Current approaches to the diagnosis and management of amyloidosis.

Amyloidosis is a collection of diseases caused by the misfolding of proteins that aggregate into insoluble amyloid fibrils and deposit in tissues. While these fibrils may aggregate to form insignificant localised deposits, they can also accumulate in multiple organs to the extent that amyloidosis can be an immediately life-threatening disease, requiring urgent treatment. Recent advances in diagnostic techniques and therapies are dramatically changing the disease landscape and patient prognosis.

Alterations in multi-layer strain in AL amyloidosis.

Background: Cardiac involvement in AL amyloidosis portends a poor prognosis. 2D-speckle tracking echocardiography (2D-STE) strain can identify subclinical cardiac involvement. This study performed multilayer and multiplanar 2D-STE myocardial strain analysis.

Correlation of Quantitative Tc DPD Scintigraphy With Echocardiographic Alterations in Left Atrial Parameters in Transthyretin Amyloidosis.

Aim: Cardiac transthyretin amyloidosis (ATTR) patients have high rates of atrial arrhythmias. We evaluated echocardiographic structural and functional left atrial (LA) parameters and correlated these with technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) bone scintigraphy tracer uptake within the LA in ATTR patients.

Methods: ATTR patients (wild-type, hereditary and asymptomatic transthyretin [TTR] variant carriers) who had undergone Tc-DPD and transthoracic echocardiogram (TTE) were selected.

Outcomes of critically ill COVID-19 survivors and caregivers: a case study-centred narrative review.

Purpose: Critical illness is a transformative experience for both patients and their family members. For COVID-19 patients admitted to the intensive care unit (ICU), survival may be the start of a long road to recovery. Our knowledge of the post-ICU long-term sequelae of acute respiratory distress syndrome (ARDS) and severe acute respiratory syndrome (SARS) may inform our understanding and management of the long-term effects of COVID-19.

Correlation Between Quantitative Uptake of TC-DPD and Echocardiographic Parameters in Cardiac ATTR: A Novel Follow-Up Strategy.

There has been a paradigm shift in diagnosis of cardiac transthyretin amyloidosis (ATTR) with non-invasive techniques including technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) bone scintigraphy. We evaluated structural and functional biventricular alterations by transthoracic echocardiography (TTE) and determined the correlation with Tc-DPD tracer uptake in ATTR. ATTR patients (wild-type, hereditary or asymptomatic transthyretin [] variant carriers) with Tc-DPD and TTE were selected; Tc-DPD uptake was analyzed quantitatively.

Software Training in HEP.

The long-term sustainability of the high-energy physics (HEP) research software ecosystem is essential to the field. With new facilities and upgrades coming online throughout the 2020s, this will only become increasingly important. Meeting the sustainability challenge requires a workforce with a combination of HEP domain knowledge and advanced software skills.

Expression of CYP24A1 and other multiple sclerosis risk genes in peripheral blood indicates response to vitamin D in homeostatic and inflammatory conditions.

Although genetic and epidemiological evidence indicates vitamin D insufficiency contributes to multiple sclerosis (MS), and serum levels of vitamin D increase on treatment with cholecalciferol, recent metanalyses indicate that this vitamin D form does not ameliorate disease. Genetic variation in genes regulating vitamin D, and regulated by vitamin D, affect MS risk. We evaluated if the expression of vitamin D responsive MS risk genes could be used to assess vitamin D response in immune cells.

Regulation of the methylome in differentiation from adult stem cells may underpin vitamin D risk in MS.

Multiple lines of evidence indicate Multiple Sclerosis (MS) is affected by vitamin D. This effect may be mediated by methylation in immune cell progenitors. We aimed to determine (1) if haematopoietic stem cell methylation constrains methylation in daughter cells and is variable between individuals, and (2) the interaction of methylation with the vitamin D receptor binding sites.

Amyloid Cardiomyopathy.

Amyloid cardiomyopathy is emerging as an important and under-recognised cause of heart failure and cardiac arrhythmias, especially in older adults. This disorder is characterised by extracellular deposition of amyloid fibrils that form due to misfolding of secreted light chains (AL) or transthyretin protein (ATTR). In ATTR, amyloid aggregates typically result from excessive accumulation of wild-type transthyretin (ATTRwt) or from protein structural defects caused by TTR gene variants (ATTRv).

The interaction of Multiple Sclerosis risk loci with Epstein-Barr virus phenotypes implicates the virus in pathogenesis.

Translating the findings of genome wide association studies (GWAS) to new therapies requires identification of the relevant immunological contexts to interrogate for genetic effects. In one of the largest GWAS, more than 200 risk loci have been identified for Multiple Sclerosis (MS) susceptibility. Infection with Epstein-Barr virus (EBV) appears to be necessary for the development of Multiple Sclerosis (MS).

Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein-Barr Virus hypomethylated regions.

Epstein-Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines-LCLs).

Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility.

Background: Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established.

The latitude-dependent autoimmune disease risk genes ZMIZ1 and IRF8 regulate mononuclear phagocytic cell differentiation in response to vitamin D.

Epidemiological, molecular and genetic studies have indicated that high serum vitamin D levels are associated with lower risk of several autoimmune diseases. The vitamin D receptor (VDR) binding sites in monocytes and dendritic cells (DCs) are more common in risk genes for diseases with latitude dependence than in risk genes for other diseases. The transcription factor genes Zinc finger MIZ domain-containing protein 1 (ZMIZ1) and interferon regulatory factor 8 (IRF8)-risk genes for many of these diseases-have VDR binding peaks co-incident with the risk single nucleotide polymorphisms (SNPs).

Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model.

Importance: Neuroinflammation appears to be a key modulator of disease progression in amyotrophic lateral sclerosis (ALS) and thereby a promising therapeutic target. The CD4+Foxp3+ regulatory T-cells (Tregs) infiltrating into the central nervous system suppress neuroinflammation and promote the activation of neuroprotective microglia in mouse models of ALS. To our knowledge, the therapeutic association of host Treg expansion with ALS progression has not been studied in vivo.

GPR65 inhibits experimental autoimmune encephalomyelitis through CD4 T cell independent mechanisms that include effects on iNKT cells.

The G protein-coupled receptor 65 (GPR65) gene has been genetically associated with several autoimmune diseases, including multiple sclerosis (MS). GPR65 is predominantly expressed in lymphoid organs and is activated by extracellular protons. In this study, we tested whether GPR65 plays a functional role in demyelinating autoimmune disease.

Differences in common heritable blood immune cell populations may underlie MS susceptibility and progression.

A promising new avenue of MS research that may lead to a better understanding of pathogenesis, progression and therapeutic response, and to development of new therapies, comes from the recent identification of defined immune cell populations that are highly heritable. Such stable populations have been identified in three recent papers using extensive flow cytometric panels to investigate twin and family cohorts. They showed that while most of the variation in immune cell populations between individuals was not heritable, some was.

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies.

Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles.

The MS Risk Allele of CD40 Is Associated with Reduced Cell-Membrane Bound Expression in Antigen Presenting Cells: Implications for Gene Function.

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e.

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRasQ61L)-driven SerpinB2 expression.

Ectopic expression of dual-specificity phosphatase 5 (DUSP5), an inducible mitogen-activated protein (MAP) kinase phosphatase, specifically inactivates and anchors extracellular signal-regulated kinase (ERK)1/2 in the nucleus. However, the role of endogenous DUSP5 in regulating the outcome of Ras/ERK kinase signaling under normal and pathological conditions is unknown. Here we report that mice lacking DUSP5 show a greatly increased sensitivity to mutant Harvey-Ras (HRas(Q61L))-driven papilloma formation in the 7,12-Dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) model of skin carcinogenesis.

Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis.

Objective: We examined a cohort of adults with aquaporin-4 (AQP4) antibody-negative neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD) for antibodies to myelin oligodendrocyte glycoprotein (MOG).

Methods: We performed a flow cytometry cell-based assay using live human lentivirus-transduced cells expressing full-length surface MOG. Serum was tested in 23 AQP4 antibody-negative NMO/NMOSD patients with bilateral and/or recurrent optic neuritis (BON, n = 11), longitudinally extensive transverse myelitis (LETM, n = 10), and sequential BON and LETM (n = 2), as well as in patients with multiple sclerosis (MS, n = 76) and controls (n = 52).

The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease.

We have identified a marked over-representation of transcription factors controlling differentiation of T, B, myeloid and NK cells among the 110 MS genes now known to be associated with multiple sclerosis (MS). To test if the expression of these genes might define molecular subtypes of MS, we interrogated their expression in blood in three independent cohorts of untreated MS (from Sydney and Adelaide) or clinically isolated syndrome (CIS, from San Francisco) patients. Expression of the transcription factors (TF) controlling T and NK cell differentiation, EOMES, TBX21 and other TFs was significantly lower in MS/CIS compared to healthy controls in all three cohorts.