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Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted [H.sub.2][O.sub.2]-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL- 1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL- 1R1dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease., Introduction The lung is equipped with a robust proteostasis network for handling protein folding, misfolding, unfolding, and degradation in response to mechanical and environmental stress (1). Consistent with the emerging [...]

Although supraphysiological concentrations of urea are known to increase oxidative stress in cultured cells, it is generally thought that the elevated levels of urea in chronic renal failure patients have negligible toxicity. We previously demonstrated that ROS increase intracellular protein modification by O-linked β-N-acetyl-glucosamine (O-GlcNAc), and others showed that increased modification of insulin signaling molecules by O-GlcNAc reduces insulin signal transduction. Because both oxidative stress and insulin resistance have been observed in patients with end-stage renal disease, we sought to determine the role of urea in these phenotypes. Treatment of 3T3-L1 adipocytes with urea at disease-relevant concentrations induced ROS production, caused insulin resistance, increased expression of adipokines retinol binding protein 4 (RBP4) and resistin, and increased O-GlcNAc-modified insulin signaling molecules. Investigation of a mouse model of surgically induced renal failure (uremic mice) revealed increased ROS production, modification of insulin signaling molecules by O-GlcNAc, and increased expression of RBP4 and resistin in visceral adipose tissue. Uremic mice also displayed insulin resistance and glucose intolerance, and treatment with an antioxidant SOD/catalase mimetic normalized these defects. The SOD/catalase mimetic treatment also prevented the development of insulin resistance in normal mice after urea infusion. These data suggest that therapeutic targeting of urea-induced ROS may help reduce the high morbidity and mortality caused by end-stage renal disease., Introduction Elevated urea in chronic renal failure (CRF) is considered to have negligible toxicity because Johnson et al. found in 1972 that in patients with far-advanced renal failure, blood urea [...]

The background of the alleles carrying the critical variant in 1611 DNA samples from 37 populations were analyzed and concluded that the [T.sub.-13910] allele was independently introduced more than once.

The solute carrier family 7A member 7 gene (SLC7A7) encodes the light chain of the heterodimeric carrier responsible for cationic amino acid (CAA) transport across the basolateral membranes of epithelial cells in intestine and kidney. Mutations affecting SLC7A7 cause lysinuric protein intolerance (LPI), a multiorgan disorder with clinical symptoms that include visceromegaly, growth retardation, osteoporosis, hyperammonemia, and hyperdibasicaminoaciduria. Here, we describe the consequences of inactivating Slc7a7 in a mouse model of LPI. The Slc7a7 mutation was generated by high-throughput retroviral gene-trapping in embryonic stem cells. The [Slc7a7.sup.-/-] mouse displayed intrauterine growth restriction (IUGR), commonly leading to neonatal lethality. Alter heavy protein ingestion, the surviving adult animals presented metabolic derangement consistent with that observed in human LPI. IUGR was investigated by examining the expression of main factors controlling fetal growth. Insulin-like growth factor 1, the dominant fetal growth regulator in late gestation, was markedly downregulated as demonstrated by quantitative real-time RT-PCR, immunostaining and Western blot analysis in fetal liver. To further explore the pathophysiology of LPI, gene expression profiling analyses were carried out by DNA microarray technology in intestine and liver of adult [Slc7a7.sup.-/-] mice. Significant upregulation or downregulation (twofold or greater) was observed for 488 transcripts in intestine, and for 521 transcripts in the liver. The largest category of differentially expressed genes corresponds to those involved in transport according to Gene Ontology classification. This mouse model offers new insights into the pathophysiology of LPI and into mechanisms linking CAA metabolic pathways and growth control. cationic amino acid transport: hyperdibasicaminoaciduria; neonatal lethality doi:10.1152/ajpcell.00583.2006

Thyroid autoimmune disorders comprise more than 30% of all organ-specific autoimmune diseases and are characterized by autoantibodies and infiltrating T cells. The pathologic role of infiltrating T cells is not well defined. To address this issue, we generated transgenic mice expressing a human T-cell receptor derived from the thyroid-infiltrating T cell of a patient with thyroiditis and specific for a cryptic thyroid-peroxidase epitope. Here we show that mouse major histocompatibility complex molecules sustain selection and activation of the transgenic T cells, as coexpression of histocompatibility leukocyte antigen molecules was not needed. Furthermore, the transgenic T cells had an activated phenotype in vivo, and mice spontaneously developed destructive thyroiditis with histological, clinical and hormonal signs comparable with human autoimmune hypothyroidism. These results highlight the pathogenic role of human T cells specific for cryptic self epitopes. This new 'humanized' model will provide a unique tool to investigate how human pathogenic self-reactive T cells initiate autoimmune diseases and to determine how autoimmunity can be modulated in vivo., Author(s): Sonia Quaratino (corresponding author) [1]; Ester Badami [1]; Yun Yun Pang [1]; Istvan Bartok [2]; Julian Dyson [2]; Dimitris Kioussis [3]; Marco Londei [4]; Luigi Maiuri [4] Autoimmune thyroiditis [...]

Abstract Background To humanize the management of children in hospitals has become a serious concern of civil society and one of the main goals of public and private health centers, health care providers and governments. Discussion The concepts of family-centered and family-oriented care are discussed with the aim to emphasize their importance in pediatrics. Notions related to family-centered care, such as cultural diversity and cultural competence, are also discussed given the importance they have gained following the recent transformations of socioeconomic, demographic and ethnic characteristics of economically advantaged Countries. Family-centered care has developed as a result of the increased awareness of the importance of meeting the psychosocial and developmental needs of children and of the role of families in promoting the health and well-being of their children. Family-oriented care aims at extending the responsibilities of the pediatrician to include screening, assessment, and referral of parents for physical, emotional, social problems or health risk behaviors that can adversely affect the health and emotional or social well-being of their child. Summary Family-centered and family-oriented care concepts should be incorporated into all aspects of pediatricians' professional practice, whether it is private practice or in public hospitals, to better serve the needs of ill children.