A recipe for myositis : nuclear factor κB and nuclear factor of activated T-cells transcription factor pathways spiced up by cytokines

Nuclear factor κB (NF-κB) is a well-known pro-inflammatory transcription factor that regulates the expression of the tissue’s immune-active components, which include cytokines, chemokines and adhesion molecules. In addition, the versatile nuclear factor of activated T-cells (NFAT) family of transcription factors plays a crucial role in the development and function of the immune system, integrating calcium signaling with other signaling pathways. NF-κB and NFAT share many structural and functional characteristics and likely regulate gene expression through shared enhancer elements. This review describes recent research data that has led to new insights into the involvement of NFκB- and NFAT-mediated pathways in the different idiopathic inflammatory myopathies. The general activation of NF-κB p65 in blood vessel endothelium, seems to flag down inflammatory cells that subsequently accumulate mostly at perimysial sites in dermatomyositis. The joint activation of p65 and NFAT5 in myofibers specifically at perifascicular areas reflects the characteristic tissue damage pattern observed in that particular subgroup of patients. In immune cells actively invading nonnecrotic muscle fibers in polymyositis and sporadic inclusion body myositis on the other hand, p65 activation is an important aspect of their cytotoxic and chemoattactant properties. In addition, both transcription factor families are generally upregulated in regenerating muscle fibers as components of the differentiation process. It can be concluded that the two transcription factor families function in close relationship with each other, representing two-edged swords for muscle disease: on the one hand promoting cell growth and regeneration, while on the other hand actively participating in inflammatory cell damage. In this respect, cytokines function as important go-betweens at the crossroads of the pathways. Beyond NF-κB and NFAT, many fascinating winding roads relevant to inflammatory myopathy disease management still lie ready for the exploring

Scanning for therapeutic targets within the cytokine network of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNF, LT, BAFF), Interferons (IFN//), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNF treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNF agents to treat other diseases, pointing to the complex effects of TNF neutralization. Treatment with anti-IFN has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction

Pharmacogenomics in children: advantages and challenges of next generation sequencing applications

Pharmacogenetics is considered as a prime example of how personalized medicine nowadays can be put into practice. However, genotyping to guide pharmacological treatment is relatively uncommon in the routine clinical practice. Several reasons can be found why the application of pharmacogenetics is less than initially anticipated, which include the contradictory results obtained for certain variants and the lack of guidelines for clinical implementation. However, more reproducible results are being generated, and efforts have been made to establish working groups focussing on evidence-based clinical guidelines. For another pharmacogenetic hurdle, the speed by which a pharmacogenetic profile for a certain drug can be obtained in an individual patient, there has been a revolution in molecular genetics through the introduction of next generation sequencing (NGS), making it possible to sequence a large number of genes up to the complete genome in a single reaction. Besides the enthusiasm due to the tremendous increase of our sequencing capacities, several considerations need to be made regarding quality and interpretation of the sequence data as well as ethical aspects of this technology. This paper will focus on the different NGS applications that may be useful for pharmacogenomics in children and the challenges that they bring on

Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy

Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed

Design sensitivity analysis of a plate-finned air-cooled condenser for waste heat recovery ORCs

The study is related to the design sensitivity analysis of a plate-finned tube bundle V-shaped air-cooled condenser design problem for a range of representative low-temperature waste heat recovery Organic Rankine Cycle (ORC) cases. An iterative design model is implemented which reveals the thermodynamic and geometric design error margins that occur when different in-tube prediction methods are used. 19 condensation heat transfer correlations are used simultaneously within arrays of geometric and thermodynamic variables. Through attained 19 different convective coefficients, a design sensitivity on the calculated overall heat transfer coefficient, total transferred heat, degree of subcooling, required tube and fin material amount, air- and refrigerant-side pressure drops is reported