Current Developments in the Use of Biomarkers for Juvenile Idiopathic Arthritis

Use of biomarkers in clinical practice has proved extremely valuable and is a rapidly expanding field. However, despite the huge potential of biomarkers, for juvenile idiopathic arthritis (JIA) there are currently no validated paediatric biomarkers available to help with setting up a more tailored approach on which drug choice could be based, to achieve remission early in the course of disease. Early remission reduces burden of disease, limits side effects from toxic and unnecessary medication, and, most importantly, enhances quality of life. Several studies have suggested promising biomarkers: these may be a protein, cellular component, mRNA, or genetic component, for example a single nucleotide polymorphism (SNP). Here we describe recent developments in the use of biomarkers for JIA and their potential to assist in management of disease by predicting disease phenotype, severity, progression, and response to treatment, and determining when patients have reached stable remission and can safely discontinue treatment.     

Effects of an adapted leisure education program as a means of support for caregivers of people with dementia

The loss of autonomy associated with dementia affects the people with dementia themselves as well as their caregivers who are often left feeling powerless and incompetent in their caregiving role. Most of the programs developed to support caregivers focus on burden and do not consider the positive aspects of caregiving. Leisure represents a way to enhance the presence of positive aspects in the caring experience. Moreover, leisure might contribute to the maintenance of satisfactory relationships between the caregivers and the person with dementia. An adapted leisure education program was developed as a means of support to caregiver involvement. This study (n = 49) aims to evaluate the impact of this program on caregivers’ well-being, self-efficacy towards adapted leisure, and quality of the relationship with the care receiver. Mixed methods were used. Pretest-posttest with a follow-up design made up the quantitative part. In addition, open-end interviews (n = 10) were conducted. The quantitative results showed few impacts of the program on caregivers. However, the qualitative analysis revealed that the intervention had positive impacts for the caregivers, care receivers and other family members. This study introduces caregiver support in a new, positive perspective by focusing on the positive aspects of caregiving rather than the burden.     

Compound heterozygosity for unstable hemoglobin Genova and beta(o)-thalassemia associated with early onset of thalassemia major syndrome

We described the case of an infant with compound heterozygozity for a b0-thalassemic mutation and Hemoglobin (Hb) Genova, an unstable Hb variant. He has required regular transfusions as early as the second month of life and since then, behaves like a thalassemia major patient. This association leads to the most severe clinical course involving an unstable variant, reported so far.     

Activins and activin antagonists in hepatocellular carcinoma

In many parts of the world hepatocellular carcinoma （HCC） is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β （TGFβ） superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homoor heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic coreceptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.     

Gab1, SHP2, and protein kinase A are crucial for the activation of the endothelial NO synthase by fluid shear stress

Fluid shear stress enhances NO production in endothelial cells by a mechanism involving the activation of the phosphatidylinositol 3-kinase and the phosphorylation of the endothelial NO synthase (eNOS). We investigated the role of the scaffolding protein Gab1 and the tyrosine phosphatase SHP2 in this signal transduction cascade in cultured and native endothelial cells. Fluid shear stress elicited the phosphorylation and activation of Akt and eNOS as well as the tyrosine phosphorylation of Gab1 and its association with the p85 subunit of phosphatidylinositol 3-kinase and SHP2. Overexpression of a Gab1 mutant lacking the pleckstrin homology domain abrogated the shear stress-induced phosphorylation of Akt but failed to affect the phosphorylation or activity of eNOS. The latter response, however, was sensitive to a protein kinase A (PKA) inhibitor. Mutation of Gab1 Tyr627 to phenylalanine (YF-Gab1) to prevent the binding of SHP2 completely prevented the shear stress-induced phosphorylation of eNOS, leaving the Akt response intact. A dominant-negative SHP2 mutant prevented the activation of PKA and phosphorylation of eNOS without affecting that of Akt. Moreover, shear stress elicited the formation of a signalosome complex including eNOS, Gab1, SHP2 and the catalytic subunit of PKA. In isolated murine carotid arteries, flow-induced vasodilatation was prevented by a PKA inhibitor as well as by overexpression of either the YF-Gab1 or the dominant-negative SHP2 mutant. Thus, the shear stress-induced activation of eNOS depends on Gab1 and SHP2, which, in turn, regulate the phosphorylation and activity of eNOS by a PKA-dependent but Akt-independent mechanism.