Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function.

Feline irradiated diet-induced demyelination; a model of the neuropathology of sub-acute combined degeneration?

Irradiation of food at 50-55 kGy results in a profound, chronic demyelinating-remyelinating disease of the entire central nervous system (CNS) in cats, named Feline Irradiated Diet-Induced Demyelination (FIDID). This study examines the early stages of demyelination and long-term consequences of demyelination and remyelination on axon survival or loss. Myelin vacuolation is the primary defect leading to myelin breakdown, demyelination then prompt remyelination in the spinal cord and brain.

Evoked potentials as a biomarker of remyelination.

Multiple sclerosis (MS) is a common cause of neurologic disease in young adults that is primarily treated with disease-modifying therapies which target the immune and inflammatory responses. Promotion of remyelination has opened a new therapeutic avenue, but how best to determine efficacy of remyelinating drugs remains unresolved. Although prolongation and then shortening of visual evoked potential (VEP) latencies in optic neuritis in MS may identify demyelination and remyelination, this has not been directly confirmed.

The adult oligodendrocyte can participate in remyelination.

Endogenous remyelination of the CNS can be robust and restore function, yet in multiple sclerosis it becomes less complete with time. Promoting remyelination is a major therapeutic goal, both to restore function and to protect axons from degeneration. Remyelination is thought to depend on oligodendrocyte progenitor cells, giving rise to nascent remyelinating oligodendrocytes.

Clemastine effects in rat models of a myelination disorder.

BackgroundPelizaeus Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system caused by impaired differentiation of oligodendrocytes. This study was prompted by findings that antimuscarinic compounds enhance oligodendrocyte differentiation and remyelination in vitro. One of these compounds, clemastine fumarate, is licensed for treatment of allergic conditions.

Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function.

The presence of thin myelin sheaths in the adult CNS is recognized as a marker of remyelination, although the reason there is not a recovery from demyelination to normal myelin sheath thickness remains unknown. Remyelination is the default pathway after myelin loss in all mammalian species, in both naturally occurring and experimental disease. However, there remains uncertainty about whether these thin sheaths thicken with time and whether they remain viable for extended periods.

Advantages of Array-Based Technologies for Pre-Emptive Pharmacogenomics Testing.

As recognised by the National Institutes of Health (NIH) Precision Medicine Initiative (PMI), microarray technology currently provides a rapid, inexpensive means of identifying large numbers of known genomic variants or gene transcripts in experimental and clinical settings. However new generation sequencing techniques are now being introduced in many clinical genetic contexts, particularly where novel mutations are involved. While these methods can be valuable for screening a restricted set of genes for known or novel mutations, implementation of whole genome sequencing in clinical practice continues to present challenges.

Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases.

We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe (-/-) xTfr2 (mut) mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family 'neurodegeneration with brain iron accumulation' (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading.

Gene co-expression networks shed light into diseases of brain iron accumulation.

Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach.

Evaluation of Different Normalization and Analysis Procedures for Illumina Gene Expression Microarray Data Involving Small Changes.

While Illumina microarrays can be used successfully for detecting small gene expression changes due to their high degree of technical replicability, there is little information on how different normalization and differential expression analysis strategies affect outcomes. To evaluate this, we assessed concordance across gene lists generated by applying different combinations of normalization strategy and analytical approach to two Illumina datasets with modest expression changes. In addition to using traditional statistical approaches, we also tested an approach based on combinatorial optimization.

Variation in SNPs of the IL7Ra gene is associated with multiple sclerosis in the Iranian population.

Interleukin-7 receptor-alpha gene (IL7Ra) is a member of the type I cytokine receptor family located on 5p13 human chromosome. Some evidence associates multiple sclerosis and single nucleotide polymorphisms in the promoter and exonic region of IL7Ra gene. In an attempt to clarify this association, the frequency of 3 SNPs located in the promoter and 1 SNP located in the 6th exon of IL7Ra gene were analyzed in a population of 100 Iranian MS patients as well as 100 controls.