New treatment strategies for growth failure caused by chronic inflammation in children

Chronic inflammation during childhood often leads to impaired bone growth and reduced height in adulthood. Interleukin-1β (IL-1β), interleukin-6 (IL-6) and the tumour necrosis factor-α (TNF-α) are pro-inflammatory cytokines up-regulated during chronic inflammation. At the same time, experimental studies indicate that those cytokines affect growth by interfering with the Growth Hormone (GH)/Insulin-like Growth Factor I (IGF-I) axis. Moreover, IL-1β and TNF-α decrease murine bone growth in vitro by acting at the growth plate level. To counteract growth retardation in children with severe forms of JIA, GH therapy has been used, with beneficial effects on growth and final height in some patients. On the other hand, the introduction of biologic agents has revolutionized the treatment of rheumatoid arthritis in children and adults. Anti-TNF therapy not only decreases disease activity but may also improve growth in some juvenile idiopathic arthritis (JIA) patients. However, there is still a group of children in which the GH or anti-TNF therapy does not affect growth positively. For this reason, it is necessary to investigate new treatment strategies to prevent and/or treat growth failure in those patients. First, the effects of TNF-α antagonism on longitudinal growth in paediatric JIA patients were studied, differentiating any response from the normal pubertal growth spurt. From this study it can be concluded that TNF inhibition with etanercept (TNF soluble receptor) improves growth in a majority of JIA patients independent of puberty. Nevertheless, there are still patients who do not respond to TNF-inhibition and therefore are in need of alternative treatment modalities to optimize their growth. In the second study, it was hypothesized that biologic agents may rescue foetal rat metatarsal bones from cytokine-induced growth impairment and that IGF-I may potentiate such an effect. Indeed, both anakinra (IL-1 receptor antagonist) and etanercept efficiently and dose-dependently prevent cytokine-induced bone growth impairment in cultured bones. Combinations of anakinra or etanercept with IGF-I further improved bone growth. In the third study, it was found that IL-1β and TNF-α are produced by growth plate chondrocytes and that both cytokine antagonists improve growth of cultured foetal rat metatarsal bones suggesting that these cytokines play a physiological role in the normal regulation of longitudinal bone growth. In the fourth study, the local effects of IL-6 on growth plate chondrocytes of foetal rat metatarsal bones were studied. It was found that in the presence of its receptor, IL-6 decreases in vitro bone growth and it further suppresses growth when combined with IL-1β or TNF-α. Furthermore, IL-6 is produced by growth plate chondrocytes in vitro after stimulation with IL-1β+TNF-α, which may partially explain the synergistic inhibitory effect of those cytokines on murine bone growth. In conclusion, pro-inflammatory cytokines, normally up-regulated in children suffering from chronic inflammatory diseases, act in a synergistic way targeting growth plate chondrocytes and thereby decrease longitudinal bone growth. Biological agents blocking the actions of pro-inflammatory cytokines may improve bone growt

El populismo penal y el principio de imparcialidad en los jueces penales del distrito judicial de La Libertad 2019

La presente investigación tuvo por finalidad analizar la influencia del populismo penal en la imparcialidad de los jueces penales del distrito judicial de La Libertad 2019, para lo cual se realizó una investigación no experimental, transversal, correlacional causal; de diseño mixto, mediante la formulación de la matriz de consistencia se determinó el objetivo, la hipótesis las variables y las técnicas que se utilizaron; la entrevista para ocho Doctores en Derecho de la ciudad de Trujillo y sesenta y dos (62) Jueces Especializados Penales de 1ra. y 2da. Instancia de este distrito judicial. Mediante el procesamiento y análisis de los datos recolectados se determinó que el populismo penal influye en un 85.5% en el principio de imparcialidad de los jueces penales del distrito judicial de La Libertad 2019

Growth And The Growth Hormone-Insulin Like Growth Factor 1 Axis In Children With Chronic Inflammation:Current Evidence, Gaps In Knowledge And Future Directions

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt is often seen during adolescence. The underlying inflammatory state mediated by pro-inflammatory cytokines, prolonged use of glucocorticoid and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the growth hormone-insulin like growth factor axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate studies further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biologic therapy may lead to improvement of growth in some of these children but approximately one third continue to grow slowly. There is increasing evidence that the use of relatively high dose recombinant human growth hormone may lead to partial catch up growth in chronic inflammatory conditions, although long term follow-up data is currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease and cystic fibrosis, systemic abnormalities of the growth hormone-insulin like growth factor axis and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human growth hormone in these conditions and discuss the role of recombinant human insulin like growth factor-1