in CTD especially useful points for differentiation from demyelinating disorders. Materials and Method: We used the relevant articles in PUBMED, Scopus and other databases especially published in recent ten years. Results: Systemic lupus erythematosus (SLE, antiphospholipid syndrome (APS, Behcet’s disease (BD, Sjogren's syndrome (SS, and some vasculitides can involve nervous system. Patients may be present by demyelination areas in the white matter of the brain and spinal cord, which are difficult to differentiate from MS and other demyelinating processes, such as transverse myelitis and optic neuritis. On the other hand, autoantibodies such as antinuclear antibodies (ANA and antiphospholipid antibodies (aPL can also occur in MS. Treatment and prognosis of these diseases are quite different. In demyelinating diseases the diagnosis is established on the basis of clinical presentation, magnetic resonance imaging (MRI, cerebrospinal fluid (CSF examination, visual evoked potentials (VEP and autoantibody investigation.Conclusion: In many patients, distinction between different etiologies of demyelination can be made by considering clinical and paraclinical data, but in some cases, accurate diagnosis can only be made after long-term follow-up

  17. Multiple changes in sialic acid biology during human evolution.

    Science.gov (United States)

    Varki, Ajit

    2009-04-01

    Humans are genetically very similar to "great apes", (chimpanzees, bonobos, gorillas and orangutans), our closest evolutionary relatives. We have discovered multiple genetic and biochemical differences between humans and these other hominids, in relation to sialic acids and in Siglecs (Sia-recognizing Ig superfamily lectins). An inactivating mutation in the CMAH gene eliminated human expression of N-glycolylneuraminic acid (Neu5Gc) a major sialic acid in "great apes". Additional human-specific changes have been found, affecting at least 10 of the dietary sources, particularly red meat and milk products. As humans also have varying and sometime high levels of circulating anti-Neu5Gc antibodies, there are implications for biotechnology products, and for some human diseases associated with chronic inflammation.

  18. Prevalence of celiac disease in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    López-Vázquez Antonio

    2011-03-01

    Full Text Available Abstract Background Celiac disease (CD is a common systemic disease related to a permanent intolerance to gluten and is often associated with different autoimmune and neurological diseases. Its mean prevalence in the general population is 1-2% worldwide. Our aim was to study the prevalence of celiac disease in a prospective series of Multiple Sclerosis (MS patients and their first-degree relatives. Methods We analyzed the prevalence of serological, histological and genetic CD markers in a series of 72 MS patients and in their 126 first-degree relatives, compared to 123 healthy controls. Results Tissue IgA-anti-transglutaminase-2 antibodies were positive in 7 MS patients (10%, compared to 3 healthy controls (2.4% (p We detected mild or moderate villous atrophy (Marsh III type in duodenal biopsies, in 8 MS patients (11.1%. We also found a high proportion of CD among first-degree relatives: 23/126 (32%. Several associated diseases were detected, mainly dermatitis 41 (57% and iron deficiency anemia in 28 (39% MS patients. We also found in them, an increased frequency of circulating auto-antibodies such as anti-TPO in 19 (26%, ANA in 11 (15% and AMA in 2 (3%. Conclusions We have found an increased prevalence of CD in 8 of the 72 MS patients (11.1% and also in their first-degree relatives (23/126 [32%]. Therefore, increased efforts aimed at the early detection and dietary treatment of CD, among antibody-positive MS patients, are advisable.

  19. Viral diseases and human evolution

    OpenAIRE

    2000-01-01

    The interaction of man with viral agents was possibly a key factor shaping human evolution, culture and civilization from its outset. Evidence of the effect of disease, since the early stages of human speciation, through pre-historical times to the present suggest that the types of viruses associated with man changed in time. As human populations progressed technologically, they grew in numbers and density. As a consequence different viruses found suitable conditions to thrive and establish l...

  20. Mitochondria: impaired mitochondrial translation in human disease.

    Science.gov (United States)

    Boczonadi, Veronika; Horvath, Rita

    2014-03-01

    Defects of the mitochondrial protein synthesis cause a subgroup of mitochondrial diseases, which are usually associated with decreased activities of multiple respiratory chain (RC) enzymes. The clinical presentations of these disorders are often disabling, progressive or fatal, affecting the brain, liver, skeletal muscle, heart and other organs. Currently there are no effective cures for these disorders and treatment is at best symptomatic. The diagnosis in patients with multiple respiratory chain complex defects is particularly difficult because of the massive number of nuclear genes potentially involved in intra-mitochondrial protein synthesis. Many of these genes are not yet linked to human disease. Whole exome sequencing rapidly changed the diagnosis of these patients by identifying the primary defect in DNA, and preventing the need for invasive and complex biochemical testing. Better understanding of the mitochondrial protein synthesis apparatus will help us to explore disease mechanisms and will provide clues for developing novel therapies.

  1. Viral diseases and human evolution

    Directory of Open Access Journals (Sweden)

    Leal Élcio de Souza

    2000-01-01

    Full Text Available The interaction of man with viral agents was possibly a key factor shaping human evolution, culture and civilization from its outset. Evidence of the effect of disease, since the early stages of human speciation, through pre-historical times to the present suggest that the types of viruses associated with man changed in time. As human populations progressed technologically, they grew in numbers and density. As a consequence different viruses found suitable conditions to thrive and establish long-lasting associations with man. Although not all viral agents cause disease and some may in fact be considered beneficial, the present situation of overpopulation, poverty and ecological inbalance may have devastating effets on human progress. Recently emerged diseases causing massive pandemics (eg., HIV-1 and HCV, dengue, etc. are becoming formidable challenges, which may have a direct impact on the fate of our species.

  2. Association of celiac disease with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Abolfazli.R

    2007-09-01

    Full Text Available   Background: Multiple sclerosis (MS and the gluten intolerance disease, celiac disease, (CD are immune-mediated diseases. Better testing for antibodies associated with CD, including anti-gliadin antibody [AGA], as well as anti-endomysial and anti-tissue transglutaminase antibodies, has improved the diagnosis of CD. Certain neurologic conditions have a reported association with CD. Previous researchers have investigated the role of a gluten-free diet in the treatment of MS and found no benefits. Here, we investigate the possible immunological association of CD with MS.Methods: Using ELISA, we estimated serum IgG and IgA anti-gliadin and IgA anti-endomysial antibodies in 34 MS patients, who were new or previous cases without immunosuppressant treatment for at least the last six months. The mean age was 29.6 years (range 15-46 years, with 30 patients relapsing-remitting, and four secondary-progressive MS. Thirty-four random anonymous blood donors were used as serologic controls (mean age 31.4 years, range 19-50 years. The individuals in both groups with elevated AGA (IgG or IgA or anti-endomysial antibody (IgA underwent duodenal biopsy.Results: In the MS group, high levels of IgG AGA were found in 5.9% of the subjects, and 5.9% had elevated IgA AGA. In the controls, elevated IgG AGA was detected in 5.9% of the subjects and IgA AGA in 2.9% (p=0.051 and 0.48, respectively. For IgG and IgA AGA levels, no significant differences were found between the patient and control groups. IgA anti-endomysial antibodies were not found in either group. Upon biopsy, the specific pathological features of celiac were absent.Conclusion: The same number of MS patients and controls had high levels of AGA, with normal levels of IgA anti-endomysial antibodies, which is more specific for CD, while the GI biopsies from both groups were not specific for CD. Therefore, AGA levels in any neurologic case should be interpreted with caution. The present study showed no

  3. Linking Microbiota to Human Diseases

    DEFF Research Database (Denmark)

    Wu, Hao; Tremaroli, Valentina; Bäckhed, F

    2015-01-01

    diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies......The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2...... may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction....

  4. Chromatin remodeling and human disease.

    Science.gov (United States)

    Huang, Cheng; Sloan, Emily A; Boerkoel, Cornelius F

    2003-06-01

    In the past few years, there has been a nascent convergence of scientific understanding of inherited human diseases with epigenetics. Identified epigenetic processes involved in human disease include covalent DNA modifications, covalent histone modifications, and histone relocation. Each of these processes influences chromatin structure and thereby regulates gene expression and DNA methylation, replication, recombination, and repair. The importance of these processes for nearly all aspects of normal growth and development is illustrated by the array of multi-system disorders and neoplasias caused by their dysregulation.

  5. New oral disease-modifying therapies for multiple sclerosis

    OpenAIRE

    2009-01-01

    Several promising, oral disease-modifying therapies for multiple sclerosis are currently being evaluated in clinical trials. The arrival of effective oral agents for multiple sclerosis will be a major advance in the global effort to alter the natural history of this chronic disease.

  6. Detection of Multiple Stationary Humans Using UWB MIMO Radar

    Directory of Open Access Journals (Sweden)

    Fulai Liang

    2016-11-01

    Full Text Available Remarkable progress has been achieved in the detection of single stationary human. However, restricted by the mutual interference of multiple humans (e.g., strong sidelobes of the torsos and the shadow effect, detection and localization of the multiple stationary humans remains a huge challenge. In this paper, ultra-wideband (UWB multiple-input and multiple-output (MIMO radar is exploited to improve the detection performance of multiple stationary humans for its multiple sight angles and high-resolution two-dimensional imaging capacity. A signal model of the vital sign considering both bi-static angles and attitude angle of the human body is firstly developed, and then a novel detection method is proposed to detect and localize multiple stationary humans. In this method, preprocessing is firstly implemented to improve the signal-to-noise ratio (SNR of the vital signs, and then a vital-sign-enhanced imaging algorithm is presented to suppress the environmental clutters and mutual affection of multiple humans. Finally, an automatic detection algorithm including constant false alarm rate (CFAR, morphological filtering and clustering is implemented to improve the detection performance of weak human targets affected by heavy clutters and shadow effect. The simulation and experimental results show that the proposed method can get a high-quality image of multiple humans and we can use it to discriminate and localize multiple adjacent human targets behind brick walls.

  7. Proteins aggregation and human diseases

    Science.gov (United States)

    Hu, Chin-Kun

    2015-04-01

    Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease.

  8. Extracellular RNAs: development as biomarkers of human disease

    Directory of Open Access Journals (Sweden)

    Joseph F. Quinn

    2015-08-01

    Full Text Available Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined.

  9. Chagas disease and human migration

    Directory of Open Access Journals (Sweden)

    Felipe Guhl

    2000-08-01

    Full Text Available Human Chagas disease is a purely accidental occurrence. As humans came into contact with the natural foci of infection might then have become infected as a single addition to the already extensive host range of Trypanosoma cruzi that includes other primates. Thus began a process of adaptation and domiciliation to human habitations through which the vectors had direct access to abundant food as well as protection from climatic changes and predators. Our work deals with the extraction and specific amplification by polymerase chain reaction of T. cruzi DNA obtained from mummified human tissues and the positive diagnosis of Chagas disease in a series of 4,000-year-old Pre-Hispanic human mummies from the northern coast of Chile. The area has been inhabited at least for 7,000 years, first by hunters, fishers and gatherers, and then gradually by more permanent settlements. The studied specimens belonged to the Chinchorro culture, a people inhabiting the area now occupied by the modern city of Arica. These were essentially fishers with a complex religious ideology, which accounts for the preservation of their dead in the way of mummified bodies, further enhanced by the extremely dry conditions of the desert. Chinchorro mummies are, perhaps, the oldest preserved bodies known to date.

  10. [Alzheimer's disease and human memory].

    Science.gov (United States)

    Eustache, F; Giffard, B; Rauchs, G; Chételat, G; Piolino, P; Desgranges, B

    2006-10-01

    Memory disorders observed in Alzheimer's disease gave rise, from the eighties, to a detailed analysis into the framework of cognitive neuropsychology which aimed at describing the deficits of very specific processes. Beyond their clinical interest, these studies contributed to the modelisation of human memory thanks to the characterization of different memory systems and their relationships. The first part of this paper gives an overview of the memory deficits in Alzheimer's disease and insists on particular cognitive phenomena. Hence, several examples are developed in the domains of semantic memory (such as hyperpriming and hypopriming effects) and autobiographical memory. Recent results highlight the existence of severe autobiographical amnesia observed in all neurodegenerative diseases, though with contrasting profiles: Ribot's gradient in Alzheimer's disease (showing that remote memories are better preserved than recent ones), reverse gradient in semantic dementia and no clear gradient in the frontal variant of frontotemporal dementia. The second part of this article presents advances in cognitive neuroscience searching to disclose the cerebral substrates of these cognitive deficits in Alzheimer's disease. The studies using functional imaging techniques are the most informative regarding this problematic. While showing the dysfunctions of an extended network, they emphasize the selectivity of cerebral damages that are at the root of very specific cognitive dysfunctions, coming close in that way to the conceptions of cognitive neuropsychology. These neuroimaging studies unravel the existence of compensatory mechanisms, which until recently were clearly missing in the literature on neurodegenerative diseases. These different researches lead to a wide conception of human memory, not just limited to simple instrumental processes (encoding, storage, retrieval), but necessarily covering models of identity and continuity of the subject, which interact in a dynamic way

  11. Transfer RNA and human disease

    Directory of Open Access Journals (Sweden)

    Jamie A Abbott

    2014-06-01

    Full Text Available Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA genes are hotspots for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase, mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing. Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

  12. Animal model of human disease. Multiple myeloma

    NARCIS (Netherlands)

    Radl, J.; Croese, J.W.; Zurcher, C.; Enden-Vieveen, M.H.M. van den; Leeuw, A.M. de

    1988-01-01

    Animal models of spontaneous and induced plasmacytomas in some inbred strains of mice have proven to be useful tools for different studies on tumorigenesis and immunoregulation. Their wide applicability and the fact that after their intravenous transplantation, the recipient mice developed bone

  13. Human genetics of infectious diseases: a unified theory

    Science.gov (United States)

    Casanova, Jean-Laurent; Abel, Laurent

    2007-01-01

    Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans. PMID:17255931

  14. Human Microbiota and Ophthalmic Disease.

    Science.gov (United States)

    Lu, Louise J; Liu, Ji

    2016-09-01

    The human ocular surface, consisting of the cornea and conjunctiva, is colonized by an expansive, diverse microbial community. Molecular-based methods, such as 16S rRNA sequencing, has allowed for more comprehensive and precise identification of the species composition of the ocular surface microbiota compared to traditional culture-based methods. Evidence suggests that the normal microbiota plays a protective immunological role in preventing the proliferation of pathogenic species and thus, alterations in the homeostatic microbiome may be linked to ophthalmic pathologies. Further investigation of the ocular surface microbiome, as well as the microbiome of other areas of the body such as the oral mucosa and gut, and their role in the pathophysiology of diseases is a significant, emerging field of research, and may someday enable the development of novel probiotic approaches for the treatment and prevention of ophthalmic diseases.

  15. Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis

    NARCIS (Netherlands)

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

    2012-01-01

    Background: Certain lifestyle factors might influence disease activity in multiple sclerosis (MS). Objectives: To investigate the consumption of alcoholic beverages, caffeinated drinks, fish and cigarette smoking in relation to disability progression in relapsing onset and progressive onset MS. Meth

  16. Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis

    NARCIS (Netherlands)

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

    2012-01-01

    Background: Certain lifestyle factors might influence disease activity in multiple sclerosis (MS). Objectives: To investigate the consumption of alcoholic beverages, caffeinated drinks, fish and cigarette smoking in relation to disability progression in relapsing onset and progressive onset MS. Meth

  17. Aluminium and human breast diseases.

    Science.gov (United States)

    Darbre, P D; Pugazhendhi, D; Mannello, F

    2011-11-01

    The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from the same breast. We have recently found increased levels of aluminium in noninvasively collected nipple aspirate fluids taken from breast cancer patients (mean 268 ± 28 μg/l) compared with control healthy subjects (mean 131 ± 10 μg/l) providing evidence of raised aluminium levels in the breast microenvironment when cancer is present. The measurement of higher levels of aluminium in type I human breast cyst fluids (median 150 μg/l) compared with human serum (median 6 μg/l) or human milk (median 25 μg/l) warrants further investigation into any possible role of aluminium in development of this benign breast disease. Emerging evidence for aluminium in several breast structures now requires biomarkers of aluminium action in order to ascertain whether the presence of aluminium has any biological impact. To this end, we report raised levels of proteins that modulate iron homeostasis (ferritin, transferrin) in parallel with raised aluminium in nipple aspirate fluids in vivo, and we report overexpression of mRNA for several S100 calcium binding proteins following long-term exposure of MCF-7 human breast cancer cells in vitro to aluminium chlorhydrate.

  18. Multiple sclerosis or neurological manifestations of Celiac disease

    Directory of Open Access Journals (Sweden)

    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.

  19. Are human endogenous retroviruses triggers of autoimmune diseases?

    DEFF Research Database (Denmark)

    Nexø, Bjørn A; Villesen, Palle; Nissen, Kari K

    2016-01-01

    Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental...... manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus...... was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte...

  20. Clinical Holistic Medicine: The Patient with Multiple Diseases

    Directory of Open Access Journals (Sweden)

    Søren Ventegodt

    2005-01-01

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

  1. Human copy number variation and complex genetic disease.

    Science.gov (United States)

    Girirajan, Santhosh; Campbell, Catarina D; Eichler, Evan E

    2011-01-01

    Copy number variants (CNVs) play an important role in human disease and population diversity. Advancements in technology have allowed for the analysis of CNVs in thousands of individuals with disease in addition to thousands of controls. These studies have identified rare CNVs associated with neuropsychiatric diseases such as autism, schizophrenia, and intellectual disability. In addition, copy number polymorphisms (CNPs) are present at higher frequencies in the population, show high diversity in copy number, sequence, and structure, and have been associated with multiple phenotypes, primarily related to immune or environmental response. However, the landscape of copy number variation still remains largely unexplored, especially for smaller CNVs and those embedded within complex regions of the human genome. An integrated approach including characterization of single nucleotide variants and CNVs in a large number of individuals with disease and normal genomes holds the promise of thoroughly elucidating the genetic basis of human disease and diversity.

  2. Epidermodysplasia verruciformis with Hansen′s disease, herpes simplex labialis and multiple eccrine hidradenoma

    Directory of Open Access Journals (Sweden)

    Padmavathy L

    2009-01-01

    Full Text Available Epidermodysplasia verruciformis (EV - a rare, lifelong heritable disease due to a unique susceptibility to human papilloma virus. The disseminated verrucous lesions or pityriasis versicolor like lesions persist from early childhood and can transform into a cutaneous malignancy in a fourth of patients. The association of EV with multiple eccrine hidradenoma, herpes simplex labialis and Hansen′s disease is a very rare occurrence and is reported in a 25-year-old woman.

  3. Role of osteocytes in multiple myeloma bone disease

    Science.gov (United States)

    Delgado-Calle, Jesus; Bellido, Teresita; Roodman, G. David

    2014-01-01

    Purpose of review Despite the increased knowledge of osteocyte biology, the contribution of this most abundant bone cell to the development and progression of multiple myeloma in bone is practically unexplored. Recent findings Multiple myeloma bone disease is characterized by exacerbated bone resorption and the presence of osteolytic lesions that do not heal because of a concomitant reduction in bone formation. Osteocytes produce molecules that regulate both bone formation and resorption. Recent findings suggest that the life span of osteocytes is compromised in multiple myeloma patients with bone lesions. In addition, multiple myeloma cells affect the transcriptional profile of osteocytes by upregulating the production of pro-osteoclastogenic cytokines, stimulating osteoclast formation and activity. Further, patients with active multiple myeloma have elevated circulating levels of sclerostin, a potent inhibitor of bone formation which is specifically expressed by osteocytes in bone. Summary Understanding the contribution of osteocytes to the mechanisms underlying the skeletal consequences of multiple myeloma bone disease has the potential to provide important new therapeutic strategies that specifically target multiple myeloma–osteocyte interactions. PMID:25289928

  4. Soluble CD23 in multiple myelomas and related diseases

    Directory of Open Access Journals (Sweden)

    Tomoaki Matsumoto

    1997-01-01

    Full Text Available The serum levels of soluble CD23 (sCD23 were examined in patients with multiple myelomas and related diseases and were compared with levels of sCD23 in healthy, age- and sex-matched controls. The mean levels (95% confidence intervals of sCD23 in the sera of 40 patients with multiple myelomas, nine patients with myeloma-related diseases (seven primary macroglobulinemia and two chronic lymphatic leukemia and 30 matched controls were 2.7 (1.9-3.8, 9.9 (5.1-19.2 and 1.5 (1.3-1.7 ng/mL, respectively, showing a significant increase in sCD23 in the circulation of patients with myelomas (P<0.01 and myeloma-related diseases (P< 0.001. The potential biologic importance of sCD23 in myelomas and related diseases is discussed.

  5. Genetically Modified Pig Models for Human Diseases

    Institute of Scientific and Technical Information of China (English)

    Nana Fan; Liangxue Lai

    2013-01-01

    Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies.Although genetically modified mice have been widely used to model human diseases,some of these mouse models do not replicate important disease symptoms or pathology.Pigs are more similar to humans than mice in anatomy,physiology,and genome.Thus,pigs are considered to be better animal models to mimic some human diseases.This review describes genetically modified pigs that have been used to model various diseases including neurological,cardiovascular,and diabetic disorders.We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.

  6. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity?

    Science.gov (United States)

    Antel, Jack; Antel, Samson; Caramanos, Zografos; Arnold, Douglas L; Kuhlmann, Tanja

    2012-05-01

    Multiple sclerosis (MS), the most frequent demyelinating disease, is characterized by a variable disease course. The majority of patients starts with relapsing remitting (RR) disease; approximately 50-60% of these patients progress to secondary progressive (SP) disease. Only about 15% of the patients develop a progressive disease course from onset, termed primary progressive multiple sclerosis (PPMS); the underlying pathogenic mechanisms responsible for onset of the disease with either PPMS or relapsing remitting multiple sclerosis (RRMS) are unknown. Patients with PPMS do not show a female predominance and usually have a later onset of disease compared to patients with RRMS. Monozygous twins can be concordant or discordant for disease courses indicating that the disease course is not only genetically determined. Primary progressive multiple sclerosis and secondary progressive multiple sclerosis (SPMS) share many similarities in imaging and pathological findings. Differences observed among the different disease courses are more of a quantitative than qualitative nature suggesting that the different phenotypes are part of a disease spectrum modulated by individual genetic predisposition and environmental influences. In this review, we summarize the knowledge regarding the clinical, epidemiological, imaging, and pathological characteristics of PPMS and compare those characteristics with RRMS and SPMS.

  7. Uncovering disease-disease relationships through the incomplete human interactome

    Science.gov (United States)

    Menche, Jörg; Sharma, Amitabh; Kitsak, Maksim; Ghiassian, Susan; Vidal, Marc; Loscalzo, Joseph; Barabási, Albert-László

    2015-01-01

    According to the disease module hypothesis the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data has sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant co-expression patterns, symptom similarity, and comorbidity, while diseases residing in separated network neighborhoods are clinically distinct. These tools represent an interactome-based platform to predict molecular commonalities between clinically related diseases, even if they do not share disease genes. PMID:25700523

  8. Multiple immune disorders in unrecognized celiac disease: a case report

    Institute of Scientific and Technical Information of China (English)

    Giorgio La Villa; Peietro Pantaleo; Roberto Tarquini; Lino Cirami; Federico Perfetto; Francesco Mancuso; Giacomo Laffi

    2003-01-01

    We reported a female patient with unrecognized celiac disease and multiple extra intestinal manifestations, mainly related to a deranged immune function, including macroamilasemia, macrolipasemia, IgA nephropathy,thyroiditis, and anti-b2-glicoprotein-1 antibodies, that disappeared or improved after the implementation of a gluten-free diet.

  9. Fusion of Multiple Pyroelectric Characteristics for Human Body Identification

    Directory of Open Access Journals (Sweden)

    Wanchun Zhou

    2014-12-01

    Full Text Available Due to instability and poor identification ability of single pyroelectric infrared (PIR detector for human target identification, this paper proposes a new approach to fuse the information collected from multiple PIR sensors for human identification. Firstly, Fast Fourier Transform (FFT, Short Time Fourier Transform (STFT, Wavelet Transform (WT and Wavelet Packet Transform (WPT are adopted to extract features of the human body, which can be achieved by single PIR sensor. Then, we apply Principal Component Analysis (PCA and Support Vector Machine (SVM to reduce the characteristic dimensions and to classify the human targets, respectively. Finally, Fuzzy Comprehensive Evaluation (FCE is utilized to fuse recognition results from multiple PIR sensors to finalize human identification. The pyroelectric characteristics under scenarios with different people and/or different paths are analyzed by various experiments, and the recognition results with/without fusion procedure are also shown and compared. The experimental results demonstrate our scheme has improved efficiency for human identification.

  10. Bone marrow invasion in multiple myeloma and metastatic disease.

    Science.gov (United States)

    Vilanova, J C; Luna, A

    2016-04-01

    Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases.

  11. The prevalence of disease clusters in older adults with multiple chronic diseases: a systematic literature review.

    NARCIS (Netherlands)

    Sinnige, J.; Braspenning, J.; Schellevis, F.; Stirbu-Wagner, I.; Westert, G.; Korevaar, J.

    2013-01-01

    Background: Since most clinical guidelines address single diseases, treatment of patients with multimorbidity, the co-occurrence of multiple (chronic) diseases within one person, can become complicated. Information on highly prevalent combinations of diseases can set the agenda for guideline develop

  12. The prevalence of disease clusters in older adults with multiple chronic diseases - a systematic literature review

    NARCIS (Netherlands)

    Sinnige, J.; Braspenning, J.C.; Schellevis, F.; Stirbu-Wagner, I.; Westert, G.P.; Korevaar, J.

    2013-01-01

    BACKGROUND: Since most clinical guidelines address single diseases, treatment of patients with multimorbidity, the co-occurrence of multiple (chronic) diseases within one person, can become complicated. Information on highly prevalent combinations of diseases can set the agenda for guideline develop

  13. Does biodiversity protect humans against infectious disease?

    Science.gov (United States)

    Wood, Chelsea L; Lafferty, Kevin D; DeLeo, Giulio; Young, Hillary S; Hudson, Peter J; Kuris, Armand M

    2014-04-01

    Control of human infectious disease has been promoted as a valuable ecosystem service arising from the conservation of biodiversity. There are two commonly discussed mechanisms by which biodiversity loss could increase rates of infectious disease in a landscape. First, loss of competitors or predators could facilitate an increase in the abundance of competent reservoir hosts. Second, biodiversity loss could disproportionately affect non-competent, or less competent reservoir hosts, which would otherwise interfere with pathogen transmission to human populations by, for example, wasting the bites of infected vectors. A negative association between biodiversity and disease risk, sometimes called the "dilution effect hypothesis," has been supported for a few disease agents, suggests an exciting win-win outcome for the environment and society, and has become a pervasive topic in the disease ecology literature. Case studies have been assembled to argue that the dilution effect is general across disease agents. Less touted are examples in which elevated biodiversity does not affect or increases infectious disease risk for pathogens of public health concern. In order to assess the likely generality of the dilution effect, we review the association between biodiversity and public health across a broad variety of human disease agents. Overall, we hypothesize that conditions for the dilution effect are unlikely to be met for most important diseases of humans. Biodiversity probably has little net effect on most human infectious diseases but, when it does have an effect, observation and basic logic suggest that biodiversity will be more likely to increase than to decrease infectious disease risk.

  14. Human placental lactogen levels in multiple pregnancies.

    Science.gov (United States)

    Spellacy, W N; Buhi, W C; Birk, S A

    1978-08-01

    Serum human placental lactogen (hPL) levels were measured in duplicate with a radioimmunoassay in 206 serum samples at 30 and 36 weeks' gestation from women with normal singleton pregnancies (75) or pregnancies with twins (37). One triplet pregnancy was also studied. The results show a significant elevation of hPL in the women with twin pregnancies at both the 30th (7.0 vs 6.0 microgram/ml) and the 36th (9.2 vs 7.4 microgram/ml) weeks. One-third of the twin pregnancies had values of hPL in excess of 8.0 microgram/ml at 30 weeks and more than half had values in excess of 9.0 microgram/ml at 36 weeks. The triplet pregnancy had an hPL value of 11.0 microgram/ml at 36 weeks' gestation. These data support the potential usefulness of serum hPL measurements in the screening profile for the detection of high-risk pregnancies.

  15. A Speedy Cardiovascular Diseases Classifier Using Multiple Criteria Decision Analysis

    Directory of Open Access Journals (Sweden)

    Wah Ching Lee

    2015-01-01

    Full Text Available Each year, some 30 percent of global deaths are caused by cardiovascular diseases. This figure is worsening due to both the increasing elderly population and severe shortages of medical personnel. The development of a cardiovascular diseases classifier (CDC for auto-diagnosis will help address solve the problem. Former CDCs did not achieve quick evaluation of cardiovascular diseases. In this letter, a new CDC to achieve speedy detection is investigated. This investigation incorporates the analytic hierarchy process (AHP-based multiple criteria decision analysis (MCDA to develop feature vectors using a Support Vector Machine. The MCDA facilitates the efficient assignment of appropriate weightings to potential patients, thus scaling down the number of features. Since the new CDC will only adopt the most meaningful features for discrimination between healthy persons versus cardiovascular disease patients, a speedy detection of cardiovascular diseases has been successfully implemented.

  16. Parasitic diseases in humans transmitted by vectors.

    Science.gov (United States)

    Cholewiński, Marcin; Derda, Monika; Hadaś, Edward

    2015-01-01

    Despite the considerable progress of medicine, parasitic diseases still pose a great threat to human health and life. Among parasitic diseases, those transmitted by vectors, mainly arthropods, play a particular role. These diseases occur most frequently in the poorest countries and affect a vast part of the human population. They include malaria, babesiosis, trypanosomiasis, leishmaniasis and filariasis. This study presents those vector-transmitted diseases that are responsible for the greatest incidence and mortality of people on a global scale. Attention is focused primarily on diseases transmitted by mosquitoes, flies, Hemiptera and ticks.

  17. Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations.

    Science.gov (United States)

    Shi, Hongbo; Zhang, Guangde; Zhou, Meng; Cheng, Liang; Yang, Haixiu; Wang, Jing; Sun, Jie; Wang, Zhenzhen

    2016-01-01

    MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD.

  18. A single-arm, open-label, phase 2 clinical trial evaluating disease response following treatment with BI-505, a human anti-intercellular adhesion molecule-1 monoclonal antibody, in patients with smoldering multiple myeloma

    Science.gov (United States)

    Wichert, Stina; Juliusson, Gunnar; Johansson, Åsa; Sonesson, Elisabeth; Teige, Ingrid; Wickenberg, Anna Teige; Frendeus, Björn; Korsgren, Magnus; Hansson, Markus

    2017-01-01

    Background Smoldering multiple myeloma (SMM) is an indolent disease stage, considered to represent the transition phase from the premalignant MGUS (Monoclonal Gammopathy of Undetermined Significance) state towards symptomatic multiple myeloma (MM). Even though this diagnosis provides an opportunity for early intervention, few treatment studies have been done and the current standard of care is observation until progression. BI-505, a monoclonal antibody directed against intercellular adhesion molecule 1 (ICAM-1) with promising anti-myeloma activity in preclinical trials, is a possible treatment approach for this patient category with potential to eliminate tumor cells with minimal long-term side effects. BI-505 was well tolerated in an earlier phase 1 trial. Methods and findings In this phase 2 trial the effects of BI-505 in patients with SMM were studied. Four patients were enrolled and three of them completed the first cycle of treatment defined as 5 doses of BI-505, a total of 43 mg/kg BW, over a 7-week period. In the three evaluable patients, BI-505 showed a benign safety profile. None of the patients achieved a response as defined per protocol. EudraCT number: 2012-004884-29. Conclusions The study was conducted to assess the efficacy, safety and pharmacodynamics of BI-505 in patients with SMM. BI-505 showed no clinically relevant efficacy on disease activity in these patients with SMM, even if well tolerated. Trial registration ClinicalTrials.gov Identifier: NCT01838369. PMID:28158311

  19. First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.

    Science.gov (United States)

    Herrmann, Ken; Schottelius, Margret; Lapa, Constantin; Osl, Theresa; Poschenrieder, Andreas; Hänscheid, Heribert; Lückerath, Katharina; Schreder, Martin; Bluemel, Christina; Knott, Markus; Keller, Ulrich; Schirbel, Andreas; Samnick, Samuel; Lassmann, Michael; Kropf, Saskia; Buck, Andreas K; Einsele, Hermann; Wester, Hans-Juergen; Knop, Stefan

    2016-02-01

    Chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radiolabeled CXCR4 ligand ((68)Ga-pentixafor) for diagnostic receptor targeting, (177)Lu- and (90)Y-pentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first-in-human experience in 3 heavily pretreated patients with intramedullary and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy. CXCR4 target expression was demonstrated by baseline (68)Ga-pentixafor PET. Each treatment was approved by the clinical ethics committee. Pretherapeutic (177)Lu-pentixather dosimetry was performed before (177)Lu-pentixather or (90)Y-pentixather treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation for bone marrow rescue. A remarkable therapeutic effect was visualized in 2 patients, who showed a significant reduction in (18)F-FDG uptake. CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous stem cell transplantation, especially for patients with advanced multiple myeloma. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  20. Statin Induced Myopathy a Patient with Multiple Systemic Diseases

    Directory of Open Access Journals (Sweden)

    Özgül Uçar

    2011-04-01

    Full Text Available Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins are the most successful class of drugs for the treatment of hypercholesterolaemia and dyslipidaemia. However, the popular profile of statins in terms of efficacy has been maligned by theiradverse effects. Statin induced myopathy, which can be seen at any time during the course of therapy, is a clinically important cause of statin intolerance and discontinuation. When a patient with multiple systemic diseases who use numerous medications represent with myalgia and muscle cramps, statin induced myopathy may not be remembered at first. We present a patient with multiple systemic diseases, alcohol and morphine abuse in whom myopathy developed. After exclusion of other etiologies, we concluded that myopathy was related to statin therapy.

  1. Multiple Sclerosis: two clinical presentations, a single disease!

    Directory of Open Access Journals (Sweden)

    Ana Margarida Ferreira da Silva

    2014-09-01

    Full Text Available Objective: this case report aims to demonstrate the diversity of clinical presentations, the symptoms evolution and the role of the primary care physician in the diagnosis and management of patients with multiple sclerosis, and their families. Case descriptions: two women, 31 and 28 years old, Caucasian, inserted within nuclear families (phases II and IV of the Duvall’ cycle, respectively belonging to the middle class of Graffar. The first one starts an insidious symptom of paraesthesia of the hands with improvement in 2 months. Within a year, she presents with difficulty raising the eyelids and marked imbalance. The second one presents sudden loss of visual acuity on the right, having been diagnosed with optic neuritis. Both were diagnosed with multiple sclerosis. Conclusion: multiple sclerosis is a chronic inflammatory, degenerative and demyelinating disease of the central nervous system that manifests heterogeneously. It is important for the family doctor to know how to deal with diagnostic uncertainties.

  2. Disease-modifying treatments for progressive multiple sclerosis.

    Science.gov (United States)

    Comi, Giancarlo

    2013-10-01

    The last 20 years have seen major progress in the treatment of relapsing-remitting multiple sclerosis (RRMS) using a variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging from laboratory science and animal models.

  3. Statin Induced Myopathy a Patient with Multiple Systemic Diseases

    OpenAIRE

    Özgül Uçar; İbrahim Kocaoğlu; Ahmet Karagöz; Serkan Gökaslan

    2011-01-01

    Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are the most successful class of drugs for the treatment of hypercholesterolaemia and dyslipidaemia. However, the popular profile of statins in terms of efficacy has been maligned by theiradverse effects. Statin induced myopathy, which can be seen at any time during the course of therapy, is a clinically important cause of statin intolerance and discontinuation. When a patient with multiple systemic diseases who use numerous medi...

  4. Stem cell differentiation and human liver disease

    Institute of Scientific and Technical Information of China (English)

    Wen-Li Zhou; Claire N Medine; Liang Zhu; David C Hay

    2012-01-01

    Human stem cells are scalable cell populations capable of cellular differentiation.This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells.Such an approach has the potential to improve our understanding of human biology and treating disease.In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases.In recent years,efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own.In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.

  5. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis?

    DEFF Research Database (Denmark)

    Dalgas, Ulrik; Stenager, Egon

    2012-01-01

    It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or...... activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise......, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data...

  6. Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases.

    Science.gov (United States)

    Schoch, Kathleen M; Miller, Timothy M

    2017-06-21

    Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases, given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Reduced penetrance in human inherited disease

    African Journals Online (AJOL)

    Rabah M. Shawky

    2014-01-31

    Jan 31, 2014 ... tant role in cellular senescence, tumorigenesis and in several diseases ... A correlation between epigenetic DNA modifications and human life span ... Most studies demonstrated that aging is associated with a relaxation in ...

  8. Molecular functions of human endogenous retroviruses in health and disease.

    Science.gov (United States)

    Suntsova, Maria; Garazha, Andrew; Ivanova, Alena; Kaminsky, Dmitry; Zhavoronkov, Alex; Buzdin, Anton

    2015-10-01

    Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

  9. Multiple isoforms of the human pentraxin serum amyloid P component

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Human serum amyloid P component (SAP) isolated from 20 healthy individuals was analyzed by anion exchange chromatography and isoelectric focusing (IEF) in order to investigate the existence of multiple forms of SAP and interindividual structural differences. Anion exchange chromatography showed one...

  10. Protein Misfolding and Human Disease

    DEFF Research Database (Denmark)

    Gregersen, Niels; Bross, Peter Gerd; Vang, Søren

    2006-01-01

    phenylketonuria, Parkinson's disease, α-1-antitrypsin deficiency, familial neurohypophyseal diabetes insipidus, and short-chain acyl-CoA dehydrogenase deficiency. Despite the differences, an emerging paradigm suggests that the cellular effects of protein misfolding provide a common framework that may contribute......Protein misfolding is a common event in living cells. In young and healthy cells, the misfolded protein load is disposed of by protein quality control (PQC) systems. In aging cells and in cells from certain individuals with genetic diseases, the load may overwhelm the PQC capacity, resulting...... in accumulation of misfolded proteins. Dependent on the properties of the protein and the efficiency of the PQC systems, the accumulated protein may be degraded or assembled into toxic oligomers and aggregates. To illustrate this concept, we discuss a number of very different protein misfolding diseases including...

  11. Physiochemical basis of human degenerative disease

    Directory of Open Access Journals (Sweden)

    Zeliger Harold I.

    2015-03-01

    Full Text Available The onset of human degenerative diseases in humans, including type 2 diabetes, cardiovascular disease, neurological disorders, neurodevelopmental disease and neurodegenerative disease has been shown to be related to exposures to persistent organic pollutants, including polychlorinated biphenyls, chlorinated pesticides, polybrominated diphenyl ethers and others, as well as to polynuclear aromatic hydrocarbons, phthalates, bisphenol-A and other aromatic lipophilic species. The onset of these diseases has also been related to exposures to transition metal ions. A physiochemical mechanism for the onset of degenerative environmental disease dependent upon exposure to a combination of lipophilic aromatic hydrocarbons and transition metal ions is proposed here. The findings reported here also, for the first time, explain why aromatic hydrocarbons exhibit greater toxicity than aliphatic hydrocarbons of equal carbon numbers.

  12. Human Echinococcosis: A Neglected Disease

    Directory of Open Access Journals (Sweden)

    António Menezes da Silva

    2010-01-01

    Full Text Available Echinococcosis is among the most neglected parasitic diseases. Development of new drugs and other treatment modalities receives very little attention, if any. In most developed countries, Cystic Echinococcosis (CE is an imported disease of very low incidence and prevalence and is found almost exclusively in migrants from endemic regions. In endemic regions, predominantly settings with limited resources, patient numbers are high. Whole communities do not have access to appropriate treatment. The choice of treatment modalities is limited because of poor infrastructure and shortage of equipment and drugs. In this context, CE meets the criteria for a neglected disease. Furthermore, the terminology related to the designations around the parasite, its evolution and some therapeutic procedures is not uniform and sometimes inappropriate terms and wrong designations are used based on incorrect concepts. Although all of us know the different aspects of the disease it is pertinent to remember some important points and, above all, to clarify some aspects concerning the hydatid cyst's nomenclature in order to understand better the therapeutic options in the liver locations, particularly the different surgical approaches.

  13. Molecular Pathology of Human Prion Diseases

    Directory of Open Access Journals (Sweden)

    2009-03-01

    Full Text Available Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis.

  14. Molecular basis of telomere dysfunction in human genetic diseases.

    Science.gov (United States)

    Sarek, Grzegorz; Marzec, Paulina; Margalef, Pol; Boulton, Simon J

    2015-11-01

    Mutations in genes encoding proteins required for telomere structure, replication, repair and length maintenance are associated with several debilitating human genetic disorders. These complex telomere biology disorders (TBDs) give rise to critically short telomeres that affect the homeostasis of multiple organs. Furthermore, genome instability is often a hallmark of telomere syndromes, which are associated with increased cancer risk. Here, we summarize the molecular causes and cellular consequences of disease-causing mutations associated with telomere dysfunction.

  15. [Primary human demodicosis. A disease sui generis].

    Science.gov (United States)

    Hsu, C-K; Zink, A; Wei, K-J; Dzika, E; Plewig, G; Chen, W

    2015-03-01

    Human Demodex mites (Demodex folliculorum and Demodex brevis) are unique in that they are an obligate human ectoparasite that can inhabit the pilosebaceous unit lifelong without causing obvious host immune response in most cases. The mode of symbiosis between humans and human Demodex mites is unclear, while the pathogenicity of human Demodex mites in many inflammatory skin diseases is now better understood. Primary human demodicosis is a skin disease sui generis not associated with local or systemic immunosuppression. Diagnosis is often underestimated and differentiation from folliculitis, papulopustular rosacea and perioral dermatitis is not always straightforward. Dependent on the morphology and degree of inflammation, the clinical manifestations can be classified into spinulate, papulopustular, nodulocystic, crustic and fulminant demodicosis. Therapy success can be achieved only with acaricides/arachidicides. The effective doses, optimal regimen and antimicrobial resistance remain to be determined.

  16. Global biogeography of human infectious diseases.

    Science.gov (United States)

    Murray, Kris A; Preston, Nicholas; Allen, Toph; Zambrana-Torrelio, Carlos; Hosseini, Parviez R; Daszak, Peter

    2015-10-13

    The distributions of most infectious agents causing disease in humans are poorly resolved or unknown. However, poorly known and unknown agents contribute to the global burden of disease and will underlie many future disease risks. Existing patterns of infectious disease co-occurrence could thus play a critical role in resolving or anticipating current and future disease threats. We analyzed the global occurrence patterns of 187 human infectious diseases across 225 countries and seven epidemiological classes (human-specific, zoonotic, vector-borne, non-vector-borne, bacterial, viral, and parasitic) to show that human infectious diseases exhibit distinct spatial grouping patterns at a global scale. We demonstrate, using outbreaks of Ebola virus as a test case, that this spatial structuring provides an untapped source of prior information that could be used to tighten the focus of a range of health-related research and management activities at early stages or in data-poor settings, including disease surveillance, outbreak responses, or optimizing pathogen discovery. In examining the correlates of these spatial patterns, among a range of geographic, epidemiological, environmental, and social factors, mammalian biodiversity was the strongest predictor of infectious disease co-occurrence overall and for six of the seven disease classes examined, giving rise to a striking congruence between global pathogeographic and "Wallacean" zoogeographic patterns. This clear biogeographic signal suggests that infectious disease assemblages remain fundamentally constrained in their distributions by ecological barriers to dispersal or establishment, despite the homogenizing forces of globalization. Pathogeography thus provides an overarching context in which other factors promoting infectious disease emergence and spread are set.

  17. Cis-regulatory mutations in human disease.

    Science.gov (United States)

    Epstein, Douglas J

    2009-07-01

    Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few.

  18. Disease-modifying therapies in relapsing–remitting multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Fabricio González-Andrade

    2010-07-01

    Full Text Available Fabricio González-Andrade1, José Luis Alcaraz-Alvarez21Department of Medicine, Metropolitan Hospital, Quito, Ecuador; 2School of Medicine, University of Mayab, Merida, MexicoClinical question: What is the best current disease-modifying therapy for relapsing–remitting multiple sclerosis?Results: The evidence shows that the most effective disease-modifying therapy for delaying short- to medium-term disability progression, prevention of relapses, reducing the area and activity of lesions on magnetic resonance imaging, with the least side effects, is high-dose, high-frequency subcutaneous interferon-β1a 44 μg three times per week.Implementation: The pitfalls in treatment of MS can be avoided by remembering the following points: • The most effective therapy to prevent or delay the appearance of permanent neurological disability with the fewest side effects should be chosen, and treatment should not be delayed.• Adherence to treatment should be monitored closely, and needs comprehensive patient information and education to establish long-term adherence, which is a critical determinant of long-term outcome.• The correct approach to the disease includes disease management, symptom management, and patient management. A combination of tools is necessary to ease the various symptoms, which fall into three broad categories, i.e. rehabilitation, pharmacological, and procedural.• It is important to understand that no treatment modality should be used alone, unless it is in itself sufficient to remedy the particular symptom/problem.Keywords: relapsing–remitting multiple sclerosis, interferon, disease-modifying therapy, relapse prevention

  19. Multiple aspects of gene dysregulation in Huntington’s Disease.

    Directory of Open Access Journals (Sweden)

    Lara eMoumne

    2013-10-01

    Full Text Available Huntington’s Disease (HD is a genetic neurodegenerative disease caused by a CAG expansion in the gene encoding Huntingtin (Htt. It is characterized by chorea, cognitive and psychiatric disorders. The most affected brain region is the striatum, and the clinical symptoms are directly correlated to the rate of striatal degeneration. The wild-type Htt is a ubiquitous protein and its deletion is lethal. Mutated (expanded Htt produces excitotoxicity, mitochondrial dysfunctions, axonal transport deficit, altered proteasome activity, and gene dysregulation. Transcriptional dysregulation occurs at early neuropathological stages in HD patients. Multiple genes are dysregulated, with overlaps of altered transcripts between mouse models of HD and patient brains. Nuclear localization of Exp-Htt interferes with transcription factors, co-activators and proteins of the transcriptional machinery. Another key mechanism described so far, is an alteration of cytoplasmic retention of the transcriptional repressor REST, which is normally associated with wild-type Htt. As such, Exp-Htt causes alteration of transcription of multiple genes involved in neuronal survival, plasticity, signaling and mitochondrial biogenesis and respiration. Besides these transcriptional dysregulations, Exp-Htt affects the chromatin structure through altered post-translational modifications (PTM of histones and methylation of DNA. Multiple alterations of histone PTM are described, including acetylation, methylation, ubiquitylation, polyamination and phosphorylation. Exp-Htt also affects the expression and regulation of non-coding microRNAs. First multiple neural microRNAs are controlled by REST, and dysregulated in HD, with concomitant de-repression of downstream mRNA targets. Second, Exp-Htt protein or RNA may also play a major role in the processing of miRNAs and hence pathogenesis. These pleiotropic effects of Exp-Htt on gene expression may represent seminal deleterious effects on the

  20. Genomic Physics. Multiple Laser Beam Treatment of Alzheimer's Disease

    Science.gov (United States)

    Stefan, V. Alexander

    2014-03-01

    The synapses affected by Alzheimer's disease can be rejuvenated by the multiple ultrashort wavelength laser beams.[2] The guiding lasers scan the whole area to detect the amyloid plaques based on the laser scattering technique. The scanning lasers pinpoint the areas with plaques and eliminate them. Laser interaction is highly efficient, because of the focusing capabilities and possibility for the identification of the damaging proteins by matching the protein oscillation eigen-frequency with laser frequency.[3] Supported by Nikola Tesla Labs, La Jolla, California, USA.

  1. Human genetic variation and the gut microbiome in disease.

    Science.gov (United States)

    Hall, Andrew Brantley; Tolonen, Andrew C; Xavier, Ramnik J

    2017-08-21

    Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

  2. A Bayesian Hierarchical Model for Relating Multiple SNPs within Multiple Genes to Disease Risk

    Directory of Open Access Journals (Sweden)

    Lewei Duan

    2013-01-01

    Full Text Available A variety of methods have been proposed for studying the association of multiple genes thought to be involved in a common pathway for a particular disease. Here, we present an extension of a Bayesian hierarchical modeling strategy that allows for multiple SNPs within each gene, with external prior information at either the SNP or gene level. The model involves variable selection at the SNP level through latent indicator variables and Bayesian shrinkage at the gene level towards a prior mean vector and covariance matrix that depend on external information. The entire model is fitted using Markov chain Monte Carlo methods. Simulation studies show that the approach is capable of recovering many of the truly causal SNPs and genes, depending upon their frequency and size of their effects. The method is applied to data on 504 SNPs in 38 candidate genes involved in DNA damage response in the WECARE study of second breast cancers in relation to radiotherapy exposure.

  3. A Case of Multiple Sclerosis and Celiac Disease

    Directory of Open Access Journals (Sweden)

    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.

  4. Expanding specificity of class I restricted CD8+ T cells for viral epitopes following multiple inoculations of swine with a human adenovirus vectored foot-and-mouth disease virus (FMDV) vaccine

    DEFF Research Database (Denmark)

    Pedersen, Lasse E.; Patch, Jared R; Kenney, Mary

    2016-01-01

    The immune response to the highly acute foot-and-mouth disease virus (FMDV) is routinely reported as a measure of serum antibody. However, a critical effector function of immune responses combating viral infection of mammals is the cytotoxic T lymphocyte (CTL) response mediated by virus specific CD......8 expressing T cells. This immune mechanism arrests viral spread by killing virus infected cells before new, mature virus can develop. We have previously shown that infection of swine by FMDV results in a measurable CTL response and have correlated CTL killing of virus-infected cells with specific...... class I major histocompatibility complex (MHC) tetramer staining. We also showed that a modified replication defective human adenovirus 5 vector expressing the FMDV structural proteins (Ad5-FMDV-T vaccine) targets the induction of a CD8(+) CTL response with a minimal humoral response. In this report, we...

  5. The complement system in human cardiometabolic disease.

    Science.gov (United States)

    Hertle, E; Stehouwer, C D A; van Greevenbroek, M M J

    2014-10-01

    The complement system has been implicated in obesity, fatty liver, diabetes and cardiovascular disease (CVD). Complement factors are produced in adipose tissue and appear to be involved in adipose tissue metabolism and local inflammation. Thereby complement links adipose tissue inflammation to systemic metabolic derangements, such as low-grade inflammation, insulin resistance and dyslipidaemia. Furthermore, complement has been implicated in pathophysiological mechanisms of diet- and alcohol induced liver damage, hyperglycaemia, endothelial dysfunction, atherosclerosis and fibrinolysis. In this review, we summarize current evidence on the role of the complement system in several processes of human cardiometabolic disease. C3 is the central component in complement activation, and has most widely been studied in humans. C3 concentrations are associated with insulin resistance, liver dysfunction, risk of the metabolic syndrome, type 2 diabetes and CVD. C3 can be activated by the classical, the lectin and the alternative pathway of complement activation; and downstream activation of C3 activates the terminal pathway. Complement may also be activated via extrinsic proteases of the coagulation, fibrinolysis and the kinin systems. Studies on the different complement activation pathways in human cardiometabolic disease are limited, but available evidence suggests that they may have distinct roles in processes underlying cardiometabolic disease. The lectin pathway appeared beneficial in some studies on type 2 diabetes and CVD, while factors of the classical and the alternative pathway were related to unfavourable cardiometabolic traits. The terminal complement pathway was also implicated in insulin resistance and liver disease, and appears to have a prominent role in acute and advanced CVD. The available human data suggest a complex and potentially causal role for the complement system in human cardiometabolic disease. Further, preferably longitudinal studies are needed to

  6. 75 FR 62487 - Compassionate Allowances for Cardiovascular Disease and Multiple Organ Transplants, Office of the...

    Science.gov (United States)

    2010-10-12

    ... Organ Transplants, Office of the Commissioner, Hearing AGENCY: Social Security Administration. ACTION... children with cardiovascular diseases and multiple organ transplants. We plan to address other medical... adults and children with cardiovascular disease and multiple organ transplants, as well as topics...

  7. Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.

    Science.gov (United States)

    Xu, You-hai; Xu, Kui; Sun, Ying; Liou, Benjamin; Quinn, Brian; Li, Rong-hua; Xue, Ling; Zhang, Wujuan; Setchell, Kenneth D R; Witte, David; Grabowski, Gregory A

    2014-08-01

    Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid β-glucosidase (GCase) and the resultant glucosylceramide (GC)/glucosylsphingosine (GS) accumulation in visceral organs (Type 1) and the central nervous system (Types 2 and 3). Recent clinical and genetic studies implicate a pathogenic link between Gaucher and neurodegenerative diseases. The aggregation and inclusion bodies of α-synuclein with ubiquitin are present in the brains of Gaucher disease patients and mouse models. Indirect evidence of β-amyloid pathology promoting α-synuclein fibrillation supports these pathogenic proteins as a common feature in neurodegenerative diseases. Here, multiple proteins are implicated in the pathogenesis of chronic neuronopathic Gaucher disease (nGD). Immunohistochemical and biochemical analyses showed significant amounts of β-amyloid and amyloid precursor protein (APP) aggregates in the cortex, hippocampus, stratum and substantia nigra of the nGD mice. APP aggregates were in neuronal cells and colocalized with α-synuclein signals. A majority of APP co-localized with the mitochondrial markers TOM40 and Cox IV; a small portion co-localized with the autophagy proteins, P62/LC3, and the lysosomal marker, LAMP1. In cultured wild-type brain cortical neural cells, the GCase-irreversible inhibitor, conduritol B epoxide (CBE), reproduced the APP/α-synuclein aggregation and the accumulation of GC/GS. Ultrastructural studies showed numerous larger-sized and electron-dense mitochondria in nGD cerebral cortical neural cells. Significant reductions of mitochondrial adenosine triphosphate production and oxygen consumption (28-40%) were detected in nGD brains and in CBE-treated neural cells. These studies implicate defective GCase function and GC/GS accumulation as risk factors for mitochondrial dysfunction and the multi-proteinopathies (α-synuclein-, APP- and Aβ-aggregates) in nGD.

  8. Closely spaced multiple mutations as potential signatures of transient hypermutability in human genes.

    Science.gov (United States)

    Chen, Jian-Min; Férec, Claude; Cooper, David N

    2009-10-01

    Data from diverse organisms suggests that transient hypermutability is a general mutational mechanism with the potential to generate multiple synchronous mutations, a phenomenon probably best exemplified by closely spaced multiple mutations (CSMMs). Here we have attempted to extend the concept of transient hypermutability from somatic cells to the germline, using human inherited disease-causing multiple mutations as a model system. Employing stringent criteria for data inclusion, we have retrospectively identified numerous potential examples of pathogenic CSMMs that exhibit marked similarities to the CSMMs reported in other systems. These examples include (1) eight multiple mutations, each comprising three or more components within a sequence tract of mutation showers"; and (3) numerous highly informative "homocoordinate" mutations. Using the proportion of CpG substitution as a crude indicator of the relative likelihood of transient hypermutability, we present evidence to suggest that CSMMs comprising at least one pair of mutations separated by mutation screening.

  9. Engineering large animal models of human disease.

    Science.gov (United States)

    Whitelaw, C Bruce A; Sheets, Timothy P; Lillico, Simon G; Telugu, Bhanu P

    2016-01-01

    The recent development of gene editing tools and methodology for use in livestock enables the production of new animal disease models. These tools facilitate site-specific mutation of the genome, allowing animals carrying known human disease mutations to be produced. In this review, we describe the various gene editing tools and how they can be used for a range of large animal models of diseases. This genomic technology is in its infancy but the expectation is that through the use of gene editing tools we will see a dramatic increase in animal model resources available for both the study of human disease and the translation of this knowledge into the clinic. Comparative pathology will be central to the productive use of these animal models and the successful translation of new therapeutic strategies.

  10. Molecular mechanisms of acrolein toxicity: relevance to human disease.

    Science.gov (United States)

    Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan; Mohammad, Mohammad; Barve, Shirish; McClain, Craig; Joshi-Barve, Swati

    2015-02-01

    Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer's disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies.

  11. Variants associated with Gaucher disease in multiple system atrophy

    Science.gov (United States)

    Mitsui, Jun; Matsukawa, Takashi; Sasaki, Hidenao; Yabe, Ichiro; Matsushima, Masaaki; Dürr, Alexandra; Brice, Alexis; Takashima, Hiroshi; Kikuchi, Akio; Aoki, Masashi; Ishiura, Hiroyuki; Yasuda, Tsutomu; Date, Hidetoshi; Ahsan, Budrul; Iwata, Atsushi; Goto, Jun; Ichikawa, Yaeko; Nakahara, Yasuo; Momose, Yoshio; Takahashi, Yuji; Hara, Kenju; Kakita, Akiyoshi; Yamada, Mitsunori; Takahashi, Hitoshi; Onodera, Osamu; Nishizawa, Masatoyo; Watanabe, Hirohisa; Ito, Mizuki; Sobue, Gen; Ishikawa, Kinya; Mizusawa, Hidehiro; Kanai, Kazuaki; Hattori, Takamichi; Kuwabara, Satoshi; Arai, Kimihito; Koyano, Shigeru; Kuroiwa, Yoshiyuki; Hasegawa, Kazuko; Yuasa, Tatsuhiko; Yasui, Kenichi; Nakashima, Kenji; Ito, Hijiri; Izumi, Yuishin; Kaji, Ryuji; Kato, Takeo; Kusunoki, Susumu; Osaki, Yasushi; Horiuchi, Masahiro; Kondo, Tomoyoshi; Murayama, Shigeo; Hattori, Nobutaka; Yamamoto, Mitsutoshi; Murata, Miho; Satake, Wataru; Toda, Tatsushi; Filla, Alessandro; Klockgether, Thomas; Wüllner, Ullrich; Nicholson, Garth; Gilman, Sid; Tanner, Caroline M; Kukull, Walter A; Stern, Mathew B; Lee, Virginia M-Y; Trojanowski, John Q; Masliah, Eliezer; Low, Phillip A; Sandroni, Paola; Ozelius, Laurie J; Foroud, Tatiana; Tsuji, Shoji

    2015-01-01

    Objective Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series. Methods We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel–Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14–5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15–5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10−3). Interpretation The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA. PMID:25909086

  12. Jointly Learning Multiple Sequential Dynamics for Human Action Recognition.

    Directory of Open Access Journals (Sweden)

    An-An Liu

    Full Text Available Discovering visual dynamics during human actions is a challenging task for human action recognition. To deal with this problem, we theoretically propose the multi-task conditional random fields model and explore its application on human action recognition. For visual representation, we propose the part-induced spatiotemporal action unit sequence to represent each action sample with multiple partwise sequential feature subspaces. For model learning, we propose the multi-task conditional random fields (MTCRFs model to discover the sequence-specific structure and the sequence-shared relationship. Specifically, the multi-chain graph structure and the corresponding probabilistic model are designed to represent the interaction among multiple part-induced action unit sequences. Moreover we propose the model learning and inference methods to discover temporal context within individual action unit sequence and the latent correlation among different body parts. Extensive experiments are implemented to demonstrate the superiority of the proposed method on two popular RGB human action datasets, KTH & TJU, and the depth dataset in MSR Daily Activity 3D.

  13. Single and Multiple Gene Manipulations in Mouse Models of Human Cancer

    Science.gov (United States)

    Lehman, Heather L; Stairs, Douglas B

    2015-01-01

    Mouse models of human cancer play a critical role in understanding the molecular and cellular mechanisms of tumorigenesis. Advances continue to be made in modeling human disease in a mouse, though the relevance of a mouse model often relies on how closely it is able to mimic the histologic, molecular, and physiologic characteristics of the respective human cancer. A classic use of a genetically engineered mouse in studying cancer is through the overexpression or deletion of a gene. However, the manipulation of a single gene often falls short of mimicking all the characteristics of the carcinoma in humans; thus a multiple gene approach is needed. Here we review genetic mouse models of cancers and their abilities to recapitulate human carcinoma with single versus combinatorial approaches with genes commonly involved in cancer. PMID:26380553

  14. Dendritic Cells and Multiple Sclerosis: Disease, Tolerance and Therapy

    Directory of Open Access Journals (Sweden)

    Mohammad G. Mohammad

    2012-12-01

    Full Text Available Multiple sclerosis (MS is a devastating neurological disease that predominantly affects young adults resulting in severe personal and economic impact. The majority of therapies for this disease were developed in, or are beneficial in experimental autoimmune encephalomyelitis (EAE, the animal model of MS. While known to target adaptive anti-CNS immune responses, they also target, the innate immune arm. This mini-review focuses on the role of dendritic cells (DCs, the professional antigen presenting cells of the innate immune system. The evidence for a role for DCs in the appropriate regulation of anti-CNS autoimmune responses and their role in MS disease susceptibility and possible therapeutic utility are discussed. Additionally, the current controversy regarding the evidence for the presence of functional DCs in the normal CNS is reviewed. Furthermore, the role of CNS DCs and potential routes of their intercourse between the CNS and cervical lymph nodes are considered. Finally, the future role that this nexus between the CNS and the cervical lymph nodes might play in site directed molecular and cellular therapy for MS is outlined.

  15. PXR- and CAR-mediated herbal effect on human diseases.

    Science.gov (United States)

    Xu, Chenshu; Huang, Min; Bi, Huichang

    2016-09-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that regulate a broad range of genes involved in drug metabolism and transport. A variety of naturally occurring compounds present in herbal medicines were identified as ligands of PXR and CAR. Recently, accumulative evidences have revealed the PXR- and CAR-mediated herbal effect against multiple human diseases, including inflammatory bowel disease (IBD), cholestatic liver disease, and jaundice. The current review summarized the recent progress in identifying the expanding libraries of herbal medicine as ligands for PXR and CAR. Moreover, the potential for herbal medicines as promising therapeutic agents which were mainly regulated through PXR/CAR signaling pathways was also discussed. The discovery of herbal medicines as modulators of PXR and CAR, and their PXR- and CAR-mediated effect on human diseases will provide a basis for rational drug design, and eventually be explored as a novel therapeutic approach against human diseases. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

  16. 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

  17. The role of melatonin in multiple sclerosis, Huntington's disease and cerebral ischemia.

    Science.gov (United States)

    Escribano, Begoña M; Colín-González, Ana L; Santamaría, Abel; Túnez, Isaac

    2014-01-01

    Melatonin is produced and released by the pineal gland in a circadian rhythm. This neurohormone has proven to be an antioxidant and anti-inflammatory molecule able to reduce or mitigate cell damage associated with oxidative stress and inflammation, and this phenomenon underlies neurodegenerative disorders. These facts have drawn attention to this indole, triggering interest in evaluating its changes and in its relationship to the processes indicated, and analyzing its role in the mechanisms involved at the onset and development of neurodegenerative diseases, as well as its therapeutic potential. Multiple sclerosis, the most common cause of non-traumatic disability in young adults, is a chronic neuroinflammatory disease, characterized by demyelination, inflammation, and neuronal and oxidative damage. In its early diagnosis, it often requires a differential screening with other neurodegenerative diseases with similar symptoms, such as Huntington's disease, an autosomal dominant disorder. The onset of both diseases occurs in the second or third decade of life. On the other hand, cerebral ischemia is a major cause of human disability all over the world. Although a cerebral stroke can occur as the result of different damaging insults, severe ischemia produces the death of neuronal cells within minutes. Changes in melatonin levels have been observed in these processes (Huntington's disease, multiple sclerosis and cerebral ischemia) as part of their pathogenic features. This review aims to update and discuss the role played by melatonin during neurodegenerative processes, specifically in multiple sclerosis, Huntington's disease, and cerebral ischemia, and its possible therapeutic use. We also provide readers with an update on the many neuroprotective mechanisms exerted by this neurohormone in the Central Nervous System.

  18. Modeling human muscle disease in zebrafish

    OpenAIRE

    Guyon, Jeffrey R.; Steffen, Leta S; Howell, Melanie H.; Pusack, Timothy J; Lawrence, Chris; Kunkel, Louis M

    2007-01-01

    Modeling human muscle disease in zebrafish correspondence: Corresponding author. Children's Hospital Boston, Enders Bldg, Rm 570, 300 Longwood Ave Boston, MA 02115. Tel.: +1 617 355 7576. (Kunkel, Louis M.) (Kunkel, Louis M.) Program in Genomics and Howard Hughes Medical Institute at Children's Hospital Boston - Boston--> , MA 02115--> - UNITED STATES (Guyon, Jeffrey R.) Program in Genomics a...

  19. Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies.

    Science.gov (United States)

    Quaio, Caio R D C; Carvalho, Jozélio F; da Silva, Clovis A; Bueno, Cleonice; Brasil, Amanda S; Pereira, Alexandre C; Jorge, Alexander A L; Malaquias, Alexsandra C; Kim, Chong A; Bertola, Débora R

    2012-05-01

    The association of RASopathies [Noonan syndrome (NS) and Noonan-related syndromes] and autoimmune disorders has been reported sporadically. However, a concomitant evaluation of autoimmune diseases and an assessment of multiple autoantibodies in a large population of patients with molecularly confirmed RASopathy have not been performed. The clinical and laboratory features were analyzed in 42 RASopathy patients, the majority of whom had NS and five individuals had Noonan-related disorders. The following autoantibodies were measured: Anti-nuclear antibodies, anti-double stranded DNA, anti-SS-A/Ro, anti-SS-B/La, anti-Sm, anti-RNP, anti-Scl-70, anti-Jo-1, anti-ribosomal P, IgG and IgM anticardiolipin (aCL), thyroid, anti-smooth muscle, anti-endomysial (AE), anti-liver cytosolic protein type 1 (LC1), anti-parietal cell (APC), anti-mitochondrial (AM) antibodies, anti-liver-kidney microsome type 1 antibodies (LKM-1), and lupus anticoagulant. Six patients (14%) fulfilled the clinical criteria for autoimmune diseases [systemic lupus erythematous, polyendocrinopathy (autoimmune thyroiditis and celiac disease), primary antiphospholipid syndrome (PAPS), autoimmune hepatitis, vitiligo, and autoimmune thyroiditis]. Autoimmune antibodies were observed in 52% of the patients. Remarkably, three (7%) of the patients had specific gastrointestinal and liver autoantibodies without clinical findings. Autoimmune diseases and autoantibodies were frequently present in patients with RASopathies. Until a final conclusion of the real incidence of autoimmunity in Rasopathy is drawn, the physicians should be alerted to the possibility of this association and the need for a fast diagnosis, proper referral to a specialist and ultimately, adequate treatment.

  20. Visual field impairment captures disease burden in multiple sclerosis.

    Science.gov (United States)

    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.

  1. Bone disease in multiple myeloma: pathophysiology and management.

    Science.gov (United States)

    Hameed, Abdul; Brady, Jennifer J; Dowling, Paul; Clynes, Martin; O'Gorman, Peter

    2014-01-01

    Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD.

  2. [Human prion diseases in the Czech Republic].

    Science.gov (United States)

    Rohan, Z; Rusina, R; Marešová, M; Matěj, R

    2015-09-01

    Human prion diseases are a group of very rare diseases with a unique pathogenesis and, due to an inauspicious prognosis and unavailability of therapy, with fatal consequences. The etiopathogenetic background is the presence of pathologically misfolded prion protein, highly resistant to denaturation, the aggregation and presence of which in the brain tissue causes irreversible neuronal damage. The most frequent prion disease in humans is Creutzfeldt-Jakob disease (CJD) which occurs in sporadic, hereditary/familial, or acquired/infectious/iatrogenic forms. A new form of CJD, variant CJD, is considered to be linked to dietary exposure to beef products from cattle infected with bovine spongiform encephalopathy (BSE) and to infection via blood transfusion. The clinical picture of these diseases is characterized by a rapidly progressing dementia, cerebellar and extrapyramidal symptoms, and rather specific MRI, EEG, and CSF findings. Clinically, the diagnosis is described as possible or probable prion disease and needs to be confirmed by neuropathological or immunological investigation of the brain tissue. Epidemiological data from the Czech Republic spanning the last decade are presented.

  3. Multiple isoforms of the human pentraxin serum amyloid P component

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Human serum amyloid P component (SAP) isolated from 20 healthy individuals was analyzed by anion exchange chromatography and isoelectric focusing (IEF) in order to investigate the existence of multiple forms of SAP and interindividual structural differences. Anion exchange chromatography showed one...... major and several minor subpopulations of SAP. IEF of all SAP isolates showed a previously unreported degree of heterogeneity with six isoelectric forms (pKi range 5.5-6.1) and with minor interindividual differences in respect of isoelectric points. Total enzymatic deglycosylation of SAP reduced...

  4. Linking multiple pathogenic pathways in Alzheimer’s disease

    Science.gov (United States)

    Bou Khalil, Rami; Khoury, Elie; Koussa, Salam

    2016-01-01

    Alzheimer’s disease (AD) is a chronic neurodegenerative disorder presenting as progressive cognitive decline with dementia that does not, to this day, benefit from any disease-modifying drug. Multiple etiologic pathways have been explored and demonstrate promising solutions. For example, iron ion chelators, such as deferoxamine, are a potential therapeutic solution around which future studies are being directed. Another promising domain is related to thrombin inhibitors. In this minireview, a common pathophysiological pathway is suggested for the pathogenesis of AD to prove that all these mechanisms converge onto the same cascade of neuroinflammatory events. This common pathway is initiated by the presence of vascular risk factors that induce brain tissue hypoxia, which leads to endothelial cell activation. However, the ensuing hypoxia stimulates the production and release of reactive oxygen species and pro-inflammatory proteins. Furthermore, the endothelial activation may become excessive and dysfunctional in predisposed individuals, leading to thrombin activation and iron ion decompartmentalization. The oxidative stress that results from these modifications in the neurovascular unit will eventually lead to neuronal and glial cell death, ultimately leading to the development of AD. Hence, future research in this field should focus on conducting trials with combinations of potentially efficient treatments, such as the combination of intranasal deferoxamine and direct thrombin inhibitors. PMID:27354962

  5. Empirical validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for suspected Lyme disease

    Directory of Open Access Journals (Sweden)

    Citera M

    2017-09-01

    Full Text Available Maryalice Citera,1 Phyllis R Freeman,2 Richard I Horowitz2 1Department of Psychology, State University of New York at New Paltz, New Paltz, NY, 2Hudson Valley Healing Arts Center, Hyde Park, NY, USA Purpose: Lyme disease is spreading worldwide, with multiple Borrelia species causing a broad range of clinical symptoms that mimic other illnesses. A validated Lyme disease screening questionnaire would be clinically useful for both providers and patients. Three studies evaluated such a screening tool, namely the Horowitz Multiple Systemic Infectious Disease Syndrome (MSIDS Questionnaire. The purpose was to see if the questionnaire could accurately distinguish between Lyme patients and healthy individuals.Methods: Study 1 examined the construct validity of the scale examining its factor structure and reliability of the questionnaire among 537 individuals being treated for Lyme disease. Study 2 involved an online sample of 999 participants, who self-identified as either healthy (N=217 or suffering from Lyme now (N=782 who completed the Horowitz MSIDS Questionnaire (HMQ along with an outdoor activity survey. We examined convergent validity among components of the scale and evaluated discriminant validity with the Big Five personality characteristics. The third study compared a sample of 236 patients with confirmed Lyme disease with an online sample of 568 healthy individuals.Results: Factor analysis results identified six underlying latent dimensions; four of these overlapped with critical symptoms identified by Horowitz – neuropathy, cognitive dysfunction, musculoskeletal pain, and fatigue. The HMQ showed acceptable levels of internal reliability using Cronbach’s coefficient alpha and exhibited evidence of convergent and divergent validity. Components of the HMQ correlated more highly with each other than with unrelated traits.Discussion: The results consistently demonstrated that the HMQ accurately differentiated those with Lyme disease from

  6. Disease Ontology 2015 update: an expanded and updated database of human diseases for linking biomedical knowledge through disease data.

    Science.gov (United States)

    Kibbe, Warren A; Arze, Cesar; Felix, Victor; Mitraka, Elvira; Bolton, Evan; Fu, Gang; Mungall, Christopher J; Binder, Janos X; Malone, James; Vasant, Drashtti; Parkinson, Helen; Schriml, Lynn M

    2015-01-01

    The current version of the Human Disease Ontology (DO) (http://www.disease-ontology.org) database expands the utility of the ontology for the examination and comparison of genetic variation, phenotype, protein, drug and epitope data through the lens of human disease. DO is a biomedical resource of standardized common and rare disease concepts with stable identifiers organized by disease etiology. The content of DO has had 192 revisions since 2012, including the addition of 760 terms. Thirty-two percent of all terms now include definitions. DO has expanded the number and diversity of research communities and community members by 50+ during the past two years. These community members actively submit term requests, coordinate biomedical resource disease representation and provide expert curation guidance. Since the DO 2012 NAR paper, there have been hundreds of term requests and a steady increase in the number of DO listserv members, twitter followers and DO website usage. DO is moving to a multi-editor model utilizing Protégé to curate DO in web ontology language. This will enable closer collaboration with the Human Phenotype Ontology, EBI's Ontology Working Group, Mouse Genome Informatics and the Monarch Initiative among others, and enhance DO's current asserted view and multiple inferred views through reasoning. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. Human lagochilascariasis-A rare helminthic disease.

    Directory of Open Access Journals (Sweden)

    Dulcinea Maria Barbosa Campos

    2017-06-01

    Full Text Available Lagochilascariasis is a parasitic disease caused by a helminth of the order Ascaroidea, genus Lagochilascaris that comprises 6 species, among which only Lagochilascaris minor Leiper, 1909, is implicated in the human form of the disease. It is remarkable that the majority of cases of human lagochilascariasis in the Americas have been reported in Brazil. The natural definitive hosts of this parasite seem to be wild felines and canines. Lagochilascariasis is mostly a chronic human disease that can persist for several years, in which the parasite burrows into the subcutaneous tissues of the neck, paranasal sinuses, and mastoid. L. minor exhibits remarkable ability to migrate through the tissues of its hosts, destroying even bone tissue. Fatal cases have been described in which the parasite was found in the lungs or central nervous system. Treatment is often palliative, with recurrence of lesions. This paper summarizes the main features of the disease and its etiologic agent, including prevalence, life cycle, clinical course, and treatment.

  8. Heartworm disease in animals and humans.

    Science.gov (United States)

    McCall, John W; Genchi, Claudio; Kramer, Laura H; Guerrero, Jorge; Venco, Luigi

    2008-01-01

    Heartworm disease due to Dirofilaria immitis continues to cause severe disease and even death in dogs and other animals in many parts of the world, even though safe, highly effective and convenient preventatives have been available for the past two decades. Moreover, the parasite and vector mosquitoes continue to spread into areas where they have not been reported previously. Heartworm societies have been established in the USA and Japan and the First European Dirofilaria Days (FEDD) Conference was held in Zagreb, Croatia, in February of 2007. These organizations promote awareness, encourage research and provide updated guidelines for the diagnosis, treatment and prevention of heartworm disease. The chapter begins with a review of the biology and life cycle of the parasite. It continues with the prevalence and distribution of the disease in domestic and wild animals, with emphasis on more recent data on the spreading of the disease and the use of molecular biology techniques in vector studies. The section on pathogenesis and immunology also includes a discussion of the current knowledge of the potential role of the Wolbachia endosymbiont in inflammatory and immune responses to D. immitis infection, diagnostic use of specific immune responses to the bacteria, immunomodulatory activity and antibiotic treatment of infected animals. Canine, feline and ferret heartworm disease are updated with regard to the clinical presentation, diagnosis, prevention, therapy and management of the disease, with special emphasis on the recently described Heartworm Associated Respiratory Disease (HARD) Syndrome in cats. The section devoted to heartworm infection in humans also includes notes on other epizootic filariae, particularly D. repens in humans in Europe. The chapter concludes with a discussion on emerging strategies in heartworm treatment and control, highlighting the potential role of tetracycline antibiotics in adulticidal therapy.

  9. CD24: from a Hematopoietic Differentiation Antigen to a Genetic Risk Factor for Multiple Autoimmune Diseases.

    Science.gov (United States)

    Tan, Yixin; Zhao, Ming; Xiang, Bo; Chang, Christopher; Lu, Qianjin

    2016-02-01

    The autoantibody is an essential characteristic of inflammatory disorders, including autoimmune diseases. Although the exact pathogenic mechanisms of these diseases remain elusive, accumulated evidence has implicated that genetic factors play important roles in autoimmune inflammation. Among these factors, CD24 was first identified as a heat-stable antigen in 1978 and first successfully cloned in 1990. Thereafter, its functional roles have been intensively investigated in various human diseases, especially autoimmune diseases and cancers. It is currently known that CD24 serves as a costimulatory factor of T cells that regulate their homeostasis and proliferation, while in B cells, CD24 is functionally involved in cell activation and differentiation. CD24 can enhance autoimmune diseases in terms of its protective role in the clonal deletion of autoreactive thymocytes. Furthermore, CD24 deficiency has been linked to mouse experimental autoimmune encephalomyelitis. Finally, CD24 genetic variants, including single-nucleotide polymorphisms and deletions, are etiologically relevant to autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus. Therefore, CD24 is a promising biomarker and novel therapeutic target for autoimmune diseases.

  10. Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis.

    Science.gov (United States)

    Inkeles, Megan S; Scumpia, Philip O; Swindell, William R; Lopez, David; Teles, Rosane M B; Graeber, Thomas G; Meller, Stephan; Homey, Bernhard; Elder, James T; Gilliet, Michel; Modlin, Robert L; Pellegrini, Matteo

    2015-01-01

    The ability to obtain gene expression profiles from human disease specimens provides an opportunity to identify relevant gene pathways, but is limited by the absence of data sets spanning a broad range of conditions. Here, we analyzed publicly available microarray data from 16 diverse skin conditions in order to gain insight into disease pathogenesis. Unsupervised hierarchical clustering separated samples by disease as well as common cellular and molecular pathways. Disease-specific signatures were leveraged to build a multi-disease classifier, which predicted the diagnosis of publicly and prospectively collected expression profiles with 93% accuracy. In one sample, the molecular classifier differed from the initial clinical diagnosis and correctly predicted the eventual diagnosis as the clinical presentation evolved. Finally, integration of IFN-regulated gene programs with the skin database revealed a significant inverse correlation between IFN-β and IFN-γ programs across all conditions. Our study provides an integrative approach to the study of gene signatures from multiple skin conditions, elucidating mechanisms of disease pathogenesis. In addition, these studies provide a framework for developing tools for personalized medicine toward the precise prediction, prevention, and treatment of disease on an individual level.

  11. Unsolved issues related to human mitochondrial diseases.

    Science.gov (United States)

    Lombès, Anne; Auré, Karine; Bellanné-Chantelot, Christine; Gilleron, Mylène; Jardel, Claude

    2014-05-01

    Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed. Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

  12. Empirical validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for suspected Lyme disease.

    Science.gov (United States)

    Citera, Maryalice; Freeman, Phyllis R; Horowitz, Richard I

    2017-01-01

    Lyme disease is spreading worldwide, with multiple Borrelia species causing a broad range of clinical symptoms that mimic other illnesses. A validated Lyme disease screening questionnaire would be clinically useful for both providers and patients. Three studies evaluated such a screening tool, namely the Horowitz Multiple Systemic Infectious Disease Syndrome (MSIDS) Questionnaire. The purpose was to see if the questionnaire could accurately distinguish between Lyme patients and healthy individuals. Study 1 examined the construct validity of the scale examining its factor structure and reliability of the questionnaire among 537 individuals being treated for Lyme disease. Study 2 involved an online sample of 999 participants, who self-identified as either healthy (N=217) or suffering from Lyme now (N=782) who completed the Horowitz MSIDS Questionnaire (HMQ) along with an outdoor activity survey. We examined convergent validity among components of the scale and evaluated discriminant validity with the Big Five personality characteristics. The third study compared a sample of 236 patients with confirmed Lyme disease with an online sample of 568 healthy individuals. Factor analysis results identified six underlying latent dimensions; four of these overlapped with critical symptoms identified by Horowitz - neuropathy, cognitive dysfunction, musculoskeletal pain, and fatigue. The HMQ showed acceptable levels of internal reliability using Cronbach's coefficient alpha and exhibited evidence of convergent and divergent validity. Components of the HMQ correlated more highly with each other than with unrelated traits. The results consistently demonstrated that the HMQ accurately differentiated those with Lyme disease from healthy individuals. Three migratory pain survey items (persistent muscular pain, arthritic pain, and nerve pain/paresthesias) robustly identified individuals with verified Lyme disease. The results support the use of the HMQ as a valid, efficient, and low

  13. The role of formins in human disease.

    Science.gov (United States)

    DeWard, Aaron D; Eisenmann, Kathryn M; Matheson, Stephen F; Alberts, Arthur S

    2010-02-01

    Formins are a conserved family of proteins that play key roles in cytoskeletal remodeling. They nucleate and processively elongate non-branched actin filaments and also modulate microtubule dynamics. Despite their significant contributions to cell biology and development, few studies have directly implicated formins in disease pathogenesis. This review highlights the roles of formins in cell division, migration, immunity, and microvesicle formation in the context of human disease. In addition, we discuss the importance of controlling formin activity and protein expression to maintain cell homeostasis.

  14. Human papillomavirus-associated diseases and cancers

    Institute of Scientific and Technical Information of China (English)

    Lan Yang; Jianbo Zhu Co-first author; Xiaoyue Song; Yan Qi; Xiaobin Cui; Feng Li 

    2015-01-01

    Human papilomaviruses (HPVs) have been detected in cervical cancer cels and skin papiloma cels, which have a variety of types, including low-risk and high-risk types. HPV genome replication requires the host cel’s DNA synthesis machinery, and HPVs encode proteins that maintain diferentiated epithelial cels in a replication-competent state. HPV types are tissue-specific and generaly produce diferent types of le-sions, either benign or malignant. This review examines diferent HPV types and their associated diseases and presents therapeutic options for the treatment of HPV-positive diseases.

  15. Chronic Inflammatory Periodontal Disease in Patients with Human Immunodeficiency Virus.

    Directory of Open Access Journals (Sweden)

    Vania López Rodríguez

    2009-07-01

    Full Text Available Background: The Chronic Inflammatory Periodontal Disease is related with multiple risk factors. Those patients with human immunodeficiency virus have higher risk of presenting this disease and it is usually more serious in these cases. Objective: To describe the prevalence of Chronic Inflammatory Periodontal Disease in patients with HIV. Methods: Descriptive, observational, cross-sectional study including patients with HIV in Sancti Spiritus province. The occurrence of the disease was determined after the Periodontics Cuban Standards, and oral hygiene was assessed through the simplified oral hygiene index. Other variables were measured, such as smoking habits, T CD4+ lymphocyte counting and virus load. The independent association of each risk factor with the disease was determined through a logistic regression model. Results: The 56, 5 % of the 154 patients presented Chronic Inflammatory Periodontal Disease; 60 (39.0% gingivitis and 27 (17,5% periodontitis. Gingivitis was associated with poor oral hygiene (OR: 3,71 and periodontitis with smoking habit (OR: 5,20. The severe forms of periodontitis occurred mainly in patients with lymphocyte counting lower than 500 cells/mm3 . Conclusions: The prevalence of Chronic Inflammatory Periodontal Disease in patients with HIV in Sancti Spiritus province is linked to known risk factors such as smoking habits and oral hygiene.

  16. Changes of multiple genes in human gastric carcinomas

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the mutual relation of the changesamong multiple genes in human gastric carcinomas (GC). Methods: By means of software package about social science (SPSS) and statistics analysis system (SAS), the mutual relation of the expression of oncogenes (p21, p185) and tumor suppressor genes (RB, p53, p16, nm23) in 78 GC is discussed. Results: There existed correlations among some genes, i.e., p21 and p185, RB and p16, p16 and p53 as well as p16 and nm23; It is relatively uncommon that the carcinogenesis of GC simultaneously related to more changes of multiple genes; The inactivation of p16 gene was independent factor to predict the metastasis of lymphaden, the mutation of p53 gene and the inactivation of p16 gene were independent factors to predict the invasive depth. Conclusion: There are not only the changes of multiple genes including oncogenes activation and tumor suppressor genes inactivation, but also they may play an important role in carcinogenesis of GC through mutual cooperation. The inactivation of p16 gene is one of the most useful index to predict the prognosis of patient with GC.

  17. Choosy but not chaste: multiple mating in human females.

    Science.gov (United States)

    Scelza, Brooke A

    2013-01-01

    When Charles Darwin set out to relate his theory of evolution by natural selection to humans he discovered that a complementary explanation was needed to properly understand the great variation seen in human behavior. The resulting work, The Descent of Man and Selection in Relation to Sex, laid out the defining principles and evidence of sexual selection. In brief, this work is best known for illuminating the typically male strategy of intrasexual competition and the typically female response of intersexual choice. While these sexual stereotypes were first laid out by Darwin, they grew in importance when, years later, A. J. Bateman, in a careful study of Drosophila mating strategies, noted that multiple mating appeared to provide great benefit to male reproductive success, but to have no such effect on females. As a result, female choice soon became synonymous with being coy, and only males were thought to gain from promiscuous behavior. However, the last thirty years of research have served to question much of the traditional wisdom about sex differences proposed by Darwin and Bateman, illuminating the many ways that women (and females more generally) can and do engage in multiple mating.

  18. Aquaporin water channels: molecular mechanisms for human diseases.

    Science.gov (United States)

    Agre, Peter; Kozono, David

    2003-11-27

    Although water is the major component of all biological fluids, the molecular pathways for water transport across cell membranes eluded identification until the discovery of the aquaporin family of water channels. The atomic structure of mammalian AQP1 illustrates how this family of proteins is freely permeated by water but not protons (hydronium ions, H3O+). Definition of the subcellular sites of expression predicted their physiological functions and potential clinical disorders. Analysis of several human disease states has confirmed that aquaporins are involved in multiple different illnesses including abnormalities of kidney function, loss of vision, onset of brain edema, starvation, and arsenic toxicity.

  19. Multiple systemic embolism in infective endocarditis underlying in Barlow's disease.

    Science.gov (United States)

    Yu, Ziqing; Fan, Bing; Wu, Hongyi; Wang, Xiangfei; Li, Chenguang; Xu, Rende; Su, Yangang; Ge, Junbo

    2016-08-11

    Systemic embolism, especially septic embolism, is a severe complication of infective endocarditis (IE). However, concurrent embolism to the brain, coronary arteries, and spleen is very rare. Because of the risk of hemorrhage or visceral rupture, anticoagulants are recommended only if an indication is present, e.g. prosthetic valve. Antiplatelet therapy in IE is controversial, but theoretically, this therapy has the potential to prevent and treat thrombosis and embolism in IE. Unfortunately, clinical trial results have been inconclusive. We describe a previously healthy 50-year-old man who presented with dysarthria secondary to bacterial endocarditis with multiple cerebral, coronary, splenic, and peripheral emboli; antibiotic therapy contributed to the multiple emboli. Emergency splenectomy was performed, with subsequent mitral valve repair. Pathological examination confirmed mucoid degeneration and mitral valve prolapse (Barlow's disease) as the underlying etiology of the endocardial lesion. Continuous antibiotics were prescribed, postoperatively. Transthoracic echocardiography at 1.5, 3, and 6 months after the onset of his illness showed no severe regurgitation, and there was no respiratory distress, fever, or lethargy during follow-up. Although antibiotic use in IE carries a risk of septic embolism, these drugs have bactericidal and antithrombotic benefits. It is important to consider that negative blood culture and symptom resolution do not confirm complete elimination of bacteria. However, vegetation size and Staphylococcus aureus infection accurately predict embolization. It is also important to consider that bacteria can be segregated from the microbicide when embedded in platelets and fibrin. Therefore, antimicrobial therapy with concurrent antiplatelet therapy should be considered carefully.

  20. [Human hantavirus diseases - still neglected zoonoses?].

    Science.gov (United States)

    Vrbovská, V; Chalupa, P; Straková, P; Hubálek, Z; Rudolf, I

    2015-10-01

    Hantavirus disease is the most common rodent-borne viral infection in the Czech Republic, with a mean annual incidence of 0.02 cases per 100 000 population and specific antibodies detected in 1% of the human population. Four hantaviruses (Puumala, Dobrava-Belgrade, Tula, and Seewis) circulate in this country, of which Puumala virus (responsible for a mild form of hemorrhagic fever with renal syndrome called nephropathia epidemica) and Dobrava-Belgrade virus (causing haemorrhagic fever with renal syndrome) have been proven to cause human disease. The aim of this study is to provide a comprehensive review of the hantaviruses occurring in the Czech Republic, based on the literature published during the past three decades, including their geographical distribution and clinical symptoms. The recent detection of Tula virus in an immunocompromised person as well as reports of Seoul virus infections in Europe highlight the possible emergence of neglected hantavirus infections in the foreseeable future.

  1. Molecular biology of human muscle disease

    Energy Technology Data Exchange (ETDEWEB)

    Dunne, P.W.; Epstein, H.F. (Baylor Coll. of Medicine, Houston, TX (United States))

    1991-01-01

    The molecular revolution that is transforming the entire biomedical field has had far-reaching impact in its application to inherited human muscle disease. The gene for Duchenne muscular dystrophy was one of the first cloned without knowledge of the defective protein product. This success was based upon the availability of key chromosomal aberrations that provided molecular landmarks for the disease locus. Subsequent discoveries regarding the mode of expression for this gene, the structure and localization of its protein product dystrophin, and molecular diagnosis of affected and carrier individuals constitute a paradigm for investigation of human genetics. Finding the gene for myotonic muscular dystrophy is requiring the brute force approach of cloning several million bases of DNA, identifying expressed sequences, and characterizing candidate genes. The gene that causes hypertrophic cardiomyopathy has been found serendipitously to be one of the genetic markers on chromosome 14, the {beta} myosin heavy chain.

  2. Serum chemical elements and oxidative status in Alzheimer's disease, Parkinson disease and multiple sclerosis.

    Science.gov (United States)

    Alimonti, Alessandro; Ristori, Giovanni; Giubilei, Franco; Stazi, Maria Antonia; Pino, Anna; Visconti, Andrea; Brescianini, Sonia; Sepe Monti, Micaela; Forte, Giovanni; Stanzione, Paolo; Bocca, Beatrice; Bomboi, Giuseppe; D'Ippolito, Cristina; Annibali, Viviana; Salvetti, Marco; Sancesario, Giuseppe

    2007-05-01

    The role of some chemical elements in neurodegeneration was suggested by various authors. To obtain a profile of chemical elements and oxidative status in complex neurological diseases, an unbiased "omics" approach, i.e., quantification of 26 elements and oxidative stress parameters (serum oxidative status (SOS) and serum anti-oxidant capacity (SAC)), combined with multivariate statistical procedures (forward discriminant analysis, FDA) to analyse the vast amount of data, was applied to four groups of subjects (53 patients with Alzheimer's disease (AD), 71 with Parkinson disease (PD), 60 with multiple sclerosis (MS) and 124 healthy individuals). Descriptive statistics revealed numerous differences between each disease and healthy status. A concordant imbalance (reduction in Fe, Zn and SAC, and increase in SOS) was shared by AD, PD and MS. The FDA yielded three significant discriminant functions based on age, SOS, Ca, Fe, Si, Sn, V, Zn and Zr, and identified disease-specific profiles of element imbalances, thus showing the appropriateness of the "omics" approach. It may help assess the contribution of chemical elements and oxidative stress to disease causation and may provide complex predictors of disease evolution or treatment response.

  3. The role of chemerin in human disease

    Directory of Open Access Journals (Sweden)

    Magdalena Stojek

    2017-02-01

    Full Text Available Adipose tissue is not merely a storage depot of triacylglycerols but also a major endocrine organ. Its cells, including adipocytes, synthesize and secrete a range of biologically active molecules termed adipokines. Adipokines that display the properties of cytokines are often called adipocytokines. In recent years there has been increasing interest in a new adipokine called chemerin. Chemerin is a protein synthesized mostly by the adipose tissue and the liver as inactive pre-pro-chemerin. After the intracellular hydrolytic cutting off of the 20-amino-acid N-terminal polypeptide, it is secreted into the bloodstream as inactive pro-chemerin. Biologically active chemerin is then derived from pro-chemerin after cleavage of the C-terminal fragment by serum proteases involved in inflammation, coagulation and fibrinolysis. Proteolytic cleavage leads to formation of several chemerin-derived peptides, both biologically active (often with opposing functions and inactive.Within the last decade, there has been a growing number of publications regarding the role of chemerin in human disease. It seems to be implicated in the inflammatory response, metabolic syndrome, cardiovascular disease and alimentary tract disorders. The article presents the most recent information on the role of chemerin in human disease, and specifically alimentary tract disorders. The available evidence suggests that chemerin is an important link between adipose tissue mass, metabolic processes, the immune system and inflammation, and therefore plays a major role in human pathophysiology.

  4. Genes of periodontopathogens expressed during human disease.

    Science.gov (United States)

    Song, Yo-Han; Kozarov, Emil V; Walters, Sheila M; Cao, Sam Linsen; Handfield, Martin; Hillman, Jeffrey D; Progulske-Fox, Ann

    2002-12-01

    Since many bacterial genes are environmentally regulated, the screening for virulence-associated factors using classical genetic and molecular biology approaches can be biased under laboratory growth conditions of a given pathogen, because the required conditions for expression of many virulence factors may not occur during in vitro growth. Thus, technologies have been developed during the past several years to identify genes that are expressed during disease using animal models of human disease. However, animal models are not always truly representative of human disease, and with many pathogens, there is no appropriate animal model. A new technology, in vivo-induced antigen technology (IVIAT) was thus engineered and tested in our laboratory to screen for genes of pathogenic organisms induced specifically in humans, without the use of animal or artificial models of infection. This technology uses pooled sera from patients to probe for genes expressed exclusively in vivo (or ivi, in vivo-induced genes). IVIAT was originally designed for the study of Actinobacillus actinomycetemcomitans pathogenesis, but we have now extended it to other oral pathogens including Porphyromonas gingivalis. One hundred seventy-one thousand (171,000) clones from P. gingivalis strain W83 were screened and 144 were confirmed positive. Over 300,000 A. actinomycetemcomitans clones were probed, and 116 were confirmed positive using a quantitative blot assay. MAT has proven useful in identifying previously unknown in vivo-induced genes that are likely involved in virulence and are thus excellent candidates for use in diagnostic : and therapeutic strategies, including vaccine design.

  5. Multiplicity of Infection and Disease Severity in Plasmodium vivax.

    Directory of Open Access Journals (Sweden)

    M Andreína Pacheco

    2016-01-01

    Full Text Available Multiplicity of infection (MOI refers to the average number of distinct parasite genotypes concurrently infecting a patient. Although several studies have reported on MOI and the frequency of multiclonal infections in Plasmodium falciparum, there is limited data on Plasmodium vivax. Here, MOI and the frequency of multiclonal infections were studied in areas from South America where P. vivax and P. falciparum can be compared.As part of a passive surveillance study, 1,328 positive malaria patients were recruited between 2011 and 2013 in low transmission areas from Colombia. Of those, there were only 38 P. vivax and 24 P. falciparum clinically complicated cases scattered throughout the time of the study. Samples from uncomplicated cases were matched in time and location with the complicated cases in order to compare the circulating genotypes for these two categories. A total of 92 P. vivax and 57 P. falciparum uncomplicated cases were randomly subsampled. All samples were genotyped by using neutral microsatellites. Plasmodium vivax showed more multiclonal infections (47.7% than P. falciparum (14.8%. Population genetics and haplotype network analyses did not detect differences in the circulating genotypes between complicated and uncomplicated cases in each parasite. However, a Fisher exact test yielded a significant association between having multiclonal P. vivax infections and complicated malaria. No association was found for P. falciparum infections.The association between multiclonal infections and disease severity in P. vivax is consistent with previous observations made in rodent malaria. The contrasting pattern between P. vivax and P. falciparum could be explained, at least in part, by the fact that P. vivax infections have lineages that were more distantly related among them than in the case of the P. falciparum multiclonal infections. Future research should address the possible role that acquired immunity and exposure may have on multiclonal

  6. Disease-modifying therapies in Chinese children with multiple sclerosis.

    Science.gov (United States)

    Yang, Fen; Huang, D Hui; Yang, Yang; Wu, Wei Ping

    2014-01-01

    Limited data are available about the use of disease-modifying therapies (DMTs) in children with multiple sclerosis (MS). This study aimed to present our experience using DMTs in Chinese children with MS and provide additional evidence to consider treating these patients with cyclophosphamide. A retrospective chart review was conducted and data were obtained from 25 children with MS. Only three (12%) of these patients received and responded well to first-line interferon β-1b therapy, while 10 (40%) chose cyclophosphamide and 12 (48%) refused to use DMTs. For the 10 patients being treated with cyclophosphamide, the median annualized relapse rate decreased from 3.0 to 1.0, and the median score on the Expanded Disability Status Scale decreased from 3.5 to 2.0. After 12 months of treatment, no gadolinium-enhancing lesions were reported in seven of the 10 patients. The use of DMTs plays an important role in the treatment of children with MS. If first-line therapies fail, cyclophosphamide may be a good option.

  7. Coronary heart disease multiple risk factor reduction. Providers' perspectives.

    Science.gov (United States)

    Rosal, Milagros C; Ockene, Judith K; Luckmann, Roger; Zapka, Jane; Goins, Karin Valentine; Saperia, Gordon; Mason, Theresa; Donnelly, Gary

    2004-08-01

    Although primary care physicians understand the importance of preventive services for patients with multiple risk factors (MRF) for coronary heart disease, physician intervention is limited. This study investigated (1) physicians' views of challenges faced in managing patients with MRF; (2) the counseling and management methods they utilize; and (3) possible strategies to enhance MRF intervention in the primary care setting. Two focus groups were conducted with primary care physicians from varying settings to gain insight into these issues noted above. Each group was co-facilitated by a physician and a behavioral scientist using a previously developed semistructured interview guide. The group discussions were tape recorded and subsequently transcribed. Transcripts were analyzed using the constant comparative method for analysis. Physicians are challenged by knowledge limitations (contribution of individual risk factors to overall risk); limited support (guidelines, materials, and staff); and logistic difficulties (organizational issues, time limitations). Their approach to MRF management tends to be highly individualized with an initial preference for lifestyle change interventions rather than prescription of medications with some qualifying circumstances. Physicians favored a serial rather than a parallel approach to MRF intervention, starting with behaviors that the patient perceives as a priority. Proposed solutions to current challenges emphasize physician education and the development of innovative approaches that include physician assistance and a team approach. Physicians are aware of and sensitive to the complexity of MRF management for their patients and themselves. However, future MRF interventions will require nonphysician staff involvement and increased systems support.

  8. 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

  9. Alterations of the human gut microbiome in multiple sclerosis

    Science.gov (United States)

    Jangi, Sushrut; Gandhi, Roopali; Cox, Laura M.; Li, Ning; von Glehn, Felipe; Yan, Raymond; Patel, Bonny; Mazzola, Maria Antonietta; Liu, Shirong; Glanz, Bonnie L.; Cook, Sandra; Tankou, Stephanie; Stuart, Fiona; Melo, Kirsy; Nejad, Parham; Smith, Kathleen; Topçuolu, Begüm D.; Holden, James; Kivisäkk, Pia; Chitnis, Tanuja; De Jager, Philip L.; Quintana, Francisco J.; Gerber, Georg K.; Bry, Lynn; Weiner, Howard L.

    2016-01-01

    The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis. PMID:27352007

  10. Humanized Mouse Model of Ebola Virus Disease Mimics the Immune Responses in Human Disease.

    Science.gov (United States)

    Bird, Brian H; Spengler, Jessica R; Chakrabarti, Ayan K; Khristova, Marina L; Sealy, Tara K; Coleman-McCray, JoAnn D; Martin, Brock E; Dodd, Kimberly A; Goldsmith, Cynthia S; Sanders, Jeanine; Zaki, Sherif R; Nichol, Stuart T; Spiropoulou, Christina F

    2016-03-01

    Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not, without adaptation, cause disease in immunocompetent adult rodents. Here, we describe EVD in mice engrafted with human immune cells (hu-BLT). hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid, lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathologic findings similar to those shown in the limited human postmortem data available. A dose- and donor-dependent clinical course was observed in hu-BLT mice infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as nonengrafted mice did not support productive EBOV replication or develop lethal disease. hu-BLT mice offer a unique model for investigating the human immune response in EVD and an alternative animal model for EVD pathogenesis studies and therapeutic screening.

  11. Human Genome Sequencing in Health and Disease

    Science.gov (United States)

    Gonzaga-Jauregui, Claudia; Lupski, James R.; Gibbs, Richard A.

    2013-01-01

    Following the “finished,” euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges. PMID:22248320

  12. Conditional Lineage Ablation to Model Human Diseases

    Science.gov (United States)

    Lee, Paul; Morley, Gregory; Huang, Qian; Fischer, Avi; Seiler, Stephanie; Horner, James W.; Factor, Stephen; Vaidya, Dhananjay; Jalife, Jose; Fishman, Glenn I.

    1998-09-01

    Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.

  13. Employment status in multiple sclerosis: impact of disease-specific and non-disease-specific factors.

    Science.gov (United States)

    Krause, Ivonne; Kern, Simone; Horntrich, Antje; Ziemssen, Tjalf

    2013-11-01

    Multiple sclerosis (MS) is associated with high rates of early retirement (ER). A German cohort of MS patients and healthy control subjects (HCs) were compared cross-sectionally to investigate disease- and non-disease-specific factors that are associated with employment status (ES) in MS and to identify predictors of ES in MS. A total of 39 ER MS patients, 48 employed MS patients, and 37 HCs completed a brief neuropsychological battery and questionnaires related to depressive symptoms, fatigue, health-related quality of life (HrQoL) and health locus of control (HLC). Neurological disability was assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC). ER compared with employed MS patients scored significantly higher in neurological disability, depressive symptoms and fatigue and significantly lower in cognitive functioning and HrQoL. Further, both groups differed with regard to age, education, disease course and duration but not in HLC. Neurological disability, age and fatigue were identified as significant predictors of ES in MS. ES in MS was associated with demographic aspects, neurological and cognitive status, depressive symptoms, fatigue and HrQoL but was not associated with HLC. Findings confirm neurological disability, age and fatigue as independent predictors of ES in MS.

  14. Allergic Diseases and Multiple Chemical Sensitivity in Korean Adults

    Science.gov (United States)

    Jeong, Inchul; Kim, Inah; Park, Hye Jung; Roh, Jaehoon; Park, Jung-Won

    2014-01-01

    Purpose Multiple chemical sensitivity (MCS) is a clinical syndrome representing multi-organ and psychological symptoms caused by chronic exposure to various chemicals in low concentrations. We evaluated the prevalence and related factors of MCS targeting Korean adults using the Quick Environmental Exposure and Sensitivity Inventory (QEESI©). Methods A total of 446 participants were recruited from Severance Hospital. Participants underwent a questionnaire interview including questions on sociodemographic factors, occupational and environmental factors, allergic diseases, and the QEESI©. Among them, 379 participants completed the questionnaire and the QEESI©. According to the QEESI© interpretation results, participants were divided into very suggestive (VS) group and less suggestive (LS) group. Results The estimated prevalence of MCS was higher in allergic patients than non-allergic participants (19.7% and 11.3%, respectively, P=0.04). In the multivariate logistic regression analysis, ages of 30-39 (OR, 2.94; 95% CI, 1.25-6.95) and those of 40-49 (OR, 2.51; 95% CI, 1.02-6.21) were significantly related to MCS compared to those aged less than 30 years. Female sex (OR, 2.16; 95% CI, 1.11-4.18), experience of dwelling in a new house (OR, 2.05; 95% CI, 1.04-4.03), and atopic dermatitis (OR, 1.95; 95% CI, 1.04-3.69) were also significantly related to MCS. However, only age of 30-39 in the allergic group was significant in the stratified analysis. Conclusions The estimated prevalence of MCS was higher among allergic patients than non-allergic participants. People with experience of dwelling in a new house and atopic dermatitis were more at risk of being intolerant to chemicals. Further studies to provide the nationally representative prevalence data and clarify risk factors and mechanisms of MCS are required. PMID:25228997

  15. Copy number variations exploration of multiple genes in Graves' disease.

    Science.gov (United States)

    Song, Rong-Hua; Shao, Xiao-Qing; Li, Ling; Wang, Wen; Zhang, Jin-An

    2017-01-01

    Few previous published papers reported copy number variations of genes could affect the predisposition of Graves' disease (GD). Herein, the aim of this study was to explore the association between copy number variations (CNV) profile and GD. The preliminary copy number microarray used to screen copy number variant genes was performed in 6 GD patients. Five CNV candidate genes (CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17) were then validated in an independent set of samples (50 GD patients and 50 matched healthy ones) by the Accucopy assay method. The CNV of the other 2 genes TRY6 and CCL3L1 was investigated in 144 GD patients and 144 healthy volunteers by the definitive genotyping technique using the Taqman quantitative polymerase-chain-reaction (Taqman qPCR). TRY6 gene-associated single nucleotide polymorphism (SNP), rs13230029, was genotyped by the PCR-ligase detection reaction (LDR) in 675 GD patients and 898 healthy controls. There were no correlation of the gene copy number (GCN) of CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17 with GD. In comparison with that of controls, the GCN distribution of TRY6 and CCL3L1 in GD patients did not show significantly differ (P > 0.05). Furthermore, TRY6-related polymorphism (rs13230029) showed no difference between GD patients and controls. No correlation was found between CNV or SNP genotype and clinical phenotypes. Generally, there were no link of the copy numbers of several genes, including CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1 to GD. Our results clearly indicated that the copy number variations of multiple genes, namely CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1, were not associated with the development of GD.

  16. Efficacy of natalizumab in multiple sclerosis patients with high disease activity: a Danish nationwide study

    DEFF Research Database (Denmark)

    Oturai, A.B.; Koch-Henriksen, N.; Petersen, T.;

    2009-01-01

    INTRODUCTION: Previous studies of natalizumab (Tysabri) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity. PATIENTS AND METHODS: We analyzed data from 234 consecutive, natalizumab-treated...

  17. Uniparental disomy and human disease: an overview.

    Science.gov (United States)

    Yamazawa, Kazuki; Ogata, Tsutomu; Ferguson-Smith, Anne C

    2010-08-15

    Uniparental disomy (UPD) refers to the situation in which both homologues of a chromosomal region/segment have originated from only one parent. This can involve the entire chromosome or only a small segment. As a consequence of UPD, or uniparental duplication/deficiency of part of a chromosome, there are two types of developmental risk: aberrant dosage of genes regulated by genomic imprinting and homozygosity of a recessive mutation. UPD models generated by reciprocal and Robertsonian translocation heterozygote intercrosses have been a powerful tool to investigate genomic imprinting in mice, whereas novel UPD patients such as those with cystic fibrosis and Prader-Willi syndrome, triggered the clarification of recessive diseases and genomic imprinting disorders in human. Newly developed genomic technologies as well as conventional microsatellite marker methods have been contributing to the functional and mechanistic investigation of UPD, leading to not only the acquisition of clinically valuable information, but also the further clarification of diverse genetic processes and disease pathogenesis.

  18. Mitochondrial Fusion Proteins and Human Diseases

    Directory of Open Access Journals (Sweden)

    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.

  19. Human brain disease recreated in mice

    Energy Technology Data Exchange (ETDEWEB)

    Marx, J.

    1990-12-14

    In the early 1980s, neurologist Stanley Prusiner suggested that scrapie, an apparently infectious degenerative brain disease of sheep, could be transmitted by prions, infectious particles made just of protein - and containing no nucleic acids. But prion research has come a long way since then. In 1985, the cloning of the gene encoding the prion protein proved that it does in fact exist. And the gene turned out to be widely expressed in the brains of higher organisms, a result suggesting that the prion protein has a normal brain function that can somehow be subverted, leading to brain degeneration. Then studies done during the past 2 years suggested that specific mutations in the prion gene might cause two similar human brain diseases, Gerstmann-Straeussler-Scheinker syndrome (GSS) and Creutzfelt-Jakob disease. Now, Prusiner's group at the University of California, San Francisco, has used genetic engineering techniques to recreate GSS by transplanting the mutated prion gene into mice. Not only will the animal model help neurobiologists answer the many remaining questions about prions and how they work, but it may also shed some light on other neurodegenerative diseases as well.

  20. The Microbiota, Chemical Symbiosis, and Human Disease

    Science.gov (United States)

    Redinbo, Matthew R.

    2014-01-01

    Our understanding of mammalian-microbial mutualism has expanded by combing microbial sequencing with evolving molecular and cellular methods, and unique model systems. Here, the recent literature linking the microbiota to diseases of three of the key mammalian mucosal epithelial compartments – nasal, lung and gastrointestinal (GI) tract – is reviewed with a focus on new knowledge about the taxa, species, proteins and chemistry that promote health and impact progression toward disease. The information presented is further organized by specific diseases now associated with the microbiota:, Staphylococcus aureus infection and rhinosinusitis in the nasal-sinus mucosa; cystic fibrosis (CF), chronic obstructive pulmonary disorder (COPD), and asthma in the pulmonary tissues. For the vast and microbially dynamic GI compartment, several disorders are considered, including obesity, atherosclerosis, Crohn’s disease, ulcerative colitis, drug toxicity, and even autism. Our appreciation of the chemical symbiosis ongoing between human systems and the microbiota continues to grow, and suggest new opportunities for modulating this symbiosis using designed interventions. PMID:25305474

  1. Functions of NOD-like receptors (NLRs in human diseases

    Directory of Open Access Journals (Sweden)

    Yifei eZhong

    2013-10-01

    Full Text Available Nucleotide-binding and oligomerization domain (NOD-like receptors (NLRs are highly conserved cytosolic pattern recognition receptors that perform critical functions in surveying the intracellular environment for the presence of infection, noxious substances, and metabolic perturbations. Sensing of these danger signals by NLRs leads to their oligomerization into large macromolecular scaffolds and the rapid deployment of effector signaling cascades to restore homeostasis. While some NLRs operate by recruiting and activating inflammatory caspases into inflammasomes, others trigger inflammation via alternative routes including the NF-κB, MAPK and IRF pathways. The critical role of NLRs in development and physiology is demonstrated by their clear implications in human diseases. Mutations in the genes encoding NLRP3 or NLRP12 lead to hereditary periodic fever syndromes, while mutations in CARD15 that encodes NOD2 are linked to Crohn’s disease or Blau’s syndrome. Genome-wide association studies (GWAS have identified a number of risk alleles encompassing NLR genes in a host of diseases including allergic rhinitis, multiple sclerosis, inflammatory bowel disease, asthma, multi-bacillary leprosy, vitiligo, early-onset menopause, and bone density loss in elderly women. Animal models have allowed the characterization of underlying effector mechanisms in a number of cases. In this review, we highlight the functions of NLRs in health and disease and discuss how the characterization of their molecular mechanisms provides new insights into therapeutic strategies for the management of inflammatory pathologies.

  2. Expanding specificity of class 1 restricted CD8+ T cells for viral epitopes following multiple inoculations of swine with a human adenivorus vectored foot-and-mouth disease virus (FMDV) vaccine

    Science.gov (United States)

    The immune response to the highly acute foot-and-mouth disease virus (FMDV) is routinely reported as a measure of serum antibody. However, a critical effector function of immune responses combating viral infection of mammals is the cytotoxic T lymphocyte (CTL) response, mediated by virus specific ...

  3. Human prion diseases in the United States.

    Directory of Open Access Journals (Sweden)

    Robert C Holman

    Full Text Available BACKGROUND: Prion diseases are a family of rare, progressive, neurodegenerative disorders that affect humans and animals. The most common form of human prion disease, Creutzfeldt-Jakob disease (CJD, occurs worldwide. Variant CJD (vCJD, a recently emerged human prion disease, is a zoonotic foodborne disorder that occurs almost exclusively in countries with outbreaks of bovine spongiform encephalopathy. This study describes the occurrence and epidemiology of CJD and vCJD in the United States. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of CJD and vCJD deaths using death certificates of US residents for 1979-2006, and those identified through other surveillance mechanisms during 1996-2008. Since CJD is invariably fatal and illness duration is usually less than one year, the CJD incidence is estimated as the death rate. During 1979 through 2006, an estimated 6,917 deaths with CJD as a cause of death were reported in the United States, an annual average of approximately 247 deaths (range 172-304 deaths. The average annual age-adjusted incidence for CJD was 0.97 per 1,000,000 persons. Most (61.8% of the CJD deaths occurred among persons >or=65 years of age for an average annual incidence of 4.8 per 1,000,000 persons in this population. Most deaths were among whites (94.6%; the age-adjusted incidence for whites was 2.7 times higher than that for blacks (1.04 and 0.40, respectively. Three patients who died since 2004 were reported with vCJD; epidemiologic evidence indicated that their infection was acquired outside of the United States. CONCLUSION/SIGNIFICANCE: Surveillance continues to show an annual CJD incidence rate of about 1 case per 1,000,000 persons and marked differences in CJD rates by age and race in the United States. Ongoing surveillance remains important for monitoring the stability of the CJD incidence rates, and detecting occurrences of vCJD and possibly other novel prion diseases in the United States.

  4. Haemolytic disease of the newborn due to multiple maternal antibodies

    National Research Council Canada - National Science Library

    Suresh B; Deepthi K; Yashovardhan A; Arun R; Sreedhar Babu KV; Jothibai DS; Bhavani V

    2014-01-01

    ...) is shortened by the action of specific maternal immunoglobulin G (IgG) antibody. Rhesus (Rh)- D haemolytic disease of the newborn is a prototype of maternal isoimmunization and foetal haemolytic disease...

  5. Haemolytic disease of the newborn due to multiple maternal antibodies

    OpenAIRE

    Suresh B; Deepthi K; Yashovardhan A; Arun R; Sreedhar Babu KV; Jothibai DS; Bhavani V

    2014-01-01

    Haemolytic disease of the foetus and newborn (HDFN) is a condition in which the lifespan of an infant’s red blood cells (RBCs) is shortened by the action of specific maternal immunoglobulin G (IgG) antibody. Rhesus (Rh)- D haemolytic disease of the newborn is a prototype of maternal isoimmunization and foetal haemolytic disease. Although rare, the other blood group antigens capable of causing alloimunization and haemolytic disease are c, C, E, Kell and Duffy. We report a case of H...

  6. Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs.

    Science.gov (United States)

    Friedenberg, Steven G; Buhrman, Greg; Chdid, Lhoucine; Olby, Natasha J; Olivry, Thierry; Guillaumin, Julien; O'Toole, Theresa; Goggs, Robert; Kennedy, Lorna J; Rose, Robert B; Meurs, Kathryn M

    2016-03-01

    Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher's exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12) and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared with the reference allele, DLA-79*001:01), resulting in F33L and N37D amino acid changes. These mutations occur in the peptide-binding pocket of the protein, and based upon our computational modeling studies, are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly and to determine the specific mechanism by which the identified variants alter canine immune system function.

  7. Plant-derived recombinant human serum transferrin demonstrates multiple functions.

    Science.gov (United States)

    Brandsma, Martin E; Diao, Hong; Wang, Xiaofeng; Kohalmi, Susanne E; Jevnikar, Anthony M; Ma, Shengwu

    2010-05-01

    Human serum transferrin (hTf) is the major iron-binding protein in human plasma, having a vital role in iron transport. Additionally, hTf has many other uses including antimicrobial functions and growth factor effects on mammalian cell proliferation and differentiation. The multitask nature of hTf makes it highly valuable for different therapeutic and commercial applications. However, the success of hTf in these applications is critically dependent on the availability of high-quality hTf in large amounts. In this study, we have developed plants as a novel platform for the production of recombinant (r)hTf. We show here that transgenic plants are an efficient system for rhTf production, with a maximum accumulation of 0.25% total soluble protein (TSP) (or up to 33.5 microg/g fresh leaf weight). Furthermore, plant-derived rhTf retains many of the biological activities synonymous with native hTf. In particular, rhTf reversibly binds iron in vitro, exhibits bacteriostatic activity, supports cell proliferation in serum-free medium and can be internalized into mammalian cells in vitro. The success of this study validates the future application of plant rhTf in a variety of fields. Of particular interest is the use of plant rhTf as a novel carrier for cell-specific or oral delivery of protein/peptide drugs for the treatment of human diseases such as diabetes.To demonstrate this hypothesis, we have additionally expressed an hTf fusion protein containing glucagon-like peptide 1 (GLP-1) or its derivative in plants. Here, we show that plant-derived hTf-GLP-1 fusion proteins retain the ability to be internalized by mammalian cells when added to culture medium in vitro.

  8. Legionella pneumophila transcriptome during intracellular multiplication in human macrophages

    Directory of Open Access Journals (Sweden)

    Sebastien P Faucher

    2011-04-01

    Full Text Available Legionella pneumophila is the causative agent of Legionnaires’ disease, an acute pulmonary infection. L. pneumophila is able to infect and multiply in both phagocytic protozoa, such as Acanthamoeba castellanii, and mammalian professional phagocytes. The best-known L. pneumophila virulence determinant is the Icm/Dot Type IVB secretion system (TFBSS, which is used to translocate more than 150 effector proteins to host cells. While the transcriptional response of Legionella to the intracellular environment of A. castellanii has been investigated, much less is known about the Legionella transcriptional response inside human macrophages. In this study, the transcriptome of L. pneumophila was monitored during exponential and post-exponential phase in rich AYE broth as well as during infection of human cultured macrophages. This was accomplished with microarrays and an RNA amplification procedure called SCOTS to detect small amounts of mRNA from low numbers of intracellular bacteria. Among the genes induced intracellularly are those involved in amino acid biosynthetic pathways leading to L-arginine, L-histidine and L-proline as well as many transport systems involved in amino acid and iron uptake. Gene involved in catabolism of glycerol is also induced during intracellular growth and could be used as a carbon source. The genes encoding the Icm/Dot system are not differentially expressed inside cells compared to control bacteria grown in rich broth, but the genes encoding several translocated effectors are strongly induced. Moreover, we used the transcriptome data to predict previously unrecognized Icm/Dot effector genes based on their expression pattern and confirmed translocation for three candidates. This study provides a comprehensive view of how L. pneumophila responds to the human macrophage intracellular environment.

  9. HIV and the spectrum of human disease.

    Science.gov (United States)

    Lucas, Sebastian; Nelson, Ann Marie

    2015-01-01

    Infection with the human immunodeficiency virus (HIV) causes systemic T cell destruction and reduced cell-mediated immunity that leads to a wide range of opportunistic infections and cancers. Second, it directly damages many tissues - gut, brain, lung - through mononuclear cell infection and activation. Third, through immune activation and effects on endothelia, it can cause more subtle systemic organ damage, such as chronic cardiovascular, hepatic, pulmonary and central nervous system disease. Antiretroviral treatment has enabled HIV-infected persons to live with chronic infection, although with some side-effects and mortality, including reactions due to the immune reconstitution inflammatory syndrome (IRIS). As cohorts of infected people get older, age-related diseases will combine with chronic HIV infection to produce disabilities whose scale is not yet understood. HIV is detectable in tissues by immunohistochemistry when infection loads are high, such as at first presentation. Pathologists should proactively consider HIV disease in routine diagnostic work, so as to identify more HIV-infected patients and enable their optimal management.

  10. Blood type biochemistry and human disease.

    Science.gov (United States)

    Ewald, D Rose; Sumner, Susan C J

    2016-11-01

    Associations between blood type and disease have been studied since the early 1900s when researchers determined that antibodies and antigens are inherited. In the 1950s, the chemical identification of the carbohydrate structure of surface antigens led to the understanding of biosynthetic pathways. The blood type is defined by oligosaccharide structures, which are specific to the antigens, thus, blood group antigens are secondary gene products, while the primary gene products are various glycosyltransferase enzymes that attach the sugar molecules to the oligosaccharide chain. Blood group antigens are found on red blood cells, platelets, leukocytes, plasma proteins, certain tissues, and various cell surface enzymes, and also exist in soluble form in body secretions such as breast milk, seminal fluid, saliva, sweat, gastric secretions, urine, and amniotic fluid. Recent advances in technology, biochemistry, and genetics have clarified the functional classifications of human blood group antigens, the structure of the A, B, H, and Lewis determinants and the enzymes that produce them, and the association of blood group antigens with disease risks. Further research to identify differences in the biochemical composition of blood group antigens, and the relationship to risks for disease, can be important for the identification of targets for the development of nutritional intervention strategies, or the identification of druggable targets. WIREs Syst Biol Med 2016, 8:517-535. doi: 10.1002/wsbm.1355 For further resources related to this article, please visit the WIREs website.

  11. HECT E3s and human disease

    Directory of Open Access Journals (Sweden)

    Staub Olivier

    2007-11-01

    Full Text Available Abstract In a simplified view, members of the HECT E3 family have a modular structure consisting of the C-terminal HECT domain, which is catalytically involved in the attachment of ubiquitin to substrate proteins, and N-terminal extensions of variable length and sequence that mediate the substrate specificity of the respective HECT E3. Although the physiologically relevant substrates of most HECT E3s have remained elusive, it is becoming increasingly clear that HECT E3s play an important role in sporadic and hereditary human diseases including cancer, cardiovascular (Liddle's syndrome and neurological (Angelman syndrome disorders, and/or in disease-relevant processes including bone homeostasis, immune response and retroviral budding. Thus, molecular approaches to target the activity of distinct HECT E3s, regulators thereof, and/or of HECT E3 substrates could prove valuable in the treatment of the respective diseases. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com.

  12. Diet, disease and pigment variation in humans.

    Science.gov (United States)

    Khan, R; Khan, B S Razib

    2010-10-01

    There are several hypotheses which explain the de-pigmentation of humans. The most prominent environmental explanation is that reduced endogenous vitamin D production due to diminished radiation at higher latitudes had a deleterious impact on fitness. This drove de-pigmentation as an adaptive response. A model of natural selection explains the high correlations found between low vitamin D levels and ill health, as vitamin D's role in immune response has clear evolutionary implications. But recent genomic techniques have highlighted the likelihood that extreme de-pigmentation in Eurasia is a feature of the last 10,000years, not the Upper Pleistocene, when modern humans first settled northern Eurasia. Additionally the data imply two independent selection events in eastern and western Eurasia. Therefore new parameters must be added to the model of natural selection so as to explain the relatively recent and parallel adaptive responses. I propose a model of gene-culture co-evolution whereby the spread of agriculture both reduced dietary vitamin D sources and led to more powerful selection on immune response because of the rise of infectious diseases with greater population densities. This model explains the persistence of relatively dark-skinned peoples at relatively high latitudes and the existence of relatively light-skinned populations at low latitudes. It also reinforces the importance of vitamin D as a micronutrient because of the evidence of extremely powerful fitness implications in the recent human past of pigmentation. Copyright 2010 Elsevier Ltd. All rights reserved.

  13. Deciphering the Molecular Basis of Human Cardiovascular Disease through Network Biology

    Science.gov (United States)

    Chan, Stephen Y.; White, Kevin; Loscalzo, Joseph

    2012-01-01

    Purpose of review This review introduces the fundamental concepts of network medicine and explores the feasibility and potential impact of network-based methods on predicting and ameliorating individual manifestations of human cardiovascular disease. Recent findings Complex cardiovascular diseases rarely result from an abnormality in a single molecular effector, but, rather, nearly always are the net result of multiple pathobiological pathways that interact through an interconnected network. In the post-genomic era, a framework has emerged of the potential complexity of the interacting pathways that govern molecular actions in the human cell. As a result, network approaches have been developed to understand more comprehensively those interconnections that influence human disease. “Network medicine” has already led to tangible discoveries of novel disease genes and pathways as well as improved mechanisms for rational drug development. Summary As methodologies evolve, network medicine may better capture the complexity of human pathogenesis and, thus, re-define personalized disease classification and therapies. PMID:22382498

  14. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.

    Science.gov (United States)

    Prusiner, Stanley B; Woerman, Amanda L; Mordes, Daniel A; Watts, Joel C; Rampersaud, Ryan; Berry, David B; Patel, Smita; Oehler, Abby; Lowe, Jennifer K; Kravitz, Stephanie N; Geschwind, Daniel H; Glidden, David V; Halliday, Glenda M; Middleton, Lefkos T; Gentleman, Steve M; Grinberg, Lea T; Giles, Kurt

    2015-09-22

    Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T-YFP) and TgM83(+/-) mice expressing α-synuclein (A53T). The TgM83(+/-) mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83(+/+) mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83(+/-) mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T-YFP in cultured cells, whereas none of six Parkinson's disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

  15. Role of thalamic diffusion for disease differentiation between multiple sclerosis and ischemic cerebral small vessel disease

    Energy Technology Data Exchange (ETDEWEB)

    Oeztoprak, Bilge; Oeztoprak, Ibrahim; Salk, Ismail [Cumhuriyet University School of Medicine, Department of Radiology, Sivas (Turkey); Topalkara, Kamil [Bayindir Hospital, Department of Neurology, Ankara (Turkey); Erkoc, Mustafa F. [Bozok University School of Medicine, Department of Radiology, Yozgat (Turkey)

    2015-04-01

    Cerebral small vessel disease (CSVD) and multiple sclerosis (MS) both harbor multiple, T2-hyperintense white matter lesions on conventional magnetic resonance imaging (MRI).We aimed to determine the microstructural changes via diffusion-weighted imaging (DWI) in normal appearing thalami. We hypothesized that the apparent diffusion coefficient (ADC) values would be different in CSVD and MS, since the extent of arterial involvement is different in these two diseases. DWI was performed for 50 patients with CSVD and 35 patients with MS along with gender- and age-matched controls whose conventional MRI revealed normal findings. DWI was done with 1.5 Tesla MR devices using echo planar imaging (EPI) for b = 0, 1000 s/mm{sup 2}. ADC values were obtained from the thalami which appeared normal on T2-weighted and FLAIR images. Standard oval regions of interest (ROIs) of 0.5 cm{sup 2} which were oriented parallel to the long axis of the thalamus were used for this purpose. The mean ADC value of the thalamus was (0.99 ± 0.16) x 10{sup -3} mm{sup 2}/s in patients with CSVD, whereas the mean ADC value was (0.78 ± 0.06) x 10{sup -3} mm{sup 2}/s in the control group. The mean ADC value was significantly higher in patients with CSVD compared to the controls (p < 0.001). The mean ADC values of the thalamus were (0.78 ± 0.08) x 10{sup -3} mm{sup 2}/s in MS patients, and (0.75 ± 0.08) x 10{sup -3} mm{sup 2}/s in the control group, which are not significantly different (p > 0.05). Our study revealed a difference in the diffusion of the thalami between CSVD and MS. DWI may aid in the radiological disease differentiation. (orig.)

  16. CRISPR-mediated genome editing and human diseases

    Directory of Open Access Journals (Sweden)

    Liquan Cai

    2016-12-01

    Full Text Available CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats technology has emerged as a powerful technology for genome editing and is now widely used in basic biomedical research to explore gene function. More recently, this technology has been increasingly applied to the study or treatment of human diseases, including Barth syndrome effects on the heart, Duchenne muscular dystrophy, hemophilia, β-Thalassemia, and cystic fibrosis. CRISPR/Cas9 (CRISPR-associated protein 9 genome editing has been used to correct disease-causing DNA mutations ranging from a single base pair to large deletions in model systems ranging from cells in vitro to animals in vivo. In addition to genetic diseases, CRISPR/Cas9 gene editing has also been applied in immunology-focused applications such as the targeting of C-C chemokine receptor type 5, the programmed death 1 gene, or the creation of chimeric antigen receptors in T cells for purposes such as the treatment of the acquired immune deficiency syndrome (AIDS or promoting anti-tumor immunotherapy. Furthermore, this technology has been applied to the genetic manipulation of domesticated animals with the goal of producing biologic medical materials, including molecules, cells or organs, on a large scale. Finally, CRISPR/Cas9 has been teamed with induced pluripotent stem (iPS cells to perform multiple tissue engineering tasks including the creation of disease models or the preparation of donor-specific tissues for transplantation. This review will explore the ways in which the use of CRISPR/Cas9 is opening new doors to the treatment of human diseases.

  17. Baboons as a model to study genetics and epigenetics of human disease.

    Science.gov (United States)

    Cox, Laura A; Comuzzie, Anthony G; Havill, Lorena M; Karere, Genesio M; Spradling, Kimberly D; Mahaney, Michael C; Nathanielsz, Peter W; Nicolella, Daniel P; Shade, Robert E; Voruganti, Saroja; VandeBerg, John L

    2013-01-01

    A major challenge for understanding susceptibility to common human diseases is determining genetic and environmental factors that influence mechanisms underlying variation in disease-related traits. The most common diseases afflicting the US population are complex diseases that develop as a result of defects in multiple genetically controlled systems in response to environmental challenges. Unraveling the etiology of these diseases is exceedingly difficult because of the many genetic and environmental factors involved. Studies of complex disease genetics in humans are challenging because it is not possible to control pedigree structure and often not practical to control environmental conditions over an extended period of time. Furthermore, access to tissues relevant to many diseases from healthy individuals is quite limited. The baboon is a well-established research model for the study of a wide array of common complex diseases, including dyslipidemia, hypertension, obesity, and osteoporosis. It is possible to acquire tissues from healthy, genetically characterized baboons that have been exposed to defined environmental stimuli. In this review, we describe the genetic and physiologic similarity of baboons with humans, the ability and usefulness of controlling environment and breeding, and current genetic and genomic resources. We discuss studies on genetics of heart disease, obesity, diabetes, metabolic syndrome, hypertension, osteoporosis, osteoarthritis, and intrauterine growth restriction using the baboon as a model for human disease. We also summarize new studies and resources under development, providing examples of potential translational studies for targeted interventions and therapies for human disease.

  18. Adherence to disease-modifying therapies and attitudes regarding disease in patients with multiple sclerosis.

    Science.gov (United States)

    Ožura, Ana; Kovač, Lea; Sega, Saša

    2013-12-01

    Although currently there is no cure for MS the course of the disease can be influenced by disease modifying therapy (DMT). For therapy to be sufficiently efficient, it is crucial that patients take their medication regularly as prescribed. Adherence describes the extent to which a patient acts in accordance with the prescribed timing, dosing, and frequency of medication administration. To date, there are no known data about adherence rates among patients with MS in Slovenia. We wanted to assess adherence in patients with MS, who are treated with first line DMTs and discover reasons for non-adherence. A number of 451 patients were invited to participate. They received two questionnaires via post mail. The adherence rate and putative reasons for non-adherence were assessed by the use of standardized self-report Multiple Sclerosis Treatment Experience Questionnaire (MSTEQ). Patients' attitudes regarding disease, therapy and relationship with their physician were assessed by another questionnaire. The analysis of results included 299 patients. Among the patients 18.5% missed at least one medication dose in the past 28 days. Patients taking Avonex were significantly more adherent then patients on other DMTs (p=0.005). Our study showed a higher then expected adherence among Slovenian patients with MS (81.5%). Our research did not confirm the influence of side effects or patients' attitudes regarding illness and therapy on adherence. However we found unexpectedly high percentage (71.8%) of patients belief that psychological factors are involved in MS aetiology.

  19. Invasive meningococcal disease in England: assessing disease burden through linkage of multiple national data sources.

    Science.gov (United States)

    Ladhani, Shamez N; Waight, Pauline A; Ribeiro, Sonia; Ramsay, Mary E

    2015-12-01

    In England, Public Health England conducts enhanced surveillance of invasive meningococcal disease (IMD). The continuing decline in reported IMD cases has raised concerns that the MRU may be underestimating true IMD incidence. We linked five national datasets to estimate disease burden over five years, including PHE Meningococcal Reference Unit (MRU) confirmations, hospital episode statistics (HES), electronic reports of significant infections by National Health Service (NHS) Hospitals, death registrations and private laboratory reports. During 2007-11, MRU confirmed 5115 IMD cases and 4275 (84%) matched to HES, including 3935 (92%) with A39* (meningococcal disease) and 340 (8%) with G00* (bacterial meningo-encephalitis) ICD-10 codes. An additional 2792 hospitalised cases with an A39* code were identified in HES. Of these, 1465 (52%) matched to one of 53,806 samples tested PCR-negative for IMD by MRU and only 73 of the remaining 1327 hospitalised A39* cases were confirmed locally or by a private laboratory. The characteristics of hospitalised cases without laboratory confirmation were similar to PCR-negative than PCR-positive IMD cases. Interrogation of multiple national data sources identified very few laboratory confirmations in addition to the MRU-confirmed cases. The large number of unconfirmed and PCR-negative cases in HES suggests increased awareness among clinicians with low thresholds for hospitalising patients with suspected IMD.

  20. [Indoor air and human health--sick house syndrome and multiple chemical sensitivity].

    Science.gov (United States)

    Ando, Masanori

    2002-01-01

    The number of complaints about the quality of indoor air has increased during the past two decades. These complaints have been frequent enough that the term "Sick House Syndrome or Sick Building Syndrome" and "Multiple Chemical Sensitivity" has been coined. Complaints are likely related to the increased use of synthetic organic materials in house, furnishing, and consumer products; and the buildings, furnishings, and consumer products; and the decreased ventilation for energy conservation in homes. Approximately thousand volatile chemicals have been identified in indoor air. The main sources of these chemicals are house materials, combustion fumes, cleaning compounds, and paints or stains. Exposure to high levels of these emissions and to others, coupled with the fact that most people spend more time indoors than outdoors, raises the possibility that the risk to human health from indoor air pollution may be potentially greater than the risk posed from outdoor pollutants. The complaints most frequently voiced with respect to Sick House Syndrome are irritations of the eye, nose, and throat; cough and hoarseness of voice; headache and mental fatigue. The syndrome of multiple chemical sensitivities is controversial subject with increasing impact on the field of indoor air quality. The controversy surrounding Multiple Chemical Sensitivity includes its definition, theories of etiology and pathogenesis, diagnostic, and life style. Multiple Chemical Sensitivity is considered the hypothesis that is a disease caused by exposure to many chemically distinct environmental substances at very low.

  1. Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

    Science.gov (United States)

    Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

    2012-01-01

    The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

  2. 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 inve

  3. Immunoglobulin Free Light Chain Dimers in Human Diseases

    Directory of Open Access Journals (Sweden)

    Batia Kaplan

    2011-01-01

    Full Text Available Immunoglobulin free light chain (FLC kappa (κ and lambda (λ isotypes exist mainly in monomeric and dimeric forms. Under pathological conditions, the level of FLCs as well as the structure of monomeric and dimeric FLCs and their dimerization properties might be significantly altered. The abnormally high fractions of dimeric FLCs were demonstrated in the serum of patients with multiple myeloma (MM and primary systemic amyloidosis (AL, as well as in the serum of anephric patients. The presence of tetra- and trimolecular complexes formed due to dimer-dimer and dimer-monomer interactions was detected in the myeloma serum. Analysis of the amyloidogenic light chains demonstrated mutations within the dimer interface, thus raising the possibility that these mutations are responsible for amyloidogenicity. Increased κ monomer and dimer levels, as well as a high κ/λ monomer ratio, were typically found in the cerebrospinal fluid from patients with multiple sclerosis (MS. In many MS cases, the elevation of κ FLCs was accompanied by an abnormally high proportion of λ dimers. This review focuses on the disease-related changes of the structure and level of dimeric FLCs, and raises the questions regarding their formation, function, and role in the pathogenesis and diagnosis of human diseases.

  4. Restoring the balance between disease and repair in multiple sclerosis: insights from mouse models

    OpenAIRE

    Robert H. Miller; Fyffe-Maricich, Sharyl L.

    2010-01-01

    Multiple sclerosis (MS) is considered an autoimmune-mediated demyelinating disease that targets the central nervous system (CNS). Despite considerable research efforts over multiple decades, our understanding of the basic biological processes that are targeted in the disease and the mechanisms of pathogenesis are poorly understood. Consequently, current therapies directed at controlling the progression of the disease are limited in their effectiveness. Historically, the primary focus of MS re...

  5. Multiple cardiovascular complications in a patient with Behcet disease

    Institute of Scientific and Technical Information of China (English)

    LIU Jing; ZHENG Jun; CUI Li; XU Xian-rong

    2010-01-01

    @@ Behcet disease (BD) is a chronic multisystem disease that presents with recurrent oral and genital ulceration and recurrent uveitis. Vascular and cardiac thromboses are rare but life threatening complications.We report a case of right internal jugular vein and brachiocephalic vein thrombus and successive cardiac thrombosis, which was finally diagnosed with BD.

  6. Discovering multiple transcripts of human hepatocytes using massively parallel signature sequencing (MPSS

    Directory of Open Access Journals (Sweden)

    Li Yi-Xue

    2007-07-01

    Full Text Available Abstract Background The liver is the largest human internal organ – it is composed of multiple cell types and plays a vital role in fulfilling the body's metabolic needs and maintaining homeostasis. Of these cell types the hepatocytes, which account for three-quarters of the liver's volume, perform its main functions. To discover the molecular basis of hepatocyte function, we employed Massively Parallel Signature Sequencing (MPSS to determine the transcriptomic profile of adult human hepatocytes obtained by laser capture microdissection (LCM. Results 10,279 UniGene clusters, representing 7,475 known genes, were detected in human hepatocytes. In addition, 1,819 unique MPSS signatures matching the antisense strand of 1,605 non-redundant UniGene clusters (such as APOC1, APOC2, APOB and APOH were highly expressed in hepatocytes. Conclusion Apart from a large number of protein-coding genes, some of the antisense transcripts expressed in hepatocytes could play important roles in transcriptional interference via a cis-/trans-regulation mechanism. Our result provided a comprehensively transcriptomic atlas of human hepatocytes using MPSS technique, which could be served as an available resource for an in-depth understanding of human liver biology and diseases.

  7. Human KATP channelopathies: diseases of metabolic homeostasis

    Science.gov (United States)

    2009-01-01

    Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in KATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, KATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within KATP channel genes and the spectrum of genotype–phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy. PMID:20033705

  8. Major trends in human parasitic diseases in China.

    Science.gov (United States)

    Li, Ting; He, Shenyi; Zhao, Hong; Zhao, Guanghui; Zhu, Xing-Quan

    2010-05-01

    Tremendous progress has been made in the control and prevention of human parasitic diseases in mainland China in the past 30 years because of China's Reform and Opening to the Outside Policies initiated in 1978. However, parasitic diseases remain a major human health problem, with significant morbidity and mortality as well as adverse socioeconomic consequences. Although soil-transmitted parasitic diseases are in the process of being gradually controlled, food-borne parasitic diseases and emerging parasitic diseases are becoming the focus of new campaigns for control and prevention. This article reviews major trends in human parasitic diseases in mainland China, with perspectives for control.

  9. Network Medicine: A Network-based Approach to Human Diseases

    Science.gov (United States)

    Ghiassian, Susan Dina

    With the availability of large-scale data, it is now possible to systematically study the underlying interaction maps of many complex systems in multiple disciplines. Statistical physics has a long and successful history in modeling and characterizing systems with a large number of interacting individuals. Indeed, numerous approaches that were first developed in the context of statistical physics, such as the notion of random walks and diffusion processes, have been applied successfully to study and characterize complex systems in the context of network science. Based on these tools, network science has made important contributions to our understanding of many real-world, self-organizing systems, for example in computer science, sociology and economics. Biological systems are no exception. Indeed, recent studies reflect the necessity of applying statistical and network-based approaches in order to understand complex biological systems, such as cells. In these approaches, a cell is viewed as a complex network consisting of interactions among cellular components, such as genes and proteins. Given the cellular network as a platform, machinery, functionality and failure of a cell can be studied with network-based approaches, a field known as systems biology. Here, we apply network-based approaches to explore human diseases and their associated genes within the cellular network. This dissertation is divided in three parts: (i) A systematic analysis of the connectivity patterns among disease proteins within the cellular network. The quantification of these patterns inspires the design of an algorithm which predicts a disease-specific subnetwork containing yet unknown disease associated proteins. (ii) We apply the introduced algorithm to explore the common underlying mechanism of many complex diseases. We detect a subnetwork from which inflammatory processes initiate and result in many autoimmune diseases. (iii) The last chapter of this dissertation describes the

  10. Wolbachia endosymbionts and human disease control.

    Science.gov (United States)

    Slatko, Barton E; Luck, Ashley N; Dobson, Stephen L; Foster, Jeremy M

    2014-07-01

    Most human filarial nematode parasites and arthropods are hosts for a bacterial endosymbiont, Wolbachia. In filaria, Wolbachia are required for normal development, fertility and survival, whereas in arthropods, they are largely parasitic and can influence development and reproduction, but are generally not required for host survival. Due to their obligate nature in filarial parasites, Wolbachia have been a target for drug discovery initiatives using several approaches including diversity and focused library screening and genomic sequence analysis. In vitro and in vivo anti-Wolbachia antibiotic treatments have been shown to have adulticidal activity, a long sought goal of filarial parasite drug discovery. In mosquitoes, it has been shown that the presence of Wolbachia can inhibit the transmission of certain viruses, such as Dengue, Chikungunya, Yellow Fever, West Nile, as well as the infectivity of the malaria-causing protozoan, Plasmodium and filarial nematodes. Furthermore, Wolbachia can cause a form of conditional sterility that can be used to suppress populations of mosquitoes and additional medically important insects. Thus Wolbachia, a pandemic endosymbiont offers great potential for elimination of a wide-variety of devastating human diseases.

  11. Integrated dataset of screening hits against multiple neglected disease pathogens.

    Directory of Open Access Journals (Sweden)

    Solomon Nwaka

    2011-12-01

    Full Text Available New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.

  12. Autologous Graft versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Anu Batra

    2014-01-01

    Full Text Available Autologous graft versus host disease (autoGVHD is a rare transplant complication with significant morbidity and mortality. It has been hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through dysregulation of the immune response resulting from either their disease, the immunomodulatory agents (IMiDs used to treat it, or transplant conditioning regimen. Hematopoietic progenitor cell (HPC products were available from 8 multiple myeloma patients with biopsy-proven autoGVHD, 16 matched multiple myeloma patients who did not develop autoGVHD, and 7 healthy research donors. The data on number of transplants prior to developing autoGVHD, mobilization regimens, exposure to proteasome inhibitors, use of IMiDs, and class I human leukocyte antigen types (HLA A and B were collected. The HPC products were analyzed by flow cytometry for expression of CD3, CD4, CD8, CD25, CD56, and FoxP3. CD3+ cell number was significantly lower in autoGVHD patients compared to unaffected controls (P=0.047. On subset analysis of CD3+ cells, CD8+ cells (but not CD4+ cells were found to be significantly lower in patients with autoGVHD (P=0.038. HLA-B55 expression was significantly associated with development of autoGVHD (P=0.032. Lower percentages of CD3+ and CD8+ T-cells and HLA-B55 expression may be predisposing factors for developing autoGVHD in myeloma.

  13. Human plantarflexor stiffness to multiple single-stretch trials.

    Science.gov (United States)

    Blanpied, P; Smidt, G L

    1992-01-01

    The purpose of this investigation was to determine the influence of different stretch velocities, different rates of pre-stretch force development, and different pre-stretch muscle lengths on the intrinsic stiffness exhibited by the quasi-statically contracting active human plantarflexors during multiple single-stretch trials at 20-60% of maximum isometric contraction. Subjects were positioned prone, with the knee flexed 1.57 rad(90 degrees), shank stabilized, and foot secured in a hard plastic orthotic. Slowly increasing isometric plantarflexion force was produced until the plantarflexors were stretched by a rapid 0.2 rad (12 degrees) dorsiflexion movement. Plantarflexion forces and ankle positions were determined during these stretches as well as during resting stretches when the muscle was inactive. Resting forces were subtracted from the active trials, forces converted to torques, and stiffnesses determined for the first 62 ms of the stretch. The slope of the stiffness vs pre-stretch torque relationship averaged 4.30 +/- 0.34 Nm rad-1 Nm-1. Little difference was found between stiffness determined through the single-stretch method and the results of previous studies employing different mechanical inputs. Differences in stiffnesses with different stretching velocities were caused by computational artifact rather than by differences in intrinsic muscular reaction. Faster rates of pre-stretch force increase prior to the stretch resulted in slightly lower stiffnesses. Different pre-stretch muscle lengths apparently did not result in different stiffnesses. The shape of the torque vs displacement curve was remarkably insensitive to the planned manipulations of the testing conditions, responding in a stereotypical manner.

  14. Multiplicity of Infection and Disease Severity in Plasmodium vivax

    DEFF Research Database (Denmark)

    Pacheco, M Andreína; Lopez-Perez, Mary; Vallejo, Andrés F

    2016-01-01

    BACKGROUND: Multiplicity of infection (MOI) refers to the average number of distinct parasite genotypes concurrently infecting a patient. Although several studies have reported on MOI and the frequency of multiclonal infections in Plasmodium falciparum, there is limited data on Plasmodium vivax. ...

  15. 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 wit

  16. Haemolytic disease of the newborn due to multiple maternal antibodies

    Directory of Open Access Journals (Sweden)

    Suresh B

    2014-07-01

    Full Text Available Haemolytic disease of the foetus and newborn (HDFN is a condition in which the lifespan of an infant’s red blood cells (RBCs is shortened by the action of specific maternal immunoglobulin G (IgG antibody. Rhesus (Rh- D haemolytic disease of the newborn is a prototype of maternal isoimmunization and foetal haemolytic disease. Although rare, the other blood group antigens capable of causing alloimunization and haemolytic disease are c, C, E, Kell and Duffy. We report a case of HDFN due to anti-D and anti-C in the maternal serum as a result of anamnestic response to Rh-D and C antigens. This report highlights the importance of antibody screening in antenatal women which could assist in diagnosing and successfully treating the foetus and newborn with appropriate antigen negative cross-matched compatible blood.

  17. Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

    Science.gov (United States)

    Li, Shirong; Feng, Rentian; Ma, Huihui; Sabeh, Farideh; Roodman, G. David; Wang, Ji; Robinson, Samuel; Guo, X. Edward; Lund, Thomas; Normolle, Daniel; Mapara, Markus Y.; Weiss, Stephen J.

    2016-01-01

    Multiple myeloma (MM) cells secrete osteoclastogenic factors that promote osteolytic lesions; however, the identity of these factors is largely unknown. Here, we performed a screen of human myeloma cells to identify pro-osteoclastogenic agents that could potentially serve as therapeutic targets for ameliorating MM-associated bone disease. We found that myeloma cells express high levels of the matrix metalloproteinase MMP-13 and determined that MMP-13 directly enhances osteoclast multinucleation and bone-resorptive activity by triggering upregulation of the cell fusogen DC-STAMP. Moreover, this effect was independent of the proteolytic activity of the enzyme. Further, in mouse xenograft models, silencing MMP-13 expression in myeloma cells inhibited the development of osteolytic lesions. In patient cohorts, MMP-13 expression was localized to BM-associated myeloma cells, while elevated MMP-13 serum levels were able to correctly predict the presence of active bone disease. Together, these data demonstrate that MMP-13 is critical for the development of osteolytic lesions in MM and that targeting the MMP-13 protein — rather than its catalytic activity — constitutes a potential approach to mitigating bone disease in affected patients. PMID:27043283

  18. MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases.

    Science.gov (United States)

    Ha, Tai-You

    2011-10-01

    MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immunity and in the prevention of autoimmunity. It has been increasingly reported that miRNAs are associated with various human diseases like autoimmune disease, skin disease, neurological disease and psychiatric disease. Recently, the identification of mi- RNAs in skin has added a new dimension in the regulatory network and attracted significant interest in this novel layer of gene regulation. Although miRNA research in the field of dermatology is still relatively new, miRNAs have been the subject of much dermatological interest in skin morphogenesis and in regulating angiogenesis. In addition, miRNAs are moving rapidly onto center stage as key regulators of neuronal development and function in addition to important contributions to neurodegenerative disorder. Moreover, there is now compelling evidence that dysregulation of miRNA networks is implicated in the development and onset of human neruodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Down syndrome, depression and schizophrenia. In this review, I briefly summarize the current studies about the roles of miRNAs in various autoimmune diseases, skin diseases, psychoneurological disorders and mental stress.

  19. An architecture model for multiple disease management information systems.

    Science.gov (United States)

    Chen, Lichin; Yu, Hui-Chu; Li, Hao-Chun; Wang, Yi-Van; Chen, Huang-Jen; Wang, I-Ching; Wang, Chiou-Shiang; Peng, Hui-Yu; Hsu, Yu-Ling; Chen, Chi-Huang; Chuang, Lee-Ming; Lee, Hung-Chang; Chung, Yufang; Lai, Feipei

    2013-04-01

    Disease management is a program which attempts to overcome the fragmentation of healthcare system and improve the quality of care. Many studies have proven the effectiveness of disease management. However, the case managers were spending the majority of time in documentation, coordinating the members of the care team. They need a tool to support them with daily practice and optimizing the inefficient workflow. Several discussions have indicated that information technology plays an important role in the era of disease management. Whereas applications have been developed, it is inefficient to develop information system for each disease management program individually. The aim of this research is to support the work of disease management, reform the inefficient workflow, and propose an architecture model that enhance on the reusability and time saving of information system development. The proposed architecture model had been successfully implemented into two disease management information system, and the result was evaluated through reusability analysis, time consumed analysis, pre- and post-implement workflow analysis, and user questionnaire survey. The reusability of the proposed model was high, less than half of the time was consumed, and the workflow had been improved. The overall user aspect is positive. The supportiveness during daily workflow is high. The system empowers the case managers with better information and leads to better decision making.

  20. Reflections on the Field of Human Genetics: A Call for Increased Disease Genetics Theory.

    Science.gov (United States)

    Schrodi, Steven J

    2016-01-01

    Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. In particular, the development of new, realistic disease genetics models will help elucidate complex disease pathogenesis, and the predicted patterns in genetic data made by these models will enable the concurrent, more comprehensive statistical testing of multiple aspects of disease genetics predictions, thereby better identifying disease loci. By theoretical human genetics, I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Hence, the scope of theoretical disease genetics work includes construction and analysis of models describing how disease-predisposing alleles (1) arise, (2) are transmitted across families and populations, and (3) interact with other risk and protective alleles across both the genome and environmental factors to produce disease states. Theoretical work improves insight into viable genetic models of diseases consistent with empirical results from linkage, transmission, and association studies as well as population genetics. Furthermore, understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. In spite of the pivotal role of disease genetics theory, such investigation is not particularly vibrant.

  1. The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease.

    Science.gov (United States)

    Peng, Xinxia; Alföldi, Jessica; Gori, Kevin; Eisfeld, Amie J; Tyler, Scott R; Tisoncik-Go, Jennifer; Brawand, David; Law, G Lynn; Skunca, Nives; Hatta, Masato; Gasper, David J; Kelly, Sara M; Chang, Jean; Thomas, Matthew J; Johnson, Jeremy; Berlin, Aaron M; Lara, Marcia; Russell, Pamela; Swofford, Ross; Turner-Maier, Jason; Young, Sarah; Hourlier, Thibaut; Aken, Bronwen; Searle, Steve; Sun, Xingshen; Yi, Yaling; Suresh, M; Tumpey, Terrence M; Siepel, Adam; Wisely, Samantha M; Dessimoz, Christophe; Kawaoka, Yoshihiro; Birren, Bruce W; Lindblad-Toh, Kerstin; Di Palma, Federica; Engelhardt, John F; Palermo, Robert E; Katze, Michael G

    2014-12-01

    The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and transmission. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease.

  2. Workshop meeting report Organs-on-Chips: human disease models.

    Science.gov (United States)

    van de Stolpe, Anja; den Toonder, Jaap

    2013-09-21

    The concept of "Organs-on-Chips" has recently evolved and has been described as 3D (mini-) organs or tissues consisting of multiple and different cell types interacting with each other under closely controlled conditions, grown in a microfluidic chip, and mimicking the complex structures and cellular interactions in and between different cell types and organs in vivo, enabling the real time monitoring of cellular processes. In combination with the emerging iPSC (induced pluripotent stem cell) field this development offers unprecedented opportunities to develop human in vitro models for healthy and diseased organ tissues, enabling the investigation of fundamental mechanisms in disease development, drug toxicity screening, drug target discovery and drug development, and the replacement of animal testing. Capturing the genetic background of the iPSC donor in the organ or disease model carries the promise to move towards "in vitro clinical trials", reducing costs for drug development and furthering the concept of personalized medicine and companion diagnostics. During the Lorentz workshop (Leiden, September 2012) an international multidisciplinary group of experts discussed the current state of the art, available and emerging technologies, applications and how to proceed in the field. Organ-on-a-chip platform technologies are expected to revolutionize cell biology in general and drug development in particular.

  3. Thymic Epithelial Cell Development and Its Dysfunction in Human Diseases

    Directory of Open Access Journals (Sweden)

    Lina Sun

    2014-01-01

    Full Text Available Thymic epithelial cells (TECs are the key components in thymic microenvironment for T cells development. TECs, composed of cortical and medullary TECs, are derived from a common bipotent progenitor and undergo a stepwise development controlled by multiple levels of signals to be functionally mature for supporting thymocyte development. Tumor necrosis factor receptor (TNFR family members including the receptor activator for NFκB (RANK, CD40, and lymphotoxin β receptor (LTβR cooperatively control the thymic medullary microenvironment and self-tolerance establishment. In addition, fibroblast growth factors (FGFs, Wnt, and Notch signals are essential for establishment of functional thymic microenvironment. Transcription factors Foxn1 and autoimmune regulator (Aire are powerful modulators of TEC development, differentiation, and self-tolerance. Dysfunction in thymic microenvironment including defects of TEC and thymocyte development would cause physiological disorders such as tumor, infectious diseases, and autoimmune diseases. In the present review, we will summarize our current understanding on TEC development and the underlying molecular signals pathways and the involvement of thymus dysfunction in human diseases.

  4. Heart Disease: A Price Humans Pay for Fertility?

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_166826.html Heart Disease: A Price Humans Pay for Fertility? Study finds ... 22, 2017 (HealthDay News) -- Certain genes linked to heart disease may also improve your chances of having children, ...

  5. Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease.

    Directory of Open Access Journals (Sweden)

    Maria Wilbe

    2015-06-01

    Full Text Available The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H and speckled ANA (ANA(S staining pattern, and also steroid-responsive meningitis-arteritis (SRMA are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAMTOR3, DDIT4L and PPP3CA located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.

  6. Classification of multiple diseases based on wavelet features

    Directory of Open Access Journals (Sweden)

    Nalini Bodasingi

    2017-03-01

    Full Text Available This study presents an efficient disease classification approach based on medical images. The approach is more efficient as it reduces the computational complexity. The implementation uses only two wavelet filters in selecting the texture features as compared with five filters used in the earlier research works. The computed average and energy features are fed to feed-forward neural network (FFNN and support vector machine (SVM classifiers. The SVM is proved as a better classifier than the FFNN for all the three diseases related to skin, breast and retina with an improved accuracies of 89%, 92% and 100%, respectively. Also, a graphical user interface is developed useful for various disease classification based on the whole dataset of size 100.

  7. Reg gene family and human diseases

    Institute of Scientific and Technical Information of China (English)

    Yu-Wei Zhang; Liu-Song Ding; Mao-De Lai

    2003-01-01

    Regenerating gene (Reg or REG) family, within the superfamily of C-type lectin, is mainly involved in the liver,pancreatic, gastric and intestinal cell proliferation or differentiation. Considerable attention has focused on Reg family and its structurally related molecules. Over the last 15 years, 17 members of the Reg family have been cloned and sequenced. They have been considered as members of a conserved protein family sharing structural and some functional properties being involved in injury, inflammation,diabetes and carcinogenesis. We previously identified Reg Ⅳ as a strong candidate for a gene that was highly expressed in colorectal adenoma when compared to normal mucosa based on suppression subtractive hybridization (SSH),reverse Northern blot, semi-quantitative reverse transcriptase PCR (RT-PCR)and Northern blot. In situ hybridization results further support that overexpression of Reg Ⅳ may be an early event in colorectal carcinogenesis. We suggest that detection of Reg Ⅳ overexpression might be useful in the early diagnosis of carcinomatous transformation of adenoma.This review summarizes the roles of Reg family in diseases in the literature as well as our recent results of Reg Ⅳ in colorectal cancer. The biological properties of Reg family and its possible roles in human diseases are discussed. We particularly focus on the roles of Reg family as sensitive reactants of tissue injury, prognostic indicators of tumor survival and early biomarkers of carcinogenesis. In addition to our current understanding of Reg gene functions, we postulate that there might be relationships between Reg family and microsatellite instability, apoptosis and cancer with a poor prognosis. Investigation of the correlation between tumor Reg expression and survival rate, and analysis of the Reg gene status in human maliganancies, are required to elucidate the biologic consequences of Reg gene expression, the implications for Reg gene regulation of cell growth, tumorigenesis

  8. Diagnosis of Parkinson's disease based on disease-specific autoantibody profiles in human sera.

    Directory of Open Access Journals (Sweden)

    Min Han

    Full Text Available Parkinson's disease (PD, hallmarked by a variety of motor disorders and neurological decline, is the second most common neurodegenerative disease worldwide. Currently, no diagnostic test exists to identify sufferers, and physicians must rely on a combination of subjective physical and neurological assessments to make a diagnosis. The discovery of definitive blood-borne biomarkers would be a major step towards early and reliable diagnosis. Despite attention devoted to this search, such biomarkers have remained elusive. In the present study, we used human protein microarrays to reveal serum autoantibodies that are differentially expressed among PD and control subjects. The diagnostic significance of each of these autoantibodies was evaluated, resulting in the selection of 10 autoantibody biomarkers that can effectively differentiate PD sera from control sera with a sensitivity of 93.1% and specificity of 100%. PD sera were also distinguishable from sera obtained from Alzheimer's disease, breast cancer, and multiple sclerosis patients with accuracies of 86.0%, 96.6%, and 100%, respectively. Results demonstrate that serum autoantibodies can be used as highly specific and accurate biomarkers for PD diagnosis throughout the course of the disease.

  9. PEMPHIGUS: an acronym for a disease with multiple etiologies.

    Science.gov (United States)

    Brenner, Sarah; Mashiah, Jacob; Tamir, Einat; Goldberg, Ilan; Wohl, Yonit

    2003-01-01

    The acronym PEMPHIGUS is suggested to encompass the numerous factors involved in the pathogenesis and course of the disease. In the following review the authors present studies documenting these factors. The acronym can serve as a handy tool to direct the physician's investigation of a case of pemphigus, aiding in its diagnosis and in the prevention of future flare-ups.

  10. Predictors of premature discontinuation of treatment in multiple disease states

    Directory of Open Access Journals (Sweden)

    Eric Nantz

    2009-01-01

    Full Text Available Eric Nantz1, Hong Liu-Seifert2, Vladimir Skljarevski21Department of Statistics, Western Michigan University, Kalamazoo, MI, USA; 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USABackground: Premature discontinuation of treatment impacts outcomes of clinical practice. The traditional perception has been patient discontinuation is mainly driven by unwanted side effects. Systematic analysis of data from clinical trials across several disease states was performed to identify predictors of premature discontinuation during clinical interventions.Methods: A post hoc analysis was conducted on 22 randomized, double-blind, placebo-controlled clinical trials for treatment of fibromyalgia, diabetic peripheral neuropathic pain, major depressive disorder, and generalized anxiety disorder. Analyses were conducted on pooled data within each disease state.Results: Lack of early therapeutic response was a significant predictor of patient discontinuation in each disease state. Visit-wise changes in therapeutic response and severity of adverse events were also significant risk factors, with change in therapeutic response having a higher significance level in three disease states. Patients who discontinued due to adverse events had similar therapeutic responses as patients completing treatment.Conclusion: Contrary to the conventional belief that premature treatment discontinuation is primarily related to adverse events, our findings suggest lack of therapeutic response also plays a significant role in patient attrition. This research highlights the importance of systematic monitoring of therapeutic response in clinical practice as a measure to prevent patients’ discontinuation from pharmacological treatments.Keywords: attrition, depression, generalized anxiety disorder, fibromyalgia, therapeutic response, adverse event

  11. [Histoplasmosis: the multiple sides of an uncommon disease].

    Science.gov (United States)

    Amadori, Francesco; Doria, Roberta; Gemignani, Giulia; Flammini, Sarah; Leonildi, Alessandro; Ciancia, Eugenio Mario; Sanguinetti, Maurizio; Menichetti, Francesco

    2015-03-01

    Disseminated histoplasmosis is an invasive fungal infection documented in patients with impaired cellular immunity coming from endemic areas (America, Asia, Africa). We report two cases of disseminated histoplasmosis in AIDS patients paradigmatic of the multifaceted nature of the disease, which may be an expression either of an advanced state of immunosuppression or the immune reconstitution inflammatory syndrome (IRIS).

  12. Cardiopulmonary fitness is related to disease severity in multiple sclerosis

    NARCIS (Netherlands)

    Heine, Martin; Wens, Inez; Langeskov-Christensen, Martin; Verschuren, Olaf|info:eu-repo/dai/nl/304819670; Eijnde, Bert O; Kwakkel, Gert; Dalgas, Ulrik

    2015-01-01

    BACKGROUND: In persons with MS (pwMS), a lower cardiopulmonary fitness has been associated with a higher risk for secondary disorders, decreased functional capacity, symptom worsening and reduced health-related quality of life. OBJECTIVE: To investigate the association between disease severity and c

  13. Multiple common variants for celiac disease influencing immune gene expression

    NARCIS (Netherlands)

    Dubois, Patrick C. A.; Trynka, Gosia; Franke, Lude; Hunt, Karen A.; Romanos, Jihane; Curtotti, Alessandra; Zhernakova, Alexandra; Heap, Graham A. R.; Adany, Roza; Aromaa, Arpo; Bardella, Maria Teresa; van den Berg, Leonard H.; Bockett, Nicholas A.; de la Concha, Emilio G.; Dema, Barbara; Fehrmann, Rudolf S. N.; Fernandez-Arquero, Miguel; Fiatal, Szilvia; Grandone, Elvira; Green, Peter M.; Groen, Harry J. M.; Gwilliam, Rhian; Houwen, Roderick H. J.; Hunt, Sarah E.; Kaukinen, Katri; Kelleher, Dermot; Korponay-Szabo, Ilma; Kurppa, Kalle; MacMathuna, Padraic; Maki, Markku; Mazzilli, Maria Cristina; McCann, Owen T.; Mearin, M. Luisa; Mein, Charles A.; Mirza, Muddassar M.; Mistry, Vanisha; Mora, Barbara; Morley, Katherine I.; Mulder, Chris J.; Murray, Joseph A.; Nunez, Concepcion; Oosterom, Elvira; Ophoff, Roel A.; Polanco, Isabel; Peltonen, Leena; Platteel, Mathieu; Rybak, Anna; Salomaa, Veikko; Schweizer, Joachim J.; Sperandeo, Maria Pia; Tack, Greetje J.; Turner, Graham; Veldink, Jan H.; Verbeek, Wieke H. M.; Weersma, Rinse K.; Wolters, Victorien M.; Urcelay, Elena; Cukrowska, Bozena; Greco, Luigi; Neuhausen, Susan L.; McManus, Ross; Barisani, Donatella; Deloukas, Panos; Barrett, Jeffrey C.; Saavalainen, Paivi; Wijmenga, Cisca; van Heel, David A.

    2010-01-01

    We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) <10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions re

  14. Multiple common variants for celiac disease influencing immune gene expression

    NARCIS (Netherlands)

    Dubois, Patrick C. A.; Trynka, Gosia; Franke, Lude; Hunt, Karen A.; Romanos, Jihane; Curtotti, Alessandra; Zhernakova, Alexandra; Heap, Graham A. R.; Adany, Roza; Aromaa, Arpo; Bardella, Maria Teresa; van den Berg, Leonard H.; Bockett, Nicholas A.; de la Concha, Emilio G.; Dema, Barbara; Fehrmann, Rudolf S. N.; Fernandez-Arquero, Miguel; Fiatal, Szilvia; Grandone, Elvira; Green, Peter M.; Groen, Harry J. M.; Gwilliam, Rhian; Houwen, Roderick H. J.; Hunt, Sarah E.; Kaukinen, Katri; Kelleher, Dermot; Korponay-Szabo, Ilma; Kurppa, Kalle; MacMathuna, Padraic; Maki, Markku; Mazzilli, Maria Cristina; McCann, Owen T.; Mearin, M. Luisa; Mein, Charles A.; Mirza, Muddassar M.; Mistry, Vanisha; Mora, Barbara; Morley, Katherine I.; Mulder, Chris J.; Murray, Joseph A.; Nunez, Concepcion; Oosterom, Elvira; Ophoff, Roel A.; Polanco, Isabel; Peltonen, Leena; Platteel, Mathieu; Rybak, Anna; Salomaa, Veikko; Schweizer, Joachim J.; Sperandeo, Maria Pia; Tack, Greetje J.; Turner, Graham; Veldink, Jan H.; Verbeek, Wieke H. M.; Weersma, Rinse K.; Wolters, Victorien M.; Urcelay, Elena; Cukrowska, Bozena; Greco, Luigi; Neuhausen, Susan L.; McManus, Ross; Barisani, Donatella; Deloukas, Panos; Barrett, Jeffrey C.; Saavalainen, Paivi; Wijmenga, Cisca; van Heel, David A.

    We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) <10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions

  15. Intensity of human prion disease surveillance predicts observed disease incidence

    NARCIS (Netherlands)

    G.M. Klug (Genevieve); H. Wand (Handan); M. Simpson (Marion); A. Boyd (Alison); M. Law (Matthew); C. Masters (Colin); R. Mateǰ (Radoslav); R. Howley (Rachel); M. Farrell (Michael); M. Breithaupt; I. Zerr (Inga); C.M. van Duijn (Cock); C.A. Ibrahim-Verbaas (Carla); J. Mackenzie; R.G. Will (Robert); J-P. Brandel (Jean-Philippe); A. Alperovitch (Annick); H. Budka (Herbert); G.G. Kovacs (Gabor); G.H. Jansen (Gerard); M. Coulthard (Michael); S.J. Collins (Steven)

    2013-01-01

    textabstractBackground: Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance

  16. Fast magnetic resonance spectroscopic imaging techniques in human brain- applications in multiple sclerosis.

    Science.gov (United States)

    Al-Iedani, Oun; Lechner-Scott, Jeannette; Ribbons, Karen; Ramadan, Saadallah

    2017-02-28

    Multi voxel magnetic resonance spectroscopic imaging (MRSI) is an important imaging tool that combines imaging and spectroscopic techniques. MRSI of the human brain has been beneficially applied to different clinical applications in neurology, particularly in neurooncology but also in multiple sclerosis, stroke and epilepsy. However, a major challenge in conventional MRSI is the longer acquisition time required for adequate signal to be collected. Fast MRSI of the brain in vivo is an alternative approach to reduce scanning time and make MRSI more clinically suitable.Fast MRSI can be categorised into spiral, echo-planar, parallel and turbo imaging techniques, each with its own strengths. After a brief introduction on the basics of non-invasive examination ((1)H-MRS) and localization techniques principles, different fast MRSI techniques will be discussed from their initial development to the recent innovations with particular emphasis on their capacity to record neurochemical changes in the brain in a variety of pathologies.The clinical applications of whole brain fast spectroscopic techniques, can assist in the assessment of neurochemical changes in the human brain and help in understanding the roles they play in disease. To give a good example of the utilities of these techniques in clinical context, MRSI application in multiple sclerosis was chosen. The available up to date and relevant literature is discussed and an outline of future research is presented.

  17. Multiple facets of HIV-associated renal disease.

    Science.gov (United States)

    da Silva, D R; Gluz, I C; Kurz, J; Thomé, G G; Zancan, R; Bringhenti, R N; Schaefer, P G; Dos Santos, M; Barros, E J G; Veronese, F V

    2016-01-01

    HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥ 200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥ 200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥ 200 cells/mm3 was associated with better renal function after 2 years of follow-up.

  18. Multiple facets of HIV-associated renal disease

    Directory of Open Access Journals (Sweden)

    D.R. da Silva

    2016-01-01

    Full Text Available HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%, acute kidney injury (28%, nephrotic syndrome (23%, and chronic kidney disease (22%. Focal segmental glomerulosclerosis (28%, mainly the collapsing form (HIVAN, acute interstitial nephritis (AIN (26%, and immune complex-mediated glomerulonephritis (ICGN (25% were the predominant renal histology. Baseline CD4 cell count ≥200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012. At last follow-up, 64% of patients with baseline CD4 ≥200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003. In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥200 cells/mm3 was associated with better renal function after 2 years of follow-up.

  19. Multiple facets of HIV-associated renal disease

    Science.gov (United States)

    da Silva, D.R.; Gluz, I.C.; Kurz, J.; Thomé, G.G.; Zancan, R.; Bringhenti, R.N.; Schaefer, P.G.; dos Santos, M.; Barros, E.J.G.; Veronese, F.V.

    2016-01-01

    HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003). In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥200 cells/mm3 was associated with better renal function after 2 years of follow-up. PMID:27007656

  20. Whole-Body MRI versus PET in assessment of multiple myeloma disease activity.

    LENUS (Irish Health Repository)

    Shortt, Conor P

    2009-04-01

    The purpose of this study was to compare FDG PET; whole-body MRI; and the reference standard, bone marrow aspiration and biopsy, to determine the best imaging technique for assessment of disease activity in multiple myeloma.

  1. Multiple Positive Solutions for Some Neutral Integral Equatious Modeling Infectious Disease

    Institute of Scientific and Technical Information of China (English)

    ZHAOHua-xiang; SUNXing-wang

    2003-01-01

    By using fixed point index theory of cone mapping and extension method,this paper discusses the existence of multiple positive solution of nonlinear neutral integral equatious modeling infectious dis-ease.

  2. Selective purging of human multiple myeloma cells from autologous stem cell transplant grafts using oncolytic myxoma virus

    OpenAIRE

    Bartee, Eric; Chan, Winnie S.; Moreb, Jan S.; Cogle, Christopher R.; McFadden, Grant

    2012-01-01

    Autologous stem cell transplantation (ASCT) and novel therapies have improved overall survival of patients with multiple myeloma; however, most patients relapse and eventually succumb to their disease. Evidence indicates that residual cancer cells contaminate autologous grafts and may contribute to early relapses after ASCT. Here, we demonstrate that ex vivo treatment with an oncolytic poxvirus called myxoma virus results in specific elimination of human myeloma cells by inducing rapid cellul...

  3. Bilateral multiple cystic kidney disease and renal cortical abscess in a Boerboel

    Directory of Open Access Journals (Sweden)

    A. M. Kitshoffa

    2011-04-01

    Full Text Available Cystic renal disease is rare in dogs and although infected renal cysts have been reported in humans, no report could be found in dogs. A 58 kg, 5-year-old, castrated, male Boerboel presented with weight loss, pyrexia, lethargy and vomiting, 20 months after an incident of haematuria was reported. The initial ultrasonographic diagnosis was bilateral multiple renal cysts of unknown aetiology. The cysts had significantly increased in size over the 20-month period and some contained echogenic specks which could be related to infection, normal cellular debris or haemorrhage. In both kidneys the renal contours were distorted (the left more than the right. The abnormal shape of the left kidney was largely due to multiple cysts and a large crescent-shaped septate mass on the cranial pole of the kidney. Aspirates of the septate mass were performed (left kidney and the cytology and culture were indicative of an abscess. It is suggested that the previous incident of haematuria provided a portal of entry for bacteria into the cysts resulting in renal cortical abscess formation.

  4. [Disease-modifying drugs in pediatric patients with multiple sclerosis].

    Science.gov (United States)

    Bykova, O V; Nankina, I A; Drozdova, I M; Kvasova, O V; Batysheva, T T; Boiko, A N

    2016-01-01

    The vast majority of therapies are being evaluated and introduced for the treatment of adult multiple sclerosis (MS). A role of these drugs in the management of pediatric MS has yet to be defined both in Russia and in the whole world. Despite the fact that today the study of new drugs in the pediatric population have included in routine practices of the big pharmaceutical agencies, such as FDA and EMA, recommendations for the treatment of pediatric patients with MS are based not so much on a long period of systematic clinical research, but on professional consensus of international expert associations, in particular, the International pediatric multiple sclerosis study group (IPMSSG). The clinical trials include the small number of patients which is not comparable to those conducted in adults. Therefore, there is a need for study designs for assessment of efficacy and safety of the drugs for MS treatment in children and adolescents. The authors present the IPMSSG concept on the treatment of pediatric MS taking into account peculiarities of the Russian legislation and experience of national experts.

  5. Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions

    Directory of Open Access Journals (Sweden)

    Timon E. Adolph

    2017-07-01

    Full Text Available Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD. Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC.

  6. Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies

    DEFF Research Database (Denmark)

    George, Michaela F; Briggs, Farren B S; Shao, Xiaorong;

    2016-01-01

    OBJECTIVE: We investigated the association between 52 risk variants identified through genome-wide association studies and disease severity in multiple sclerosis (MS). METHODS: Ten unique MS case data sets were analyzed. The Multiple Sclerosis Severity Score (MSSS) was calculated using the Expanded...

  7. A Low-Cost Method for Multiple Disease Prediction.

    Science.gov (United States)

    Bayati, Mohsen; Bhaskar, Sonia; Montanari, Andrea

    Recently, in response to the rising costs of healthcare services, employers that are financially responsible for the healthcare costs of their workforce have been investing in health improvement programs for their employees. A main objective of these so called "wellness programs" is to reduce the incidence of chronic illnesses such as cardiovascular disease, cancer, diabetes, and obesity, with the goal of reducing future medical costs. The majority of these wellness programs include an annual screening to detect individuals with the highest risk of developing chronic disease. Once these individuals are identified, the company can invest in interventions to reduce the risk of those individuals. However, capturing many biomarkers per employee creates a costly screening procedure. We propose a statistical data-driven method to address this challenge by minimizing the number of biomarkers in the screening procedure while maximizing the predictive power over a broad spectrum of diseases. Our solution uses multi-task learning and group dimensionality reduction from machine learning and statistics. We provide empirical validation of the proposed solution using data from two different electronic medical records systems, with comparisons to a statistical benchmark.

  8. Multiple Targets for the Management of Alzheimer's Disease.

    Science.gov (United States)

    Ahmad, Syed Sayeed; Akhtar, Salman; Jamal, Qazi Mohammad Sajid; Rizvi, Syed Mohd Danish; Kamal, Mohammad A; Khan, M Kalim A; Siddiqui, Mohd Haris

    2016-01-01

    AD is a progressive and irreversible neurodegenerative disease and the most common cause of dementia in the elderly population. Βeta- amyloid cascade formation along with several cytoskeleton abnormalities succeeding to the hyperphosphorylation of microtubule-associated tau protein in neurons leads to the elicitation of several neurotoxic incidents. As an outcome of these phenomena, steady growth of dementia in aged population is becoming ubiquitous in both developed and developing countries. Thus, the key aspiration is to endow with stable daily life functionality to the person suffering from dementia and to cut down or slower the symptoms of disease leading to disruptive behavior. In sight of this, the proteins amyloid-beta, BACE-1, RAGE and AChE are being aimed for the treatment of AD successfully. Currently, there are several medicines for the treatment of AD under survey like Galangin, Cymserine, Tolserine, Bisnorcymserine and Huperzine A. The article emphasizes clinical and neurobiological aspects of AD. The purpose of this review article is to provide a brief introduction of AD along with the related concept of beta-secretase, beta amyloid and neurotransmitter in the progression of disease. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and neurotransmitter in the AD.

  9. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

    Directory of Open Access Journals (Sweden)

    Ronald C Hendrickson

    Full Text Available Disease modifying treatments for Alzheimer's disease (AD constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001 and SME-2 (p = 0.0004 for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR, in AD were 21% (p = 0.039 and 17% (p = 0.026 lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

  10. Disease-modifying therapies and infectious risks in multiple sclerosis.

    Science.gov (United States)

    Winkelmann, Alexander; Loebermann, Micha; Reisinger, Emil C; Hartung, Hans-Peter; Zettl, Uwe K

    2016-04-01

    Immunomodulatory and immunosuppressive treatments for multiple sclerosis (MS) are associated with an increased risk of infection, which makes treatment of this condition challenging in daily clinical practice. Use of the expanding range of available drugs to treat MS requires extensive knowledge of treatment-associated infections, risk-minimizing strategies and approaches to monitoring and treatment of such adverse events. An interdisciplinary approach to evaluate the infectious events associated with available MS treatments has become increasingly relevant. In addition, individual stratification of treatment-related infectious risks is necessary when choosing therapies for patients with MS, as well as during and after therapy. Determination of the individual risk of infection following serial administration of different immunotherapies is also crucial. Here, we review the modes of action of the available MS drugs, and relate this information to the current knowledge of drug-specific infectious risks and risk-minimizing strategies.

  11. The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Badea, Alexandra; Kane, Lauren; Anderson, Robert J; Qi, Yi; Foster, Mark; Cofer, Gary P; Medvitz, Neil; Buckley, Anne F; Badea, Andreas K; Wetsel, William C; Colton, Carol A

    2016-11-15

    Multivariate biomarkers are needed for detecting Alzheimer's disease (AD), understanding its etiology, and quantifying the effect of therapies. Mouse models provide opportunities to study characteristics of AD in well-controlled environments that can help facilitate development of early interventions. The CVN-AD mouse model replicates multiple AD hallmark pathologies, and we identified multivariate biomarkers characterizing a brain circuit disruption predictive of cognitive decline. In vivo and ex vivo magnetic resonance imaging (MRI) revealed that CVN-AD mice replicate the hippocampal atrophy (6%), characteristic of humans with AD, and also present changes in subcortical areas. The largest effect was in the fornix (23% smaller), which connects the septum, hippocampus, and hypothalamus. In characterizing the fornix with diffusion tensor imaging, fractional anisotropy was most sensitive (20% reduction), followed by radial (15%) and axial diffusivity (2%), in detecting pathological changes. These findings were strengthened by optical microscopy and ultrastructural analyses. Ultrastructual analysis provided estimates of axonal density, diameters, and myelination-through the g-ratio, defined as the ratio between the axonal diameter, and the diameter of the axon plus the myelin sheath. The fornix had reduced axonal density (47% fewer), axonal degeneration (13% larger axons), and abnormal myelination (1.5% smaller g-ratios). CD68 staining showed that white matter pathology could be secondary to neuronal degeneration, or due to direct microglial attack. In conclusion, these findings strengthen the hypothesis that the fornix plays a role in AD, and can be used as a disease biomarker and as a target for therapy.

  12. A paper/polymer hybrid microfluidic microplate for rapid quantitative detection of multiple disease biomarkers

    Science.gov (United States)

    Sanjay, Sharma T.; Dou, Maowei; Sun, Jianjun; Li, Xiujun

    2016-07-01

    Enzyme linked immunosorbent assay (ELISA) is one of the most widely used laboratory disease diagnosis methods. However, performing ELISA in low-resource settings is limited by long incubation time, large volumes of precious reagents, and well-equipped laboratories. Herein, we developed a simple, miniaturized paper/PMMA (poly(methyl methacrylate)) hybrid microfluidic microplate for low-cost, high throughput, and point-of-care (POC) infectious disease diagnosis. The novel use of porous paper in flow-through microwells facilitates rapid antibody/antigen immobilization and efficient washing, avoiding complicated surface modifications. The top reagent delivery channels can simply transfer reagents to multiple microwells thus avoiding repeated manual pipetting and costly robots. Results of colorimetric ELISA can be observed within an hour by the naked eye. Quantitative analysis was achieved by calculating the brightness of images scanned by an office scanner. Immunoglobulin G (IgG) and Hepatitis B surface Antigen (HBsAg) were quantitatively analyzed with good reliability in human serum samples. Without using any specialized equipment, the limits of detection of 1.6 ng/mL for IgG and 1.3 ng/mL for HBsAg were achieved, which were comparable to commercial ELISA kits using specialized equipment. We envisage that this simple POC hybrid microplate can have broad applications in various bioassays, especially in resource-limited settings.

  13. Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.

    Science.gov (United States)

    Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A; Jenkins, Andrew; Traynelis, Stephen F

    2015-07-01

    The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

  14. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function.

    Science.gov (United States)

    Ontaneda, Daniel; Thompson, Alan J; Fox, Robert J; Cohen, Jeffrey A

    2016-11-23

    Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future.

  15. Recent efforts to model human diseases in vivo in Drosophila.

    Science.gov (United States)

    Pfleger, Cathie M; Reiter, Lawrence T

    2008-01-01

    Upon completion of sequencing the Drosophila genome, it was estimated that 61% of human disease-associated genes had sequence homologs in flies, and in some diseases such as cancer, the number was as high as 68%. We now know that as many as 75% of the genes associated with genetic disease have counterparts in Drosophila. Using better tools for mutation detection, association studies and whole genome analysis the number of human genes associated with genetic disease is steadily increasing. These detection efforts are outpacing the ability to assign function and understand the underlying cause of the disease at the molecular level. Drosophila models can therefore advance human disease research in a number of ways by: establishing the normal role of these gene products during development, elucidating the mechanism underlying disease pathology, and even identifying candidate therapeutic agents for the treatment of human disease. At the 49(th) Annual Drosophila Research Conference in San Diego this year, a number of labs presented their exciting findings on Drosophila models of human disease in both platform presentations and poster sessions. Here we can only briefly review some of these developments, and we apologize that we do not have the time or space to review all of the findings presented which use Drosophila to understand human disease etiology.

  16. Predicting human movement with multiple accelerometers using movelets

    DEFF Research Database (Denmark)

    He, Bing; Bai, Jiawei; Zipunnikov, Vadim V

    2014-01-01

    developed, which, instead of extracting features, build activity-specific dictionaries composed of short signal segments called movelets. Three alternative approaches were proposed to integrate the information from the multiple accelerometers. RESULTS: With at most several seconds of training data per......-worn accelerometers performed almost as well as hip-worn accelerometers (the median difference in accuracy between wrist and hip ranged from -2.7% to 5.8%). Modest improvements in prediction accuracy were achieved by integrating information from multiple accelerometers. DISCUSSION AND CONCLUSIONS: It is possible...... to achieve high prediction accuracy at the second-level temporal resolution with very limited training data. To increase prediction accuracy from the simultaneous use of multiple accelerometers, a careful selection of integrative approaches is required....

  17. Human motion estimation with multiple frequency modulated continuous wave radars

    NARCIS (Netherlands)

    Dorp, Ph. van; Groen, F.C.A.

    2010-01-01

    Human motion estimation is an important issue in automotive, security or home automation applications. Radar systems are well suited for this because they are robust, are independent of day or night conditions and have accurate range and speed domain. The human response in a radar range-speed-time m

  18. Human motion estimation with multiple frequency modulated continuous wave radars

    NARCIS (Netherlands)

    Dorp, Ph. van; Groen, F.C.A.

    2010-01-01

    Human motion estimation is an important issue in automotive, security or home automation applications. Radar systems are well suited for this because they are robust, are independent of day or night conditions and have accurate range and speed domain. The human response in a radar range-speed-time

  19. Human pluripotent stem cells: applications and challenges in neurological diseases

    Directory of Open Access Journals (Sweden)

    Youssef eHIBAOUI

    2012-07-01

    Full Text Available The ability to generate human pluripotent stem cells (hPSCs holds great promise for the understanding and the treatment of human neurological diseases in modern medicine. The hPSCs are considered for their in vitro use as research tools to provide relevant cellular model for human diseases, drug discovery and toxicity assays and for their in vivo use in regenerative medicine applications. In this review, we highlight recent progress, promises and challenges of hPSC applications in human neurological disease modelling and therapies.

  20. Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma.

    Science.gov (United States)

    Xu, Linlin; Mohammad, Khalid S; Wu, Hao; Crean, Colin; Poteat, Bradley; Cheng, Yinghua; Cardoso, Angelo A; Machal, Christophe; Hanenberg, Helmut; Abonour, Rafat; Kacena, Melissa A; Chirgwin, John; Suvannasankha, Attaya; Srour, Edward F

    2016-12-01

    Multiple myeloma is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here, we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in multiple myeloma cell lines and primary bone marrow cells from patients. CD166(+) multiple myeloma cells homed more efficiently than CD166(-) cells to the bone marrow of engrafted immunodeficient NSG mice. CD166 silencing in multiple myeloma cells enabled longer survival, a smaller tumor burden, and less osteolytic lesions, as compared with mice bearing control cells. CD166 deficiency in multiple myeloma cell lines or CD138(+) bone marrow cells from multiple myeloma patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Furthermore, CD166 deficiency in multiple myeloma cells also reduced the formation of osteolytic disease in vivo after intratibial engraftment. Mechanistic investigation revealed that CD166 expression in multiple myeloma cells inhibited osteoblastogenesis of bone marrow-derived osteoblast progenitors by suppressing Runx2 gene expression. Conversely, CD166 expression in multiple myeloma cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in multiple myeloma cell homing to the bone marrow and multiple myeloma progression, rationalizing its further study as a candidate therapeutic target for multiple myeloma treatment. Cancer Res; 76(23); 6901-10. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Modeling human disease using organotypic cultures

    DEFF Research Database (Denmark)

    Schweiger, Pawel J; Jensen, Kim B

    2016-01-01

    Reliable disease models are needed in order to improve quality of healthcare. This includes gaining better understanding of disease mechanisms, developing new therapeutic interventions and personalizing treatment. Up-to-date, the majority of our knowledge about disease states comes from in vivo...

  2. Genetic evidence for common pathways in human age-related diseases.

    Science.gov (United States)

    Johnson, Simon C; Dong, Xiao; Vijg, Jan; Suh, Yousin

    2015-10-01

    Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified in model organisms, such as nutrient-sensing signaling, translation, proteostasis, stress responses, and genome maintenance. Taking advantage of the vast amount of genetic data from the GWAS, our findings provide the first direct evidence that conserved pathways of aging simultaneously influence multiple age-related diseases in humans as has been demonstrated in model organisms. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  3. Identification of multiple independent susceptibility loci in the HLA region in Behcet's disease

    NARCIS (Netherlands)

    Hughes, Travis; Coit, Patrick; Adler, Adam; Yilmaz, Vuslat; Aksu, Kenan; Duzgun, Nursen; Keser, Gokhan; Cefle, Ayse; Yazici, Ayten; Ergen, Andac; Alpsoy, Erkan; Salvarani, Carlo; Casali, Bruno; Koetter, Ina; Gutierrez-Achury, Javier; Wijmenga, Cisca; Direskeneli, Haner; Saruhan-Direskeneli, Guher; Sawalha, Amr H.

    2013-01-01

    Behcet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behcet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are comp

  4. The Prevalence of Disease Clusters in Older Adults with Multiple Chronic Diseases – A Systematic Literature Review

    Science.gov (United States)

    Sinnige, Judith; Braspenning, Jozé; Schellevis, François; Stirbu-Wagner, Irina; Westert, Gert; Korevaar, Joke

    2013-01-01

    Background Since most clinical guidelines address single diseases, treatment of patients with multimorbidity, the co-occurrence of multiple (chronic) diseases within one person, can become complicated. Information on highly prevalent combinations of diseases can set the agenda for guideline development on multimorbidity. With this systematic review we aim to describe the prevalence of disease combinations (i.e. disease clusters) in older patients with multimorbidity, as assessed in available studies. In addition, we intend to acquire information that can be supportive in the process of multimorbidity guideline development. Methods We searched MEDLINE, Embase and the Cochrane Library for all types of studies published between January 2000 and September 2012. We included empirical studies focused on multimorbidity or comorbidity that reported prevalence rates of combinations of two or more diseases. Results Our search yielded 3070 potentially eligible articles, of which 19 articles, representing 23 observational studies, turned out to meet all our quality and inclusion criteria after full text review. These studies provided prevalence rates of 165 combinations of two diseases (i.e. disease pairs). Twenty disease pairs, concerning 12 different diseases, were described in at least 3 studies. Depression was found to be the disease that was most commonly clustered, and was paired with 8 different diseases, in the available studies. Hypertension and diabetes mellitus were found to be the second most clustered diseases, both with 6 different diseases. Prevalence rates for each disease combination varied considerably per study, but were highest for the pairs that included hypertension, coronary artery disease, and diabetes mellitus. Conclusions Twenty disease pairs were assessed most frequently in patients with multimorbidity. These disease combinations could serve as a first priority setting towards the development of multimorbidity guidelines, starting with the diseases

  5. The prevalence of disease clusters in older adults with multiple chronic diseases--a systematic literature review.

    Directory of Open Access Journals (Sweden)

    Judith Sinnige

    Full Text Available BACKGROUND: Since most clinical guidelines address single diseases, treatment of patients with multimorbidity, the co-occurrence of multiple (chronic diseases within one person, can become complicated. Information on highly prevalent combinations of diseases can set the agenda for guideline development on multimorbidity. With this systematic review we aim to describe the prevalence of disease combinations (i.e. disease clusters in older patients with multimorbidity, as assessed in available studies. In addition, we intend to acquire information that can be supportive in the process of multimorbidity guideline development. METHODS: We searched MEDLINE, Embase and the Cochrane Library for all types of studies published between January 2000 and September 2012. We included empirical studies focused on multimorbidity or comorbidity that reported prevalence rates of combinations of two or more diseases. RESULTS: Our search yielded 3070 potentially eligible articles, of which 19 articles, representing 23 observational studies, turned out to meet all our quality and inclusion criteria after full text review. These studies provided prevalence rates of 165 combinations of two diseases (i.e. disease pairs. Twenty disease pairs, concerning 12 different diseases, were described in at least 3 studies. Depression was found to be the disease that was most commonly clustered, and was paired with 8 different diseases, in the available studies. Hypertension and diabetes mellitus were found to be the second most clustered diseases, both with 6 different diseases. Prevalence rates for each disease combination varied considerably per study, but were highest for the pairs that included hypertension, coronary artery disease, and diabetes mellitus. CONCLUSIONS: Twenty disease pairs were assessed most frequently in patients with multimorbidity. These disease combinations could serve as a first priority setting towards the development of multimorbidity guidelines

  6. CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson's disease.

    NARCIS (Netherlands)

    Abdo, W.; Bloem, B.R.; Geel, W.J.A. van; Esselink, R.A.J.; Verbeek, M.M.

    2007-01-01

    BACKGROUND: In early disease stages it can be clinically difficult to differentiate idiopathic Parkinson's disease (IPD) from patients with multiple system atrophy predominated by parkinsonism (MSA-P). METHODS: In CSF of 31 patients with IPD, 19 patients with MSA-P, we analyzed tau, neurofilament

  7. CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson's disease.

    NARCIS (Netherlands)

    Abdo, W.; Bloem, B.R.; Geel, W.J.A. van; Esselink, R.A.J.; Verbeek, M.M.

    2007-01-01

    BACKGROUND: In early disease stages it can be clinically difficult to differentiate idiopathic Parkinson's disease (IPD) from patients with multiple system atrophy predominated by parkinsonism (MSA-P). METHODS: In CSF of 31 patients with IPD, 19 patients with MSA-P, we analyzed tau, neurofilament li

  8. 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…

  9. Health-related needs of people with multiple chronic diseases: differences and underlying factors.

    NARCIS (Netherlands)

    Hopman, P.; Schellevis, F.G.; Rijken, M.

    2016-01-01

    Purpose: To examine the health-related needs of people with multiple chronic diseases in the Netherlands compared to people with one chronic disease, and to identify different subgroups of multimorbid patients based on differences in their health problems. Methods: Participants were 1092 people with

  10. Association of IgA multiple myeloma with pre-existing disease

    Energy Technology Data Exchange (ETDEWEB)

    Schafer, A.I.; Miller, J.B.

    1979-01-01

    A retrospective analysis of 153 patients with multiple myeloma was performed for evaluation of the possible significance of pre-existing disease. 37% of the group had no significant antecedent disorder. The most common prior illnesses were peptic ulcer disease and gallbladder disease. Of 12 patients in the group who had prior biliary tract disease and for whom immunoelectrophoretic studies were available, eight (66.7%) had IgA paraproteins. This figure is statistically higher than the 14.1% of prevalence of IgA paraproteins in those myeloma patients without biliary disease. We conclude that prior inflammatory gastrointestinal, pulmonary, and, particularly, biliary disease may be implicated in the pathogenesis of the IgA subset of multiple myeloma.

  11. Kidney failure during HIV disease treated with tenofovir, multiple concurrent diseases and drug therapies

    Directory of Open Access Journals (Sweden)

    Roberto Manfredi

    2012-04-01

    Full Text Available A significant case report of a HIV infected patient in his fifties who experienced an excellent virological and immunological response to antiretroviral therapy (which has been modified just to prevent or avoid some adverse events, but developed a severe, sudden acute kidney failure while under a polypharmacy due to some underlying and overwhelming disorders (i.e. arterial hypertension, non-insulin-dependent diabetes mellitus, a recent acute heart infarction with remarkable remnants, and finally an anecdotal muscle-joint pain with self-prescription of non-steroideal anti-inflammatory drugs, represents the key point for a debate around the increasing frequency of “polypharmacy” in the field of HIV infection, even when HIV resistance to antiretroviral is not a concern. The continuing increase of mean age of HIV-infected population, plus the existing, sometimes unmodifiable risk factors for cardiovascular, dysmetabolic, and renal disorders, plus the adjunct of anecdotal illnesses prompting the resort to different drugs and medications, either prescribed for HIV infection itself, or taken for concurrent or subsequent diseases, or self-prescribed occasionally due to an intercurrent, trivial disorders per se, may prompt a complicated scenario culminating with a life-threatening acute renal failure of tubular origin. Our report gives us the opportunity to revise and discuss the expected interactions between antiretroviral therapy and the even growing exposure to multiple different drug and drug classes, which may be responsible for relevant drug interactions and direct or adjunctive end-organ impairment, up to life-threatening conditions, which may be avoided or prevented by considering carefully all comorbidites and co-treatments potentially administered to HIV infected patients, thirty years after the discovery of AIDS.

  12. Development and characterization of human monoclonal antibodies that neutralize multiple TGFβ isoforms.

    Science.gov (United States)

    Bedinger, Daniel; Lao, Llewelyn; Khan, Shireen; Lee, Steve; Takeuchi, Toshihiko; Mirza, Amer M

    2016-01-01

    Transforming growth factor (TGF)β levels are elevated in, and drive the progression of, numerous disease states such as advanced metastatic cancer and systemic and ocular fibrosis. There are 3 main isoforms, TGFβ1, 2, and 3. As multiple TGFβ isoforms are involved in disease processes, maximal therapeutic efficacy may require neutralization of 2 or more of the TGFβ isoforms. Fully human antibody phage display libraries were used to discover a number of antibodies that bind and neutralize various combinations of TGFβ1, 2 or 3. The primary panning did not yield any uniformly potent pan-isoform neutralizing antibodies; therefore, an antibody that displayed potent TGFβ 1, 2 inhibition, but more modest affinity versus TGFβ3, was affinity matured by shuffling with a light chain sub-library and further screening. This process yielded a high affinity pan-isoform neutralizing clone. Antibodies were analyzed and compared by binding affinity, as well as receptor and epitope competition by surface plasmon resonance methods. The antibodies were also shown to neutralize TGFβ effects in vitro in 3 assays: 1) interleukin (IL)-4 induced HT-2 cell proliferation; 2) TGFβ-mediated IL-11 release by A549 cells; and 3) decreasing SMAD2 phosphorylation in Detroit 562 cells. The antibodies' potency in these in vitro assays correlated well with their isoform-specific affinities. Furthermore, the ability of the affinity-matured clone to decrease tumor burden in a Detroit 562 xenograft study was superior to that of the parent clone. This affinity-matured antibody acts as a very potent inhibitor of all 3 main isoforms of TGFβ and may have utility for therapeutic intervention in human disease.

  13. Multinational corporations and infectious disease: Embracing human rights management techniques.

    Science.gov (United States)

    Salcito, Kendyl; Singer, Burton H; Weiss, Mitchell G; Winkler, Mirko S; Krieger, Gary R; Wielga, Mark; Utzinger, Jürg

    2014-01-01

    Global health institutions have called for governments, international organisations and health practitioners to employ a human rights-based approach to infectious diseases. The motivation for a human rights approach is clear: poverty and inequality create conditions for infectious diseases to thrive, and the diseases, in turn, interact with social-ecological systems to promulgate poverty, inequity and indignity. Governments and intergovernmental organisations should be concerned with the control and elimination of these diseases, as widespread infections delay economic growth and contribute to higher healthcare costs and slower processes for realising universal human rights. These social determinants and economic outcomes associated with infectious diseases should interest multinational companies, partly because they have bearing on corporate productivity and, increasingly, because new global norms impose on companies a responsibility to respect human rights, including the right to health. We reviewed historical and recent developments at the interface of infectious diseases, human rights and multinational corporations. Our investigation was supplemented with field-level insights at corporate capital projects that were developed in areas of high endemicity of infectious diseases, which embraced rights-based disease control strategies. Experience and literature provide a longstanding business case and an emerging social responsibility case for corporations to apply a human rights approach to health programmes at global operations. Indeed, in an increasingly globalised and interconnected world, multinational corporations have an interest, and an important role to play, in advancing rights-based control strategies for infectious diseases. There are new opportunities for governments and international health agencies to enlist corporate business actors in disease control and elimination strategies. Guidance offered by the United Nations in 2011 that is widely embraced

  14. Development and characterization of human monoclonal antibodies that neutralize multiple TGFβ isoforms

    National Research Council Canada - National Science Library

    Bedinger, Daniel; Lao, Llewelyn; Khan, Shireen; Lee, Steve; Takeuchi, Toshihiko; Mirza, Amer M

    .... There are 3 main isoforms, TGFβ1, 2, and 3. As multiple TGFβ isoforms are involved in disease processes, maximal therapeutic efficacy may require neutralization of 2 or more of the TGFβ isoforms...

  15. Multiple distinct stimuli increase measured nucleosome occupancy around human promoters.

    Directory of Open Access Journals (Sweden)

    Chuong D Pham

    Full Text Available Nucleosomes can block access to transcription factors. Thus the precise localization of nucleosomes relative to transcription start sites and other factor binding sites is expected to be a critical component of transcriptional regulation. Recently developed microarray approaches have allowed the rapid mapping of nucleosome positions over hundreds of kilobases (kb of human genomic DNA, although these approaches have not yet been widely used to measure chromatin changes associated with changes in transcription. Here, we use custom tiling microarrays to reveal changes in nucleosome positions and abundance that occur when hormone-bound glucocorticoid receptor (GR binds to sites near target gene promoters in human osteosarcoma cells. The most striking change is an increase in measured nucleosome occupancy at sites spanning ∼1 kb upstream and downstream of transcription start sites, which occurs one hour after addition of hormone, but is lost at 4 hours. Unexpectedly, this increase was seen both on GR-regulated and GR-non-regulated genes. In addition, the human SWI/SNF chromatin remodeling factor (a GR co-activator was found to be important for increased occupancy upon hormone treatment and also for low nucleosome occupancy without hormone. Most surprisingly, similar increases in nucleosome occupancy were also seen on both regulated and non-regulated promoters during differentiation of human myeloid leukemia cells and upon activation of human CD4+ T-cells. These results indicate that dramatic changes in chromatin structure over ∼2 kb of human promoters may occur genomewide and in response to a variety of stimuli, and suggest novel models for transcriptional regulation.

  16. Protein kinase CK2 in human diseases

    DEFF Research Database (Denmark)

    Guerra, Barbara; Issinger, Olaf-Georg

    2008-01-01

    in various disease processes including cancer has been gained in recent years, and the present review may help to further elucidate its aberrant role in many disease states. Its peculiar structural features [3-9] may be advantageous in designing tailor-made compounds with the possibility to specifically...

  17. The Long and the Short of It: Comments on Multiple Timescale Studies of Human Activity.

    Science.gov (United States)

    Lemke, Jay L.

    2001-01-01

    Comments on four articles in a special issue of the Journal of the Learning Sciences on methodology in learning sciences. Analyzes the articles within a general model seeking to analyze human activity across multiple time scales. (Author/MM)

  18. Humanizing Outgroups Through Multiple Categorization: The Roles of Individuation and Threat.

    Science.gov (United States)

    Prati, Francesca; Crisp, Richard J; Meleady, Rose; Rubini, Monica

    2016-04-01

    In three studies, we examined the impact of multiple categorization on intergroup dehumanization. Study 1 showed that perceiving members of a rival university along multiple versus simple categorical dimensions enhanced the tendency to attribute human traits to this group. Study 2 showed that multiple versus simple categorization of immigrants increased the attribution of uniquely human emotions to them. This effect was explained by the sequential mediation of increased individuation of the outgroup and reduced outgroup threat. Study 3 replicated this sequential mediation model and introduced a novel way of measuring humanization in which participants generated attributes corresponding to the outgroup in a free response format. Participants generated more uniquely human traits in the multiple versus simple categorization conditions. We discuss the theoretical implications of these findings and consider their role in informing and improving efforts to ameliorate contemporary forms of intergroup discrimination.

  19. The genus Malassezia and human disease

    Directory of Open Access Journals (Sweden)

    Inamadar A

    2003-07-01

    Full Text Available Sabouraud's Pityrosporum is now recognized as Malassezia. With taxonomic revision of the genus, newer species have been included. The role of this member of the normal human skin flora in different cutaneous and systemic disorders is becoming clearer. The immunological responses it induces in the human body are conflicting and their relevance to clinical features is yet to be explored.

  20. Multiple successional pathways in human-modified tropical landscapes

    NARCIS (Netherlands)

    Arroyo-Rodríguez, Víctor; Melo, Felipe P.L.; Martínez-Ramos, Miguel; Bongers, Frans; Chazdon, Robin L.; Meave, Jorge A.; Norden, Natalia; Santos, Bráulio A.; Leal, Inara R.; Tabarelli, Marcelo

    2017-01-01

    Old-growth tropical forests are being extensively deforested and fragmented worldwide. Yet forest recovery through succession has led to an expansion of secondary forests in human-modified tropical landscapes (HMTLs). Secondary forests thus emerge as a potential repository for tropical biodiversi

  1. Detecting multiple DNA human profile from a mosquito blood meal.

    Science.gov (United States)

    Rabêlo, K C N; Albuquerque, C M R; Tavares, V B; Santos, S M; Souza, C A; Oliveira, T C; Moura, R R; Brandão, L A C; Crovella, S

    2016-08-26

    Criminal traces commonly found at crime scenes may present mixtures from two or more individuals. The scene of the crime is important for the collection of various types of traces in order to find the perpetrator of the crime. Thus, we propose that hematophagous mosquitoes found at crime scenes can be used to perform genetic testing of human blood and aid in suspect investigation. The aim of the study was to obtain a single Aedes aegypti mosquito profile from a human DNA mixture containing genetic materials of four individuals. We also determined the effect of blood acquisition time by setting time intervals of 24, 48, and 72 h after the blood meal. STR loci and amelogenin were analyzed, and the results showed that human DNA profiles could be obtained from hematophagous mosquitos at 24 h following the blood meal. It is possible that hematophagous mosquitoes can be used as biological remains at the scene of the crime, and can be used to detect human DNA profiles of up to four individuals.

  2. Statistical insights into major human muscular diseases.

    Science.gov (United States)

    Gupta, Shakti; Kim, Sung-Min; Wang, Yu; Dinasarapu, Ashok Reddy; Subramaniam, Shankar

    2014-07-15

    Muscular diseases lead to muscle fiber degeneration, impairment of mobility, and in some cases premature death. Many of these muscular diseases are largely idiopathic. The goal of this study was to identify biomarkers based on their functional role and possible mechanisms of pathogenesis, specific to individual muscular disease. We analyzed the muscle transcriptome from five major muscular diseases: acute quadriplegic myopathy (AQM), amyotrophic lateral sclerosis (ALS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), dermatomyositis (DM) and polymyositis (PM) using pairwise statistical comparison to identify uniquely regulated genes in each muscular disease. The genome-wide information encoded in the transcriptome provided biomarkers and functional insights into dysregulation in each muscular disease. The analysis showed that the dysregulation of genes in forward membrane pathway, responsible for transmitting action potential from neural excitation, is unique to AQM, while the dysregulation of myofibril genes, determinant of the mechanical properties of muscle, is unique to ALS, dysregulation of ER protein processing, responsible for correct protein folding, is unique to DM, and upregulation of immune response genes is unique to PM. We have identified biomarkers specific to each muscular disease which can be used for diagnostic purposes.

  3. Physical status of multiple human papillomavirus genotypes in flow-sorted cervical cancer cells

    NARCIS (Netherlands)

    Vermeulen, Christine F. W.; Jordanova, Ekaterina S.; Szuhai, Karoly; Kolkman-Uljee, Sandra; Vrede, M. Albert; Peters, Alexander A. W.; Schtturing, Ed; Fleuren, Gert Jan

    2007-01-01

    Multiple human papilloma virus (HPV) infections have been detected in cervical cancer. To investigate the significance of multiple HPV infections, we studied their prevalence in cancer samples from a low-risk (Dutch) and a high-risk (Surinamese) population and the correlation of HPV infection with t

  4. Metatranscriptomics of the human oral microbiome during health and disease.

    Science.gov (United States)

    Jorth, Peter; Turner, Keith H; Gumus, Pinar; Nizam, Nejat; Buduneli, Nurcan; Whiteley, Marvin

    2014-04-01

    The human microbiome plays important roles in health, but when disrupted, these same indigenous microbes can cause disease. The composition of the microbiome changes during the transition from health to disease; however, these changes are often not conserved among patients. Since microbiome-associated diseases like periodontitis cause similar patient symptoms despite interpatient variability in microbial community composition, we hypothesized that human-associated microbial communities undergo conserved changes in metabolism during disease. Here, we used patient-matched healthy and diseased samples to compare gene expression of 160,000 genes in healthy and diseased periodontal communities. We show that health- and disease-associated communities exhibit defined differences in metabolism that are conserved between patients. In contrast, the metabolic gene expression of individual species was highly variable between patients. These results demonstrate that despite high interpatient variability in microbial composition, disease-associated communities display conserved metabolic profiles that are generally accomplished by a patient-specific cohort of microbes. IMPORTANCE The human microbiome project has shown that shifts in our microbiota are associated with many diseases, including obesity, Crohn's disease, diabetes, and periodontitis. While changes in microbial populations are apparent during these diseases, the species associated with each disease can vary from patient to patient. Taking into account this interpatient variability, we hypothesized that specific microbiota-associated diseases would be marked by conserved microbial community behaviors. Here, we use gene expression analyses of patient-matched healthy and diseased human periodontal plaque to show that microbial communities have highly conserved metabolic gene expression profiles, whereas individual species within the community do not. Furthermore, disease-associated communities exhibit conserved changes

  5. The coexistence of terms to describe the presence of multiple concurrent diseases

    Directory of Open Access Journals (Sweden)

    José Almirall

    2013-08-01

    Full Text Available Background: Consensus on terminology for multiple diseases is lacking. Because of the clinical relevance and social impact of multiple concurrent diseases, it is important that concepts are clear. Objective: To highlight the diversity of terms in the literature referring to the presence of multiple concurrent diseases/conditions and make recommendations. Design: A bibliometric analysis of English-language publications indexed in the MEDLINE database from 1970 to 2012 for the terms comorbidity, multimorbidity, polymorbidity, polypathology, pluripathology, multipathology, and multicondition, and a review of definitions of multimorbidity found in English-language publications indexed from 1970 to 2012 in the MEDLINE and SCOPUS databases. Results: Comorbidity was used in 67,557 publications, multimorbidity in 434, and the other terms in three to 31 publications. At least 144 publications used the term comorbidity without referring to an index disease. Thirteen general definitions of multimorbidity were identified, but only two were frequently used (91% of publications. The most frequently used definition (48% of publications was “more than one or multiple chronic or long-term diseases/conditions”. Multimorbidity was not defined in 51% of the publications using the term. Conclusions: Comorbidity was overwhelmingly used to describe any clinical entity coexisting with an index disease under study. Multimorbidity was the term most frequently used when no index disease was designated. Several definitions of multimorbidity were found. However, most authors using the term did not define it. The use of clearly defined terms in the literature is recommended until a general consensus on the terminology of multiple coexistent diseases is reached.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Human Milk and Allergic Diseases: An Unsolved Puzzle

    Science.gov (United States)

    Peroni, Diego G.; Boix-Amorós, Alba; Hsu, Peter S.; Van’t Land, Belinda; Skevaki, Chrysanthi; Collado, Maria Carmen; Garssen, Johan; Geddes, Donna T.; Nanan, Ralph; Slupsky, Carolyn; Wegienka, Ganesa; Kozyrskyj, Anita L.; Warner, John O.

    2017-01-01

    There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development. PMID:28817095

  8. Mental stress and human cardiovascular disease.

    Science.gov (United States)

    Esler, Murray

    2017-03-01

    The London physician and neuroanatomist Thomas Willis in the 17th century correctly attributed the source of emotions to the brain, not the heart as believed in antiquity. Contemporary research documents the phenomenon of "triggered" heart disease, when the autonomic nervous system control of the heart by the brain goes awry, producing heart disease of sudden onset, precipitated by acute emotional upheaval. This can take the form of, variously, cardiac arrhythmias, myocardial infarction, Takotsubo cardiomyopathy and sudden death. Chronic psychological distress also can have adverse cardiovascular consequences, in the causal linkage of depressive illness to heart disease, and in the probable causation of atherosclerosis and hypertension by chronic mental stress. In patients with essential hypertension, stress biomarkers are present. The sympathetic nervous system is the usual mediator between these acute and chronic psychological substrates and cardiovascular disease.

  9. Disease Human - MDC_CLRDMortality2006

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — Polygon feature class based on Zip Code boundaries showing the rate of deaths per 100,000 residents due to Chronic Lower Respiratory Disease (CLRD) in Miami-Dade...

  10. "Miniguts" from plucked human hair meet Crohn's disease.

    Science.gov (United States)

    Hohwieler, M; Renz, S; Liebau, S; Lin, Q; Lechel, A; Klaus, J; Perkhofer, L; Zenke, M; Seufferlein, T; Illing, A; Müller, M; Kleger, A

    2016-08-01

    Human pluripotent stem cells represent a powerful tool to study human embryonic development and disease but also open up novel strategies for cell replacement therapies. Their capacity to give rise to every cell type of the human body, meanwhile, enables researchers to generate high yields of mesodermal, ectodermal, but also endodermal-derived tissues such as hepatic, pancreatic, or intestinal cells. Another progress in the field came with the advent of 3-dimensional culture conditions, so-called organoids, which facilitate maturation of stem cells and in turn more faithfully recapitulate human tissue architecture. While several studies reported the derivation of organoid cultures from adult intestinal tissue, the derivation of intestinal organoids derived from plucked human hair of Crohn's disease patients has not been reported. The current research project reports such successful generation and characterization of induced pluripotent stem cells (iPSCs) derived from hair sheet keratinocyte cultures of a patient with Crohn's disease. Stepwise differentiation along the intestinal lineage showed no differences in intermediate stages such as definitive endoderm formation. We also directed the patterned primitive gut tube toward intestinal organoids resembling the cellular architecture of human "miniguts". As expected from current pathophysiological knowledge on Crohn's disease, there were no obvious morphological differences in the "miniguts" derived from healthy control and diseased patient-induced pluripotent stem cells. Taken together, our platform will enable for detailed and complementary phenotyping of the pathophysiology of Crohn's disease in a novel disease-in-a-dish format.

  11. Contribution of individual diseases to death in older adults with multiple diseases.

    Science.gov (United States)

    Tinetti, Mary E; McAvay, Gail J; Murphy, Terrence E; Gross, Cary P; Lin, Haiqun; Allore, Heather G

    2012-08-01

    To determine empirically the diseases contributing most commonly and strongly to death in older adults, accounting for coexisting diseases. Longitudinal. United States. Twenty-two thousand eight hundred ninety Medicare Current Beneficiary Survey participants, a national representative sample of Medicare beneficiaries, enrolled during 2002 to 2006. Information on chronic and acute diseases was ascertained from Medicare claims data. Diseases contributing to death during follow-up were identified empirically using regression models for all diseases with a frequency of 1% or greater and hazard ratio for death of greater than 1. The additive contributions of these diseases, adjusting for coexisting diseases, were calculated using a longitudinal extension of average attributable fraction; 95% confidence intervals were estimated from bootstrapping. Fifteen diseases and acute events contributed significantly to death, together accounting for nearly 70% of death. Heart failure (20.0%), dementia (13.6%), chronic lower respiratory disease (12.4%), and pneumonia (5.3%) made the largest contributions to death. Cancer, including lung, colorectal, lymphoma, and head and neck, together contributed to 5.6% of death. Other diseases and events included acute kidney injury, stroke, septicemia, liver disease, myocardial infarction, and unintentional injuries. The use of methods that focus on determining a single underlying cause may lead to underestimation of the extent of the contribution of some diseases such as dementia and respiratory disease to death in older adults and overestimation of the contribution of other diseases. Current conceptualization of a single underlying cause may not account adequately for the contribution to death of coexisting diseases that older adults experience. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.

  12. Multiple capillary hemangiomas: A distinctive lesion of multicentric Castleman′s disease and POEMS syndrome

    Directory of Open Access Journals (Sweden)

    Misri Rachita

    2008-01-01

    Full Text Available A diagnosed case of Castleman′s disease, proven by biopsy from enlarged inguinal lymph nodes, presented with multiple, asymptomatic, erythematous papules and nodules prevalent since nine years over the trunk and extremities. The lesions had been gradually increasing in number and size. The patient had had plasmacytoma of the lower thoracic vertebra 12 years ago, for which he was adequately treated with chemotherapy and local radiotherapy. Dermatological examination revealed erythematous papules and nodules on the face, trunk, and extremities that were diagnostic of capillary hemangiomas. Histopathology of the erythematous, soft papule was suggestive of capillary hemangioma. Contrast-enhanced computerized tomography of the abdomen and pelvis showed multiple retroperitoneal nodes suggestive of Castleman′s disease along with multiple osteolytic lesions in the pelvic girdle and vertebrae. The patient was treated with injection rituximab and is currently under follow-up. We report this case to highlight a rare association between Castleman′s disease and POEMS syndrome.

  13. A case of disseminated hydatid disease by surgery involving multiple organs

    Directory of Open Access Journals (Sweden)

    Asli Tanrivermis Sayit

    2014-09-01

    Full Text Available Hydatid disease is the most common parasitic infection in the world, and is caused by the parasite Echinococcus granulosus. The most common site of this disease is the liver (75%, followed by the lungs, kidney, bones, and brain. Multiple abdominal organ and peritoneal involvement can also be seen in some cases. The dissemination of hydatid cyst disease can develop spontaneously or secondary to trauma or surgery. Here, we present the case of a 69-year-old man with multiple cyst hydatidosis, who underwent surgery for acute appendicitis approximately 20 years previously. Computed tomography of the abdomen shows the multiple active and inactive cystic lesions in the liver, spleen, right kidney, and mesentery. This patient required surgery several times, as well as medical treatment, after the rupture of a mesenteric hydatid cyst during the appendectomy. Combined anthelmintic treatment was recommended to the patient who refused further surgical treatment.

  14. Segmentation of human upper body movement using multiple IMU sensors.

    Science.gov (United States)

    Aoki, Takashi; Lin, Jonathan Feng-Shun; Kulic, Dana; Venture, Gentiane

    2016-08-01

    This paper proposes an approach for the segmentation of human body movements measured by inertial measurement unit sensors. Using the angular velocity and linear acceleration measurements directly, without converting to joint angles, we perform segmentation by formulating the problem as a classification problem, and training a classifier to differentiate between motion end-point and within-motion points. The proposed approach is validated with experiments measuring the upper body movement during reaching tasks, demonstrating classification accuracy of over 85.8%.

  15. Exosome enrichment of human serum using multiple cycles of centrifugation.

    Science.gov (United States)

    Kim, Jeongkwon; Tan, Zhijing; Lubman, David M

    2015-09-01

    In this work, we compared the use of repeated cycles of centrifugation at conventional speeds for enrichment of exosomes from human serum compared to the use of ultracentrifugation (UC). After removal of cells and cell debris, a speed of 110 000 × g or 40 000 × g was used for the UC or centrifugation enrichment process, respectively. The enriched exosomes were analyzed using the bicinchoninic acid assay, 1D gel separation, transmission electron microscopy, Western blotting, and high-resolution LC-MS/MS analysis. It was found that a five-cycle repetition of UC or centrifugation is necessary for successful removal of nonexosomal proteins in the enrichment of exosomes from human serum. More significantly, 5× centrifugation enrichment was found to provide similar or better performance than 5× UC enrichment in terms of enriched exosome protein amount, Western blot band intensity for detection of CD-63, and numbers of identified exosome-related proteins and cluster of differentiation (CD) proteins. A total of 478 proteins were identified in the LC-MS/MS analyses of exosome proteins obtained from 5× UCs and 5× centrifugations including many important CD membrane proteins. The presence of previously reported exosome-related proteins including key exosome protein markers demonstrates the utility of this method for analysis of proteins in human serum.

  16. Genomic responses in mouse models poorly mimic human inflammatory diseases.

    Science.gov (United States)

    Seok, Junhee; Warren, H Shaw; Cuenca, Alex G; Mindrinos, Michael N; Baker, Henry V; Xu, Weihong; Richards, Daniel R; McDonald-Smith, Grace P; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C; López, Cecilia M; Honari, Shari; Moore, Ernest E; Minei, Joseph P; Cuschieri, Joseph; Bankey, Paul E; Johnson, Jeffrey L; Sperry, Jason; Nathens, Avery B; Billiar, Timothy R; West, Michael A; Jeschke, Marc G; Klein, Matthew B; Gamelli, Richard L; Gibran, Nicole S; Brownstein, Bernard H; Miller-Graziano, Carol; Calvano, Steve E; Mason, Philip H; Cobb, J Perren; Rahme, Laurence G; Lowry, Stephen F; Maier, Ronald V; Moldawer, Lyle L; Herndon, David N; Davis, Ronald W; Xiao, Wenzhong; Tompkins, Ronald G

    2013-02-26

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

  17. Genomic responses in mouse models poorly mimic human inflammatory diseases

    Science.gov (United States)

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  18. Human papillomavirus infection and disease in men: Impact of HIV ...

    African Journals Online (AJOL)

    Human papillomavirus infection and disease in men: Impact of HIV. ... Journal Home > Vol 14, No 4 (2013) > ... HIV infection increases HPV prevalence, incidence and persistence and is strongly associated with the development of anogenital ...

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

    OpenAIRE

    Azzam Maghazachi; Zaidoon Salim Kashkoul Al-Jaderi

    2016-01-01

    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...

  20. The human microbiome in rheumatic autoimmune diseases: A comprehensive review.

    Science.gov (United States)

    Coit, Patrick; Sawalha, Amr H

    2016-09-01

    The human microbiome consists of the total diversity of microbiota and their genes. High-throughput sequencing has allowed for inexpensive and rapid evaluation of taxonomic representation and functional capability of the microbiomes of human body sites. Autoimmune and inflammatory rheumatic diseases are characterized by dysbiosis of the microbiome. Microbiome dysbiosis can be influenced by host genetics and environmental factors. Dysbiosis is also associated with shifts in certain functional pathways. The goal of this article is to provide a current and comprehensive review of the unique characteristics of the microbiome of patients with autoimmune and inflammatory rheumatic diseases, measured using high-throughput sequencing. We also highlight the need for broader studies utilizing a longitudinal approach to better understand how the human microbiome contributes to disease susceptibility, and to characterize the role of the interaction between host genetics and microbial diversity in the pathogenesis of autoimmune diseases, disease manifestations, and progression.

  1. Multiple Pyarthrosis in Human Immunodeficiency Virus-Infected Hemophiliacs

    Directory of Open Access Journals (Sweden)

    Alistair Ingram

    1994-01-01

    Full Text Available Classically, a swollen, painful joint in a patient with hemophilia has been considered to be due to a hemarthrosis until otherwise proven, and treated immediately with appropriate coagulation factor replacement. Two cases of human immunodeficiency virus (hiv-infected hemophiliacs presenting with an initial apparent hemarthrosis, complicated subsequently by numerous pyarthroses and sepsis are described. In light of the prevalence of hiv infection in the adult hemophiliac population with arthropathy, a reappraisal of the clinical caveat of immediate infusion without joint aspiration is required.

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

    KAUST Repository

    Kannan, Venkateshan

    2017-03-29

    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 the immune system and CNS that generates the principal subtypes of the disease observed in patients. The model captures several key features of MS, especially those that distinguish the chronic progressive phase from that of the relapse-remitting. In addition, a rare subtype of the disease, progressive relapsing MS naturally emerges from the model. The model posits the existence of two key thresholds, one in the immune system and the other in the CNS, that separate dynamically distinct behavior of the model. Exploring the two-dimensional space of these thresholds, we obtain multiple phases of disease evolution and these shows greater variation than the clinical classification of MS, thus capturing the heterogeneity that is manifested in patients.

  3. The biological clock modulates the human cortisol response in a multiplicative fashion

    NARCIS (Netherlands)

    van de Werken, Maan; Booij, Sanne H.; van der Zwan, J Esi; Simons, Mirre J. P.; Gordijn, Marijke C. M.; Beersma, Domien G. M.

    2014-01-01

    Human cortisol levels follow a clear circadian rhythm. We investigated the contribution of alternation of sleep and wakefulness and the circadian clock, using forced desynchrony. Cortisol levels were best described by a multiplication of a circadian and a wake-time component. The human cortisol resp

  4. Students' Learning Strategies with Multiple Representations: Explanations of the Human Breathing Mechanism

    Science.gov (United States)

    Won, Mihye; Yoon, Heojeong; Treagust, David F.

    2014-01-01

    The purpose of this study was to understand how students utilized multiple representations to learn and explain science concepts, in this case the human breathing mechanism. The study was conducted with Grade 11 students in a human biology class. Semistructured interviews and a two-tier diagnostic test were administered to evaluate students'…

  5. Discoidin Domain Receptors Role in Human Diseases

    Directory of Open Access Journals (Sweden)

    Iker BADIOLA

    2011-11-01

    Full Text Available Discoidin Domain Receptor 1 and Discodin Domain Receptor 2 are the two only members of the DDR family. The DDR family is a Tyrosine Kinase Receptor (TKR family with some peculiarities compared with other Tyrosine Kinase Receptors such as their natural ligand; which in this case is the fibrillar collagen; or the slow phosphorylation pattern. These peculiarities confer a special role to the receptors present in many diseases development processes as cancer, cirrhosis or lung fibrosis. In this review it is described the overview of the DDRs structure and their role in the different disease development and the possibility to consider them as therapeutic targets.

  6. Advances in chromatin remodeling and human disease.

    Science.gov (United States)

    Cho, Kyoung Sang; Elizondo, Leah I; Boerkoel, Cornelius F

    2004-06-01

    Epigenetic factors alter phenotype without changing genotype. A primary molecular mechanism underlying epigenetics is the alteration of chromatin structure by covalent DNA modifications, covalent histone modifications, and nucleosome reorganization. Remodeling of chromatin structure regulates DNA methylation, replication, recombination, and repair as well as gene expression. As these functions would predict, dysfunction of the proteins that remodel chromatin causes an array of multi-system disorders and neoplasias. Insights from these diseases suggest that during embryonic and fetal life, environmental distortions of chromatin remodeling encode a 'molecular memory' that predispose the individual to diseases in adulthood.

  7. Protein kinase CK2 in human diseases

    DEFF Research Database (Denmark)

    Guerra, Barbara; Issinger, Olaf-Georg

    2008-01-01

    in various disease processes including cancer has been gained in recent years, and the present review may help to further elucidate its aberrant role in many disease states. Its peculiar structural features [3-9] may be advantageous in designing tailor-made compounds with the possibility to specifically...... target this protein kinase [10]. Since not all the aspects of what has been published on CK2 can be covered in this review, we would like to recommend the following reviews; (i) for general information on CK2 [11-18] and (ii) with a focus on aberrant CK2 [19-22]....

  8. Polymorphisms of the Toll-like receptors and human disease.

    Science.gov (United States)

    Schwartz, David A; Cook, Donald N

    2005-11-15

    The Toll-like receptor (TLR) family regulates both innate and adaptive immune responses. Given its broad effect on immunity, the function of TLRs in various human diseases has been investigated largely by comparing the incidence of disease among persons with different polymorphisms in the genes that participate in TLR signaling. These studies demonstrate that TLR function affects several diseases, including sepsis, immunodeficiencies, atherosclerosis, and asthma. These findings have resulted in new opportunities to study the pathogenesis of disease, identify subpopulations at greater risk of disease, and, potentially, identify novel therapeutic approaches.

  9. SERUM YKL-40 IS ASSOCIATED WITH BONE DISEASE IN MULTIPLE MYELOMA

    DEFF Research Database (Denmark)

    Mylin, Anne Kjærsgaard; Abildgaard, Niels; Johansen, Julia S.

    2007-01-01

     Introduction. The secreted glycoprotein YKL-40 (CHI3L1, HC gp-39) is a potential player in the tumor-host interactions affecting several aspects of multiple myeloma (MM) including bone destruction. Previous studies support a role for YKL-40 in remodelling of the extracellular matrix...... to progression of myeloma-related bone disease. A potential role for YKL-40 in the bone disease of MM must be considered....

  10. 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

  11. Multiple trajectories in the developmental psychobiology of human handedness.

    Science.gov (United States)

    Michel, George F; Nelson, Eliza L; Babik, Iryna; Campbell, Julie M; Marcinowski, Emily C

    2013-01-01

    We show that handedness is a product of a multifaceted biosocial developmental process that begins prenatally and continues into adulthood. Although right-handedness predominates, handedness varies continuously across the population. Therefore, our phrase "multiple trajectories"refers to both differences in developmental pathways that can lead to similarities in handedness and similarities in pathways that can lead to differences in handedness. The task for the researcher is to identify how, when, and for what actions the trajectory of handedness development can be maintained or changed for an individual. Given the complexity of these developmental pathways, it is likely that the asymmetric sensorimotor activity that occurs during the development of handedness influences other hemispheric variations in neural processing. Indeed, researchers have investigated how handedness relates to cognitive, social, and emotional functioning because handedness represents different patterns of hemispheric specialization. Although the story of handedness development is not complete, it is well worth pursuing because it makes the development of brain-behavior relations more transparent, especially for hemispheric differences in function.

  12. Immunoregulatory networks in human Chagas disease

    Science.gov (United States)

    Dutra, Walderez O.; Menezes, Cristiane A.S.; Magalhães, Luisa M. D.; Gollob, Kenneth J.

    2014-01-01

    Summary Chagas disease, caused by the infection with Trypanosoma cruzi, is endemic in all Latin America. Due to the increase in population migration, Chagas disease has spread worldwide and is now considered a health issue not only in endemic countries. While most chronically infected individuals remain asymptomatic, approximately 30% of the patients develop a potentially deadly cardiomyopathy. The exact mechanisms that underlie the establishment and maintenance of the cardiac pathology are not clear. However, there is consistent evidence that immunoregulatory cytokines are critical for orchestrating the immune response and, thus, influence disease development or control. While the asymptomatic (indeterminate) form represents a state of balance between the host and the parasite, the establishment of the cardiac form represents the loss of this balance. Analysis of data obtained from several studies have led to the hypothesis that the indeterminate form is associated with an anti-inflammatory cytokine profile, represented by high expression of IL-10, while cardiac form is associated with a high production of IFN-gamma and TNF-alpha in relation to IL-10, leading to an inflammatory profile. Here, we discuss the immunoregulatory events that might influence disease outcome, as well as the mechanisms that influence the establishment of these complex immunoregulatory networks. PMID:24611805

  13. Cognitive impairment in human chronic Chagas' disease

    Directory of Open Access Journals (Sweden)

    C.A. Mangone

    1994-06-01

    Full Text Available We proposed to investigate subclinical cognitive impairment secondary to chronic Chagas' disease (CCD. No similar study was previously done. The neuropsychological performance of 45 chronic Chagasic patients and 26 matched controls (age, education place and years of residency in endemic area was compared using the Mini Mental State Exam (MMSE, Weschler Memory Scale (WMS and the Weschler Adult Intelligent Scale (WAIS. Non-parametric tests and Chi2 were used to compare group means and multivariate statistics in two way frequency tables for measures of independence and association of categorical variables with the disease. Results: Chagasic patients showed lower MMSE scores (p<004, poor orientation (p<.004, and attention (p<.007. Lower WMS MQ were associated with CCD (Chi2 5.9; p<.01; Fisher test p<.02. Lower WAIS IQ were associated with CCD (Chi2 6.3, p<.01; Fisher test p<.01 being the digit symbol (p<.03, picture completion (p<.03, picture arrangement (p<.01 and object assembly (p<.03 subtests the most affected. The impairment in non-verbal reasoning, speed of information processing, problem solving, learning and sequencing observed in chronic Chagas disease patients resembles the cognitive dysfunction associated with white matter disease.

  14. The DNA-damage response in human biology and disease

    DEFF Research Database (Denmark)

    Jackson, Stephen P; Bartek, Jiri

    2009-01-01

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

  15. Skin Diseases: Cross-section of human skin

    Science.gov (United States)

    Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Cross-section of human skin Past Issues / Fall 2008 Table of Contents For ... Logical Images, Inc. I n the areas of skin health and skin diseases, the NIH's National Institute ...

  16. The multiple burdens of zoonotic disease and an Ecohealth approach to their assessment.

    Science.gov (United States)

    Grace, Delia; Gilbert, Jeff; Randolph, Thomas; Kang'ethe, Erastus

    2012-09-01

    Zoonoses occur at the interface of human and animal disease and partly because their impact and management fall across two sectors they are often neglected. The Global Burden of Disease captures the impact of zoonoses on human health in terms of disability-adjusted life years (DALYs). Based on this, we estimate that in low income countries, zoonoses and diseases which recently emerged from animals make up 26 % of the DALYs lost to infectious disease and 10 % of the total DALYs lost. In contrast, in high income countries, zoonoses and diseases recently which emerged from animals represent less than 1 % of DALYs lost to infectious disease and only 0.02 % of the total disease burden. We present a framework that captures the costs of zoonoses and emerging disease to human, animal and ecosystem health in terms of cost of treatment, cost of prevention, health burden and intangible and opportunity costs. We also discuss how ecohealth concepts of transdisciplinarity, participation and equity can help in assessing the importance of zoonoses in developing countries and illustrate these with an example of assessing milk-borne disease.

  17. Calcium binding protein-mediated regulation of voltage-gated calcium channels linked to human diseases

    Institute of Scientific and Technical Information of China (English)

    Nasrin NFJATBAKHSH; Zhong-ping FENG

    2011-01-01

    Calcium ion entry through voltage-gated calcium channels is essential for cellular signalling in a wide variety of cells and multiple physiological processes. Perturbations of voltage-gated calcium channel function can lead to pathophysiological consequences. Calcium binding proteins serve as calcium sensors and regulate the calcium channel properties via feedback mechanisms. This review highlights the current evidences of calcium binding protein-mediated channel regulation in human diseases.

  18. Fisetin Acts on Multiple Pathways to Reduce the Impact of Age and Disease on CNS Function

    Science.gov (United States)

    Maher, Pamela

    2017-01-01

    It is becoming increasingly clear that neurological diseases are multi-factorial involving disruptions in multiple cellular systems. Thus, while each disease has its own initiating mechanisms and pathologies, certain common pathways appear to be involved in most, if not all, neurological diseases described to date. Thus, it is unlikely that modulating only a single factor will be effective at either preventing disease development or slowing disease progression. A better approach is to identify small (fisetin. Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also activate key neurotrophic factor signaling pathways. In addition, it has anti-inflammatory activity against microglial cells and inhibits the activity of lipoxygenases, thereby reducing the production of pro-inflammatory eicosanoids and their by-products. This wide range of actions suggests that fisetin has the ability to reduce the impact of age-related neurological diseases on brain function. PMID:25961687

  19. Genetics and epigenetics of repeat derepression in human disease

    NARCIS (Netherlands)

    Thijssen, P.E.

    2016-01-01

    A large part of the human genome consists of repetitive DNA. In this thesis two human diseases have been studied in which deregulation of repetitive DNA is a central feature: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromere instability and facial anomalies (ICF) syndrom

  20. The impact of disease characteristics on multiple sclerosis patients' quality of life.

    Science.gov (United States)

    Rezapour, Aziz; Almasian Kia, Abdollah; Goodarzi, Sahar; Hasoumi, Mojtaba; Nouraei Motlagh, Soraya; Vahedi, Sajad

    2017-01-01

    The aim of this study was to assess the quality of life (QoL) of patients with multiple sclerosis (MS), and to investigate the effects of characteristics of MS such as disease course, severity, and relapses on patients' QoL. This was a cross-sectional study, in which 171 patients were enrolled. Health-related QoL was assessed using the Persian version of the Multiple Sclerosis Quality of Life-54 questionnaire. To measure patients' disability status, we used the Expanded Disability Status Scale. Other variables included in the study were disease course and relapses of the disease. The average scores for patients' physical and mental QoL were 60.9±22.3 and 59.5±21.4, respectively. In a bivariate analysis, disease course, severity of the disease, and relapses were significantly associated with the physical and mental health composite scores. In a hierarchal regression analysis, disease course, severity of the disease, and relapses were responsible for 38 and 16% of the variance in physical and mental QoL, respectively. It was also observed that relapses were a strong predictor of both physical and mental QoL. Our results showed that disease characteristics significantly affected both dimensions of QoL. It is therefore suggested that health care providers should be aware of these characteristics of MS to more successfully improve MS patients' QoL.

  1. [Pulmonary cystic disease may be a rare complication to recurrent respiratory human papilloma virus infection].

    Science.gov (United States)

    Laurberg, Peter Thaysen; Weinreich, Ulla M Øller

    2014-12-01

    A 19-year-old woman with a history of juvenile laryngeal papillomatosis (JLP), treated since childhood with multiple resections, was admitted with symptoms of pneumonia. A chest X-ray and CAT-scan revealed multiple lung cysts and a bronchoalveolar lavage detected human papilloma virus 11. The patient responded well to antibiotics. A body plethysmography showed small lung volumes and low diffusion capacity for carbon monoxide, but normal volume diffusion capacity divided by alveolar volume. Pulmonary cystic disease should be considered when patients with JLP have symptoms of pneumonia.

  2. DEGAS: de novo discovery of dysregulated pathways in human diseases.

    Directory of Open Access Journals (Sweden)

    Igor Ulitsky

    Full Text Available BACKGROUND: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems. METHODOLOGY/PRINCIPAL FINDINGS: We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks, a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package (http://acgt.cs.tau.ac.il/matisse. CONCLUSIONS/SIGNIFICANCE: The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.

  3. Immunofluorescence patterns in selected dermatoses, including blistering skin diseases utilizing multiple fluorochromes

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu-Velez

    2015-01-01

    Full Text Available Background: Autoimmune vesiculobullous disorders represent a heterogeneous group of dermatoses whose diagnosis is made based on clinical history, histologic features, and immunopathologic features. The most commonly used techniques for the diagnosis of these diseases are direct and indirect immunofluorescence (DIF and IIF, including salt-split processing. NaCl split skin is used to determine the level of blister formation, and the localization of autoantibodies relative to the split. Classically, immunofluorescence has been performed with one fluorochrome in the diagnosis of autoimmune bullous skin diseases. Aims: To compare DIF and IIF of the skin, using a single fluorochrome versus multiple fluorochromes. Materials and Methods: We studied 20 autoimmune skin disease cases using fluorescein isothiocyanate (FITC alone, in comparison to multiple fluorochromes (with or without DNA counterstaining. Results: The use of multiple fluorochromes helped to simultaneously visualize reactivity in multiple skin areas, in contrast to using FITC alone. Conclusions: Using multiple fluorochromes allows simultaneous labeling of two or more antigens within the same cell/or tissue section, assists in colocalization of unknown antigens with known molecules, and helps in ruling out "background" staining.

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

    Science.gov (United States)

    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.

  5. Comparison of Intelligibility Measures for Adults with Parkinson's Disease, Adults with Multiple Sclerosis, and Healthy Controls

    Science.gov (United States)

    Stipancic, Kaila L.; Tjaden, Kris; Wilding, Gregory

    2016-01-01

    Purpose: This study obtained judgments of sentence intelligibility using orthographic transcription for comparison with previously reported intelligibility judgments obtained using a visual analog scale (VAS) for individuals with Parkinson's disease and multiple sclerosis and healthy controls (K. Tjaden, J. E. Sussman, & G. E. Wilding, 2014).…

  6. The phenomenon of disproportionate antecollis in Parkinson's disease and multiple system atrophy.

    NARCIS (Netherlands)

    Warrenburg, B.P.C. van de; Cordivari, C.; Ryan, A.M.; Phadke, R.; Holton, J.L.; Bhatia, K.P.; Hanna, M.G.; Quinn, N.P.

    2007-01-01

    We sought to explore the phenomenon of disproportionate antecollis in multiple system atrophy (MSA) and Parkinson's disease (PD). The etiology is much debated and the main issue is whether it represents a primary myopathy or is secondary to the underlying motor disorder. The clinical, electrophysiol

  7. 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....

  8. When to Initiate Disease-Modifying Drugs for Relapsing Remitting Multiple Sclerosis in Adults?

    Directory of Open Access Journals (Sweden)

    Mona Alkhawajah

    2011-01-01

    Full Text Available For patients with Relapsing Remitting Multiple Scierosis Beta Interfaerons and Glatiramer Acetate were the first to be licensed for treatment. This review deals with one major question: when to initiate therapy? Through exploring the unique characteristics of the disease and treatement we suggest an approach that should be helpful in the process of decision-making.

  9. Autoimmune antibody decline in Parkinson's disease and Multiple System Atrophy; a step towards immunotherapeutic strategies

    DEFF Research Database (Denmark)

    Brudek, Tomasz; Winge, Kristian; Folke, Jonas

    2017-01-01

    BACKGROUND: Parkinson's' disease (PD) and Multiple System Atrophy (MSA) are progressive brain disorders characterized by intracellular accumulations of α-synuclein and nerve cell loss in specific brain areas. This loss causes problems with movement, balance and/or autonomic functions. Naturally...

  10. Developing maize germplasm lines with multiple insect and disease resistance and low aflatoxin contamination

    Science.gov (United States)

    Yield and quality losses caused BY insects, diseases, and mycotoxin contaminations are the critical impediments for maize production under warm climate. In order to develop maize germplasm lines with resistance to multiple insect pests and aflatoxin accumulation, a set of 13 reciprocal breeding cro...

  11. Pain in Parkinson's disease and multiple sclerosis : Its relation to the medial and lateral pain systems

    NARCIS (Netherlands)

    Scherder, E; Wolters, E; Polman, C; Sergeant, J; Swaab, D

    2005-01-01

    Although pain is one of the major clinical symptoms of Parkinson's disease (PD) and multiple sclerosis (MS), it is often neglected and therefore undertreated. The question why the perception of pain in stages without cognitive impairment is not affected by the neuropathology has not been addressed s

  12. [Bacillus cereus bacteremia in Crohn's disease with multiple ileal stricture on maintenance azathioprine therapy].

    Science.gov (United States)

    Hizawa, Kazuoki; Nagata, Yuko; Taniguchi, Masahiko; Nakamori, Mari; Matsumoto, Takayuki; Iida, Mitsuo

    2009-01-01

    We describe a case of 36-year-old Japanese man with Crohn's disease, complicated by Bacillus cereus bacteremia on maintenance azathioprine therapy. Although anti-microbial agents were ineffective, the patient became well immediately after a partial resection of the ileum with multiple severe stenosis.

  13. [Peripheral blood monocyte hepcidin in patients with multiple myeloma is associated with anemia of chronic disease].

    Science.gov (United States)

    Han, Xiao; Zhou, Dao-Bin; Duan, Ming-Hui; Wang, Xuan; Zhang, Jie-Ping; Zhao, Yong-Qiang; Shen, Ti; Wu, Yong-Ji

    2013-04-01

    Disorders of iron utilization caused by abnormal elevation of hepcidin levels are the main mechanism of anemia of chronic disease. Hepcidin is mainly produced by the liver. Recently it has been found that monocytes are another source of hepcidin. The increased hepcidin in serum and urine of multiple myeloma patients may be one cause of anemia of chronic disease (ACD). However it is unclear whether the peripheral blood monocyte hepcidin is involved in the pathogenesis of anemia of chronic disease. This study was purposed to investigate the role of monocyte hepcidin in multiple myeloma patients with anemia of chronic disease. The clinical data and peripheral venous blood of multiple myeloma patients were collected.Serum concentration of IL-6 and TNF-α was detected by ELISA. Peripheral blood monocytes were isolated by CD14(+) magnetic beads. Hepcidin, IL-6 and TNF-α mRNA of monocytes were detected by real time quantitative PCR. The results showed that the expression level of monocyte hepcidin mRNA in myeloma patients was higher than that in normal controls. In untreated patients, the expression level of monocyte hepcidin mRNA was negatively correlated with hemoglobin, and positively correlated with serum ferritin and IL-6 levels, but unrelated with TNF-α levels.It is concluded that the increased monocyte hepcidin levels in multiple myeloma patients may play an etiologic role in ACD.

  14. Nonenzymatic glycosylation of human hemoglobin at multiple sites

    Energy Technology Data Exchange (ETDEWEB)

    Shapiro, R.; McManus, M.; Garrick, L.; McDonald, M.J.; Bunn, H.F.

    1979-04-01

    The most abundant minor hemoglobin component of human hemolysate is Hb A1c, which has glucose bound to the N-terminus of the beta chain by a ketoamine linkage. Hb A1c is formed slowly and continuously throughout the 120 day lifespan of the red cell. It can be synthesized in vitro by incubating purified hemoglobin with 14C-glucose. Other minor components, Hb A1a1 and Hb A1a2 are adducts of sugar phosphates at the N-terminus of the beta chain. Hb A1b contains an unidentified nonphosphorylated sugar at the beta N-terminus. In addition, a significant portion of the major hemoglobin component (Hb Ao) is also glycosylated by a glucose ketoamine linkage at other sites on the molecule, including the N-terminus of the alpha chain and the epsilon-amino group of several lysine residues on both the alpha and the beta chains. The results indicate that the interaction of glucose and hemoglobin is rather nonspecific and suggests that other proteins are modified in a similar fashion.

  15. Generative models: Human embryonic stem cells and multiple modeling relations.

    Science.gov (United States)

    Fagan, Melinda Bonnie

    2016-04-01

    Model organisms are at once scientific models and concrete living things. It is widely assumed by philosophers of science that (1) model organisms function much like other kinds of models, and (2) that insofar as their scientific role is distinctive, it is in virtue of representing a wide range of biological species and providing a basis for generalizations about those targets. This paper uses the case of human embryonic stem cells (hESC) to challenge both assumptions. I first argue that hESC can be considered model organisms, analogous to classic examples such as Escherichia coli and Drosophila melanogaster. I then discuss four contrasts between the epistemic role of hESC in practice, and the assumptions about model organisms noted above. These contrasts motivate an alternative view of model organisms as a network of systems related constructively and developmentally to one another. I conclude by relating this result to other accounts of model organisms in recent philosophy of science. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, Finn Thorup; Hedegaard, Chris Juul; Krakauer, M;

    2011-01-01

    Background: Glatiramer acetate (GA) treatment suppresses disease activity in multiple sclerosis (MS). The immunological response to treatment may differ in patients who are stable on GA therapy and patients with breakthrough disease activity, but the results of previous studies are inconsistent....... Objectives: We studied the immunological response to GA and its relationship with disease activity. Methods: Anti-GA antibodies in plasma and the expression of genes encoding cytokines and T-cell-polarizing transcription factors in blood cells were analysed by flow cytometric bead array and polymerase chain...

  17. Characterization of annual disease progression of multiple sclerosis patients: A population-based study

    DEFF Research Database (Denmark)

    Freilich, Jonatan; Manouchehrinia, Ali; Trusheim, Mark

    2017-01-01

    the milestone. To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition......Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan-Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching...

  18. Impacts of Gut Bacteria on Human Health and Diseases

    Directory of Open Access Journals (Sweden)

    Yu-Jie Zhang

    2015-04-01

    Full Text Available Gut bacteria are an important component of the microbiota ecosystem in the human gut, which is colonized by 1014 microbes, ten times more than the human cells. Gut bacteria play an important role in human health, such as supplying essential nutrients, synthesizing vitamin K, aiding in the digestion of cellulose, and promoting angiogenesis and enteric nerve function. However, they can also be potentially harmful due to the change of their composition when the gut ecosystem undergoes abnormal changes in the light of the use of antibiotics, illness, stress, aging, bad dietary habits, and lifestyle. Dysbiosis of the gut bacteria communities can cause many chronic diseases, such as inflammatory bowel disease, obesity, cancer, and autism. This review summarizes and discusses the roles and potential mechanisms of gut bacteria in human health and diseases.

  19. Connexin mutant embryonic stem cells and human diseases

    Institute of Scientific and Technical Information of China (English)

    Kiyomasa; Nishii; Yosaburo; Shibata; Yasushi; Kobayashi

    2014-01-01

    Intercellular communication via gap junctions allows cells within multicellular organisms to share small molecules. The effect of such interactions has been elucidated using mouse gene knockout strategies. Although several mutations in human gap junction-encoding connexin(Cx) have been described, Cx mutants in mice do not always recapitulate the human disease. Among the 20 mouse Cxs, Cx26, Cx43, and Cx45 play roles in early cardiac or placental development, and disruption of the genes results in lethality that hampers further analyses. Embryonic stem cells(ESCs) that lack Cx43 or Cx45 have made analysis feasible in both in vitro differentiated cell cultures and in vivo chimeric tissues. The success of mouse ESCs studies is leading to the use of induced pluripotent stem cells to learn more about the pathogenesis of human Cx diseases. This review summarizes the current status of mouse Cx disruption models and ESC differentiation studies, and discusses their implication for understanding human Cx diseases.

  20. Human Microbiome and its Association With Health and Diseases.

    Science.gov (United States)

    Althani, Asmaa A; Marei, Hany E; Hamdi, Wedad S; Nasrallah, Gheyath K; El Zowalaty, Mohamed E; Al Khodor, Souhaila; Al-Asmakh, Maha; Abdel-Aziz, Hassan; Cenciarelli, Carlo

    2016-08-01

    Human microbiota are distinct communities of microorganisms that resides at different body niches. Exploration of the human microbiome has become a reality due to the availability of powerful metagenomics and metatranscriptomic analysis technologies. Recent advances in sequencing and bioinformatics over the past decade help provide a deep insight into the nature of the host-microbial interactions and identification of potential deriver genes and pathways associated with human health, well-being, and predisposition to different diseases. In the present review, we outline recent studies devoted to elucidate the possible link between the microbiota and various type of diseases. The present review also highlights the potential utilization of microbiota as a potential therapeutic option to treat a wide array of human diseases. J. Cell. Physiol. 231: 1688-1694, 2016. © 2015 Wiley Periodicals, Inc.

  1. Connexin mutant embryonic stem cells and human diseases.

    Science.gov (United States)

    Nishii, Kiyomasa; Shibata, Yosaburo; Kobayashi, Yasushi

    2014-11-26

    Intercellular communication via gap junctions allows cells within multicellular organisms to share small molecules. The effect of such interactions has been elucidated using mouse gene knockout strategies. Although several mutations in human gap junction-encoding connexin (Cx) have been described, Cx mutants in mice do not always recapitulate the human disease. Among the 20 mouse Cxs, Cx26, Cx43, and Cx45 play roles in early cardiac or placental development, and disruption of the genes results in lethality that hampers further analyses. Embryonic stem cells (ESCs) that lack Cx43 or Cx45 have made analysis feasible in both in vitro differentiated cell cultures and in vivo chimeric tissues. The success of mouse ESCs studies is leading to the use of induced pluripotent stem cells to learn more about the pathogenesis of human Cx diseases. This review summarizes the current status of mouse Cx disruption models and ESC differentiation studies, and discusses their implication for understanding human Cx diseases.

  2. Multiple Drug Transport Pathways through Human P-Glycoprotein.

    Science.gov (United States)

    McCormick, James W; Vogel, Pia D; Wise, John G

    2015-07-21

    P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.

  3. MicroRNA in human cancer and chronic inflammatory diseases.

    Science.gov (United States)

    Kanwar, Jagat R; Mahidhara, Ganesh; Kanwar, Rupinder K

    2010-06-01

    MicroRNAs (miRNAs) are the non-coding RNAs that act as post-translational regulators to their complimentary messenger RNAs (mRNA). Due to their specific gene silencing property, miRNAs have been implicated in a number of cellular and developmental processes. Also, it has been proposed that a particular set of miRNA spectrum is expressed only in a particular type of tissue. Many interesting findings related to the differential expression of miRNAs in various human diseases including several types of cancers, neurodegenerative diseases and metabolic diseases have been reported. Deregulation of miRNA expression in different types of human diseases and the roles various miRNAs play as tumour suppressors as well as oncogenes, suggest their contribution to cancer and/or in other disease development. These findings have possible implications in the development of diagnostics and/or therapeutics in human malignancies. In this review, we discuss various miRNAs that are differentially expressed in human chronic inflammatory diseases, neurodegenerative diseases, cancer and the further prospective development of miRNA based diagnostics and therapeutics.

  4. Natural selection on genes that underlie human disease susceptibility

    Science.gov (United States)

    Blekhman, Ran; Man, Orna; Herrmann, Leslie; Boyko, Adam R.; Indap, Amit; Kosiol, Carolin; Bustamante, Carlos D.; Teshima, Kosuke M.; Przeworski, Molly

    2008-01-01

    What evolutionary forces shape genes that contribute to the risk of human disease? Do similar selective pressures act on alleles that underlie simple vs. complex disorders? [1-3]. Answers to these questions will shed light on the origin of human disorders (e.g., [4]), and help to predict the population frequencies of alleles that contribute to disease risk, with important implications for the efficient design of mapping studies [5-7]. As a first step towards addressing them, we created a hand-curated version of the Mendelian Inheritance in Man database (OMIM). We then examined selective pressures on Mendelian disease genes, genes that contribute to complex disease risk and genes known to be essential in mouse, by analyzing patterns of human polymorphism and of divergence between human and rhesus macaque. We find that Mendelian disease genes appear to be under widespread purifying selection, especially when the disease mutations are dominant (rather than recessive). In contrast, the class of genes that influence complex disease risk shows little signs of evolutionary conservation, possibly because this category includes both targets of purifying and positive selection. PMID:18571414

  5. Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

    DEFF Research Database (Denmark)

    Fu, Jing; Li, Shirong; Feng, Rentian

    2016-01-01

    Multiple myeloma (MM) cells secrete osteoclastogenic factors that promote osteolytic lesions; however, the identity of these factors is largely unknown. Here, we performed a screen of human myeloma cells to identify pro-osteoclastogenic agents that could potentially serve as therapeutic targets f...

  6. Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network.

    Science.gov (United States)

    Al-Harazi, Olfat; Al Insaif, Sadiq; Al-Ajlan, Monirah A; Kaya, Namik; Dzimiri, Nduna; Colak, Dilek

    2016-06-20

    A disease phenotype generally reflects various pathobiological processes that interact in a complex network. The highly interconnected nature of the human protein interaction network (interactome) indicates that, at the molecular level, it is difficult to consider diseases as being independent of one another. Recently, genome-wide molecular measurements, data mining and bioinformatics approaches have provided the means to explore human diseases from a molecular basis. The exploration of diseases and a system of disease relationships based on the integration of genome-wide molecular data with the human interactome could offer a powerful perspective for understanding the molecular architecture of diseases. Recently, subnetwork markers have proven to be more robust and reliable than individual biomarker genes selected based on gene expression profiles alone, and achieve higher accuracy in disease classification. We have applied one of these methodologies to idiopathic dilated cardiomyopathy (IDCM) data that we have generated using a microarray and identified significant subnetworks associated with the disease. In this paper, we review the recent endeavours in this direction, and summarize the existing methodologies and computational tools for network-based analysis of complex diseases and molecular relationships among apparently different disorders and human disease network. We also discuss the future research trends and topics of this promising field.

  7. Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls.

    Directory of Open Access Journals (Sweden)

    Andreas Keller

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system, which is heterogenous with respect to clinical manifestations and response to therapy. Identification of biomarkers appears desirable for an improved diagnosis of MS as well as for monitoring of disease activity and treatment response. MicroRNAs (miRNAs are short non-coding RNAs, which have been shown to have the potential to serve as biomarkers for different human diseases, most notably cancer. Here, we analyzed the expression profiles of 866 human miRNAs. In detail, we investigated the miRNA expression in blood cells of 20 patients with relapsing-remitting MS (RRMS and 19 healthy controls using a human miRNA microarray and the Geniom Real Time Analyzer (GRTA platform. We identified 165 miRNAs that were significantly up- or downregulated in patients with RRMS as compared to healthy controls. The best single miRNA marker, hsa-miR-145, allowed discriminating MS from controls with a specificity of 89.5%, a sensitivity of 90.0%, and an accuracy of 89.7%. A set of 48 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 95%, a sensitivity of 97.6%, and an accuracy of 96.3%. While 43 of the 165 miRNAs deregulated in patients with MS have previously been related to other human diseases, the remaining 122 miRNAs are so far exclusively associated with MS. The implications of our study are twofold. The miRNA expression profiles in blood cells may serve as a biomarker for MS, and deregulation of miRNA expression may play a role in the pathogenesis of MS.

  8. 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.

  9. Selection and Assessment of Plant Growth-Promoting Rhizobacteria for Biological Control of Multiple Plant Diseases.

    Science.gov (United States)

    Liu, Ke; Newman, Molli; McInroy, John A; Hu, Chia-Hui; Kloepper, Joseph W

    2017-08-01

    A study was designed to screen individual strains of plant growth-promoting rhizobacteria (PGPR) for broad-spectrum disease suppression in vitro and in planta. In a preliminary screen, 28 of 196 strains inhibited eight different tested pathogens in vitro. In a secondary screen, these 28 strains showed broad spectrum antagonistic activity to six different genera of pathogens, and 24 of the 28 strains produced five traits reported to be related to plant growth promotion, including nitrogen fixation, phosphate solubilization, indole-3-acetic acid production, siderophore production, and biofilm formation. In advanced screens, the 28 PGPR strains selected in vitro were tested in planta for biological control of multiple plant diseases including bacterial spot of tomato caused by Xanthomonas axonopodis pv. vesicatoria, bacterial speck of tomato caused by Pseudomonas syringae pv. tomato, damping-off of pepper caused by Rhizoctonia solani, and damping-off of cucumber caused by Pythium ultimum. In all, 5 of the 28 tested strains significantly reduced three of the four tested diseases, and another 19 strains showed biological control to two tested diseases. To understand the observed broad-spectrum biocontrol capacity, antiSMASH was used to predict secondary metabolite clusters of selected strains. Multiple gene clusters encoding for secondary metabolites, e.g., bacillibactin, bacilysin, and microcin, were detected in each strain. In conclusion, selected individual PGPR strains showed broad-spectrum biocontrol activity to multiple plant diseases.

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

    Directory of Open Access Journals (Sweden)

    Alessandro Finkelsztejn

    2012-10-01

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

  11. Long Non-Coding RNAs and Complex Human Diseases

    Directory of Open Access Journals (Sweden)

    Changning Liu

    2013-09-01

    Full Text Available Long non-coding RNAs (lncRNAs are a heterogeneous class of RNAs that are generally defined as non-protein-coding transcripts longer than 200 nucleotides. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes, such as chromatin remodeling, gene transcription, and protein transport and trafficking. Moreover, lncRNAs are dysregulated in a number of complex human diseases, including coronary artery diseases, autoimmune diseases, neurological disorders, and various cancers, which indicates their important roles in these diseases. Here, we reviewed the current understanding of lncRNAs, including their definition and subclassification, regulatory functions, and potential roles in different types of complex human diseases.

  12. Oxygen radical production in leukocytes and disease severity in multiple sclerosis.

    Science.gov (United States)

    Mossberg, Natalia; Movitz, Charlotta; Hellstrand, Kristoffer; Bergström, Tomas; Nilsson, Staffan; Andersen, Oluf

    2009-08-18

    This study investigated the relationship between the formation of NADPH oxidase-dependent oxygen radicals in peripheral blood leukocytes ('respiratory burst') and disease severity in patients with multiple sclerosis (MS). Oxygen radical production was induced by formyl-Met-Leu-Phe (fMLF), Trp-Lys-Tyr-Met-Val-Met-NH2 (WKYMVM) or phorbol myristate acetate (PMA) and was assessed by quantifying superoxide anion, i.e. the initial radical formed by the NADPH oxidase. Disease severity was evaluated using the Multiple Sclerosis Severity Score (MSSS). In patients with severe disease, the production of superoxide anion was significantly lower for all three inducers of radical formation (p=0.04-0.004). Our findings are supportive of a protective role of oxygen radicals in autoimmunity.

  13. Recovery from Multiple APAs Delays Gait Initiation in Parkinson’s Disease

    Science.gov (United States)

    Cohen, Rajal G.; Nutt, John G.; Horak, Fay B.

    2017-01-01

    Background: Freezing of gait in Parkinson’s disease (PD) has been linked with deficits in inhibitory control, but causal mechanisms are not established. Freezing at gait initiation (start hesitation) is often accompanied by multiple anticipatory postural adjustments (APAs). If inhibition deficits contribute to freezing by interfering with ability to inhibit initial weight shifts in the wrong direction, then PD subjects should experience more episodes of multiple APAs than healthy controls (HCs) do. If inhibition deficits contribute to freezing by interfering with ability to release a previously inhibited step following multiple APAs, then step onset following multiple APAs should be delayed more in people with PD than in HCs. Methods: Older adults with PD and HC subjects rapidly initiated stepping in response to a light cue in blocks of simple (SRT) and choice (CRT) conditions. We recorded kinematics and ground reaction forces, and we administered the Stroop task to assess inhibitory control. Results: Multiple APAs were more common in CRT than SRT conditions but were equally common in HC and PD subjects. Step onsets were delayed in both conditions and further delayed in trials with multiple APAs, except for HC subjects in SRT trials. Poor Stroop performance correlated with many multiple APAs, late step onset, and rearward position of center of mass (COM) at cue presentation. Forward motion of the COM during the APA was higher in trials with multiple APAs than in trials with single APAs, especially in CRT trials and in PD subjects without self-reported freezing. Conclusion: Start hesitation is not caused by multiple APAs per se, but may be associated with difficulty recovering from multiple APAs, due to difficulty releasing a previously inhibited step. PMID:28261073

  14. Central nervous system infectious diseases mimicking multiple sclerosis: recognizing distinguishable features using MRI

    Directory of Open Access Journals (Sweden)

    Antonio Jose da Rocha

    2013-09-01

    Full Text Available The current diagnostic criteria for multiple sclerosis (MS confirm the relevant role of magnetic resonance imaging (MRI, supporting the possibility of characterizing the dissemination in space (DIS and the dissemination in time (DIT in a single scan. To maintain the specificity of these criteria, it is necessary to determine whether T2/FLAIR visible lesions and the gadolinium enhancement can be attributed to diseases that mimic MS. Several diseases are included in the MS differential diagnosis list, including diseases with exacerbation, remitting periods and numerous treatable infectious diseases, which can mimic the MRI features of MS. We discuss the most relevant imaging features in several infectious diseases that resemble MS and examine the primary spatial distributions of lesions and the gadolinium enhancement patterns related to MS. Recognizing imaging "red flags" can be useful for the proper diagnostic evaluation of suspected cases of MS, facilitating the correct differential diagnosis by assessing the combined clinical, laboratory and MR imaging information.

  15. DUF1220 domains, cognitive disease, and human brain evolution.

    Science.gov (United States)

    Dumas, L; Sikela, J M

    2009-01-01

    We have established that human genome sequences encoding a novel protein domain, DUF1220, show a dramatically elevated copy number in the human lineage (>200 copies in humans vs. 1 in mouse/rat) and may be important to human evolutionary adaptation. Copy-number variations (CNVs) in the 1q21.1 region, where most DUF1220 sequences map, have now been implicated in numerous diseases associated with cognitive dysfunction, including autism, autism spectrum disorder, mental retardation, schizophrenia, microcephaly, and macrocephaly. We report here that these disease-related 1q21.1 CNVs either encompass or are directly flanked by DUF1220 sequences and exhibit a dosage-related correlation with human brain size. Microcephaly-producing 1q21.1 CNVs are deletions, whereas macrocephaly-producing 1q21.1 CNVs are duplications. Similarly, 1q21.1 deletions and smaller brain size are linked with schizophrenia, whereas 1q21.1 duplications and larger brain size are associated with autism. Interestingly, these two diseases are thought to be phenotypic opposites. These data suggest a model which proposes that (1) DUF1220 domain copy number may be involved in influencing human brain size and (2) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human lineage has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders.

  16. The Leeuwenhoek Lecture 2001. Animal origins of human infectious disease.

    Science.gov (United States)

    Weiss, R A

    2001-06-29

    Since time immemorial animals have been a major source of human infectious disease. Certain infections like rabies are recognized as zoonoses caused in each case by direct animal-to-human transmission. Others like measles became independently sustained with the human population so that the causative virus has diverged from its animal progenitor. Recent examples of direct zoonoses are variant Creutzfeldt-Jakob disease arising from bovine spongiform encephalopathy, and the H5N1 avian influenza outbreak in Hong Kong. Epidemics of recent animal origin are the 1918-1919 influenza pandemic, and acquired immune deficiency syndrome caused by human immunodeficiency virus (HIV). Some retroviruses jump into and out of the chromosomal DNA of the host germline, so that they oscillate between being inherited Mendelian traits or infectious agents in different species. Will new procedures like animal-to-human transplants unleash further infections? Do microbes become more virulent upon cross-species transfer? Are animal microbes a threat as biological weapons? Will the vast reservoir of immunodeficient hosts due to the HIV pandemic provide conditions permissive for sporadic zoonoses to take off as human-to-human transmissible diseases? Do human infections now pose a threat to endangered primates? These questions are addressed in this lecture.

  17. Interneurons in the human olfactory system in Alzheimer's disease.

    Science.gov (United States)

    Saiz-Sanchez, Daniel; Flores-Cuadrado, Alicia; Ubeda-Bañon, Isabel; de la Rosa-Prieto, Carlos; Martinez-Marcos, Alino

    2016-02-01

    The principal olfactory structures display Alzheimer's disease (AD) related pathology at early stages of the disease. Consequently, olfactory deficits are among the earliest symptoms. Reliable olfactory tests for accurate clinical diagnosis are rarely made. In addition, neuropathological analysis postmortem of olfactory structures is often not made. Therefore, the relationship between the clinical features and the underlying pathology is poorly defined. Traditionally, research into Alzheimer's disease has focused on the degeneration of cortical temporal projection neurons and cholinergic neurons. Recent evidence has demonstrated the neurodegeneration of interneuron populations in AD. This review provides an updated overview of the pathological involvement of interneuron populations in the human olfactory system in Alzheimer's disease.

  18. Acrolein and Human Disease: Untangling the Knotty Exposure Scenarios Accompanying Several Diverse Disorders.

    Science.gov (United States)

    Burcham, Philip C

    2017-01-17

    Acrolein is a highly toxic electrophile that participates in many diseases, yet efforts to delineate its precise mechanistic contributions to specific conditions are complicated by its wide distribution within human environments. This Perspective develops the proposal that due to its mixed status as environmental pollutant, metabolic byproduct, and endotoxicant which forms via ubiquitous pathophysiological processes, many diseases likely involve acrolein released from multiple sources. Although the category boundaries are indistinct, at least four identifiable exposure scenarios are identifiable. First, in some syndromes, such as those accompanying chronic or acute intoxication with smoke, whatever role acrolein plays in disease pathogenesis mainly traces to exogenous sources such as the combustion of tobacco or other organic matter. A second exposure category involves xenobiotics that undergo metabolism within the body to release acrolein. Still other health conditions, however, involve acrolein that forms via several endogenous pathways, some of which are activated upon intoxication with xenobiotics (i.e., Exposure Category 3), while still others accompany direct physical trauma to body tissues (Exposure Category 4). Further complicating efforts to clarify the role of endogenous acrolein in human disease is the likelihood that many such syndromes are complex phenomena that resemble "chemical mixture exposures" by involving multiple toxic substances simultaneously. This Perspective contends that while recent decades have witnessed much progress in describing the deleterious effects of acrolein at the cellular and molecular levels, more work is needed to define the contributions of different acrolein sources to "real-world" health conditions in human subjects.

  19. A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis

    Science.gov (United States)

    Lund, Maria E.; Greer, Judith; Dixit, Aakanksha; Alvarado, Raquel; McCauley-Winter, Padraig; To, Joyce; Tanaka, Akane; Hutchinson, Andrew T.; Robinson, Mark W.; Simpson, Ann M.; O’Brien, Bronwyn A.; Dalton, John P.; Donnelly, Sheila

    2016-01-01

    Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases. PMID:27883079

  20. Human Placenta-Derived Adherent Cells Prevent Bone loss, Stimulate Bone formation, and Suppress Growth of Multiple Myeloma in Bone

    Science.gov (United States)

    Li, Xin; Ling, Wen; Pennisi, Angela; Wang, Yuping; Khan, Sharmin; Heidaran, Mohammad; Pal, Ajai; Zhang, Xiaokui; He, Shuyang; Zeitlin, Andy; Abbot, Stewart; Faleck, Herbert; Hariri, Robert; Shaughnessy, John D.; van Rhee, Frits; Nair, Bijay; Barlogie, Bart; Epstein, Joshua; Yaccoby, Shmuel

    2011-01-01

    Human placenta has emerged as a valuable source of transplantable cells of mesenchymal and hematopoietic origin for multiple cytotherapeutic purposes, including enhanced engraftment of hematopoietic stem cells, modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDACs) are mesenchymal-like stem cells isolated from postpartum human placenta. Multiple myeloma is closely associated with induction of bone disease and large lytic lesions, which are often not repaired and are usually the sites of relapses. We evaluated the antimyeloma therapeutic potential, in vivo survival, and trafficking of PDACs in the severe combined immunodeficiency (SCID)–rab model of medullary myeloma-associated bone loss. Intrabone injection of PDACs into non-myelomatous and myelomatous implanted bone in SCID-rab mice promoted bone formation by stimulating endogenous osteoblastogenesis, and most PDACs disappeared from bone within 4 weeks. PDACs inhibitory effects on myeloma bone disease and tumor growth were dose-dependent and comparable with those of fetal human mesenchymal stem cells (MSCs). Intrabone, but not subcutaneous, engraftment of PDACs inhibited bone disease and tumor growth in SCID-rab mice. Intratumor injection of PDACs had no effect on subcutaneous growth of myeloma cells. A small number of intravenously injected PDACs trafficked into myelomatous bone. Myeloma cell growth rate in vitro was lower in coculture with PDACs than with MSCs from human fetal bone or myeloma patients. PDACs also promoted apoptosis in osteoclast precursors and inhibited their differentiation. This study suggests that altering the bone marrow microenvironment with PDAC cytotherapy attenuates growth of myeloma and that PDAC cytotherapy is a promising therapeutic approach for myeloma osteolysis. PMID:21732484

  1. Pathogenic role of the CRL4 ubiquitin ligase in human disease

    Directory of Open Access Journals (Sweden)

    Pengbo eZhou

    2012-03-01

    Full Text Available The cullin 4-RING ubiquitin ligase (CRL4 family employs multiple DCAF (DDB1-CUL4 associated factors substrate receptors to direct the degradation of proteins involved in a wide spectrum of cellular functions. Aberrant expression of the cullin 4A (CUL4A gene is found in many tumor types, while mutations of the cullin 4B (CUL4B gene are causally associated with human X-linked mental retardation. This focused review will summarize our current knowledge of the two CUL4 family members in the pathogenesis of human malignancy and neuronal disease, and discuss their potential as new targets for cancer prevention and therapeutic intervention.

  2. Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Lu Chen

    2014-06-01

    Full Text Available Using a viral model of the demyelinating disease multiple sclerosis (MS, we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination. Evidence indicates that the reduced neuroinflammation is correlated with an increased number of CD4+CD25+FOXP3+ regulatory T cells (Tregs within the spinal cords. Coculture of hNPCs with activated T cells resulted in reduced T cell proliferation and increased Treg numbers. The hNPCs acted, in part, through secretion of TGF-β1 and TGF-β2. These findings indicate that the transient presence of hNPCs transplanted in an animal model of MS has powerful immunomodulatory effects and mediates recovery. Further investigation of the restorative effects of hNPC transplantation may aid in the development of clinically relevant MS treatments.

  3. Part 1: The Human Gut Microbiome in Health and Disease

    OpenAIRE

    Bull, Matthew J.; Plummer, Nigel T.

    2014-01-01

    The bacterial cells harbored within the human gastrointestinal tract (GIT) outnumber the host’s cells by a factor of 10 and the genes encoded by the bacteria resident within the GIT outnumber their host’s genes by more than 100 times. These human digestive-tract associated microbes are referred to as the gut microbiome. The human gut microbiome and its role in both health and disease has been the subject of extensive research, establishing its involvement in human metabolism, nutrition, physi...

  4. An Evidenced-Based Scale of Disease Severity following Human Challenge with Enteroxigenic Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Chad K Porter

    Full Text Available Experimental human challenge models have played a major role in enhancing our understanding of infectious diseases. Primary outcomes have typically utilized overly simplistic outcomes that fail to entirely account for complex illness syndromes. We sought to characterize clinical outcomes associated with experimental infection with enterotoxigenic Escherichia coli (ETEC and to develop a disease score.Data were obtained from prior controlled human ETEC infection studies. Correlation and univariate regression across sign and symptom severity was performed. A multiple correspondence analysis was conducted. A 3-parameter disease score with construct validity was developed in an iterative fashion, compared to standard outcome definitions and applied to prior vaccine challenge trials.Data on 264 subjects receiving seven ETEC strains at doses from 1x105 to 1x1010 cfu were used to construct a standardized dataset. The strongest observed correlation was between vomiting and nausea (r = 0.65; however, stool output was poorly correlated with subjective activity-impacting outcomes. Multiple correspondence analyses showed covariability in multiple signs and symptoms, with severity being the strongest factor corresponding across outcomes. The developed disease score performed well compared to standard outcome definitions and differentiated disease in vaccinated and unvaccinated subjects.Frequency and volumetric definitions of diarrhea severity poorly characterize ETEC disease. These data support a disease severity score accounting for stool output and other clinical signs and symptoms. Such a score could serve as the basis for better field trial outcomes and gives an additional outcome measure to help select future vaccines that warrant expanded testing in pivotal pre-licensure trials.

  5. FISH CONSUMPTION, METHYLMERCURY, AND HUMAN HEART DISEASE.

    Energy Technology Data Exchange (ETDEWEB)

    LIPFERT, F.W.; SULLIVAN, T.M.

    2005-09-21

    Environmental mercury continues to be of concern to public health advocates, both in the U.S. and abroad, and new research continues to be published. A recent analysis of potential health benefits of reduced mercury emissions has opened a new area of public health concern: adverse effects on the cardiovascular system, which could account for the bulk of the potential economic benefits. The authors were careful to include caveats about the uncertainties of such impacts, but they cited only a fraction of the applicable health effects literature. That literature includes studies of the potentially harmful ingredient (methylmercury, MeHg) in fish, as well as of a beneficial ingredient, omega-3 fatty acids or ''fish oils''. The U.S. Food and Drug Administration (FDA) recently certified that some of these fat compounds that are primarily found in fish ''may be beneficial in reducing coronary heart disease''. This paper briefly summarizes and categorizes the extensive literature on both adverse and beneficial links between fish consumption and cardiovascular health, which are typically based on studies of selected groups of individuals (cohorts). Such studies tend to comprise the ''gold standard'' of epidemiology, but cohorts tend to exhibit a great deal of variability, in part because of the limited numbers of individuals involved and in part because of interactions with other dietary and lifestyle considerations. Note that eating fish will involve exposure to both the beneficial effects of fatty acids and the potentially harmful effects of contaminants like Hg or PCBs, all of which depend on the type of fish but tend to be correlated within a population. As a group, the cohort studies show that eating fish tends to reduce mortality, especially due to heart disease, for consumption rates up to about twice weekly, above which the benefits tend to level off. A Finnish cohort study showed increased mortality risks

  6. Research priorities for Chagas disease, human African trypanosomiasis and leishmaniasis.

    Science.gov (United States)

    2012-01-01

    This report provides a review and analysis of the research landscape for three diseases - Chagas disease, human African trypanosomiasis and leishmaniasis - that disproportionately afflict poor and remote populations with limited access to health services. It represents the work of the disease reference group on Chagas Disease, Human African Trypanosomiasis and Leishmaniasis (DRG3) which was established to identify key research priorities through review of research evidence and input from stakeholders' consultations. The diseases, which are caused by related protozoan parasites, are described in terms of their epidemiology and diseases burden, clinical forms and pathogenesis, HIV coinfection, diagnosis, drugs and drug resistance, vaccines, vector control, and health-care interventions. Priority areas for research are identified based on criteria such as public health relevance, benefit and impact on poor populations and equity, and feasibility. The priorities are found in the areas of diagnostics, drugs, vector control, asymptomatic infection, economic analysis of treatment and vector control methods, and in some specific issues such as surveillance methods or transmission-blocking vaccines for particular diseases. This report will be useful to researchers, policy and decision-makers, funding bodies, implementation organizations, and civil society. This is one of ten disease and thematic reference group reports that have come out of the TDR Think Tank, all of which have contributed to the development of the Global Report for Research on Infectious Diseases of Poverty, available at: www.who.int/tdr/stewardship/global_report/en/index.html.

  7. Clinical perspective: Linking psychosocial care to the disease continuum in patients with multiple myeloma.

    Science.gov (United States)

    Zabora, James; Buzaglo, Joanne; Kennedy, Vicki; Richards, Tiffany; Schapmire, Tara; Zebrack, Brad; Ghobrial, Irene M

    2015-08-01

    A model of psychosocial care specific for patients with multiple myeloma and their caregivers has not yet been proposed. We sought to develop a model of care that considers the specific profile of this disease. The authors, representing a multidisciplinary care team, met in December of 2012 to identify a model of psychosocial care for patients with multiple myeloma and their caregivers. This model was determined by consensus during the meeting and via total agreement following the meeting. The meeting was sponsored by Onyx Pharmaceuticals. The need for targeted psychosocial care for the multiple myeloma patient and caregiver throughout the disease process is essential to ensure quality of life and optimal treatment outcomes. We propose herein the first known model of care for the treatment of multiple myeloma that engages both the patient and their caregivers. Innovative partnerships between psychosocial providers and other entities such as pharmaceutical companies can maximize resources for comprehensive program development. This manuscript proposes a model of care that promotes active engagement in therapies for multiple myeloma while engaging the individual patient and their family caregivers. This treatment approach must be evidence based in terms of distress screening tools, comprehensive psychosocial assessments, and, most importantly, in the interventions and measurements of response that clinicians apply to this population.

  8. Diagnosis and Treatment of Bone Disease in Multiple Myeloma: Spotlight on Spinal Involvement

    Directory of Open Access Journals (Sweden)

    Patrizia Tosi

    2013-01-01

    Full Text Available Bone disease is observed in almost 80% of newly diagnosed symptomatic multiple myeloma patients, and spine is the bone site that is more frequently affected by myeloma-induced osteoporosis, osteolyses, or compression fractures. In almost 20% of the cases, spinal cord compression may occur; diagnosis and treatment must be carried out rapidly in order to avoid a permanent sensitive or motor defect. Although whole body skeletal X-ray is considered mandatory for multiple myeloma staging, magnetic resonance imaging is presently considered the most appropriate diagnostic technique for the evaluation of vertebral alterations, as it allows to detect not only the exact morphology of the lesions, but also the pattern of bone marrow infiltration by the disease. Multiple treatment modalities can be used to manage multiple myeloma-related vertebral lesions. Surgery or radiotherapy is mainly employed in case of spinal cord compression, impending fractures, or intractable pain. Percutaneous vertebroplasty or balloon kyphoplasty can reduce local pain in a significant fraction of treated patients, without interfering with subsequent therapeutic programs. Systemic antimyeloma therapy with conventional chemotherapy or, more appropriately, with combinations of conventional chemotherapy and compounds acting on both neoplastic plasma cells and bone marrow microenvironment must be soon initiated in order to reduce bone resorption and, possibly, promote bone formation. Bisphosphonates should also be used in combination with antimyeloma therapy as they reduce bone resorption and prolong patients survival. A multidisciplinary approach is thus needed in order to properly manage spinal involvement in multiple myeloma.

  9. Multiple sclerosis in Japan appears to be a milder disease compared to the UK.

    Science.gov (United States)

    Piccolo, L; Kumar, G; Nakashima, I; Misu, T; Kong, Y; Wakerley, B; Ryan, S; Cavey, A; Fujihara, K; Palace, Jacqueline

    2015-01-01

    Multiple sclerosis (MS) is relatively common in the West, but rare in Japan. In the literature, there are few comparative data regarding disease severity throughout the world. The objective of this study was to compare disability in patients from a UK and a Japanese MS cohort. We retrospectively analysed the clinical features of patients with MS from a UK and Japanese MS centre. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Expanded Disability Status Scale score according to disease duration, was used as a marker of disease severity. One thousand one hundred forty-eight UK patients and 104 Japanese patient were identified representing the relative national prevalence. Demographics and disease duration did not differ between the groups. Median MSSS was significantly different between the two groups (Japan 3.34 vs. UK 5.87, p UK (12.9%) than in the Japanese cohort (3%, p = 0.044). The majority of Japanese patients (83.7% vs. UK 17%) had been exposed to disease modifying treatments (DMTs). Exposure to DMTs did not show a significant effect on disability. In conclusion, this study suggests that MS in Japan may be associated with less disability than in UK. More Japanese patients were treated with DMTs. Differences in treatments do not seem to explain the disparity in disability severity. This suggests either genetic or environmental influences on disease severity.

  10. Detection of multiple viral infections in cattle and buffalo with suspected vesicular disease in Brazil.

    Science.gov (United States)

    Laguardia-Nascimento, Mateus; Sales, Érica Bravo; Gasparini, Marcela Ribeiro; de Souza, Natália Mendes; da Silva, Josiane Aparecida Gonçalina; Souza, Giovana Gonçalves; Carani, Fernanda Rezek; Dos Santos, Alyane Figueiredo; Rivetti Júnior, Anselmo Vasconcelos; Camargos, Marcelo Fernandes; Fonseca Júnior, Antônio Augusto

    2016-07-01

    Vesicular diseases are of high importance for livestock, primarily because of foot-and-mouth disease (FMD), which is a high-morbidity disease that generates direct losses caused by low milk production, weight loss, and indirect losses because of the need for sanitary barriers. Other vesicular diseases are also of importance for livestock because of direct impacts or because their clinical signs may be confused with those of FMD. We report herein the detection of multiple infections in cattle with suspected vesicular disease in the Brazilian states of Amazonas (AM), Mato Grosso (MT), and Roraima. Thirty-seven epithelial samples from cattle and 1 sample from a buffalo were sent to the laboratory for testing for FMDV and similar disease agents. All samples from MT were positive for parapoxvirus (Pseudocowpox virus and Bovine papular stomatitis virus). In addition, 3 samples were positive for Bluetongue virus, and 5 samples were positive for Bovine herpesvirus 1 Among these samples, 1 was positive for all of these 3 agents. Only 2 samples from AM were negative for parapoxvirus. The molecular tests conducted in this study detected multiple infections, with a high prevalence of parapoxvirus.

  11. Infectious prion diseases in humans: cannibalism, iatrogenicity and zoonoses.

    Science.gov (United States)

    Haïk, Stéphane; Brandel, Jean-Philippe

    2014-08-01

    In contrast with other neurodegenerative disorders associated to protein misfolding, human prion diseases include infectious forms (also called transmitted forms) such as kuru, iatrogenic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease. The transmissible agent is thought to be solely composed of the abnormal isoform (PrP(Sc)) of the host-encoded prion protein that accumulated in the central nervous system of affected individuals. Compared to its normal counterpart, PrP(Sc) is β-sheet enriched and aggregated and its propagation is based on an autocatalytic conversion process. Increasing evidence supports the view that conformational variations of PrP(Sc) encoded the biological properties of the various prion strains that have been isolated by transmission studies in experimental models. Infectious forms of human prion diseases played a pivotal role in the emergence of the prion concept and in the characterization of the very unconventional properties of prions. They provide a unique model to understand how prion strains are selected and propagate in humans. Here, we review and discuss how genetic factors interplay with strain properties and route of transmission to influence disease susceptibility, incubation period and phenotypic expression in the light of the kuru epidemics due to ritual endocannibalism, the various series iatrogenic diseases secondary to extractive growth hormone treatment or dura mater graft and the epidemics of variant Creutzfeldt-Jakob disease linked to dietary exposure to the agent of bovine spongiform encephalopathy.

  12. Spectroscopy techniques for human disease diagnosis

    Science.gov (United States)

    Navas-Moreno, Maria

    2011-12-01

    Modern medicine would benefit from the pursuit of new, more specific and easier to implement diagnosis tools. In recent years, Raman scattering, surface-enhanced Raman scattering and fluorescence spectroscopy have proven to be successful diagnostic techniques for a wide range of diseases including atherosclerosis, kidney stones, bone diseases, diabetes, and a wide collection of neoplasms. Optical spectroscopy has several advantages over more traditional diagnostic methods (i.e., histopathology, quantitative PCR, etc.) such as faster data analysis, nonspecific sample preparation, nonspecific labels/reagents/antibodies usage requirements, and immediate on-site implementation. In the present work, label-free in vitro fluorescence and surface enhanced Raman scattering (SERS) spectroscopy have been used to differentiate between blood cells of patients affected with myeloproliferative neoplasms (MPN) and those of healthy subjects. The SERS technique has also been applied to hemoglobin variants as well as to serum obtained from patients affected with chronic heart failure who positively or negatively responded to the seasonal influenza vaccine. We found that spectral ratios of the background fluorescence intensity that accompanies the SERS spectra of granulocytes serve as excellent markers for the presence of MPNs. In addition, we also found expression dysregulation of two hypoxia induced factor regulated genes, which correlates with our results obtained by SERS spectroscopy assay in MPN patients and supports the presence of the Warburg effect in MPNs. We hypothesize that SERS measures metabolic change in granulocytes through two possible mechanisms: (i) Changes in dielectric properties of the environment surrounding the silver-cell interface; and (ii) changes in flavin adenine dinucleotide concentrations, which in turn changes the relative contribution of the autofluorescence to the emission spectrum. These hypotheses are supported by SERS measurement of 2-deoxy

  13. Current immune therapies of autoimmune disease of the nervous system with special emphasis to multiple sclerosis.

    Science.gov (United States)

    Vass, Karl

    2012-01-01

    Autoimmune diseases of the nervous system such as myasthenia gravis, inflammatory demyelinating polyneuropathies, multiple sclerosis and others are still not curable. Yet the introduction of modern immune therapies could significantly improve the prospects of many patients affected by these disorders. In addition to steroids and immunosuppression i.v. immunoglobulins are used for treatment of myasthenia gravis and chronic inflammatory demyelinating polyneuropathy. Interferons, glatiramer acetate, natalizumab and fingolimod are applied in multiple sclerosis. The ever-improving efficacy of the drugs has to be balanced against the increasing risk of possible severe adverse effects.

  14. Stem Cell Physics. Multiple-Laser-Beam Treatment of Parkinson's Disease

    Science.gov (United States)

    Stefan, V.

    2013-03-01

    A novel method for the treatment of Parkinson's disease is proposed. Pluripotent stem cells are laser cultured, using ultrashort wavelength, (around 0.1 micron-ultraviolet radiation-with intensities of a few mW/cm2) , multiple laser beams.[2] The multiple-energy laser photons[3] interact with the neuron DNA molecules to be cloned. The laser created dopaminergic substantia nigra neurons can be, (theoretically), laser transplanted, (a higher focusing precision as compared to a syringe method), into the striatum or substantia nigra regions of the brain, or both. Supported by Nikola Tesla Labs, Stefan University.

  15. Behçet's disease complicated by multiple aseptic abscesses of the liver and spleen.

    Science.gov (United States)

    Maeshima, Keisuke; Ishii, Koji; Inoue, Megumi; Himeno, Katsuro; Seike, Masataka

    2013-05-28

    Aseptic abscesses are an emergent entity and have been described in inflammatory bowel disease, especially in Crohn's disease, and in other diseases. However, aseptic abscesses associated with Behçet's disease are extremely rare. We report a Japanese male diagnosed with an incomplete type of Behçet's disease who developed multiple aseptic abscesses of the spleen and liver. In 2002, the spleen abscesses were accompanied by paroxysmal oral aphthous ulcers and erythema nodosum. As the patient's response to antibiotic treatment was inadequate, a splenectomy was performed. Severe inflammatory cell infiltration, largely of polymorphonuclear neutrophils, was observed without evidence of bacterial or fungal growth. Although the patient had no history of ocular symptoms or genital ulcers, a diagnosis of incomplete Behçet's disease was made according to the Japanese diagnostic criteria because of the presence of paroxysmal arthritis and epididymitis since 2002. In 2005, multiple liver abscesses developed with right hypochondrial pain and seemed to be attributed to Behçet's disease because the abscesses yielded negative results during a microbiologic investigation and failed to go into remission under antibiotic therapy. Oral prednisone (15 mg/d) was started in May 2006, and the abscesses dramatically disappeared 4 wk after treatment. Although the patient had a relapse of the liver abscesses in association with the tapering of prednisone, the augmentation of prednisone dosage yielded a response. The abscesses of the liver and spleen were strongly suggested to be attributed to Behçet's disease. Clinician should be aware of the existence of aseptic abscesses as uncommon manifestations of Behçet's disease.

  16. Early Stage Disease Diagnosis System Using Human Nail Image Processing

    Directory of Open Access Journals (Sweden)

    Trupti S. Indi

    2016-07-01

    Full Text Available Human’s hand nail is analyzed to identify many diseases at early stage of diagnosis. Study of person hand nail color helps in identification of particular disease in healthcare domain. The proposed system guides in such scenario to take decision in disease diagnosis. The input to the proposed system is person nail image. The system will process an image of nail and extract features of nail which is used for disease diagnosis. Human nail consist of various features, out of which proposed system uses nail color changes for disease diagnosis. Here, first training set data is prepared using Weka tool from nail images of patients of specific diseases. A feature extracted from input nail image is compared with the training data set to get result. In this experiment we found that using color feature of nail image average 65% results are correctly matched with training set data during three tests conducted.

  17. Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

    DEFF Research Database (Denmark)

    Hall, Vanessa J.

    2016-01-01

    Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer’s disease......, frontotemporal dementia and Parkinson’s disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only...... that includes studying more complex 3D cell cultures, as well as accelerating aging of the neurons, may help to yield stronger phenotypes in the cultured cells. Thus, the use and application of pluripotent stem cells for modelling disease have already shown to be a powerful approach for discovering more about...

  18. Rare human diseases: 9p deletion syndrome

    Directory of Open Access Journals (Sweden)

    Galagan V.O.

    2014-09-01

    Full Text Available Objective of the study was to review the anamnesis, pheno - and genotype in patients with rare chromosome disorders such as 9p deletion syndrome. Genetic methods of investigation (clinical and genealogical, cytogenetic, FISH- method, paraclinical and instrumental methods of examination were used. Karyotyping was performed by the G-method of differential staining of chromosomes. Only three cases of pathology were diagnosed in the Medical Genetics Center over the last 10 years. By anamnesis data nobody in the probands’ families had bad habits, was exposed to occupational hazards, took part in the elimination of the Chernobyl accident or lived in contaminated areas. Clinical signs of diseases have not been identified in probands’ parents. All probands had trigonocephaly, bilateral epicanthal folds, ocular hypertelorism, downslanting palpebral fissures, long philtrum, flat face and nasal bridge, low set ears with malformed auricles. Two patients of three ones had exophthalmos, contracture of the second and third fingers, abnormal external genitalia. In all three cases there was monosomy of chromosome 9 of critical segment p 24. Normal karyotypes were seen in all parents, so there were three cases of new mutations of 9p deletion syndrome. Retardation of physical, psycho-spech, mental development in proband with or without congenital anomalies requires medical genetic counseling in a specialized institution. Cases of reproductive loss in anamnesis require cytogenetic investigation of fetal membranes and amniotic fluid.

  19. Human Disease Diagnosis Using a Fuzzy Expert System

    CERN Document Server

    Hasan, Mir Anamul; Chowdhury, Ahsan Raja

    2010-01-01

    Human disease diagnosis is a complicated process and requires high level of expertise. Any attempt of developing a web-based expert system dealing with human disease diagnosis has to overcome various difficulties. This paper describes a project work aiming to develop a web-based fuzzy expert system for diagnosing human diseases. Now a days fuzzy systems are being used successfully in an increasing number of application areas; they use linguistic rules to describe systems. This research project focuses on the research and development of a web-based clinical tool designed to improve the quality of the exchange of health information between health care professionals and patients. Practitioners can also use this web-based tool to corroborate diagnosis. The proposed system is experimented on various scenarios in order to evaluate it's performance. In all the cases, proposed system exhibits satisfactory results.

  20. Human Disease Insight: An integrated knowledge-based platform for disease-gene-drug information.

    Science.gov (United States)

    Tasleem, Munazzah; Ishrat, Romana; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-01-01

    The scope of the Human Disease Insight (HDI) database is not limited to researchers or physicians as it also provides basic information to non-professionals and creates disease awareness, thereby reducing the chances of patient suffering due to ignorance. HDI is a knowledge-based resource providing information on human diseases to both scientists and the general public. Here, our mission is to provide a comprehensive human disease database containing most of the available useful information, with extensive cross-referencing. HDI is a knowledge management system that acts as a central hub to access information about human diseases and associated drugs and genes. In addition, HDI contains well-classified bioinformatics tools with helpful descriptions. These integrated bioinformatics tools enable researchers to annotate disease-specific genes and perform protein analysis, search for biomarkers and identify potential vaccine candidates. Eventually, these tools will facilitate the analysis of disease-associated data. The HDI provides two types of search capabilities and includes provisions for downloading, uploading and searching disease/gene/drug-related information. The logistical design of the HDI allows for regular updating. The database is designed to work best with Mozilla Firefox and Google Chrome and is freely accessible at http://humandiseaseinsight.com.

  1. High throughput multiple locus variable number of tandem repeat analysis (MLVA) of Staphylococcus aureus from human, animal and food sources.

    Science.gov (United States)

    Sobral, Daniel; Schwarz, Stefan; Bergonier, Dominique; Brisabois, Anne; Feßler, Andrea T; Gilbert, Florence B; Kadlec, Kristina; Lebeau, Benoit; Loisy-Hamon, Fabienne; Treilles, Michaël; Pourcel, Christine; Vergnaud, Gilles

    2012-01-01

    Staphylococcus aureus is a major human pathogen, a relevant pathogen in veterinary medicine, and a major cause of food poisoning. Epidemiological investigation tools are needed to establish surveillance of S. aureus strains in humans, animals and food. In this study, we investigated 145 S. aureus isolates recovered from various animal species, disease conditions, food products and food poisoning events. Multiple Locus Variable Number of Tandem Repeat (VNTR) analysis (MLVA), known to be highly efficient for the genotyping of human S. aureus isolates, was used and shown to be equally well suited for the typing of animal S. aureus isolates. MLVA was improved by using sixteen VNTR loci amplified in two multiplex PCRs and analyzed by capillary electrophoresis ensuring a high throughput and high discriminatory power. The isolates were assigned to twelve known clonal complexes (CCs) and--a few singletons. Half of the test collection belonged to four CCs (CC9, CC97, CC133, CC398) previously described as mostly associated with animals. The remaining eight CCs (CC1, CC5, CC8, CC15, CC25, CC30, CC45, CC51), representing 46% of the animal isolates, are common in humans. Interestingly, isolates responsible for food poisoning show a CC distribution signature typical of human isolates and strikingly different from animal isolates, suggesting a predominantly human origin.

  2. High throughput multiple locus variable number of tandem repeat analysis (MLVA of Staphylococcus aureus from human, animal and food sources.

    Directory of Open Access Journals (Sweden)

    Daniel Sobral

    Full Text Available Staphylococcus aureus is a major human pathogen, a relevant pathogen in veterinary medicine, and a major cause of food poisoning. Epidemiological investigation tools are needed to establish surveillance of S. aureus strains in humans, animals and food. In this study, we investigated 145 S. aureus isolates recovered from various animal species, disease conditions, food products and food poisoning events. Multiple Locus Variable Number of Tandem Repeat (VNTR analysis (MLVA, known to be highly efficient for the genotyping of human S. aureus isolates, was used and shown to be equally well suited for the typing of animal S. aureus isolates. MLVA was improved by using sixteen VNTR loci amplified in two multiplex PCRs and analyzed by capillary electrophoresis ensuring a high throughput and high discriminatory power. The isolates were assigned to twelve known clonal complexes (CCs and--a few singletons. Half of the test collection belonged to four CCs (CC9, CC97, CC133, CC398 previously described as mostly associated with animals. The remaining eight CCs (CC1, CC5, CC8, CC15, CC25, CC30, CC45, CC51, representing 46% of the animal isolates, are common in humans. Interestingly, isolates responsible for food poisoning show a CC distribution signature typical of human isolates and strikingly different from animal isolates, suggesting a predominantly human origin.

  3. Exploring human disease using the Rat Genome Database

    Directory of Open Access Journals (Sweden)

    Mary Shimoyama

    2016-10-01

    Full Text Available Rattus norvegicus, the laboratory rat, has been a crucial model for studies of the environmental and genetic factors associated with human diseases for over 150 years. It is the primary model organism for toxicology and pharmacology studies, and has features that make it the model of choice in many complex-disease studies. Since 1999, the Rat Genome Database (RGD; http://rgd.mcw.edu has been the premier resource for genomic, genetic, phenotype and strain data for the laboratory rat. The primary role of RGD is to curate rat data and validate orthologous relationships with human and mouse genes, and make these data available for incorporation into other major databases such as NCBI, Ensembl and UniProt. RGD also provides official nomenclature for rat genes, quantitative trait loci, strains and genetic markers, as well as unique identifiers. The RGD team adds enormous value to these basic data elements through functional and disease annotations, the analysis and visual presentation of pathways, and the integration of phenotype measurement data for strains used as disease models. Because much of the rat research community focuses on understanding human diseases, RGD provides a number of datasets and software tools that allow users to easily explore and make disease-related connections among these datasets. RGD also provides comprehensive human and mouse data for comparative purposes, illustrating the value of the rat in translational research. This article introduces RGD and its suite of tools and datasets to researchers – within and beyond the rat community – who are particularly interested in leveraging rat-based insights to understand human diseases.

  4. Exploring human disease using the Rat Genome Database

    Science.gov (United States)

    Laulederkind, Stanley J. F.; De Pons, Jeff; Nigam, Rajni; Smith, Jennifer R.; Tutaj, Marek; Petri, Victoria; Hayman, G. Thomas; Wang, Shur-Jen; Ghiasvand, Omid; Thota, Jyothi; Dwinell, Melinda R.

    2016-01-01

    ABSTRACT Rattus norvegicus, the laboratory rat, has been a crucial model for studies of the environmental and genetic factors associated with human diseases for over 150 years. It is the primary model organism for toxicology and pharmacology studies, and has features that make it the model of choice in many complex-disease studies. Since 1999, the Rat Genome Database (RGD; http://rgd.mcw.edu) has been the premier resource for genomic, genetic, phenotype and strain data for the laboratory rat. The primary role of RGD is to curate rat data and validate orthologous relationships with human and mouse genes, and make these data available for incorporation into other major databases such as NCBI, Ensembl and UniProt. RGD also provides official nomenclature for rat genes, quantitative trait loci, strains and genetic markers, as well as unique identifiers. The RGD team adds enormous value to these basic data elements through functional and disease annotations, the analysis and visual presentation of pathways, and the integration of phenotype measurement data for strains used as disease models. Because much of the rat research community focuses on understanding human diseases, RGD provides a number of datasets and software tools that allow users to easily explore and make disease-related connections among these datasets. RGD also provides comprehensive human and mouse data for comparative purposes, illustrating the value of the rat in translational research. This article introduces RGD and its suite of tools and datasets to researchers – within and beyond the rat community – who are particularly interested in leveraging rat-based insights to understand human diseases. PMID:27736745

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

    Directory of Open Access Journals (Sweden)

    Ali Dehghani

    2017-01-01

    Full Text Available Background: 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. Methods: 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. Results: 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. Conclusions: 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.

  6. 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.

  7. Linking disease associations with regulatory information in the human genome

    KAUST Repository

    Schaub, M. A.

    2012-09-01

    Genome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify "functional SNPs" that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.

  8. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.

    Science.gov (United States)

    Langer-Gould, Annette; Qian, Lei; Tartof, Sara Y; Brara, Sonu M; Jacobsen, Steve J; Beaber, Brandon E; Sy, Lina S; Chao, Chun; Hechter, Rulin; Tseng, Hung Fu

    2014-12-01

    Because vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health. To determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS. A nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code. Vaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system. All forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset. We identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy.

  9. Linking Microbiota to Human Diseases: A Systems Biology Perspective.

    Science.gov (United States)

    Wu, Hao; Tremaroli, Valentina; Bäckhed, Fredrik

    2015-12-01

    The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction.

  10. Hydrogen sulfide slows down progression of experimental Alzheimer's disease by targeting multiple pathophysiological mechanisms.

    Science.gov (United States)

    Giuliani, Daniela; Ottani, Alessandra; Zaffe, Davide; Galantucci, Maria; Strinati, Flavio; Lodi, Renzo; Guarini, Salvatore

    2013-09-01

    It has been previously reported that brain hydrogen sulfide (H2S) synthesis is severely decreased in Alzheimer's disease (AD) patients, and plasma H2S levels are negatively correlated with the severity of AD. Here we extensively investigated whether treatment with a H2S donor and spa-waters rich in H2S induces neuroprotection and slows down progression of AD. Studies with sodium hydrosulfide (a H2S donor) and Tabiano's spa-water were carried out in three experimental models of AD. Short-term and long-term treatments with sodium hydrosulfide and/or Tabiano's spa-water significantly protected against impairment in learning and memory in rat models of AD induced by brain injection of β-amyloid1-40 (Aβ) or streptozotocin, and in an AD mouse model harboring human transgenes APPSwe, PS1M146V and tauP301L (3xTg-AD mice). The improvement in behavioral performance was associated with hippocampus was size of Aβ plaques and preservation of the morphological picture, as found in AD rats. Further, lowered concentration/phosphorylation levels of proteins thought to be the central events in AD pathophysiology, namely amyloid precursor protein, presenilin-1, Aβ1-42 and tau phosphorylated at Thr181, Ser396 and Ser202, were detected in 3xTg-AD mice treated with spa-water. The excitotoxicity-triggered oxidative and nitrosative stress was counteracted in 3xTg-AD mice, as indicated by the decreased levels of malondialdehyde and nitrites in the cerebral cortex. Hippocampus reduced activity of c-jun N-terminal kinases, extracellular signal-regulated kinases and p38, which have an established role not only in phosphorylation of tau protein but also in inflammation and apoptosis, was also found. Consistently, decrease in tumor necrosis factor-α level, up-regulation of Bcl-2, and down-regulation of BAX and the downstream executioner caspase-3, also occurred in the hippocampus of 3xTg-AD mice after treatment with Tabiano's spa-water, thus suggesting that it is also able to modulate

  11. Multiple Sclerosis and autoimmune diseases: clinical cases and review of the literature

    Directory of Open Access Journals (Sweden)

    A. Protti

    2011-09-01

    Full Text Available Multiple sclerosis (MS, the most frequent demyelinating disease in adults, is thought to be an autoimmune disease. Symptoms and signs observed in MS reflect lesions present mainly in the white matter of the central nervous system (CNS. The diagnosis remains difficult, at least concerning presenting symptoms, because of their low specificity. Diagnosis criteria are usually based on dissemination of signs in time and space, evoked potentials, findings of magnetic resonance imaging, results of cerebrospinal fluid examination, and the exclusion of other diagnosis possibly explaining the clinical signs. However, no clinical and paraclinical investigation can distinguish with certainity MS from other conditions such as autoimmune or inflammatory diseases predominantly affecting the central nervous system. These other disorders include systemic lupus erythematosus, antiphospholipid syndrome, Behcet disease, Sjogren syndrome, sarcoidosis and vasculitides. We present four clinical cases showing the difficulty in reaching a proper diagnosis...

  12. DNA Aptamers in the Diagnosis and Treatment of Human Diseases

    Directory of Open Access Journals (Sweden)

    Qinchang Zhu

    2015-11-01

    Full Text Available Aptamers have a promising role in the field of life science and have been extensively researched for application as analytical tools, therapeutic agents and as vehicles for targeted drug delivery. Compared with RNA aptamers, DNA aptamers have inherent advantages in stability and facility of generation and synthesis. To better understand the specific potential of DNA aptamers, an overview of the progress in the generation and application of DNA aptamers in human disease diagnosis and therapy are presented in this review. Special attention is given to researches that are relatively close to practical application. DNA aptamers are expected to have great potential in the diagnosis and treatment of human diseases.

  13. Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

    Institute of Scientific and Technical Information of China (English)

    Konstantinos Dean BOUDOULAS; Peter J MOHLER

    2011-01-01

    Over the past fifteen years, our understanding of the molecular mechanisms underlying human disease has flourished in large part due to the discovery of gene mutations linked with membrane ion channels and transporters. In fact, ion channel defects ("channelopathies" - the focus of this review series) have been associated with a spectrum of serious human disease phenotypes including cystic fibrosis, cardiac arrhythmia, diabetes, skeletal muscle defects, and neurological disorders. However, we now know that human disease, particularly excitable cell disease, may be caused by defects in non-ion channel polypeptides including in cellular components residing well beneath the plasma membrane. For example, over the past few years, a new class of potentially fatal cardiac arrhythmias has been linked with cytoplasmic proteins that include sub-membrane adapters such as ankyrin-B (ANK2),ankyrin-G (ANK3), and alpha-1 syntrophin, membrane coat proteins including caveolin-3 (CAV3), signaling platforms including yotiao (AKAPg), and cardiac enzymes (GPD1L). The focus of this review is to detail the exciting role of lamins, yet another class of gene products that have provided elegant new insight into human disease.

  14. Role of Epigenetics in Biology and Human Diseases

    OpenAIRE

    Moosavi, Azam; Ardekani, Ali Motevalizadeh

    2016-01-01

    For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification o...

  15. Linking adult hippocampal neurogenesis with human physiology and disease.

    Science.gov (United States)

    Bowers, Megan; Jessberger, Sebastian

    2016-07-01

    We here review the existing evidence linking adult hippocampal neurogenesis and human brain function in physiology and disease. Furthermore, we aim to point out where evidence is missing, highlight current promising avenues of investigation, and suggest future tools and approaches to foster the link between life-long neurogenesis and human brain function. Developmental Dynamics 245:702-709, 2016. © 2016 Wiley Periodicals, Inc.

  16. Therapy of Human Papillomavirus-Related Disease

    Science.gov (United States)

    Stern, Peter L.; van der Burg, Sjoerd H.; Hampson, Ian N.; Broker, Thomas; Fiander, Alison; Lacey, Charles J.; Kitchener, Henry C.; Einstein, Mark H.

    2014-01-01

    This chapter reviews the current treatment of chronic and neoplastic HPV-associated conditions and the development of novel therapeutic approaches. Surgical excision of HPV-associated lower genital tract neoplasia is very successful but largely depends on secondary prevention programmes for identification of disease. Only high-risk HPV-driven chronic, preneoplastic lesions and some very early cancers cannot be successfully treated by surgical procedures alone. Chemoradiation therapy of cervical cancer contributes to the 66–79% cervical cancer survival at 5 years. Outlook for those patients with persistent or recurrent cervical cancer following treatment is very poor. Topical agents such as imiquimod (immune response modifier), cidofovir (inhibition of viral replication; induction apoptosis) or photodynamic therapy (direct damage of tumour and augmentation of anti-tumour immunity) have all shown some useful efficacy (~50–60%) in treatment of high grade vulvar intraepithelial neoplasia. Provider administered treatments of genital warts include cryotherapy, trichloracetic acid, or surgical removal which has the highest primary clearance rate. Patient applied therapies include podophyllotoxin and imiquimod. Recurrence after “successful” treatment is 30–40%. Further improvements could derive from a rational combination of current therapy with new drugs targeting molecular pathways mediated by HPV in cancer. Small molecule inhibitors targeting the DNA binding activities of HPV E1/E2 or the anti-apoptotic consequences of E6/E7 oncogenes are in preclinical development. Proteasome and histone deacetylase inhibitors, which can enhance apoptosis in HPV positive tumour cells, are being tested in early clinical trials. Chronic high-risk HPV infection/neoplasia is characterised by systemic and/or local immune suppressive regulatory or escape factors. Recently two E6/E7 vaccines have shown some clinical efficacy in high grade VIN patients and this correlated with strong

  17. Genome editing of human pluripotent stem cells to generate human cellular disease models

    Directory of Open Access Journals (Sweden)

    Kiran Musunuru

    2013-07-01

    Full Text Available Disease modeling with human pluripotent stem cells has come into the public spotlight with the awarding of the Nobel Prize in Physiology or Medicine for 2012 to Drs John Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent. This discovery has opened the door for the generation of pluripotent stem cells from individuals with disease and the differentiation of these cells into somatic cell types for the study of disease pathophysiology. The emergence of genome-editing technology over the past few years has made it feasible to generate and investigate human cellular disease models with even greater speed and efficiency. Here, recent technological advances in genome editing, and its utility in human biology and disease studies, are reviewed.

  18. Genome editing of human pluripotent stem cells to generate human cellular disease models.

    Science.gov (United States)

    Musunuru, Kiran

    2013-07-01

    Disease modeling with human pluripotent stem cells has come into the public spotlight with the awarding of the Nobel Prize in Physiology or Medicine for 2012 to Drs John Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent. This discovery has opened the door for the generation of pluripotent stem cells from individuals with disease and the differentiation of these cells into somatic cell types for the study of disease pathophysiology. The emergence of genome-editing technology over the past few years has made it feasible to generate and investigate human cellular disease models with even greater speed and efficiency. Here, recent technological advances in genome editing, and its utility in human biology and disease studies, are reviewed.

  19. Automated whole-genome multiple alignment of rat, mouse, and human

    Energy Technology Data Exchange (ETDEWEB)

    Brudno, Michael; Poliakov, Alexander; Salamov, Asaf; Cooper, Gregory M.; Sidow, Arend; Rubin, Edward M.; Solovyev, Victor; Batzoglou, Serafim; Dubchak, Inna

    2004-07-04

    We have built a whole genome multiple alignment of the three currently available mammalian genomes using a fully automated pipeline which combines the local/global approach of the Berkeley Genome Pipeline and the LAGAN program. The strategy is based on progressive alignment, and consists of two main steps: (1) alignment of the mouse and rat genomes; and (2) alignment of human to either the mouse-rat alignments from step 1, or the remaining unaligned mouse and rat sequences. The resulting alignments demonstrate high sensitivity, with 87% of all human gene-coding areas aligned in both mouse and rat. The specificity is also high: <7% of the rat contigs are aligned to multiple places in human and 97% of all alignments with human sequence > 100kb agree with a three-way synteny map built independently using predicted exons in the three genomes. At the nucleotide level <1% of the rat nucleotides are mapped to multiple places in the human sequence in the alignment; and 96.5% of human nucleotides within all alignments agree with the synteny map. The alignments are publicly available online, with visualization through the novel Multi-VISTA browser that we also present.

  20. The Exposome Research Paradigm: an Opportunity to Understand the Environmental Basis for Human Health and Disease.

    Science.gov (United States)

    Buck Louis, Germaine M; Smarr, Melissa M; Patel, Chirag J

    2017-03-01

    This paper presents an overview of the exposome research paradigm with particular application to understanding human reproduction and development and its implications for health across a lifespan. The exposome research paradigm has generated considerable discussion about its feasibility and utility for delineating the impact of environmental exposures on human health. Early initiatives are underway, including smaller proof-of-principle studies and larger concerted efforts. Despite the notable challenges underlying the exposome paradigm, analytic techniques are being developed to handle its untargeted approach and correlated and multi-level or hierarchical data structures such initiatives generate, while considering multiple comparisons. The relatively short intervals for critical and sensitive windows of human reproduction and development seem well suited for exposome research and may revolutionize our understanding of later onset diseases. Early initiatives suggest that the exposome paradigm is feasible, but its utility remains to be established with applications to population human health research.

  1. Endotherapia: a new frontier in the treatment of multiple sclerosis and other chronic diseases.

    Science.gov (United States)

    Geffard, Michel; de Bisschop, Laetitia; Duleu, Sébastien; Hassaine, Nadine; Mangas, Arturo; Coveñas, Rafael

    2010-11-01

    Currently, several drugs are accessible for the treatment of many chronic diseases (multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, etc.), but most of them have a large list of side effects. Here, we propose a new therapeutic approach called Endotherapia for the treatment of chronic diseases. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. The therapy proposed here is a "tailor-made" combination of small molecules (e.g., fatty acids and vitamins) linked to a non-immunogenic chain of poly-L.Lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. Endotherapia also involves clinical aspects, allowing an exact diagnosis of the disease and the identification of specific circulating antibodies in the serum of patients in several clinical trials (e.g., multiple sclerosis). Endotherapia has been shown to be very safe. In summary, Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. In light of the results obtained, it seems that Endotherapia is a promising therapy for chronic diseases, with no side effects, which is evidently mandatory in the management of long-term pathologies.

  2. Multiple intracranial aneurysms and moyamoya disease associated with microcephalic osteodysplastic primordial dwarfism type II: surgical considerations.

    Science.gov (United States)

    Waldron, James S; Hetts, Steven W; Armstrong-Wells, Jennifer; Dowd, Christopher F; Fullerton, Heather J; Gupta, Nalin; Lawton, Michael T

    2009-11-01

    Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare genetic syndrome characterized by extremely small stature and microcephaly, and is associated in 25% of patients with intracranial aneurysms and moyamoya disease. Although aneurysmal subarachnoid hemorrhage and stroke are leading causes of morbidity and death in these patients, MOPD II is rarely examined in the neurosurgical literature. The authors report their experience with 3 patients who presented with MOPD II, which includes a patient with 8 aneurysms (the most aneurysms reported in the literature), and the first report of a patient with both moyamoya disease and multiple aneurysms. The poor natural history of these lesions indicates aggressive microsurgical and/or endovascular therapy. Microsurgery, whether for aneurysm clip placement or extracranial-intracranial bypass, is challenging due to tight surgical corridors and diminutive arteries in these patients, but is technically feasible and strongly indicated when multiple aneurysms must be treated or cerebral revascularization is needed.

  3. Human prion diseases: surgical lessons learned from iatrogenic prion transmission.

    Science.gov (United States)

    Bonda, David J; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L; Schonberger, Lawrence B; Cali, Ignazio

    2016-07-01

    The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission

  4. Fatal multiple deer tick-borne infections in an elderly patient with advanced liver disease

    Science.gov (United States)

    Chabria, Shiven; Ogbuagu, Onyema

    2015-01-01

    SUMMARY We present a case of a 66-year-old woman with decompensated alcoholic liver cirrhosis and poorly controlled non-insulin-dependent diabetes mellitus who was admitted with a 1 day history of altered mental status, high-grade fevers, worsening jaundice and generalised malaise with subsequent development of hypotension requiring intensive care. She was diagnosed with severe babesiosis with high-grade parasitaemia. She was also found to have Lyme disease coinfection. Despite aggressive therapeutic measures including appropriate antibiotics and multiple exchange blood transfusions, she developed septic shock and fulminant multiple organ failure with eventual demise. In this article, we highlight multiple tick-borne illnesses in a vulnerable host, in this case an elderly patient with liver cirrhosis, as risk factors for severe morbidity and potentially fatal outcomes. PMID:25733088

  5. Individual and social determinants of multiple chronic disease behavioral risk factors among youth

    Directory of Open Access Journals (Sweden)

    Alamian Arsham

    2012-03-01

    Full Text Available Abstract Background Behavioral risk factors are known to co-occur among youth, and to increase risks of chronic diseases morbidity and mortality later in life. However, little is known about determinants of multiple chronic disease behavioral risk factors, particularly among youth. Previous studies have been cross-sectional and carried out without a sound theoretical framework. Methods Using longitudinal data (n = 1135 from Cycle 4 (2000-2001, Cycle 5 (2002-2003 and Cycle 6 (2004-2005 of the National Longitudinal Survey of Children and Youth, a nationally representative sample of Canadian children who are followed biennially, the present study examines the influence of a set of conceptually-related individual/social distal variables (variables situated at an intermediate distance from behaviors, and individual/social ultimate variables (variables situated at an utmost distance from behaviors on the rate of occurrence of multiple behavioral risk factors (physical inactivity, sedentary behavior, tobacco smoking, alcohol drinking, and high body mass index in a sample of children aged 10-11 years at baseline. Multiple behavioral risk factors were assessed using a multiple risk factor score. All statistical analyses were performed using SAS, version 9.1, and SUDAAN, version 9.01. Results Multivariate longitudinal Poisson models showed that social distal variables including parental/peer smoking and peer drinking (Log-likelihood ratio (LLR = 187.86, degrees of freedom (DF = 8, p p p p = .05 contributed minimally to the rate of co-occurrence of behavioral risk factors. Conclusions The results suggest targeting individual/social distal variables in prevention programs of multiple chronic disease behavioral risk factors among youth.

  6. Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease.

    Science.gov (United States)

    Tallantyre, E C; Bø, L; Al-Rawashdeh, O; Owens, T; Polman, C H; Lowe, J; Evangelou, N

    2009-05-01

    The pathological substrate of progressive disability in multiple sclerosis is hypothesized to be axonal loss. Differences in the demographic, pathological and radiological features of patients with primary progressive compared with secondary progressive multiple sclerosis raise the question as to whether they actually represent separate clinical entities. So far, large pathological studies comparing axonal damage between primary progressive and secondary progressive multiple sclerosis have not been reported. In this clinico-pathological study we examined the cervical spinal cord in patients with primary and secondary progressive multiple sclerosis. Human cervical spinal cord was derived at autopsy from 54 patients (17 primary progressive, 30 secondary progressive and 7 controls). Tissue was stained immunohistochemically and examined to determine: (i) the number of surviving corticospinal tract axons; (ii) the extent of grey and white matter demyelination; (iii) the degree of inflammation inside and outside of lesions; and (iv) the relationship between demyelination and axonal loss. Associated clinical data was used to calculate expanded disability status scale for each patient preceding death. Motor disability in the primary progressive and secondary progressive groups was similar preceding death. Secondary progressive multiple sclerosis patients showed considerably more extensive demyelination of both the white and grey matter of the cervical spinal cord. The total number of corticospinal axons was equally low in primary progressive and secondary progressive multiple sclerosis groups versus controls. The reduction of axonal density in demyelinated regions compared to normal appearing white matter was significantly more extensive in primary progressive versus secondary progressive patients (33% reduction versus 16% reduction, P progressive multiple sclerosis with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in primary

  7. Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease.

    Directory of Open Access Journals (Sweden)

    James E Peters

    2016-03-01

    Full Text Available Genome-wide association studies (GWAS have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs is crucial to addressing this. eQTLs vary between tissues and following in vitro cellular activation, but have not been examined in the context of human inflammatory diseases. We performed eQTL mapping in five primary immune cell types from patients with active inflammatory bowel disease (n = 91, anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 46 and healthy controls (n = 43, revealing eQTLs present only in the context of active inflammatory disease. Moreover, we show that following treatment a proportion of these eQTLs disappear. Through joint analysis of expression data from multiple cell types, we reveal that previous estimates of eQTL immune cell-type specificity are likely to have been exaggerated. Finally, by analysing gene expression data from multiple cell types, we find eQTLs not previously identified by database mining at 34 inflammatory bowel disease-associated loci. In summary, this parallel eQTL analysis in multiple leucocyte subsets from patients with active disease provides new insights into the genetic basis of immune-mediated diseases.

  8. A study of patients with aggressive multiple sclerosis at disease onset

    Directory of Open Access Journals (Sweden)

    Kaunzner UW

    2016-08-01

    Full Text Available Ulrike W Kaunzner,1 Gaurav Kumar,2 Gulce Askin,3 Susan A Gauthier,1 Nancy N Nealon,1 Timothy Vartanian,1 Jai S Perumal1 1Judit Jaffe Multiple Sclerosis Center, Weill-Cornell Medical College, New York City, NY, 2Department of Cell Biology and Neuroscience, Rutgers University, New Brunswick, NJ, 3Institute for Biostatistics and Epidemiology, Weill-Cornell Medical College, New York City, NY, USA Objective: Identify aggressive onset multiple sclerosis (AOMS and describe its clinical course.Methods: AOMS patients were identified from a multiple sclerosis (MS database based on a set of criteria. The subsequent clinical course of AOMS patients was then reviewed with the goal of potentially identifying the best approaches to manage these patients.Results: Fifty-eight of 783 (7.4% patients in the MS database met the criteria for AOMS, and 43 patients who had complete data for the duration of their follow-up were included in the subsequent analysis. The mean duration of the follow-up was 54 months. Thirty-five patients (81% were started on a conventional first-line agent (injectable therapies for MS. Only two of these 35 patients (5.7% had no evidence of disease activity. Twenty-two of 35 patients suffering from refractory disease were switched to a more aggressive treatment (natalizumab, rituximab, alemtuzumab, cyclophosphamide. Eight patients were started on aggressive treatment as their initial therapy, and seven of these eight (87.5% patients showed no evidence of disease activity.Conclusion: With recognition of the crucial significance of early optimal treatment during the potential window of opportunity for best long-term outcomes, we describe AOMS within 1 year of disease onset and discuss possible treatment considerations for these patients. Keywords: aggressive multiple sclerosis, algorithm, treatment course, database, retrospective analysis

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

    OpenAIRE

    Spessotto,Caroline Vieira; Cavalli,Hanaie; Eboni,Audred Cristina Biondo; Machado,Rafael Berlezi; Mousquer,Analara Munardi; Palazzo,Lara Both; Finkelsztejn, Alessandro; Goncalves, Marcus Vinicius Magno; Sato,Henry Koiti; Siquineli,Fabio; Fragoso,Yara Dadalti

    2016-01-01

    ABSTRACT Objective The treatment of multiple sclerosis (MS) with disease-modifying-drugs (DMDs) is evolving and new drugs are reaching the market. Efficacy and safety aspects of the drugs are crucial, but the patients’ satisfaction with the treatment must be taken into consideration. Methods Individual interview with patients with MS regarding their satisfaction and points of view on the treatment with DMDs. Results One hundred and twenty eight patients attending specialized MS Un...

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

    OpenAIRE

    Caroline Vieira Spessotto; Hanaie Cavalli; Audred Cristina Biondo Eboni; Rafael Berlezi Machado; Analara Munardi Mousquer; Lara Both Palazzo; Alessandro Finkelsztejn; Marcus Vinicius Magno Goncalves; Henry Koiti Sato; Fabio Siquineli; Yara Dadalti Fragoso

    2016-01-01

    ABSTRACT Objective The treatment of multiple sclerosis (MS) with disease-modifying-drugs (DMDs) is evolving and new drugs are reaching the market. Efficacy and safety aspects of the drugs are crucial, but the patients’ satisfaction with the treatment must be taken into consideration. Methods Individual interview with patients with MS regarding their satisfaction and points of view on the treatment with DMDs. Results One hundred and twenty eight patients attending specialized MS Units in...

  11. Scoring System for Multiple Organ Dysfunction in Adult Horses with Acute Surgical Gastrointestinal Disease

    OpenAIRE

    McConachie, E.; Giguère, S; Barton, M.H.

    2016-01-01

    Background The prevalence of multiple organ dysfunction syndrome (MODS) in horses with acute surgical gastrointestinal (GI) disease is unknown. Currently, there are no validated criteria to confirm MODS in adult horses. Objectives To develop criteria for a MODS score for horses with acute surgical colic (MODS SGI) and evaluate the association with 6‐month survival. To compare the MODS SGI score with a MODS score extrapolated from criteria used in people (MODS EQ). Animals Adult horses that re...

  12. Successful imiquimod treatment of multiple basal cell carcinomas after radiation therapy for Hodgkin's disease.

    Science.gov (United States)

    Beyeler, Mirjam; Urosevic, Mirjana; Pestalozzi, Bernhard; Dummer, Reinhard

    2005-01-01

    We present a case of a 55-year-old male patient who developed five basal cell carcinomas 23 years after radiation therapy of Hodgkin's disease. In 1980 he received radiation therapy twice. Due to relapses, he was treated with aggressive polychemotherapy and underwent autologous stem cell transplantation, which then led to complete remission. Until now he is in complete remission. However, multiple superficial basal cell carcinomas have developed on irradiation fields that have been successfully treated by imiquimod.

  13. Oral lesions associated with human immunodeficiency virus disease.

    Science.gov (United States)

    Patton, Lauren L

    2013-10-01

    Human immunodeficiency virus (HIV)-associated oral disease among people living with HIV infection includes oral candidiasis, oral hairy leukoplakia, Kaposi sarcoma, oral warts, herpes simplex virus ulcers, major aphthous ulcers or ulcers not otherwise specified, HIV salivary gland disease, and atypical gingival and periodontal diseases. Diagnosis of some oral lesions is based on clinical appearance and behavior, whereas others require biopsy, culture, or imaging for definitive diagnosis. Management strategies including pharmacologic and nonpharmacologic approaches are discussed in this article. Dentists also need to be cognizant of the potential oral side effects of HIV antiretroviral medications.

  14. Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

    Science.gov (United States)

    Liu, Ying; Deng, Wenbin

    2016-05-01

    With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control

  15. Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells

    Institute of Scientific and Technical Information of China (English)

    Xiao-hong XU; Zhong ZHONG

    2013-01-01

    With the general decline of pharmaceutical research productivity,there are concerns that many components of the drug discovery process need to be redesigned and optimized.For example,the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases,leading to biases in assays,targets,or compounds that do not effectively address disease mechanisms.Recent advances in stem cell research,especially in the development of induced pluripotent stem cell (iPSC) technology,provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells.In this article,we will review the progress made to date on cellular disease models using human stem cells,with a focus on patient-specific iPSCs for neurological diseases.We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases,diseases with various known genetic components,and complex diseases caused by a combination of genetic,environmental and other factors.

  16. Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells.

    Science.gov (United States)

    Xu, Xiao-hong; Zhong, Zhong

    2013-06-01

    With the general decline of pharmaceutical research productivity, there are concerns that many components of the drug discovery process need to be redesigned and optimized. For example, the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases, leading to biases in assays, targets, or compounds that do not effectively address disease mechanisms. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells. In this article, we will review the progress made to date on cellular disease models using human stem cells, with a focus on patient-specific iPSCs for neurological diseases. We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases, diseases with various known genetic components, and complex diseases caused by a combination of genetic, environmental and other factors.

  17. Human gene therapy and imaging in neurological diseases

    Energy Technology Data Exchange (ETDEWEB)

    Jacobs, Andreas H.; Winkler, Alexandra [Max Planck-Institute for Neurological Research, Center of Molecular Medicine (CMMC) and Department of Neurology, Cologne (Germany); MPI for Neurological Research, Laboratory for Gene Therapy and Molecular Imaging, Cologne (Germany); Castro, Maria G.; Lowenstein, Pedro [University of California Los Angeles (United States). Department of Medicine

    2005-12-01

    Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and ''phenotyping'' of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy's experimental knowledge into clinical applications and the way in which this process is being

  18. Modeling Human Graft-Versus-Host Disease in Immunocompromised Mice.

    Science.gov (United States)

    Norelli, Margherita; Camisa, Barbara; Bondanza, Attilio

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) from an allogeneic donor is an effective form of cancer immunotherapy, especially for acute leukemias. HSCT is however frequently complicated by the occurrence of graft-versus-host disease (GVHD). Immunocompromised mice infused with human T cells often develop a clinical syndrome resembling human GVHD (xenogeneic or X-GVHD). Herein, we describe a method for inducing X-GVHD in a highly reproducible manner. Given the human nature of immune effectors, this xenogeneic model can be routinely adopted for screening the efficacy of new treatments for GVHD.

  19. Geographic associations between lactase phenotype, multiple sclerosis, and inflammatory bowel diseases; Does obesity trump geography?

    Science.gov (United States)

    Szilagyi, Andew; Xue, Xiaoqing

    2016-11-01

    Geographic patterns with diminishing rates from north to south toward the equator have been described for a number of diseases, putatively related largely to "western" lifestyle. Among these the inflammatory bowel diseases; Crohn's (CD) and Ulcerative colitis (UC) have been prominent in sharing distributions with a number of autoimmune diseases. One of the interesting associations is the epidemiologic similarity with multiple sclerosis (MS). However, in addition, at least some of these diseases also correlated inversely with lactase non persistent population (LNP) distributions. It is hypothesized that MS should also have an inverse relationship with LNP. We provide support for this by comparing published MS, CD, UC and LNP national rates to the beginning of the new millennium. Possible links among these diseases may be an evolutionary signature of new genes which may have accompanied emergence of lactase persistence millennia ago. The emergent phenotypic dichotomy also forced different assimilation responses to lactose digestion. While intestinal retention of lactase results in direct host enzymatic digestion, in LNP persons intestinal bacterial metabolism of lactose impacts on the host micro-flora. These microbial changes may play some role in altering rates of diseases including IBD and MS. However, since the late 20th century previously observed patterns are changing. Although industrialization is considered to play an important modifying role, the rising rates of obesity with an emphasis on diet, and microfloral pathogenesis, but with an independent geographic pattern may also facilitate altering rates and geographic distributions of both of these and other diseases.

  20. Mapping gene associations in human mitochondria using clinical disease phenotypes.

    Directory of Open Access Journals (Sweden)

    Curt Scharfe

    2009-04-01

    Full Text Available Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects

  1. New glimpses of caveolin-1 functions in embryonic development and human diseases

    Institute of Scientific and Technical Information of China (English)

    Saijun MO; Shengli YANG; Zongbin CUI

    2011-01-01

    Caveolin-1 (Cav-1) isoforms,including Cav-1α and Cav-1β,were identified as integral membrane proteins and the major components of caveolae.Cav-1 proteins are highly conserved during evolution from Caenorhabditis elegans to human and are capable of interacting with many signaling molecules through their caveolin scaffolding domains to regulate the activities of multiple signaling pathways.Thus,Cav-1 plays crucial roles in the regulation of cellular proliferation,differentiation and apoptosis in a cell-specific and contextual manner.In addition,Cav-1 is essential for embryonic development of vertebrates owing to its regulation of BMP,Wnt,TGF-β and other key signaling molecules.Moreover,Cav-1 is mainly expressed in terminally differentiated cells and its abnormal expression is often associated with human diseases,such as tumor progression,cardiovascular diseases,fibrosis,lung regeneration,and diseases related to virus.In this review,we will further discuss the potential of Cav-1 as a target for disease therapy and multiple drug resistance.

  2. Evidence of Multiple Disease Resistance (MDR and implication of meta-analysis in marker assisted selection.

    Directory of Open Access Journals (Sweden)

    Farhan Ali

    Full Text Available Meta-analysis was performed for three major foliar diseases with the aim to find out the total number of QTL responsible for these diseases and depict some real QTL for molecular breeding and marker assisted selection (MAS in maize. Furthermore, we confirmed our results with some major known disease resistance genes and most well-known gene family of nucleotide binding site (NBS encoding genes. Our analysis revealed that disease resistance QTL were randomly distributed in maize genome, but were clustered at different regions of the chromosomes. Totally 389 QTL were observed for these three major diseases in diverse maize germplasm, out of which 63 QTL were controlling more than one disease revealing the presence of multiple disease resistance (MDR. 44 real-QTLs were observed based on 4 QTL as standard in a specific region of genome. We also confirmed the Ht1 and Ht2 genes within the region of real QTL and 14 NBS-encoding genes. On chromosome 8 two NBS genes in one QTL were observed and on chromosome 3, several cluster and maximum MDR QTL were observed indicating that the apparent clustering could be due to genes exhibiting pleiotropic effect. Significant relationship was observed between the number of disease QTL and total genes per chromosome based on the reference genome B73. Therefore, we concluded that disease resistance genes are abundant in maize genome and these results can unleash the phenomenon of MDR. Furthermore, these results could be very handy to focus on hot spot on different chromosome for fine mapping of disease resistance genes and MAS.

  3. Spatial Analysis of Multiple Sclerosis Disease in Tehran Metropolitan Zone, Iran, 2001-2012.

    Directory of Open Access Journals (Sweden)

    Mahbubeh Saei

    2014-05-01

    Full Text Available Multiple Sclerosis (MS is a disease with high disabling disorders and considerable social and economic impacts. This study was conducted to analyze the spatial distribution of MS disease in Tehran, Iran during 2001-2012.The existing information in the MS patients' medical files who had registered in Iranian MS Society (IMSS, located in Tehran office, was used for analysis. The relationship between diseases incidences in 22 zones of Tehran based on estimated socio-economic status (SES of each zone was evaluated. High and low clustering approach was used in order to investigate the disease's distribution pattern meanwhile, Getis Ord's Gi test and Hot Spot analysis approach has been used to detect high risk zones of the disease.A total of 6027 MS patients were registered between 2001- 2012 which 4580 (%75.99 were women. During the study period, zone number 6 figured as the most high risk zone for the disease (P<0.1. A heterogeneous distribution was shown for the disease. Cumulative incidence of the disease in northern zones (101.73 per 100,000 inhabitants was two times more of Southern zones (53.79 per 100,000 inhabitants. There seems to be a direct linear relationship between estimated incidence rate of the disease in each zones with the level of SES (P<0.001.Heterogeneous geographical distribution of MS and its higher estimated incidence for northern zones in Tehran may be because of higher SES and other factors in mentioned zones. It is recommended to consider the surveillance with long-term and cost-effective interventional strategies along with disease in high risk zones.

  4. Molecular Genetic Approaches to Human Diseases Involving Mental Retardation.

    Science.gov (United States)

    Latt, Samuel A.; And Others

    1984-01-01

    Recombinant DNA techniques provide new approaches to the diagnosis and analysis of inherited human diseases associated with mental retardation, such as Lesch-Nyhan syndrome, phenylketonauria, the Fragile X syndrome, Down syndrome, and those associated with deletions or duplications of subchromosomal regions. (Author/CL)

  5. Recognizing filamentous basidiomycetes as agents of human disease: A review

    NARCIS (Netherlands)

    Chowdhary, A.; Kathuria, S.; Agarwal, K.; Meis, J.F.G.M.

    2014-01-01

    Filamentous basidiomycetes (BM) are common environmental fungi that have recently emerged as important human pathogens, inciting a wide array of clinical manifestations that include allergic and invasive diseases. We reviewed 218 reported global cases of BM fungi. The most common etiologic agent was

  6. Lyme disease: a unique human model for an infectious etiology of rheumatic disease.

    Science.gov (United States)

    Malawista, S. E.; Steere, A. C.; Hardin, J. A.

    1984-01-01

    Lyme disease is a complex immune-mediated multi-system disorder that is infectious in origin and inflammatory or "rheumatic" in expression. Through its epidemiologic characteristics, large numbers of a seasonally synchronized patient population are readily available for prospective study. Lyme disease has a known clinical onset ("zero time"), marked by the characteristic expanding skin lesion, erythema chronicum migrans, and a clearly defined pre-articular phase. At least some manifestations of the disorder are responsive to antibiotics, and the causative agent--a spirochete--is now known. These advantages make Lyme disease unique as a human model for an infectious etiology of rheumatic disease. PMID:6516449

  7. Viral hepatitis E: A disease of humans and animals

    Directory of Open Access Journals (Sweden)

    Kureljušić Branislav

    2012-01-01

    Full Text Available The hepatitis E virus is ubiquitous in all parts of the world where pig production exists. The infection occurs in several animal species and its course is mostly asymptomatic. Viral strains isolated from pigs and humans are genetically similar, which indicates a potential zoonotic nature of the disease, and the possibility that pigs, and perhaps also other species of animals diseased with viral hepatitis E are a source of infection to humans. The pig hepatitis E virus, which is similar to the hepatitis E virus in humans, was isolated and described for the first time in the USA in 1997. The infection of pigs with hepatitis E virus occurs through faeco-oral transmission, by ingestion of feed and water contaminated with the virus, or through direct contact between infected and healthy animals. The pathogenesis of this infection in pigs differs from its pathogenesis in humans and it has not been sufficiently examined in all its aspects. Even though viral hepatitis E in pigs has been described as a subclinical disease, some authors describe changes in the concentration of certain biochemical parameters in blood serum of the infected pigs. Histologically, a mild to moderate lymphotic-plasma cellular infiltration is observed in livers of infected pigs, as well as focal areas of hepatocyte necrosis. Viral hepatitis E is an endemic disease of humans in Asia, Africa, and Latin America. In developed countries, hepatitis E sporadically occurs in humans, but it is becoming of increasing importance in particular in Japan, North America, and Europe, because the populations of these areas travel extensively to the endemic regions or as a result of the consumption of thermally untreated meat of wild boar and products made from thermally untreated meat. Pork products can be contaminated with hepatitis E virus. Further proof that indicates the zoonotic potential of this virus and places this diseases among the group of professional diseases of farmers and

  8. Variable structure multiple model for articulated human motion tracking from monocular video sequences

    Institute of Scientific and Technical Information of China (English)

    HAN Hong; TONG MingLei; CHEN ZhiChao; FAN YouJian

    2012-01-01

    A new model-based human body tracking framework with learning-based theory is introduced inthis paper.We propose a variable structure multiple model (VSMM) framework to address challenging problems such as uncertainty of motion styles,imprecise detection of feature points,and ambiguity of joint locations.Key human joint points are detected automatically and the undetected points are estimated with Kalman filters.Multiple motion models are learned from motion capture data using a ridge regression method.The model set that covers the total motion set is designed on the basis of topological and compatibility relationships,while the VSMM algorithm is used to estimate quaternion vectors of joint rotation.Experiments using real image sequences and simulation videos demonstrate the high efficiency of our proposed human tracking framework.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Crohn's disease complicated by multiple stenoses and internal fistulas clinically mimicking small bowel endometriosis

    Institute of Scientific and Technical Information of China (English)

    Zafer Teke; Faruk Onder Aytekin; Ali Ozgur Atalay; Nese Calli Demirkan

    2008-01-01

    We report a 31-year-old woman with Crohn's disease complicated by multiple stenoses and internal fistulas clinically misdiagnosed as small bowell endometriosis, due to the patient's perimenstrual symptoms of mechanical subileus for 3 years; at first monthly, but later continuous, and gradually increasing in severity. We performed an exploratory laparotomy for small bowel obstruction, and found multiple ileal strictures and internal enteric fistulas. Because intraoperative findings were thought to indicate Crohn's disease, a right hemicolectomy and partial distal ileum resection were performed for obstructive Crohn's ileitis. Histopathology of the resected specimen revealed Crohn's disease without endometrial tissue. The patient made an uneventful recovery from this procedure and was discharged home 10 d post-operatively. The differential diagnosis of Crohn's diease with intestinal endometriosis may be difficult pre-operatively. The two entities share many overlapping clinical, radiological and pathological features. Nevertheless, when it is difficult to identify the cause of intestinal obstruction in a woman of child- bearing age with cyclical symptoms suggestive of small bowel endometriosis, Crohn's disease should be included in the differential diagnosis.

  11. Development of therapies for autoimmune disease at Stanford: a tale of multiple shots and one goal.

    Science.gov (United States)

    Steinman, Lawrence

    2014-05-01

    The title of this contribution on Immunology at Stanford is purposely ambiguous. One goal is the development of safe and effective therapy for autoimmune diseases. Another definition of goal is to score, and this would ultimately mean the development of an approved drug. Indeed, the efforts in my four decades at Stanford, have included the discovery and subsequent development of a monoclonal antibody to block homing to the inflamed brain, leading to natalizumab, an approved therapeutic for two autoimmune diseases: relapsing-remitting MS and for inflammatory bowel disease. Multiple attempts to develop new therapies for autoimmune disease are described here: The trimolecular complex and the immune synapse serve as one major set of targets, with attempts to inhibit particular major histocompatibility molecules, the variable regions of the T cell receptor, and CD4. Other approaches focusing on antigen-specific tolerance include ongoing attempts with tolerizing DNA vaccines in type 1 diabetes. Finally, the repurposing of popular drugs approved for other indications, including statins and inhibitors of angiotensin converting enzyme is under development and showing promise in the clinic, particularly for secondary progressive multiple sclerosis. The milieu within Stanford Immunology has helped to nurture these efforts to translate discoveries in immunology and to take them from bench to bedside.

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

    Science.gov (United States)

    Flores, Jose; González, Silvia; Morales, Ximena; Yescas, Petra; Ochoa, Adriana; Corona, Teresa

    2012-01-01

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Leveraging human-centered design in chronic disease prevention.

    Science.gov (United States)

    Matheson, Gordon O; Pacione, Chris; Shultz, Rebecca K; Klügl, Martin

    2015-04-01

    Bridging the knowing-doing gap in the prevention of chronic disease requires deep appreciation and understanding of the complexities inherent in behavioral change. Strategies that have relied exclusively on the implementation of evidence-based data have not yielded the desired progress. The tools of human-centered design, used in conjunction with evidence-based data, hold much promise in providing an optimal approach for advancing disease prevention efforts. Directing the focus toward wide-scale education and application of human-centered design techniques among healthcare professionals will rapidly multiply their effective ability to bring the kind of substantial results in disease prevention that have eluded the healthcare industry for decades. This, in turn, would increase the likelihood of prevention by design.

  15. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases.

    Directory of Open Access Journals (Sweden)

    Gavin Hudson

    2014-05-01

    Full Text Available Mitochondrial DNA (mtDNA is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the "missing heritability" of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases.

  16. Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases.

    Science.gov (United States)

    Sun, Yan V; Hu, Yi-Juan

    2016-01-01

    Complex and dynamic networks of molecules are involved in human diseases. High-throughput technologies enable omics studies interrogating thousands to millions of makers with similar biochemical properties (eg, transcriptomics for RNA transcripts). However, a single layer of "omics" can only provide limited insights into the biological mechanisms of a disease. In the case of genome-wide association studies, although thousands of single nucleotide polymorphisms have been identified for complex diseases and traits, the functional implications and mechanisms of the associated loci are largely unknown. Additionally, the genomic variants alone are not able to explain the changing disease risk across the life span. DNA, RNA, protein, and metabolite often have complementary roles to jointly perform a certain biological function. Such complementary effects and synergistic interactions between omic layers in the life course can only be captured by integrative study of multiple molecular layers. Building upon the success in single-omics discovery research, population studies started adopting the multi-omics approach to better understanding the molecular function and disease etiology. Multi-omics approaches integrate data obtained from different omic levels to understand their interrelation and combined influence on the disease processes. Here, we summarize major omics approaches available in population research, and review integrative approaches and methodologies interrogating multiple omic layers, which enhance the gene discovery and functional analysis of human diseases. We seek to provide analytical recommendations for different types of multi-omics data and study designs to guide the emerging multi-omic research, and to suggest improvement of the existing analytical methods. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Impact of climate change on human infectious diseases: Empirical evidence and human adaptation.

    Science.gov (United States)

    Wu, Xiaoxu; Lu, Yongmei; Zhou, Sen; Chen, Lifan; Xu, Bing

    2016-01-01

    Climate change refers to long-term shifts in weather conditions and patterns of extreme weather events. It may lead to changes in health threat to human beings, multiplying existing health problems. This review examines the scientific evidences on the impact of climate change on human infectious diseases. It identifies research progress and gaps on how human society may respond to, adapt to, and prepare for the related changes. Based on a survey of related publications between 1990 and 2015, the terms used for literature selection reflect three aspects--the components of infectious diseases, climate variables, and selected infectious diseases. Humans' vulnerability to the potential health impacts by climate change is evident in literature. As an active agent, human beings may control the related health effects that may be effectively controlled through adopting proactive measures, including better understanding of the climate change patterns and of the compound disease-specific health effects, and effective allocation of technologies and resources to promote healthy lifestyles and public awareness. The following adaptation measures are recommended: 1) to go beyond empirical observations of the association between climate change and infectious diseases and develop more scientific explanations, 2) to improve the prediction of spatial-temporal process of climate change and the associated shifts in infectious diseases at various spatial and temporal scales, and 3) to establish locally effective early warning systems for the health effects of predicated climate change.

  18. Urine-derived induced pluripotent stem cells as a modeling tool to study rare human diseases.

    Science.gov (United States)

    Shi, Liang; Cui, Yazhou; Luan, Jing; Zhou, Xiaoyan; Han, Jinxiang

    2016-08-01

    Rare diseases with a low prevalence are a key public health issue because the causes of those diseases are difficult to determine and those diseases lack a clearly established or curative treatment. Thus, investigating the molecular mechanisms that underlie the pathology of rare diseases and facilitating the development of novel therapies using disease models is crucial. Human induced pluripotent stem cells (iPSCs) are well suited to modeling rare diseases since they have the capacity for self-renewal and pluripotency. In addition, iPSC technology provides a valuable tool to generate patient-specific iPSCs. These cells can be differentiated into cell types that have been affected by a disease. These cells would circumvent ethical concerns and avoid immunological rejection, so they could be used in cell replacement therapy or regenerative medicine. To date, human iPSCs could have been generated from multiple donor sources, such as skin, adipose tissue, and peripheral blood. However, these cells are obtained via invasive procedures. In contrast, several groups of researchers have found that urine may be a better source for producing iPSCs from normal individuals or patients. This review discusses urinary iPSC (UiPSC) as a candidate for modeling rare diseases. Cells obtained from urine have overwhelming advantages compared to other donor sources since they are safely, affordably, and frequently obtained and they are readily obtained from patients. The use of iPSC-based models is also discussed. UiPSCs may prove to be a key means of modeling rare diseases and they may facilitate the treatment of those diseases in the future.

  19. Multiple-reflection model of human skin and estimation of pigment concentrations

    Science.gov (United States)

    Ohtsuki, Rie; Tominaga, Shoji; Tanno, Osamu

    2012-07-01

    We describe a new method for estimating the concentrations of pigments in the human skin using surface spectral reflectance. We derive an equation that expresses the surface spectral reflectance of the human skin. First, we propose an optical model of the human skin that accounts for the stratum corneum. We also consider the difference between the scattering coefficient of the epidermis and that of the dermis. We then derive an equation by applying the Kubelka-Munk theory to an optical model of the human skin. Unlike a model developed in a recent study, the present equation considers pigments as well as multiple reflections and the thicknesses of the skin layers as factors that affect the color of the human skin. In two experiments, we estimate the pigment concentrations using the measured surface spectral reflectances. Finally, we confirm the feasibility of the concentrations estimated by the proposed method by evaluating the estimated pigment concentrations in the skin.

  20. Melanin and blood concentration in human skin studied by multiple regression analysis: experiments

    Science.gov (United States)

    Shimada, M.; Yamada, Y.; Itoh, M.; Yatagai, T.

    2001-09-01

    Knowledge of the mechanism of human skin colour and measurement of melanin and blood concentration in human skin are needed in the medical and cosmetic fields. The absorbance spectrum from reflectance at the visible wavelength of human skin increases under several conditions such as a sunburn or scalding. The change of the absorbance spectrum from reflectance including the scattering effect does not correspond to the molar absorption spectrum of melanin and blood. The modified Beer-Lambert law is applied to the change in the absorbance spectrum from reflectance of human skin as the change in melanin and blood is assumed to be small. The concentration of melanin and blood was estimated from the absorbance spectrum reflectance of human skin using multiple regression analysis. Estimated concentrations were compared with the measured one in a phantom experiment and this method was applied to in vivo skin.

  1. Infectious Bursal Disease Virus-Host Interactions: Multifunctional Viral Proteins that Perform Multiple and Differing Jobs

    Science.gov (United States)

    Qin, Yao; Zheng, Shijun J.

    2017-01-01

    Infectious bursal disease (IBD) is an acute, highly contagious and immunosuppressive poultry disease caused by IBD virus (IBDV). The consequent immunosuppression increases susceptibility to other infectious diseases and the risk of subsequent vaccination failure as well. Since the genome of IBDV is relatively small, it has a limited number of proteins inhibiting the cellular antiviral responses and acting as destroyers to the host defense system. Thus, these virulence factors must be multifunctional in order to complete the viral replication cycle in a host cell. Insights into the roles of these viral proteins along with their multiple cellular targets in different pathways will give rise to a rational design for safer and effective vaccines. Here we summarize the recent findings that focus on the virus–cell interactions during IBDV infection at the protein level. PMID:28098808

  2. Renal manifestations of human brucellosis: First report of minimal change disease

    Directory of Open Access Journals (Sweden)

    Nikolaos Sabanis

    2016-01-01

    Full Text Available Human brucellosis is considered a great example of the complexity of clinical manifestations possibly affecting multiple organs or systems. Renal manifestations of human brucellosis have been documented in few case reports and one case series. Herein, we present a case of Nephrotic syndrome (NS due to minimal change disease in the course of acute brucellosis. A 53-year-old male farmer was admitted to our department with acute brucellosis and NS. Renal biopsy revealed minimal change disease. Combined treatment with prednisone (1 mg/kg, rifampicin (600 mg/day, and doxycycline (200 mg/day was initiated. Complete remission of NS was achieved at the end of the fourth week. One year later, the patient remained in complete remission of NS without any sign of relapse of brucellosis.

  3. Renal manifestations of human brucellosis: First report of minimal change disease.

    Science.gov (United States)

    Sabanis, Nikolaos; Gavriilaki, Eleni; Paschou, Eleni; Tsotsiou, Eleni; Kalaitzoglou, Asterios; Kavlakoudis, Christos; Vasileiou, Sotirios

    2016-05-01

    Human brucellosis is considered a great example of the complexity of clinical manifestations possibly affecting multiple organs or systems. Renal manifestations of human brucellosis have been documented in few case reports and one case series. Herein, we present a case of Nephrotic syndrome (NS) due to minimal change disease in the course of acute brucellosis. A 53-year-old male farmer was admitted to our department with acute brucellosis and NS. Renal biopsy revealed minimal change disease. Combined treatment with prednisone (1 mg/kg), rifampicin (600 mg/day), and doxycycline (200 mg/day) was initiated. Complete remission of NS was achieved at the end of the fourth week. One year later, the patient remained in complete remission of NS without any sign of relapse of brucellosis.

  4. Humane killing of animals for disease control purposes.

    Science.gov (United States)

    Thornber, P M; Rubira, R J; Styles, D K

    2014-04-01

    Killing for disease control purposes is an emotional issue for everyone concerned. Large-scale euthanasia or depopulation of animals may be necessary for the emergency control or eradication of animal diseases, to remove animals from a compromised situation (e.g. following flood, storm, fire, drought or a feed contamination event), to effect welfare depopulation when there is an oversupply due to a dysfunctional or closed marketing channel, or to depopulate and dispose of animals with minimal handling to decrease the risk of a zoonotic disease infecting humans. The World Organisation for Animal Health (OIE) developed international standards to provide advice on humane killing for various species and situations. Some fundamental issues are defined, such as competency of animal handling and implementation of humane killing techniques. Some of these methods have been used for many years, but novel approaches for the mass killing of particular species are being explored. Novel vaccines and new diagnostic techniques that differentiate between vaccinated and infected animals will save many animals from being killed as part of biosecurity response measures. Unfortunately, the destruction of affected livestock will still be required to control diseases whilst vaccination programmes are activated or where effective vaccines are not available. This paper reviews the principles of humane destruction and depopulation and explores available techniques with their associated advantages and disadvantages. It also identifies some current issues that merit consideration, such as legislative conflicts (emergency disease legislation versus animal welfare legislation, occupational health and safety), media issues, opinions on the future approaches to killing for disease control, and animal welfare.

  5. OAS1: a multiple sclerosis susceptibility gene that influences disease severity.

    LENUS (Irish Health Repository)

    O'Brien, M

    2012-02-01

    BACKGROUND: Type 1 interferons upregulate oligoadenylate synthetase 1 (OAS1). A single nucleotide polymorphism (SNP) in exon 7 of OAS1 results in differential RNAseL enzyme activity, the A allele coding for a truncated form with low activity and the G conferring high activity. We hypothesized that OAS1 genotypes would influence both susceptibility to multiple sclerosis (MS) and disease activity with the AA genotype being overrepresented and the GG genotype underrepresented in relapsing-remitting MS (RRMS) with increased disease activity. METHODS: We examined OAS1 genotype distribution in 401 patients with MS, 394 healthy controls, and 178 patients with RRMS receiving interferon-beta (IFNbeta) assessed as 1) having no or minimal disease activity on IFNbeta, 2) having disease activity despite IFNbeta, and 3) 65 patients with RRMS with highly active disease. RESULTS: The OAS1 genotype distribution differed between patients with MS and controls (p = 0.000003), with lower frequency of GG homozygotes in patients with MS (6%) compared with controls (17%). In relation to disease severity, 34 (32%) patients with no or minimal disease activity on IFNbeta had the AA and 8 (8%) the GG genotype; of patients with disease activity despite IFNbeta, 27 (51%) were AA, while only 1 (2%) was GG (p = 0.03). Median time to first relapse on IFNbeta was 24 months in patients with RRMS with AA genotype and 33 months with AG or GG genotype (p = 0.04). The GG genotype was absent in 65 patients with highly active RRMS (p = 0.03). CONCLUSIONS: A functional OAS1 SNP, AA genotype, confers susceptibility to MS and the GG genotype may protect against increased disease activity.

  6. Transgenic rabbits as therapeutic protein bioreactors and human disease models.

    Science.gov (United States)

    Fan, Jianglin; Watanabe, Teruo

    2003-09-01

    Genetically modified laboratory animals provide a powerful approach for studying gene expression and regulation and allow one to directly examine structure-function and cause-and-effect relationships in pathophysiological processes. Today, transgenic mice are available as a research tool in almost every research institution. On the other hand, the development of a relatively large mammalian transgenic model, transgenic rabbits, has provided unprecedented opportunities for investigators to study the mechanisms of human diseases and has also provided an alternative way to produce therapeutic proteins to treat human diseases. Transgenic rabbits expressing human genes have been used as a model for cardiovascular disease, AIDS, and cancer research. The recombinant proteins can be produced from the milk of transgenic rabbits not only at lower cost but also on a relatively large scale. One of the most promising and attractive recombinant proteins derived from transgenic rabbit milk, human alpha-glucosidase, has been successfully used to treat the patients who are genetically deficient in this enzyme. Although the pronuclear microinjection is still the major and most popular method for the creation of transgenic rabbits, recent progress in gene targeting and animal cloning has opened new avenues that should make it possible to produce transgenic rabbits by somatic cell nuclear transfer in the future. Based on a computer-assisted search of the studies of transgenic rabbits published in the English literature here, we introduce to the reader the achievements made thus far with transgenic rabbits, with emphasis on the application of these rabbits as human disease models and live bioreactors for producing human therapeutic proteins and on the recent progress in cloned rabbits.

  7. Simultaneous occurrence of diabetic ketoacidosis, thyroid storm, and multiple cerebral infarctions due to Moyamoya disease.

    Science.gov (United States)

    Noh, Byoungho H; Cho, Sang-Won; Ahn, Sung Yeon

    2016-02-01

    Diabetic ketoacidosis (DKA) is one of the precipitating factors that can evoke a thyroid storm. Thyroid storm may cause cerebral ischemia in Moyamoya disease, which can coexist in patients with Graves' disease. A 16-year-old girl complaining of dizziness and palpitations visited the emergency department and was diagnosed with DKA combined with hyperthyroidism. A thyroid storm occurred 6 h after the start of DKA management. Her Burch and Wartofsky score was 65 points. Right hemiplegia developed during the thyroid storm, and brain magnetic resonance (MR) diffusion-weighted images revealed multiple acute infarcts in both hemispheres. MR angiography showed stenosis of both distal internal carotid arteries and both M1 portions of the middle cerebral arteries, consistent with Moyamoya disease. After acute management for the thyroid storm with methimazole, Lugol solution and hydrocortisone, the patient's neurological symptoms completely resolved within 1 month, and free T4 level normalized within 2 months. Thyroid storm may trigger cerebral ischemia in Moyamoya disease and lead to rapid progression of cerebrovascular occlusive disease. As a simultaneous occurrence of DKA, thyroid storm and cerebrovascular accident in Moyamoya disease highly elevates morbidity and mortality, prompt recognition and management are critical to save the patient's life.

  8. Health care utilization of patients with multiple chronic diseases in The Netherlands: Differences and underlying factors.

    Science.gov (United States)

    Hopman, Petra; Heins, Marianne J; Rijken, Mieke; Schellevis, François G

    2015-04-01

    To examine health care utilization of people with multiple chronic diseases in The Netherlands compared to people with one chronic disease, and to identify different subgroups of multimorbid patients based on differences in health care utilization. All patients diagnosed with one or more chronic diseases in 2008-2009 (N=17,443) were selected from the nationwide NIVEL Primary Care Database, and data on their GP contacts were included. Data on hospital admissions (from the Dutch Hospital Data database) and household size and income (from the Integral Household Incomes database 2010) were added. Chi-square-tests and multivariate regression analyses were performed to test for differences between multimorbid patients and patients with one chronic disease, and between subgroups of multimorbid patients derived from cluster analysis. Multimorbid patients (40% of the total sample) had more GP contacts, prescribed medications, and hospital admissions (all putilization. Two smaller clusters comprised patients with a (very) high level of health care utilization - these people were mainly older, more often female, had a lower income, a smaller household size, and suffered from more chronic diseases. Among the vast majority of multimorbid patients health care utilization is only slightly higher compared to patients with one chronic disease. Extensive health care utilization among people with multimorbidity seems to be related to patient characteristics as well as illness characteristics. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  9. Comparison of Statistical Algorithms for the Detection of Infectious Disease Outbreaks in Large Multiple Surveillance Systems

    Science.gov (United States)

    Farrington, C. Paddy; Noufaily, Angela; Andrews, Nick J.; Charlett, Andre

    2016-01-01

    A large-scale multiple surveillance system for infectious disease outbreaks has been in operation in England and Wales since the early 1990s. Changes to the statistical algorithm at the heart of the system were proposed and the purpose of this paper is to compare two new algorithms with the original algorithm. Test data to evaluate performance are created from weekly counts of the number of cases of each of more than 2000 diseases over a twenty-year period. The time series of each disease is separated into one series giving the baseline (background) disease incidence and a second series giving disease outbreaks. One series is shifted forward by twelve months and the two are then recombined, giving a realistic series in which it is known where outbreaks have been added. The metrics used to evaluate performance include a scoring rule that appropriately balances sensitivity against specificity and is sensitive to variation in probabilities near 1. In the context of disease surveillance, a scoring rule can be adapted to reflect the size of outbreaks and this was done. Results indicate that the two new algorithms are comparable to each other and better than the algorithm they were designed to replace. PMID:27513749

  10. Human Endogenous Retrovirus HERV-Fc1 Association with Multiple Sclerosis Susceptibility: A Meta-Analysis

    Science.gov (United States)

    García-Montojo, Marta; Alcina, Antonio; Fedetz, María; Alloza, Iraide; Astobiza, Ianire; Leyva, Laura; Fernández, Oscar; Izquierdo, Guillermo; Antigüedad, Alfredo; Arroyo, Rafael; Álvarez-Lafuente, Roberto; Vandenbroeck, Koen; Matesanz, Fuencisla; Urcelay, Elena

    2014-01-01

    Background Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts. Methods A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data. Results Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11–1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14–1.53)]. Conclusion Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts. PMID:24594754

  11. Human endogenous retrovirus HERV-Fc1 association with multiple sclerosis susceptibility: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Belén de la Hera

    Full Text Available BACKGROUND: Human endogenous retroviruses (HERVs are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts. METHODS: A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls, Central (883 patients and 692 controls and Southern (1021 patients and 1359 controls Spain. Our results were pooled in a meta-analysis with previously published data. RESULTS: Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI = 1.27 (1.11-1.45]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI = 1.32 (1.14-1.53]. CONCLUSION: Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.

  12. Characterization of the Toll-like receptor expression profile in human multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Jahangir Abdi

    Full Text Available Expression and function of Toll-like receptors (TLRs in multiple myeloma (MM has recently become the focus of several studies. Knowledge of expression and biology of these receptors in MM will provide us with a new insight into the role of an inflammatory environment in disease progression or pathogenesis of MM. However, to date a quite heterogeneous expression pattern of TLRs in MM particularly at gene level has been described while information on the TLR expression at the protein level is largely unavailable. In this study, we investigated the TLR expression in human myeloma cell lines (HMCLs Fravel, L363, UM6, UM9, OPM1, OPM2, U266, RPMI 8226, XG1, and NCI H929 and primary cells from MM patients at both mRNA and protein level (western blot and flow cytometry. We found that all cell lines and primary cells expressed TLR1, TLR3, TLR4, TLR7, TLR8, and TLR9 mRNA and protein. TLR2 and TLR5 were expressed by the majority of HMCLs at mRNA but were not detectable at protein level, while primary samples showed a low level of TLR2, TLR3 and TLR5 protein expression. Our results indicate that MM cells express a broad range of TLRs with a degree of disparity between gene and protein expression pattern. The clear expression of TLRs in MM cells indicates a propensity for responding to tumor-induced inflammatory signals, which seem inevitable in the MM bone marrow environment.

  13. The human environment and the vitamin D compromise: Scotland as a case study in human biocultural adaptation and disease susceptibility.

    Science.gov (United States)

    Chaplin, George; Jablonski, Nina G

    2013-08-01

    Year-round human habitation of environments with highly seasonal regimes of ultraviolet B radiation (UVB) depended on adaptive complexes of biological and cultural traits to ensure adequacy of vitamin D. Perturbations of such adaptive complexes resulting from changes in the physical environment, human behavior and culture, or both have had unexpected and untoward consequences for health. Scotland is an excellent case study of the changing nature of human biocultural adaptation to low-UVB environments. Occupation of Scotland after the last Pleistocene glaciation event about 14,000 YBP was made possible by maximally depigmented skin, which facilitated cutaneous biosynthesis of vitamin D3, and by a diet that emphasized foods rich in vitamin D. Changes in human subsistence and diet began with the introduction of agriculture and grazing about 5,000 YBP and accelerated greatly in the last 200 years through industrialization and urbanization. The resulting changes in domiciles, patterns of daily activity and behavior, and diet have led to reduced exposure to UVB and reduced consumption of vitamin D-rich foods. This has perturbed the "vitamin D compromise," an adaptive complex established in Scotland during the Mesolithic and Neolithic. We describe the UVB environment of Scotland from remotely sensed data and combine these data with information from the archaeological record to describe the vitamin D compromise in Scotland. Changes in human exposure to UVB and vitamin D consumption, which occurred as the result of urbanization and the dietary shift away from the consumption of oily fish, are traced. Vitamin D deficiency contributes to increased disease prevalence in Scotland, including that of the autoimmune disease multiple sclerosis, a debilitating neurodegenerative disease caused by demyelination of the central nervous system. These conditions have created an "imperfect storm" of poor health that should command the attention of public health experts and policy makers.

  14. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

    DEFF Research Database (Denmark)

    Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie

    2016-01-01

    (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial......The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells...... survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder....

  15. Virtual test: A student-centered software to measure student's critical thinking on human disease

    Science.gov (United States)

    Rusyati, Lilit; Firman, Harry

    2016-02-01

    The study "Virtual Test: A Student-Centered Software to Measure Student's Critical Thinking on Human Disease" is descriptive research. The background is importance of computer-based test that use element and sub element of critical thinking. Aim of this study is development of multiple choices to measure critical thinking that made by student-centered software. Instruments to collect data are (1) construct validity sheet by expert judge (lecturer and medical doctor) and professional judge (science teacher); and (2) test legibility sheet by science teacher and junior high school student. Participants consisted of science teacher, lecturer, and medical doctor as validator; and the students as respondent. Result of this study are describe about characteristic of virtual test that use to measure student's critical thinking on human disease, analyze result of legibility test by students and science teachers, analyze result of expert judgment by science teachers and medical doctor, and analyze result of trial test of virtual test at junior high school. Generally, result analysis shown characteristic of multiple choices to measure critical thinking was made by eight elements and 26 sub elements that developed by Inch et al.; complete by relevant information; and have validity and reliability more than "enough". Furthermore, specific characteristic of multiple choices to measure critical thinking are information in form science comic, table, figure, article, and video; correct structure of language; add source of citation; and question can guide student to critical thinking logically.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Mariana Andrade Baptista

    2014-06-01

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

  18. [Recent knowledge on the linkage of strain specific genotypes with clinical manifestations of human citomegalovirus disease].

    Science.gov (United States)

    Pignatelli, Sara

    2011-01-01

    Human citomegalovirus (CMV) is a beta-herpesvirus able to establish lifelong persistent infections which usually remain asymptomatic. However, severe diseases may develop in immunocompromised subjects (e.g., AIDS patients and transplant recipients) and if acquired in utero. Circulating CMV clinical strains display genetic polymorphisms in multiple genes, which may be implicated in CMV-induced immunopathogenesis, as well as strain-specific tissue-tropism, viral spread in the host cells and virulence, finally determining the wide spectrum of clinical manifestations of CMV disease. Current literature report a number of studies regarding the main CMV polymorphic genes (UL55-gB, UL144, UL73-gN, UL74-gO), their diagnostic and therapeutic impact, their potential clinical relevance as prognostic markers. This paper aims to critically analyse the results of these studies and evaluate the linkage of strain-specific genotypes with clinical manifestations of CMV disease and their perspective implications.

  19. The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

    Science.gov (United States)

    Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Terranova Barberio, Manuela; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D; Nestle, Frank O

    2015-04-09

    Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases.

  20. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: Application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM)

    Energy Technology Data Exchange (ETDEWEB)

    Risch, N. (Yale Univ. School of Medicine, New Haven, CT (United States)); Ghosh, S.; Todd, J.A.

    1993-09-01

    Common, familial human disorders generally do not follow Mendelian inheritance patterns, presumably because multiple loci are involved in disease susceptibility. One approach to mapping genes for such traits in humans is to first study an analogous form in an animal model, such as mouse, by using inbred strains and backcross experiments. Here the authors describe methodology for analyzing multiple-locus linkage data from such experimental backcrosses, particularly in light of multilocus genetic models, including the effects of epistasis. They illustrate these methods by using data from backcrosses involving nonobese diabetic mouse, which serves as an animal model for human insulin-dependent diabetes mellitus. They show that it is likely that a minimum of nine loci contribute to susceptibility, with strong epistasis effects among these loci. Three of the loci actually confer a protective effect in the homozygote, compared with the heterozygote. Further, they discuss the relevance of these studies for analogous studies of the human form of the trait. Specifically, they show that the magnitude of the gene effect in the experimental backcross is likely to correlate only weakly, at best, with the expected magnitude of effect for a human form, because in humans the gene effect will depend more heavily on disease allele frequencies than on the observed penetrance ratios; such allele frequencies are unpredictable. Hence, the major benefit from animal studies may be a better understanding of the disease process itself, rather than identification of cells through comparison mapping in humans by using regions of homology. 12 refs., 7 tabs.

  1. MULTIPLE LOGISTIC REGRESSION MODEL TO PREDICT RISK FACTORS OF ORAL HEALTH DISEASES

    Directory of Open Access Journals (Sweden)

    Parameshwar V. Pandit

    2012-06-01

    Full Text Available Purpose: To analysis the dependence of oral health diseases i.e. dental caries and periodontal disease on considering the number of risk factors through the applications of logistic regression model. Method: The cross sectional study involves a systematic random sample of 1760 permanent dentition aged between 18-40 years in Dharwad, Karnataka, India. Dharwad is situated in North Karnataka. The mean age was 34.26±7.28. The risk factors of dental caries and periodontal disease were established by multiple logistic regression model using SPSS statistical software. Results: The factors like frequency of brushing, timings of cleaning teeth and type of toothpastes are significant persistent predictors of dental caries and periodontal disease. The log likelihood value of full model is –1013.1364 and Akaike’s Information Criterion (AIC is 1.1752 as compared to reduced regression model are -1019.8106 and 1.1748 respectively for dental caries. But, the log likelihood value of full model is –1085.7876 and AIC is 1.2577 followed by reduced regression model are -1019.8106 and 1.1748 respectively for periodontal disease. The area under Receiver Operating Characteristic (ROC curve for the dental caries is 0.7509 (full model and 0.7447 (reduced model; the ROC for the periodontal disease is 0.6128 (full model and 0.5821 (reduced model. Conclusions: The frequency of brushing, timings of cleaning teeth and type of toothpastes are main signifi cant risk factors of dental caries and periodontal disease. The fitting performance of reduced logistic regression model is slightly a better fit as compared to full logistic regression model in identifying the these risk factors for both dichotomous dental caries and periodontal disease.

  2. Mutations in inhibin and activin genes associated with human disease.

    Science.gov (United States)

    Shelling, Andrew N

    2012-08-15

    Inhibins and activins are members of the transforming growth factor (TGFβ) superfamily, that includes the TGFβs, inhibins and activins, bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). The family members are expressed throughout the human body, and are involved in the regulation of a range of important functions. The precise regulation of the TGFβ pathways is critical, and mutations of individual molecules or even minor alterations of signalling will have a significant affect on function, that may lead to development of disease or predisposition to the development of disease. The inhibins and activins regulate aspects of the male and female reproductive system, therefore, it is not surprising that most of the diseases associated with abnormalities of the inhibin and activin genes are focused on reproductive disorders and reproductive cancers. In this review, I highlight the role of genetic variants in the development of conditions such as premature ovarian failure, pre-eclampsia, and various reproductive cancers. Given the recent advances in human genetic research, such as genome wide association studies and next generation sequencing, it is likely that inhibins and activins will be shown to play more important roles in a range of human genetic diseases in the future.

  3. Human anthrax as a re-emerging disease.

    Science.gov (United States)

    Doganay, Mehmet; Demiraslan, Hayati

    2015-01-01

    Anthrax is primarily a disease of herbivores and the etiological agent is B. anthracis which is a gram-positive, aerobic, spore-forming, and rod shaped bacterium. Bacillus anthracis spores are highly resistant to heat, pressure, ultraviolet and ionizing radiation, chemical agents and disinfectants. For these reasons, B. anthracis spores are an attractive choice as biological agents for the use of bioweapon and/or bioterrorism. Soil is the main reservoir for the infectious agent. The disease most commonly affects wild and domestic mammals. Human are secondarily infected by contact with infected animals and contaminated animal products or directly expose to B. anthracis spores. Anthrax occurs worldwide. This infection is still endemic or hyperendemic in both animals and humans in some part of areas of the world; particularly in Middle East, West Africa, Central Asia, some part of India, South America. However, some countries are claiming free of anthrax, and anthrax has become a re-emerging disease in western countries with the intentional outbreak. Currently, anthrax is classified according to its setting as (1) naturally occurring anthrax, (2) bioterrorism-related anthrax. Vast majority of human anthrax are occurring as naturally occurring anthrax in the world. It is also a threaten disease for western countries. The aim of this paper is to review the relevant patents, short historical perspective, microbiological and epidemiological features, clinical presentations and treatment.

  4. Proteomics in farm animals models of human diseases.

    Science.gov (United States)

    Ceciliani, Fabrizio; Restelli, Laura; Lecchi, Cristina

    2014-10-01

    The need to provide in vivo complex environments to understand human diseases strongly relies on the use of animal models, which traditionally include small rodents and rabbits. It is becoming increasingly evident that the few species utilised to date cannot be regarded as universal. There is a great need for new animal species that are naturally endowed with specific features relevant to human diseases. Farm animals, including pigs, cows, sheep and horses, represent a valid alternative to commonly utilised rodent models. There is an ample scope for the application of proteomic techniques in farm animals, and the establishment of several proteomic maps of plasma and tissue has clearly demonstrated that farm animals provide a disease environment that closely resembles that of human diseases. The present review offers a snapshot of how proteomic techniques have been applied to farm animals to improve their use as biomedical models. Focus will be on specific topics of biomedical research in which farm animal models have been characterised through the application of proteomic techniques.

  5. Noncommunicable diseases and human rights: a promising synergy.

    Science.gov (United States)

    Gruskin, Sofia; Ferguson, Laura; Tarantola, Daniel; Beaglehole, Robert

    2014-05-01

    Noncommunicable diseases (NCDs) have finally emerged onto the global health and development agenda. Despite the increasingly important role human rights play in other areas of global health, their contribution to NCD prevention and control remains nascent. The recently adopted Global Action Plan for the Prevention and Control of NCDs 2013-2020 is an important step forward, but the lack of concrete attention to human rights is a missed opportunity. With practical implications for policy development, priority setting, and strategic design, human rights offer a logical, robust set of norms and standards; define the legal obligations of governments; and provide accountability mechanisms that can be used to enhance current approaches to NCD prevention and control. Harnessing the power of human rights can strengthen action for NCDs at the local, national, and global levels.

  6. The consequences of human actions on risks for infectious diseases: a review

    Science.gov (United States)

    Lindahl, Johanna F.; Grace, Delia

    2015-01-01

    The human population is growing, requiring more space for food production, and needing more animals to feed it. Emerging infectious diseases are increasing, causing losses in both human and animal lives, as well as large costs to society. Many factors are contributing to disease emergence, including climate change, globalization and urbanization, and most of these factors are to some extent caused by humans. Pathogens may be more or less prone to emergence in themselves, and rapidly mutating viruses are more common among the emerging pathogens. The climate-sensitive vector-borne diseases are likely to be emerging due to climate changes and environmental changes, such as increased irrigation. This review lists the factors within pathogens that make them prone to emergence, and the modes of transmission that are affected. The anthropogenic changes contributing to disease emergence are described, as well as how they directly and indirectly cause either increased numbers of susceptible or exposed individuals, or cause increased infectivity. Many actions may have multiple direct or indirect effects, and it may be difficult to assess what the consequences may be. In addition, most anthropogenic drivers are related to desired activities, such as logging, irrigation, trade, and travelling, which the society is requiring. It is important to research more about the indirect and direct effects of the different actions to understand both the benefits and the risks. PMID:26615822

  7. Role of Vitamin D in human Diseases and Disorders – An Overview

    Directory of Open Access Journals (Sweden)

    Priyanshee Gohil

    2014-06-01

    Full Text Available Vitamin D is a fat soluble vitamin and generated in human skin by ultraviolet (UV light. Today, vitamin D is considered to be a steroidal hormone and plays a central role in bone mineralization and calcium homeostasis. The active form of the vitamin D is 1, 25-dihydroxyvitamin D [1, 25-dihydroxycholecalciferol (DHCC] which mediatesproliferation, differentiation and various functions at the cellular level through Vitamin D receptors (VDR.Therefore, compromised vitamin D status is likely to be involved in progression or pathogenesis of various disorders. This assumption is consistent with findings from epidemiological studies that a compromised vitamin D status in humans increases the risk of autoimmune diseases, such as inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus (SLE, multiple sclerosis and type I diabetes mellitus. However, diseases like cancer, cardiovascular disorders and bone disorders are yet not focused. Thus the role of vitamin D in pathogenesis of various diseases is complex and controversial. This review briefly summarizes the role of vitamin D in development and progression of different human disorders.

  8. The consequences of human actions on risks for infectious diseases: a review.

    Science.gov (United States)

    Lindahl, Johanna F; Grace, Delia

    2015-01-01

    The human population is growing, requiring more space for food production, and needing more animals to feed it. Emerging infectious diseases are increasing, causing losses in both human and animal lives, as well as large costs to society. Many factors are contributing to disease emergence, including climate change, globalization and urbanization, and most of these factors are to some extent caused by humans. Pathogens may be more or less prone to emergence in themselves, and rapidly mutating viruses are more common among the emerging pathogens. The climate-sensitive vector-borne diseases are likely to be emerging due to climate changes and environmental changes, such as increased irrigation. This review lists the factors within pathogens that make them prone to emergence, and the modes of transmission that are affected. The anthropogenic changes contributing to disease emergence are described, as well as how they directly and indirectly cause either increased numbers of susceptible or exposed individuals, or cause increased infectivity. Many actions may have multiple direct or indirect effects, and it may be difficult to assess what the consequences may be. In addition, most anthropogenic drivers are related to desired activities, such as logging, irrigation, trade, and travelling, which the society is requiring. It is important to research more about the indirect and direct effects of the different actions to understand both the benefits and the risks.

  9. Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease.

    Directory of Open Access Journals (Sweden)

    Jesse M Engreitz

    Full Text Available Chromosomal translocations are frequent features of cancer genomes that contribute to disease progression. These rearrangements result from formation and illegitimate repair of DNA double-strand breaks (DSBs, a process that requires spatial colocalization of chromosomal breakpoints. The "contact first" hypothesis suggests that translocation partners colocalize in the nuclei of normal cells, prior to rearrangement. It is unclear, however, the extent to which spatial interactions based on three-dimensional genome architecture contribute to chromosomal rearrangements in human disease. Here we intersect Hi-C maps of three-dimensional chromosome conformation with collections of 1,533 chromosomal translocations from cancer and germline genomes. We show that many translocation-prone pairs of regions genome-wide, including the cancer translocation partners BCR-ABL and MYC-IGH, display elevated Hi-C contact frequencies in normal human cells. Considering tissue specificity, we find that translocation breakpoints reported in human hematologic malignancies have higher Hi-C contact frequencies in lymphoid cells than those reported in sarcomas and epithelial tumors. However, translocations from multiple tissue types show significant correlation with Hi-C contact frequencies, suggesting that both tissue-specific and universal features of chromatin structure contribute to chromosomal alterations. Our results demonstrate that three-dimensional genome architecture shapes the landscape of rearrangements directly observed in human disease and establish Hi-C as a key method for dissecting these effects.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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.

  12. Multiple sclerosis: patients' information sources and needs on disease symptoms and management.

    Science.gov (United States)

    Matti, Albert I; McCarl, Helen; Klaer, Pamela; Keane, Miriam C; Chen, Celia S

    2010-06-24

    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. 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. 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. 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. 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.

  13. Multiple diseases and polypharmacy in the elderly: challenges for the internist of the third millennium

    Directory of Open Access Journals (Sweden)

    Alessandro Nobili

    2011-12-01

    Full Text Available The pattern of patients admitted to internal medicine wards has dramatically changed in the last 20–30 years. Elderly people are now the most rapidly growing proportion of the patient population in the majority of Western countries, and aging seldom comes alone, often being accompanied by chronic diseases, comorbidity, disability, frailty, and social isolation. Multiple diseases and multimorbidity inevitably lead to the use of multiple drugs, a condition known as polypharmacy. Over the last 20–30 years, problems related to aging, multimorbidity, and polypharmacy have become a prominent issue in global healthcare. This review discusses how internists might tackle these new challenges of the aging population. They are called to play a primary role in promoting a new, integrated, and comprehensive approach to the care of elderly people, which should incorporate age-related issues into routine clinical practice and decisions. The development of new approaches in the frame of undergraduate and postgraduate training and of clinical research is essential to improve and implement suitable strategies meant to evaluate and manage frail elderly patients with chronic diseases, comorbidity, and polypharmacy.

  14. Downregulation of sulfotransferase expression and activity in diseased human livers.

    Science.gov (United States)

    Yalcin, Emine B; More, Vijay; Neira, Karissa L; Lu, Zhenqiang James; Cherrington, Nathan J; Slitt, Angela L; King, Roberta S

    2013-09-01

    Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics. In the present study of normal subjects with nonfatty livers and patients with steatosis, diabetic cirrhosis, and alcoholic cirrhosis, we sought to determine SULT1A1, SULT2A1, SULT1E1, and SULT1A3 activity and mRNA and protein expression in human liver tissue. In general, sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Specifically, SULT1A1 and SULT1A3 activities were lower in disease states relative to nonfatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than those affected by either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced both in diabetic cirrhosis and in alcoholic cirrhosis tissues, relative to nonfatty liver tissues. In conclusion, the reduced levels of sulfotransferase expression and activity in diseased versus nondiseased liver tissue may alter the metabolism and disposition of xenobiotics and affect homeostasis of endobiotic sulfotransferase substrates.

  15. Credit scores, cardiovascular disease risk, and human capital.

    Science.gov (United States)

    Israel, Salomon; Caspi, Avshalom; Belsky, Daniel W; Harrington, HonaLee; Hogan, Sean; Houts, Renate; Ramrakha, Sandhya; Sanders, Seth; Poulton, Richie; Moffitt, Terrie E

    2014-12-02

    Credit scores are the most widely used instruments to assess whether or not a person is a financial risk. Credit scoring has been so successful that it has expanded beyond lending and into our everyday lives, even to inform how insurers evaluate our health. The pervasive application of credit scoring has outpaced knowledge about why credit scores are such useful indicators of individual behavior. Here we test if the same factors that lead to poor credit scores also lead to poor health. Following the Dunedin (New Zealand) Longitudinal Study cohort of 1,037 study members, we examined the association between credit scores and cardiovascular disease risk and the underlying factors that account for this association. We find that credit scores are negatively correlated with cardiovascular disease risk. Variation in household income was not sufficient to account for this association. Rather, individual differences in human capital factors—educational attainment, cognitive ability, and self-control—predicted both credit scores and cardiovascular disease risk and accounted for ∼45% of the correlation between credit scores and cardiovascular disease risk. Tracing human capital factors back to their childhood antecedents revealed that the characteristic attitudes, behaviors, and competencies children develop in their first decade of life account for a significant portion (∼22%) of the link between credit scores and cardiovascular disease risk at midlife. We discuss the implications of these findings for policy debates about data privacy, financial literacy, and early childhood interventions.

  16. Credit scores, cardiovascular disease risk, and human capital

    Science.gov (United States)

    Israel, Salomon; Caspi, Avshalom; Belsky, Daniel W.; Harrington, HonaLee; Hogan, Sean; Houts, Renate; Ramrakha, Sandhya; Sanders, Seth; Poulton, Richie; Moffitt, Terrie E.

    2014-01-01

    Credit scores are the most widely used instruments to assess whether or not a person is a financial risk. Credit scoring has been so successful that it has expanded beyond lending and into our everyday lives, even to inform how insurers evaluate our health. The pervasive application of credit scoring has outpaced knowledge about why credit scores are such useful indicators of individual behavior. Here we test if the same factors that lead to poor credit scores also lead to poor health. Following the Dunedin (New Zealand) Longitudinal Study cohort of 1,037 study members, we examined the association between credit scores and cardiovascular disease risk and the underlying factors that account for this association. We find that credit scores are negatively correlated with cardiovascular disease risk. Variation in household income was not sufficient to account for this association. Rather, individual differences in human capital factors—educational attainment, cognitive ability, and self-control—predicted both credit scores and cardiovascular disease risk and accounted for ∼45% of the correlation between credit scores and cardiovascular disease risk. Tracing human capital factors back to their childhood antecedents revealed that the characteristic attitudes, behaviors, and competencies children develop in their first decade of life account for a significant portion (∼22%) of the link between credit scores and cardiovascular disease risk at midlife. We discuss the implications of these findings for policy debates about data privacy, financial literacy, and early childhood interventions. PMID:25404329

  17. Mitochondrial Genome Analyses Suggest Multiple Trichuris Species in Humans, Baboons, and Pigs from Different Geographical Regions.

    Directory of Open Access Journals (Sweden)

    Mohamed B F Hawash

    Full Text Available The whipworms Trichuris trichiura and Trichuris suis are two parasitic nematodes of humans and pigs, respectively. Although whipworms in human and non-human primates historically have been referred to as T. trichiura, recent reports suggest that several Trichuris spp. are found in primates.We sequenced and annotated complete mitochondrial genomes of Trichuris recovered from a human in Uganda, an olive baboon in the US, a hamadryas baboon in Denmark, and two pigs from Denmark and Uganda. Comparative analyses using other published mitochondrial genomes of Trichuris recovered from a human and a porcine host in China and from a françois' leaf-monkey (China were performed, including phylogenetic analyses and pairwise genetic and amino acid distances. Genetic and protein distances between human Trichuris in Uganda and China were high (~19% and 15%, respectively suggesting that they represented different species. Trichuris from the olive baboon in US was genetically related to human Trichuris in China, while the other from the hamadryas baboon in Denmark was nearly identical to human Trichuris from Uganda. Baboon-derived Trichuris was genetically distinct from Trichuris from françois' leaf monkey, suggesting multiple whipworm species circulating among non-human primates. The genetic and protein distances between pig Trichuris from Denmark and other regions were roughly 9% and 6%, respectively, while Chinese and Ugandan whipworms were more closely related.Our results indicate that Trichuris species infecting humans and pigs are phylogenetically distinct across geographical regions, which might have important implications for the implementation of suitable and effective control strategies in different regions. Moreover, we provide support for the hypothesis that Trichuris infecting primates represents a complex of cryptic species with some species being able to infect both humans and non-human primates.

  18. Characterization of annual disease progression of multiple sclerosis patients: A population-based study.

    Science.gov (United States)

    Freilich, Jonatan; Manouchehrinia, Ali; Trusheim, Mark; Baird, Lynn G; Desbiens, Sophie; Berndt, Ernst; Hillert, Jan

    2017-05-01

    Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan-Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching the milestone. To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition from each full EDSS with explanatory variables age, sex, age at onset, time in current EDSS, highest prior EDSS, MS course and treatment. All factors (except sex) investigated had statistically significant impacts on transitions from at least one EDSS. However, significance and size of the effect are dependent on the EDSS state of the patient. Greater age, longer time in a state, highest prior EDSS, having progressive MS and treatment had significant impacts, whereas age at onset had minor impact. Our study confirms that established factors associated with MS disease worsening in time to disease milestones also have impacts on annual progression. This approach adds granularity to what EDSS these factors have an influence.

  19. Multiple-locus variable-number tandem-repeat analysis (MLVA) genotyping of human Brucella isolates in Malaysia.

    Science.gov (United States)

    Tay, Bee Yong; Ahmad, Norazah; Hashim, Rohaidah; Mohamed Zahidi, Jama'ayah; Thong, Kwai Lin; Koh, Xiu Pei; Mohd Noor, Azura

    2015-06-02

    Brucellosis is one of the most common zoonotic diseases worldwide. It can cause acute febrile illness in human and is a major health problem. Studies in human brucellosis in Malaysia is limited and so far no genotyping studies has been done on Brucella isolates. The aim of the study was to determine the genetic diversity among Brucella species isolated from human brucellosis, obtained over a 6-year period (2009-2014). In this study, the genotypic characteristics of 43 human Brucella melitensis isolates were analysed using multiple-locus variable-number tandem-repeat analysis (MLVA) which consisted of eight minisatellite loci (panel 1) and eight microsatellite loci; panels 2A (3 microsatellite loci) and panel 2B (5 microsatellite loci). Two human Brucella suis isolates were also investigated using the MLVA assay. Using panel 1 (MLVA8), two genotypes namely genotype 43 and 44 were obtained from the 43 B. melitensis isolates. Using the combination of panels 1 and 2A loci (MLVA11), two genotypes were obtained while using the complete panels 1, 2A and 2B, nine genotypes were obtained. The polymorphisms in using the complete panels (MLVA16) were observed in three loci from panel 2B, which showed a diversity index higher than 0.17. All B. melitensis isolates were closely related to the East Mediterranean group. For B. suis isolates, only genotype 6 and genotype 33 were obtained using panel 1 and MLVA11 respectively. In conclusion, the results of the present study showed a low genetic diversity among B. melitensis and B. suis isolates from human patients. Based on the MLVA16 assay, B. melitensis belonging to the East Mediterranean group is responsible for the vast majority of Brucella infections in our Malaysian patients. To our knowledge, this is the first genotyping study of human Brucella isolates in Malaysia.

  20. Fostering adherence to injectable disease-modifying therapies in multiple sclerosis.

    Science.gov (United States)

    Lugaresi, Alessandra; Rottoli, Maria Rosa; Patti, Francesco

    2014-09-01

    Multiple sclerosis requires long-term management, often with disease-modifying therapies. Poor medication adherence, especially to injectables, can increase relapse and hospitalisation rates and consume healthcare resources. We discuss adherence definitions and terminology and its prevalence in multiple sclerosis (MS). Typical causes of poor adherence in patients with MS include: insufficient efficacy or tolerability, concurrent disorders, and consequences of MS (e.g., forgetfulness, depression, fatigue and poor motor skills). Ways to improve adherence rates are reviewed, focusing on interdisciplinary healthcare teams, good communication between healthcare workers and patients (and their families), ongoing support and digital tools to promote adherence. We consider open communication and continuing education to be key, and that MS nurses have a pivotal role in ensuring patients' adherence to MS medicines.

  1. Telmisartan Ameliorates Fibrocystic Liver Disease in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

    Science.gov (United States)

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M.; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  2. Lipidomics of human brain aging and Alzheimer's disease pathology.

    Science.gov (United States)

    Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

    2015-01-01

    Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

  3. Plant Polyphenols as Dietary Antioxidants in Human Health and Disease

    Directory of Open Access Journals (Sweden)

    Kanti Bhooshan Pandey

    2009-01-01

    Full Text Available Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In the last decade, there has been much interest in the potential health benefits of dietary plant polyphenols as antioxidant. Epidemiological studies and associated meta-analyses strongly suggest that long term consumption of diets rich in plant polyphenols offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases. Here we present knowledge about the biological effects of plant polyphenols in the context of relevance to human health.

  4. Pulmonary disease in patients with human immunodeficiency virus infection

    DEFF Research Database (Denmark)

    Lundgren, J D; Orholm, Marianne; Lundgren, B

    1989-01-01

    Pulmonary disease is the most important cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV). All parts of the hospital system are expected to be involved in the diagnosis and treatment of HIV infected patients in the coming years. Many different processes...... cause pulmonary disease alone or in combination. Bilateral interstitial infiltrates are the most frequent chest x-ray abnormality and are most frequently caused by infection with Pneumocystis carinii. Cytomegalovirus, Mycobacterium tuberculosis, nonspecific interstitial pneumonitis and pulmonary Kaposi...

  5. Tracking and Recognition of Multiple Human Targets Moving in a Wireless Pyroelectric Infrared Sensor Network

    Directory of Open Access Journals (Sweden)

    Ji Xiong

    2014-04-01

    Full Text Available With characteristics of low-cost and easy deployment, the distributed wireless pyroelectric infrared sensor network has attracted extensive interest, which aims to make it an alternate infrared video sensor in thermal biometric applications for tracking and identifying human targets. In these applications, effectively processing signals collected from sensors and extracting the features of different human targets has become crucial. This paper proposes the application of empirical mode decomposition and the Hilbert-Huang transform to extract features of moving human targets both in the time domain and the frequency domain. Moreover, the support vector machine is selected as the classifier. The experimental results demonstrate that by using this method the identification rates of multiple moving human targets are around 90%.

  6. Association of Parkinson disease-related protein PINK1 with Alzheimer disease and multiple sclerosis brain lesions.

    Science.gov (United States)

    Wilhelmus, Micha M M; van der Pol, Susanne M A; Jansen, Quentin; Witte, Maarten E; van der Valk, Paul; Rozemuller, Annemieke J M; Drukarch, Benjamin; de Vries, Helga E; Van Horssen, Jack

    2011-02-01

    Mitochondrial dysfunction and oxidative stress are hallmarks of various neurological disorders, including multiple sclerosis (MS), Alzheimer disease (AD), and Parkinson disease (PD). Mutations in PINK1, a mitochondrial kinase, have been linked to the occurrence of early onset parkinsonism. Currently, various studies support the notion of a neuroprotective role for PINK1, as it protects cells from stress-mediated mitochondrial dysfunction, oxidative stress, and apoptosis. Because information about the distribution pattern of PINK1 in neurological diseases other than PD is scarce, we here investigated PINK1 expression in well-characterized brain samples derived from MS and AD individuals using immunohistochemistry. In control gray matter PINK1 immunoreactivity was observed in neurons, particularly neurons in layers IV-VI. Astrocytes were the most prominent cell type decorated by anti-PINK1 antibody in the white matter. In addition, PINK1 staining was observed in the cerebrovasculature. In AD, PINK1 was found to colocalize with classic senile plaques and vascular amyloid depositions, as well as reactive astrocytes associated with the characteristic AD lesions. Interestingly, PINK1 was absent from neurofibrillary tangles. In active demyelinating MS lesions we observed a marked astrocytic PINK1 immunostaining, whereas astrocytes in chronic lesions were weakly stained. Taken together, we observed PINK1 immunostaining in both AD and MS lesions, predominantly in reactive astrocytes associated with these lesions, suggesting that the increase in astrocytic PINK1 protein might be an intrinsic protective mechanism to limit cellular injury. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. [Concordance between stratification systems and identification of patients with multiple chronic diseases in Primary Care].

    Science.gov (United States)

    Sánchez Mollá, M; Candela García, I; Gómez-Romero, F J; Orozco Beltrán, D; Ollero Baturone, M

    To determine the prevalence of patients with multiple chronic diseases in Primary Care using the multiple morbidity criteria and Clinical Risk Groups, and the agreement in identifying high-risk patients that require case management with both methods. A cross-sectional study was conducted on 240 patients, selected by random sampling of 16 care quotas from two Primary Health Care centres of a health area. Informed consent was obtained to access their electronic medical records for the study, and a record was made of age, sex, health status of Clinical Risk Groups, severity, multiple morbidity criteria, and Charlson index by physicians during clinical practice. Three patients were excluded due to incomplete data. The prevalence of patients with multiple chronic diseases following the criteria of the Ministry of Health among users was 4.11 (95% CI; 2.13-7.30). The frequency of patients with high risk Clinical Risk Groups (G3) in the chronicity strategy of Valencian Community was 7.59 (95% CI; 4.70-11.70), which includes patients with health status 6 and complexity level 5-6, and health status 7, 8, and 9. Agreement between the two classifications was low, with a kappa index 0.17 (95% CI; 0-0.5) CONCLUSIONS: The prevalence did not differ significantly from that expected, and the agreement between the two stratifications was very weak, not selecting the same patients for highly complex case management. Copyright © 2016 SECA. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. 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.

  9. Recent genetic discoveries implicating ion channels in human cardiovascular diseases.

    Science.gov (United States)

    George, Alfred L

    2014-04-01

    The term 'channelopathy' refers to human genetic disorders caused by mutations in genes encoding ion channels or their interacting proteins. Recent advances in this field have been enabled by next-generation DNA sequencing strategies such as whole exome sequencing with several intriguing and unexpected discoveries. This review highlights important discoveries implicating ion channels or ion channel modulators in cardiovascular disorders including cardiac arrhythmia susceptibility, cardiac conduction phenotypes, pulmonary and systemic hypertension. These recent discoveries further emphasize the importance of ion channels in the pathophysiology of human disease and as important druggable targets.

  10. Adult human metapneumonovirus (hMPV) pneumonia mimicking Legionnaire's disease.

    Science.gov (United States)

    Cunha, Burke A; Irshad, Nadia; Connolly, James J

    2016-01-01

    In adults hospitalized with viral pneumonias the main differential diagnostic consideration is influenza pneumonia. The respiratory viruses causing viral influenza like illnesses (ILIs), e.g., RSV may closely resemble influenza. Rarely, extrapulmonary findings of some ILIs may resemble Legionnaire's disease (LD), e.g., adenovirus, human parainfluenza virus (HPIV-3). We present a most unusual case of human metapneumonovirus pneumonia (hMPV) with some characteristic extrapulmonary findings characteristic of LD, e.g., relative bradycardia, as well as mildly elevated serum transaminases and hyphosphatemia. We believe this is the first reported case of hMPV pneumonia in a hospitalized adult that had some features of LD.

  11. One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug.

    Science.gov (United States)

    Hughes, Rebecca E; Nikolic, Katarina; Ramsay, Rona R

    2016-01-01

    HIGHLIGHTS Many AD target combinations are being explored for multi-target drug design.New databases and models increase the potential of computational drug designLiraglutide and other antidiabetics are strong candidates for repurposing to AD.Donecopride a dual 5-HT/AChE inhibitor shows promise in pre-clinical studies Alzheimer's Disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs (MTDs). Intended as an introduction for non-experts, this review describes the key MTD design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch, and the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer's Disease are rasagiline, originally developed for the treatment of Parkinson's Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

  12. 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.

  13. Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome

    DEFF Research Database (Denmark)

    Lohmueller, Kirk E; Albrechtsen, Anders; Li, Yingrui

    2011-01-01

    A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries...... affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations....... these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination...

  14. Cellular reprogramming for understanding and treating human disease.

    Directory of Open Access Journals (Sweden)

    Riya Rajan Kanherkar

    2014-11-01

    Full Text Available In the last two decades we have witnessed a paradigm shift in our understanding of cells so radical that it has rewritten the rules of biology. The study of cellular reprogramming has gone from little more than a hypothesis, to applied bioengineering, with the creation of a variety of important cell types. By way of metaphor, we can compare the discovery of reprogramming with the archaeological discovery of the Rosetta stone. This stone slab made possible the initial decipherment of Egyptian hieroglyphics because it allowed us to see this language in a way that was previously impossible. We propose that cellular reprogramming will have an equally profound impact on understanding and curing human disease, because it allows us to perceive and study molecular biological processes such as differentiation, epigenetics, and chromatin in ways that were likewise previously impossible. Stem cells could be called cellular Rosetta stones because they allow also us to perceive the connections between development, disease, cancer, aging, and regeneration in novel ways. Here we present a comprehensive historical review of stem cells and cellular reprogramming, and illustrate the developing synergy between many previously unconnected fields. We show how stem cells can be used to create in vitro models of human disease and provide examples of how reprogramming is being used to study and treat such diverse diseases as cancer, aging and accelerated aging syndromes, infectious diseases such as AIDS, and epigenetic diseases such as polycystic ovary syndrome. While the technology of reprogramming is being developed and refined there have also been significant ongoing developments in other complementary technologies such as gene editing, progenitor cell production, and tissue engineering. These technologies are the foundations of what is becoming a fully-functional field of regenerative medicine and are converging to a point that will allow us to treat almost any

  15. MiR-191 Regulates Primary Human Fibroblast Proliferation and Directly Targets Multiple Oncogenes.

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    Damon Polioudakis

    Full Text Available miRNAs play a central role in numerous pathologies including multiple cancer types. miR-191 has predominantly been studied as an oncogene, but the role of miR-191 in the proliferation of primary cells is not well characterized, and the miR-191 targetome has not been experimentally profiled. Here we utilized RNA induced silencing complex immunoprecipitations as well as gene expression profiling to construct a genome wide miR-191 target profile. We show that miR-191 represses proliferation in primary human fibroblasts, identify multiple proto-oncogenes as novel miR-191 targets, including CDK9, NOTCH2, and RPS6KA3, and present evidence that miR-191 extensively mediates target expression through coding sequence (CDS pairing. Our results provide a comprehensive genome wide miR-191 target profile, and demonstrate miR-191's regulation of primary human fibroblast proliferation.

  16. MiR-191 Regulates Primary Human Fibroblast Proliferation and Directly Targets Multiple Oncogenes.

    Science.gov (United States)

    Polioudakis, Damon; Abell, Nathan S; Iyer, Vishwanath R

    2015-01-01

    miRNAs play a central role in numerous pathologies including multiple cancer types. miR-191 has predominantly been studied as an oncogene, but the role of miR-191 in the proliferation of primary cells is not well characterized, and the miR-191 targetome has not been experimentally profiled. Here we utilized RNA induced silencing complex immunoprecipitations as well as gene expression profiling to construct a genome wide miR-191 target profile. We show that miR-191 represses proliferation in primary human fibroblasts, identify multiple proto-oncogenes as novel miR-191 targets, including CDK9, NOTCH2, and RPS6KA3, and present evidence that miR-191 extensively mediates target expression through coding sequence (CDS) pairing. Our results provide a comprehensive genome wide miR-191 target profile, and demonstrate miR-191's regulation of primary human fibroblast proliferation.

  17. Human bulbar conjunctival hemodynamics in hemoglobin SS and SC disease.

    Science.gov (United States)

    Wanek, Justin; Gaynes, Bruce; Lim, Jennifer I; Molokie, Robert; Shahidi, Mahnaz

    2013-08-01

    The known biophysical variations of hemoglobin (Hb) S and Hb C may result in hemodynamic differences between subjects with SS and SC disease. The purpose of this study was to measure and compare conjunctival hemodynamics between subjects with Hb SS and SC hemoglobinopathies. Image sequences of the conjunctival microcirculation were acquired in 9 healthy control subjects (Hb AA), 24 subjects with SC disease, and 18 subjects with SS disease, using a prototype imaging system. Diameter (D) and blood velocity (V) measurements were obtained in multiple venules of each subject. Data were categorized according to venule caliber by averaging V and D for venules with diameters less than (vessel size 1) or greater than (vessel size 2) 15 µm. V in vessel size 2 was significantly greater than V in vessel size 1 in the AA and SS groups (P ≥ 0.009), but not in the SC group (P = 0.1). V was significantly lower in the SC group as compared to the SS group (P = 0.03). In AA and SS groups, V correlated with D (P ≤ 0.005), but the correlation was not statistically significant in the SC group (P = 0.08). V was inversely correlated with hematocrit in the SS group for large vessels (P = 0.03); however, no significant correlation was found in the SC group (P ≥ 0.2). Quantitative assessment of conjunctival microvascular hemodynamics in SS and SC disease may advance understanding of sickle cell disease pathophysiology and thereby improve therapeutic interventions.

  18. Multiple de novo vascular malformations in relation to diffuse venous occlusive disease: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Desal, H.A. [Hopital Laennec, University of Nantes, Department of Neuroradiology, Nantes (France); Toronto Western Hospital, Department of Medical Imaging, University Health Network, Toronto, Ont. (Canada); Lee, S.K.; Kim, B.S.; TerBrugge, K.G. [Toronto Western Hospital, Department of Medical Imaging, University Health Network, Toronto, Ont. (Canada); Raoul, S.; Tymianski, M. [Toronto Western Hospital, Department of Neurosurgery, University Health Network, Toronto, Ont. (Canada)

    2005-01-01

    Brain vascular malformations are dynamic disorders. Although mostly considered to be of congenital origin, the improvement of clinical imaging and vasculogenesis knowledge has shown that they might also result from a biological dysfunction of the remodeling process after birth. Venous occlusive disease and ishemia may represent powerful revealing triggers and support the capillary venous origin of some vascular malformations. We report a unique case of the development of multiple de novo vascular malformations (transverse sinus dural fistula and posterior fossa cavernomas) following acoustic neuroma surgery. (orig.)

  19. On the multiple roles of the voltage gated sodium channel β1 subunit in genetic diseases

    Directory of Open Access Journals (Sweden)

    Debora eBaroni

    2015-05-01

    Full Text Available Voltage-gated sodium channels are intrinsic plasma membrane proteins that initiate the action potential in electrically excitable cells. They are composed of a pore-forming α-subunit and associated β-subunits. The β1-subunit was the first accessory subunit to be cloned. It can be important for controlling cell excitability and modulating multiple aspects of sodium channel physiology. Mutations of β1 are implicated in a wide variety of inherited pathologies, including epilepsy and cardiac conduction diseases. This review summarizes β1-subunit related channelopathies pointing out the current knowledge concerning their genetic background and their underlying molecular mechanisms.

  20. Multiple luteinizing hormone receptor (LHR protein variants, interspecies reactivity of anti-LHR mAb clone 3B5, subcellular localization of LHR in human placenta, pelvic floor and brain, and possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders and Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Fernando Romaine I

    2003-06-01

    Full Text Available Abstract Distinct luteinizing hormone receptor (LHR protein variants exist due to the posttranslational modifications. Besides ovaries, LHR immunoreactivity (LHRI was also found in other tissues, such as the brain, fallopian tube, endometrium, trophoblast and resident tissue macrophages. The 3B5 mouse monoclonal antibody was raised against purified rat LHR. In rat, porcine and human ovaries, the 3B5 identified six distinct LHR bands migrating at ~92, 80, 68, 59, 52 and 48 kDa. Characteristic LHRI was detected in rat, human and porcine corpora lutea. During cellular differentiation, subcellular LHR distribution changed from none to granular cytoplasmic, perinuclear, surface, nuclear and no staining. There were also differences in vascular LHR expression – lack of LHRI in ovarian vessels and strong staining of vessels in other tissues investigated. In normal human term placentae, villous LHRI was associated with blood sinusoids and cytotrophoblast cells, and rarely detected in trophoblastic syncytium. In all abnormal placentae, the LHRI of sinusoids was absent, and syncytium showed either enhanced (immature placental phenotypes or no LHRI (aged placental phenotype. LHRI in human brain was identified in microglial cells (CD68+ resident macrophages. Protein extracts from human vaginal wall and levator ani muscle and fascia showed strong ~92 and 68 kDa species, and LHRI was detected in smooth muscle cells, fibroblasts, resident macrophages and nuclei of skeletal muscle fibers. Our observations indicate that, in contrast to the theory on the role of vascular hormone receptors in preferential pick up of circulating hormones, there is no need to enhance selective pick up rather only prevent LH/CG transport to inappropriate sites. Abnormal placental LHR expression may play a role in the development of abnormal pregnancy. Expression of LHR in the pelvic floor compartments suggests that high LH levels in postmenopausal women may contribute to the pelvic

  1. Multiple luteinizing hormone receptor (LHR) protein variants, interspecies reactivity of anti-LHR mAb clone 3B5, subcellular localization of LHR in human placenta, pelvic floor and brain, and possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders and Alzheimer's disease.

    Science.gov (United States)

    Bukovsky, Antonin; Indrapichate, Korakod; Fujiwara, Hiroshi; Cekanova, Maria; Ayala, Maria E; Dominguez, Roberto; Caudle, Michael R; Wimalsena, Jay; Elder, Robert F; Copas, Pleas; Foster, James S; Fernando, Romaine I; Henley, Donald C; Upadhyaya, Nirmala B

    2003-06-03

    Distinct luteinizing hormone receptor (LHR) protein variants exist due to the posttranslational modifications. Besides ovaries, LHR immunoreactivity (LHRI) was also found in other tissues, such as the brain, fallopian tube, endometrium, trophoblast and resident tissue macrophages. The 3B5 mouse monoclonal antibody was raised against purified rat LHR. In rat, porcine and human ovaries, the 3B5 identified six distinct LHR bands migrating at approximately 92, 80, 68, 59, 52 and 48 kDa. Characteristic LHRI was detected in rat, human and porcine corpora lutea. During cellular differentiation, subcellular LHR distribution changed from none to granular cytoplasmic, perinuclear, surface, nuclear and no staining. There were also differences in vascular LHR expression--lack of LHRI in ovarian vessels and strong staining of vessels in other tissues investigated. In normal human term placentae, villous LHRI was associated with blood sinusoids and cytotrophoblast cells, and rarely detected in trophoblastic syncytium. In all abnormal placentae, the LHRI of sinusoids was absent, and syncytium showed either enhanced (immature placental phenotypes) or no LHRI (aged placental phenotype). LHRI in human brain was identified in microglial cells (CD68+ resident macrophages). Protein extracts from human vaginal wall and levator ani muscle and fascia showed strong approximately 92 and 68 kDa species, and LHRI was detected in smooth muscle cells, fibroblasts, resident macrophages and nuclei of skeletal muscle fibers. Our observations indicate that, in contrast to the theory on the role of vascular hormone receptors in preferential pick up of circulating hormones, there is no need to enhance selective pick up rather only prevent LH/CG transport to inappropriate sites. Abnormal placental LHR expression may play a role in the development of abnormal pregnancy. Expression of LHR in the pelvic floor compartments suggests that high LH levels in postmenopausal women may contribute to the pelvic

  2. Grape Polyphenols’ Effects in Human Cardiovascular Diseases and Diabetes

    Directory of Open Access Journals (Sweden)

    Zuriñe Rasines-Perea

    2017-01-01

    Full Text Available The consumption of fruits and vegetables, as well as foods enriched in bioactive compounds and nutraceuticals, has increased due to consumers’ interest in the relevance of food composition for human health. Considerable recent interest has focused on bioactive phenolic compounds in grape, as they possess many biological activities, such as antioxidant, cardioprotective, anticancer, anti-inflammation, anti-ageing and antimicrobial properties. Observational studies indicate that the intake of polyphenol-rich foods improves vascular health, thereby significantly reducing the risk of hypertension, and cardiovascular disease (CVD. Other researchers have described the benefits of a grape polyphenol-rich diet for other types of maladies such as diabetes mellitus. This is a comprehensive review on the consumption of polyphenolic grape compounds, concerning their potential benefits for human health in the treatment of cardiovascular diseases and diabetes.

  3. Grape Polyphenols' Effects in Human Cardiovascular Diseases and Diabetes.

    Science.gov (United States)

    Rasines-Perea, Zuriñe; Teissedre, Pierre-Louis

    2017-01-01

    The consumption of fruits and vegetables, as well as foods enriched in bioactive compounds and nutraceuticals, has increased due to consumers' interest in the relevance of food composition for human health. Considerable recent interest has focused on bioactive phenolic compounds in grape, as they possess many biological activities, such as antioxidant, cardioprotective, anticancer, anti-inflammation, anti-ageing and antimicrobial properties. Observational studies indicate that the intake of polyphenol-rich foods improves vascular health, thereby significantly reducing the risk of hypertension, and cardiovascular disease (CVD). Other researchers have described the benefits of a grape polyphenol-rich diet for other types of maladies such as diabetes mellitus. This is a comprehensive review on the consumption of polyphenolic grape compounds, concerning their potential benefits for human health in the treatment of cardiovascular diseases and diabetes.

  4. Mitochondrial protein import and human health and disease.

    Science.gov (United States)

    MacKenzie, James A; Payne, R Mark

    2007-05-01

    The targeting and assembly of nuclear-encoded mitochondrial proteins are essential processes because the energy supply of humans is dependent upon the proper functioning of mitochondria. Defective import of mitochondrial proteins can arise from mutations in the targeting signals within precursor proteins, from mutations that disrupt the proper functioning of the import machinery, or from deficiencies in the chaperones involved in the proper folding and assembly of proteins once they are imported. Defects in these steps of import have been shown to lead to oxidative stress, neurodegenerative diseases, and metabolic disorders. In addition, protein import into mitochondria has been found to be a dynamically regulated process that varies in response to conditions such as oxidative stress, aging, drug treatment, and exercise. This review focuses on how mitochondrial protein import affects human health and disease.

  5. Assessing the human gut microbiota in metabolic diseases.

    Science.gov (United States)

    Karlsson, Fredrik; Tremaroli, Valentina; Nielsen, Jens; Bäckhed, Fredrik

    2013-10-01

    Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens-derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology.

  6. Genetic control of human brain transcript expression in Alzheimer disease.

    Science.gov (United States)

    Webster, Jennifer A; Gibbs, J Raphael; Clarke, Jennifer; Ray, Monika; Zhang, Weixiong; Holmans, Peter; Rohrer, Kristen; Zhao, Alice; Marlowe, Lauren; Kaleem, Mona; McCorquodale, Donald S; Cuello, Cindy; Leung, Doris; Bryden, Leslie; Nath, Priti; Zismann, Victoria L; Joshipura, Keta; Huentelman, Matthew J; Hu-Lince, Diane; Coon, Keith D; Craig, David W; Pearson, John V; Heward, Christopher B; Reiman, Eric M; Stephan, Dietrich; Hardy, John; Myers, Amanda J

    2009-04-01

    We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

  7. Diagnosis of human heritable diseases--laboratory approaches and outcomes.

    Science.gov (United States)

    Dowton, S B; Slaugh, R A

    1995-05-01

    Detection of mutant human genes is rapidly becoming an integral part of clinical practice. Human disease may arise by genetic deletion, insertion, fusion, point mutation, or amplification of unstable sequences. Such changes in structure may occur in germ cells or somatically. Rapid advances in understanding the complex nuclear and mitochondrial genomes necessitates deployment of a variety of methods to identify aberrant genes. These techniques include polymerase chain reaction, Southern transfer, and allele-specific hybridization studies, as well as methods to unmask mismatches between mutant and normal sequences. Development of protein truncation tests has added a vehicle for assessing larger DNA segments for mutations that cause premature translational termination. Linkage analysis remains an important tool where direct assay of disease-causing mutations is not possible. Considerations of confidentiality, informed consent, and insurability are important whenever genetic testing is used. These issues will assume increasing importance as presymptomatic testing for heritable predispositions emerges for common conditions.

  8. High Leptospira Diversity in Animals and Humans Complicates the Search for Common Reservoirs of Human Disease in Rural Ecuador

    Science.gov (United States)

    Chiriboga, Jorge; Miller, Erin; Olivas, Sonora; Birdsell, Dawn; Hepp, Crystal; Hornstra, Heidie; Schupp, James M.; Morales, Melba; Gonzalez, Manuel; Reyes, Soraya; de la Cruz, Carmen; Keim, Paul; Hartskeerl, Rudy; Trueba, Gabriel; Pearson, Talima

    2016-01-01

    Background Leptospirosis is a zoonotic disease responsible for high morbidity around the world, especially in tropical and low income countries. Rats are thought to be the main vector of human leptospirosis in urban settings. However, differences between urban and low-income rural communities provide additional insights into the epidemiology of the disease. Methodology/Principal findings Our study was conducted in two low-income rural communities near the coast of Ecuador. We detected and characterized infectious leptospira DNA in a wide variety of samples using new real time quantitative PCR assays and amplicon sequencing. We detected infectious leptospira in a high percentage of febrile patients (14.7%). In contrast to previous studies on leptospirosis risk factors, higher positivity was not found in rats (3.0%) but rather in cows (35.8%) and pigs (21.1%). Six leptospira species were identified (L. borgpetersenii, L kirschnerii, L santarosai, L. interrogans, L noguchii, and an intermediate species within the L. licerasiae and L. wolffii clade) and no significant differences in the species of leptospira present in each animal species was detected (χ2 = 9.89, adj.p-value = 0.27). Conclusions/Significance A large portion of the world’s human population lives in low-income, rural communities, however, there is limited information about leptospirosis transmission dynamics in these settings. In these areas, exposure to peridomestic livestock is particularly common and high prevalence of infectious leptospira in cows and pigs suggest that they may be the most important reservoir for human transmission. Genotyping clinical samples show that multiple species of leptospira are involved in human disease. As these genotypes were also detected in samples from a variety of animals, genotype data must be used in conjunction with epidemiological data to provide evidence of transmission and the importance of different potential leptospirosis reservoirs. PMID:27622673

  9. International Frameworks Dealing with Human Risk Assessment of Combined Exposure to Multiple Chemicals

    Directory of Open Access Journals (Sweden)

    European Food Safety Authority

    2013-07-01

    Full Text Available The development of harmonised terminology and frameworks for the human risk assessment of combined exposure to multiple chemicals (“chemical mixtures” is an important area for EFSA and a number of activities have already been undertaken, i.e. in the fields of pesticides and contaminants. The first step prior to a risk assessment of combined exposure to multiple chemicals is problem formulation defining the relevant exposure, hazard and population to be considered. In practice, risk assessment of multiple chemicals is conducted using a tiered approach for exposure assessment, hazard assessment and risk characterisation. Higher tiers require increasing knowledge about the group of chemicals under assessment and the tiers can range from tier 0 (default values, data poor situation to tier 3 (full probabilistic models. This scientific report reviews the terminology, methodologies and frameworks developed by national and international agencies for the human risk assessment of combined exposure to multiple chemicals and provides recommendations for future activities at EFSA in this area.

  10. Multiple endocrine neoplasia type II B with symptoms suggesting Hirschsprung's disease: a case report.

    Science.gov (United States)

    Mahaffey, S M; Martin, L W; McAdams, A J; Ryckman, F C; Torres, M

    1990-01-01

    A 3-year-old child was referred with a tentative diagnosis of Hirschsprung's disease because of life-long constipation and "megacolon" demonstrated radiographically. Our rectal biopsy revealed hyperganglionosis suggestive of multiple endocrine neoplasia (MEN) type II B. This, in addition to an elevated serum calcitonin level, prompted surgical removal of her thyroid, which appeared grossly normal but on sectioning, contained a medullary carcinoma in each lobe. She remains disease-free 5 years later. Gastrointestinal symptoms are a significant component of the MEN type II B syndrome, and often antedate the full phenotypic expression of the syndrome and the development of potentially lethal endocrine neoplasms. On the basis of this experience, it is recommended that MEN II B be included in the differential diagnosis of chronic constipation.

  11. The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases.

    Science.gov (United States)

    Mao-Draayer, Yang; Sarazin, Jeffrey; Fox, David; Schiopu, Elena

    2017-02-01

    Multiple sclerosis (MS) is a prototype autoimmune disease of the central nervous system (CNS). Currently, there is no drug that provides a cure for MS. To date, all immunotherapeutic drugs target relapsing remitting MS (RR-MS); it remains a daunting medical challenge in MS to develop therapy for secondary progressive MS (SP-MS). Since the approval of the non-selective sphingosine-1-phosphate (S1P) receptor modulator FTY720 (fingolimod [Gilenya®]) for RR-MS in 2010, there have been many emerging studies with various selective S1P receptor modulators in other autoimmune conditions. In this article, we will review how S1P receptor may be a promising therapeutic target for SP-MS and other autoimmune diseases such as psoriasis, polymyositis and lupus.

  12. Ileal atresia and multiple jejunal perforations in a premature neonate with gestational alloimmune liver disease

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    Ryan M. McAdams, MD

    2017-04-01

    Full Text Available Recovery after surgical repair of an ileal atresia with or without intestinal perforation requires prolonged exposure to parenteral nutrition (PN that may lead to PN-associated liver disease. Early liver failure and cholestasis out of proportion for PN exposure may be a harbinger for gestational alloimmune liver disease (GALD, a potentially life-threatening condition that often requires liver transplant if not treated in a timely manner. This case report presents a premature neonate with ileal atresia and multiple jejunal perforations who developed liver failure and was later determined to have GALD. Recognition of clinical and laboratory findings consistent with GALD is essential to promote early treatment, which can enhance neonatal outcomes and impact future pregnancies.

  13. Under the lash: Demodex mites in human diseases.

    Science.gov (United States)

    Lacey, Noreen; Kavanagh, Kevin; Tseng, Scheffer C G

    2009-08-01

    Demodex mites, class Arachnida and subclass Acarina, are elongated mites with clear cephalothorax and abdomens, the former with four pairs of legs. There are more than 100 species of Demodex mite, many of which are obligatory commensals of the pilosebaceous unit of mammals including cats, dogs, sheep, cattle, pigs, goats, deer, bats, hamsters, rats and mice. Among them, Demodex canis, which is found ubiquitously in dogs, is the most documented and investigated. In excessive numbers D. canis causes the inflammatory disease termed demodicosis (demodectic mange, follicular mange or red mange), which is more common in purebred dogs and has a hereditary predisposition in breeding kennels1. Two distinct Demodex species have been confirmed as the most common ectoparasite in man. The larger Demodex folliculorum, about 0.3-0.4 mm long, is primarily found as a cluster in the hair follicle (Figure 1a), while the smaller Demodex brevis, about 0.2-0.3 mm long with a spindle shape and stubby legs, resides solitarily in the sebaceous gland (Figure 1b). These two species are also ubiquitously found in all human races without gender preference. The pathogenic role of Demodex mites in veterinary medicine is not as greatly disputed as in human diseases. In this article, we review the key literature and our joint research experience regarding the pathogenic potential of these two mites in causing inflammatory diseases of human skin and eye. We hope that the evidence summarized herein will invite readers to take a different look at the life of Demodex mites in several common human diseases.

  14. Does biodiversity protect humans against infectious disease? Reply

    Science.gov (United States)

    Wood, Chelsea L.; Lafferty, Kevin D.; DeLeo, Giulio; Young, Hillary S.; Hudson, Peter J.; Kuris, Armand M.

    2016-01-01

    The dilution effect is the sort of idea that everyone wants to be true. If nature protects humans against infectious disease, imagine the implications: nature's value could be tallied in terms of human suffering avoided. This makes a potent argument for conservation, convincing even to those who would otherwise be disinclined to support conservation initiatives. The appeal of the dilution effect has been recognized by others: “the desire to make the case for conservation has led to broad claims regarding the benefits of nature conservation for human health” (Bauch et al. 2015). Randolph and Dobson (2012) were among the first to critique these claims, making the case that promotion of conservation to reduce Lyme disease risk, although well intentioned, was flawed. Along with Randolph and Dobson's critique, there have been several calls for a more nuanced scientific assessment of the relationship between biodiversity and disease transmission (Dunn 2010, Salkeld et al. 2013, Wood and Lafferty 2013, Young et al. 2013). In response, supporters of the dilution effect have instead increased the scope of their generalizations with review papers, press rele