Multifactorial Disease Model Research Articles

Degenerative Nucleus Pulposus Cells Derived Exosomes Promoted Cartilage Endplate Cells Apoptosis and Aggravated Intervertebral Disc Degeneration.

Intervertebral disc (IVD) degeneration is a complex multifactorial disease model, which pathogenesis has not been fully defined. There are few studies on the information interaction between nucleus pulposus (NP) cells and cartilage endplate (CEP) cells. Exosomes, as a carrier of information communication between cells, have become a research hotspot recently. The purpose of this study was to explore whether degenerative NP cells-derived exosomes promoted CEP cells apoptosis and aggravated IVD degeneration. The degenerative NP cells model was induced by TNFα. NPC exosomes were isolated from the supernatant of the NP cell culture medium. The viability of NP cells and CEP cells was examined by CCK-8 assays. The exosomes were identified by TEM, NTA, and western blot. Extracellular matrix (ECM) metabolism was measured by cellular immunofluorescence and qRT-PCR. Apoptosis was detected by flow cytometry and TUNEL. X-ray and magnetic resonance imaging (MRI), as well as hematoxylin-eosin (H&E), Safranine O-Green staining was adopted to evaluate IVD degeneration grades. TNFα had a minor impact on NPC viability but inhibited ECM synthesis and promoted ECM degradation. TNFα-NPC-Exo had less effect on CEPC proliferation but promoted CEPC apoptosis and affect ECM metabolism, inhibiting aggrecan and collagen II expression and enhancing MMP-3 expression. TNFα-NPC-Exo aggravates IVD degeneration in a rat model and promoted CEPC apoptosis. In conclusion, this study demonstrated that degenerated NPC-exosome could induce apoptosis of CEPCs, inhibit ECM synthesis, and promote ECM degradation. In addition, it was proved that degenerated NPC-exosome aggravates IVD degeneration.

The Molecular Pathophysiology of Psoriatic Arthritis-The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome.

Psoriasis is a symmetric autoimmune/inflammatory disease that primarily affects the skin. In a significant proportion of cases, it is accompanied by arthritis that can affect any joint, the spine, and/or include enthesitis. Psoriasis and psoriatic arthritis are multifactor disorders characterized by aberrant immune responses in genetically susceptible individuals in the presence of additional (environmental) factors, including changes in microbiota and/or epigenetic marks. Epigenetic changes can be heritable or acquired (e.g., through changes in diet/microbiota or as a response to therapeutics) and, together with genetic factors, contribute to disease expression. In psoriasis, epigenetic alterations are mainly related to cell proliferation, cytokine signaling and microbial tolerance. Understanding the complex interplay between heritable and acquired pathomechanistic factors contributing to the development and maintenance of psoriasis is crucial for the identification and validation of diagnostic and predictive biomarkers, and the introduction of individualized effective and tolerable new treatments. This review summarizes the current understanding of immune activation, genetic, and environmental factors that contribute to the pathogenesis of psoriatic arthritis. Particular focus is on the interactions between these factors to propose a multifactorial disease model.

A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer\u2019s disease

Presenilin-1 (PSEN1) mutations cause familial Alzheimer’s disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30 years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 patients focusing on generation and deposition of beta-amyloid (Aβ) and Tau pathology profile. In 14 patients distributed at the extremes of AoO, we performed whole-exome capture to identify genotype–phenotype correlations. We also studied kinome activity, proteasome activity, and protein polyubiquitination in brain tissue, associating it with Tau phosphorylation profiles. PSEN1-E280A patients showed a bimodal distribution for AoO. Besides AoO, there were no clinical differences between analyzed groups. Despite the effect of mutant PSEN1 on production of Aβ, there were no relevant differences between groups in generation and deposition of Aβ. However, differences were found in hyperphosphorylated Tau (pTau) pathology, where early onset patients showed severe pathology with diffuse aggregation pattern associated with increased activation of stress kinases. In contrast, late-onset patients showed lesser pTau pathology and a distinctive kinase activity. Furthermore, we identified new protective genetic variants affecting ubiquitin–proteasome function in early onset patients, resulting in higher ubiquitin-dependent degradation of differentially phosphorylated Tau. In PSEN1-E280A carriers, altered γ-secretase activity and resulting Aβ accumulation are prerequisites for early AoO. However, Tau hyperphosphorylation pattern, and its degradation by the proteasome, drastically influences disease onset in individuals with otherwise similar Aβ pathology, hinting toward a multifactorial model of disease for FAD. In sporadic AD (SAD), a wide range of heterogeneity, also influenced by Tau pathology, has been identified. Thus, Tau-induced heterogeneity is a common feature in both AD variants, suggesting that a multi-target therapeutic approach should be used to treat AD.

Towards a Central Role of ISL1 in the Bladder Exstrophy⁻Epispadias Complex (BEEC): Computational Characterization of Genetic Variants and Structural Modelling.

Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). At this point, ISL1 (ISL LIM homeobox 1) has emerged as the major susceptibility gene for classic bladder exstrophy (CBE), in a multifactorial disease model. Here, GWAS (Genome wide association studies) discovery and replication studies, as well as the re-sequencing of ISL1, identified sequence variants (rs9291768, rs6874700, c.137C > G (p.Ala46Gly)) associated with CBE. Here, we aimed to determine the molecular and functional consequences of these sequence variants and estimate the dependence of ISL1 protein on other predicted candidates. We used: (i) computational analysis of conserved sequence motifs to perform an evolutionary conservation analysis, based on a Bayesian algorithm, and (ii) computational 3D structural modeling. Furthermore, we looked into long non-coding RNAs (lncRNAs) residing within the ISL1 region, aiming to predict their targets. Our analysis suggests that the ISL1 protein specific N-terminal LIM domain (which harbors the variant c.137C > G), limits its transcriptional ability, and might interfere with ISL1-estrogen receptor α interactions. In conclusion, our analysis provides further useful insights about the ISL1 gene, which is involved in the formation of the BEEC, and in the development of the urinary bladder.

Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

BackgroundIntrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies.Methods and resultsUsing Illumina’s 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM.ConclusionsOur study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures.

Epigenetic Dysregulation in the Prefrontal Cortex of Suicide Completers

The epigenome is thought to mediate between genes and the environment, particularly in response to adverse life experiences. Similar to other psychiatric diseases, the suicide liability of an individual appears to be influenced by many genetic factors of small effect size as well as by environmental stressors. To identify epigenetic marks associated with suicide, which is considered the endpoint of complex gene-environment interactions, we compared the cortex DNA methylation patterns of 6 suicide completers versus 6 non-psychiatric sudden-death controls, using Illumina 450K methylation arrays. Consistent with a multifactorial disease model, we found DNA methylation changes in a large number of genes, but no changes with large effects reaching genome-wide significance. Global methylation of all analyzed CpG sites was significantly (0.25 percentage point) lower in suicide than in control brains, whereas the vast majority (97%) of the top 1,000 differentially methylated regions (DMRs) were higher methylated (0.6 percentage point) in suicide brains. Annotation analysis of the top 1,000 DMRs revealed an enrichment of differentially methylated promoters in functional categories associated with transcription and expression in the brain. In addition, we performed a comprehensive literature research to identify suicide genes that have been replicated in independent genetic association, brain methylation and/or expression studies. Although, in general, there was no significant overlap between different published data sets or between our top 1,000 DMRs and published data sets, our methylation screen strengthens a number of candidate genes (APLP2, BDNF, HTR1A, NUAK1, PHACTR3, MSMP, SLC6A4, SYN2, and SYNE2) and supports a role for epigenetics in the pathophysiology of suicide.

Functional (psychogenic) movement disorders.

This review provides an overview of recent developments in diagnosis, pathophysiology, neuroimaging and management of functional (psychogenic) movement disorders (FMD). There has been increasing interest to study the underlying pathophysiology of FMD, which has resulted in a broadened disease model, taking neurobiologic and psychosocial factors equally into account. In this context, the term 'psychogenic' has been replaced by 'functional' movement disorders by many authors in the field to express the changing focus toward a multifactorial disease model. The need for establishing a positive diagnosis of FMD as opposed to providing a diagnosis of exclusion is increasingly recognized and reflected by the introduction of 'laboratory-supported' diagnostic criteria of FMD. Important advances have been made through behavioral, electrophysiological and neuroimaging studies, although the fundamental cause of FMD remains poorly understood. Of particular interest have been several reports on abnormal sensorimotor features and cortical inhibition in both organic and functional dystonia, highlighting possible shared traits of both conditions. In terms of treatment, recent studies have reported benefit from both psychiatric and physical therapy-based interventions. Increasing efforts have been made toward better understanding of FMD, and the disease model has been broadened to include neurobiologic and psychosocial factors. Laboratory-based diagnostic criteria have been established for many FMD to support the clinical diagnosis. To determine the most effective management strategies for FMD, a closer collaboration between neurologists and psychiatrists and intensified research efforts with prospective treatment trials are needed.

Causation and models of disease in epidemiology

Nineteenth-century medical advances were entwined with a conceptual innovation: the idea that many cases of disease which were previously thought to have diverse causes could be explained by the action of a single kind of cause, for example a certain bacterial or parasitic infestation. The focus of modern epidemiology, however, is on chronic non-communicable diseases, which frequently do not seem to be attributable to any single causal factor. This paper is an effort to resolve the resulting tension. The paper criticises the monocausal model of disease, so successful in the nineteenth century. It also argues that a multifactorial model of disease can only be satisfactory if it amounts to more than a mere rejection of the monocausal model. A third alternative, the contrastive model, is proposed and defended on the grounds that it links the notions of disease and of general explanation, while avoiding the philosophical naiveties and practical difficulties of the monocausal model.

Diseases associated with multiple sclerosis and epilepsy

A defined general population of 159,200 male and female native Swedes born in the period 1911-1940 from an urban catchment area of the then only general hospital, was followed over a decade (1970-79) with regard to in-patient hospitalization for all kinds of diagnoses. As a part of this population cohort study, multiple sclerosis cases (n = 351) and epilepsy cases (n = 648) were studied for association with other diseases. Unexpectedly, a cluster of diseases encompassing tuberculosis, bronchial asthma, diabetes mellitus and myocardial infarction, among the diseases associated with multiple sclerosis, also forms a gradient; this suggests a quantitative rather than a qualitative multifactorial model of disease for the understanding of the pathogenesis of MS. In epilepsy, heterogeneity was suggested as being mainly linked to the presence or absence of co-existing alcoholism. Brain tumours in cases of epilepsy were found almost exclusively in the latter subset and prevailing among younger people independent of sex (with an almost 100-fold excess rate of that disease combination as expected by chance only).

Pre-B lymphomas in SL/Kh mice: a multifactorial disease model.

The pre-B lymphoma in the inbred mouse strain SL/Kh is an excellent multifactorial disease model. The endogenous murine leukemia virus provirus Emv11, genetically acquired from an AKR progenitor, is the pathogenetic agent that reintegrates to dysregulate several host genes, i.e., Stat5a, Evi3, c-Myc, N-Myc, Stat5b, and others. Constitutive activation of Stat5a either by provirus integration or by transfection of the active mutant Stat5a cDNA transforms pre-B cells in bone marrow. Genetically determined expansion of early B cells and a dominant SL/Kh MHC allele predispose the animals to succumb to pre-B lymphomas. A number of other host genetic and epigenetic factors that determine the types of lymphomas, susceptibility to lymphomas, and length of the latent period are discussed.

A Novel Multifactorial Disease Model of Autoimmune Pancreatitis in MRL Mice Treated with Polyinosinic: Polycytidylic Acid

A Novel Multifactorial Disease Model of Autoimmune Pancreatitis in MRL Mice Treated with Polyinosinic: Polycytidylic Acid

Stress and Bodily Illness

The relationship between stress and the development of illness is not that simple or straightforward. To understand the role of stress in a multifactorial disease model and to pinpoint areas in which psychological interventions might be useful, we must evaluate the empirical work supporting a link between stress and disease, and specify the mechanisms that might be involved. What is meant by the word “stress” is clarified, and some methodologic problems in the data base are considered.