Cobi J. Heijnen

Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?

Aim: To compare short‐term effects and neurodevelopmental outcome of neonatal glucocorticoid therapy between two centres. Methods: A retrospective study was performed in two centres using a tapering course of either 5 to 1 mgkg−1 hydrocortisone (HC; 22 d) or 0.5 to 0.1 mg kg−1 dexamethasone (DEX; 21 d). In both centres glucocorticoid‐treated infants and control patients were matched for gestational age, birthweight, severity of infant respiratory distress syndrome and periventricular‐intraventricular haemorrhage. The following short‐term glucocorticoid‐induced effects were investigated in 25 HC‐treated and 25 control patients in centre A, and in 23 DEX‐treated and 23 control patients in centre B: oxygen dependency (inspiratory oxygen fraction), arterial pressure, blood glucose and urea concentrations, weight gain and head circumference before, during and after therapy (in treated infants), or at an interval comparable to treated infants (in control infants). Neurological outcome, psychomotor development and school performance at 5–7 y of age was evaluated in all groups. Results: HC and DEX were equally potent in reducing oxygen dependency. Mean arterial pressure as well as blood glucose and urea concentrations were significantly increased during DEX, but not during HC treatment. Weight gain stopped during DEX therapy, but not during HC. Head circumference in both treatment groups was decreased after therapy compared with controls. Neonatally DEX ‐treated children needed special school education significantly more often (p < 0.01) than controls at 5–7 y of age. No differences between neonatally HC‐treated children and controls on neurodevelopmental outcome were found at 5–7 y of age.

Neonatal Dexamethasone Treatment Increases Susceptibility to Experimental Autoimmune Disease in Adult Rats

Major concern has emerged about the possible long term adverse effects of glucocorticoid treatment, which is frequently used for the prevention of chronic lung disease in preterm infants. Here we show that neonatal glucocorticoid treatment of rats increases the severity (p ≤ 0.01) and incidence (p ≤ 0.01) of the inflammatory autoimmune disease experimental autoimmune encephalomyelitis in adult life. In search of possible mechanisms responsible for the increased susceptibility to experimental autoimmune encephalomyelitis, we investigated the reactivity of the hypothalamo-pituitary-adrenal axis and of immune cells in adult rats after neonatal glucocorticoid treatment. We observed that neonatal glucocorticoid treatment reduces the corticosterone response after an LPS challenge in adult rats (p ≤ 0.001). Interestingly, LPS-stimulated macrophages of glucocorticoid-treated rats produce less TNF-α and IL-1β in adult life than control rats (p < 0.05). In addition, splenocytes obtained from adult rats express increased mRNA levels of the proinflammatory cytokines IFN-γ (p < 0.01) and TNF-β (p < 0.05) after neonatal glucocorticoid treatment. Apparently, neonatal glucocorticoid treatment has permanent programming effects on endocrine as well as immune functioning in adult life. In view of the frequent clinical application of glucocorticoids to preterm infants, our data demonstrate that neonatal glucocorticoid treatment may be a risk factor for the development of (auto)immune disease in man.

Neonatal glucocorticoids and the developing brain: Short-term treatment with life-long consequences?

Although synthetic glucocorticoids are frequently used in hospital for the prevention of chronic lung disease in premature infants, major concern has arisen about the possible long-term consequences of these treatments. Animal research provides evidence for the idea that neonatal glucocorticoid treatment enhances susceptibility to autoimmune disease in adult life. Altered functioning of the hypothalamo-pituitary-adrenal axis, and/or changes at higher brain levels might underlie alterations in disease susceptibility.

Pain in childhood rheumatic arthritis

Pain is a major symptom in chronic inflammatory arthropathies such as rheumatoid arthritis and affects the health status of arthritis patients negatively. There has been much debate about the role of pain in juvenile chronic arthritis and this review deals with the controversies about this subject. Pain in children is best understood as a multifactorial concept in which pain is the result of somatosensory, behavioural and environmental factors. The role of the different factors contributing to pain will be assessed with special reference to mechanisms relevant to children with chronic pain, the various instruments to measure pain, such as visual analogue scales and algometry, and the treatment of chronic pain in juvenile chronic arthritis. For a true understanding of chronic pain in children, these multidimensional assessments should be integrated into a biobehavioural model, by means of which a better understanding should lead to new therapeutic interventions for one of the most common symptoms of rheumatic diseases in childhood: pain.

Neonatale behandeling met corticosteroïden en consequenties op de lange termijn

SummaryCorticosteroids are administered to prematurely born infants for the prevention of chronic lung disease. In addition to a number of side effects, growing concern has arisen about the possible long-term sequelae of neonatal corticosteroid treatments. Little is known about the consequences of exposure to corticosteroids in humans. However, in laboratory animals ample evidence has been provided for the induction of permanent changes in brain development, behavior and neuroendocrine functioning by corticosteroid treatment of rodents in the early neonatal period. Recent evidence shows that neonatal corticosteroid treatment also increases disease susceptibility. Possibly, neonatally treated animals develop a pro-inflammatory phenotype with increased production of pro-inflammatory cytokines by T-cells. Corticosteroid-induced changes in neuroendocrine functioning may underlie augmented disease susceptibility. The animal studies further support the hypothesis that intensive neonatal corticosteroid treatment of prematurely born babies has important consequences for health in later life.SamenvattingCorticosteroïden worden toegediend aan premature kinderen ter voorkoming van chronische longschade. Naast allerlei neveneffecten is vooral grote bezorgdheid ontstaan over de effecten op de lange termijn van behandeling met corticosteroïden. Over deze langetermijneffecten bij de mens is nog niet veel bekend. Experimenteel onderzoek met dieren geeft echter voldoende aanwijzingen dat neonatale behandeling met corticosteroïden permanente veranderingen induceert in hersenontwikkeling en gedrag. De laatste jaren wordt duidelijk dat ook de ziektegevoeligheid toeneemt na neonatale behandeling met corticosteroïden. Ratten lijken een pro-inflammatoir fenotype te krijgen na blootstelling aan corticosteroïden in de neonatale periode. Dit fenotype kan direct zijn ontstaan door effecten van corticosteroïden op bijvoorbeeld T-cellen en indirect via veranderingen in het functioneren van het neuro-endocriene systeem. In elk geval doet dit onderzoek sterk vermoeden dat toediening van corticosteroïden niet zonder risico is voor veranderingen in de ontwikkeling van het kind op de lange termijn.

HUMAN B CELL ACTIVATION IN VITRO: ANTIGEN-SPECIFIC HELPER AND SUPPRESSOR EFFECTS ARE MEDIATED BY DISTINCT T CELL SUBPOPULATIONS

Publisher Summary This chapter explores human B cell activation in vitro. In a study described in the chapter, the the Tγ-enriched, the Tγ-depleted, and the Tμ-enriched cells were isolated by rosetting. The regulatory effects on the antigen-induced PFC response were tested using the method of Dosch and Gelfand. To test helper cell activity, the various T cell fractions were cultured with B cells, 5% adherent cells, and either 5 × 10 6 sheep red-blood cells (SE)/culture or 3 μg Ovalbumin (OA)/ml of culture medium. It was demonstrated that the helper activity is residing in the Tγ depleted- and the Tγ-enriched fraction. It was also demonstrated that peripheral blood T cells expressing helper function in the antigen-induced antibody response are located in the Tμ cell subpopulation, whereas T suppressor function is exerted by T cells present in the Tγ subpopulation. These subpopulations differ in their sensitivity toward irradiation. The activity of T helper cells can be replaced in vitro by a T cell factor that is released into the medium after 120 h of culture.

155 Combined Inhibition of Neuronal and Inducible Nos Provides Neuroprotection After Hypoxia-Ischaemia in P3 and P7 Rat Pups

Background, aim: Nitric oxide (NO) contributes to neuronal damage following perinatal hypoxia-ischaemia (HI). We examined the neuroprotective effects of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthae (iNOS), after HI in P3 and P7 rat pups as model of more immature developmental stages of the human brain.Methods: P3 and P7 rat pups were subjected to occlusion of the right carotid artery followed by 60 (P3) or 120 min (P7) of hypoxia (FiO2 0.08). Immediately after HI, and 12 and 24 h later, pups received s.c. 10 mg/kg 2-IB or vehicle. Heat-Shock Protein-70 (HSP70) was determined 48 h post-HI using Western blotting. Cytochrome c and nitrotyrosine were determined at 24 h post-HI. At 6 weeks post-HI neuronal damage of hippocampus and cortex was assessed using a 4-point histological scale, the maximal score of normal animals being 33.Results: In both P3 and P7 rat pups, 2-IB reduced HSP70 production after HI by 50%. The increase in cytochrome c was also 50% reduced by 2-IB treatment (P<0.05). No changes in nitrotyrosine levels were observed in any group at 24h post-HI. Brain histology score of the ipsilateral hemisphere rose significantly from 27 ± 2 (P3, vehicle) to 29 ± 2 (P3, 2-IB) and from 5 ± 5 (P7, vehicle) to 13 ± 9 (P7, 2-IB).Conclusion: selective inhibition of nNOS and iNOS post-HI provides both short-term (HSP70, cytochrome c) as well as long-term neuroprotection (histology) in both the P3 and the P7 rat without affecting nitrotyrosine levels.

Some Aspects of T Cell Regulation in Autoimmune Diseases

There is ample evidence that the immune response in man is regulated, although not exclusively, by T cells which have the capacity to induce, amplify or suppress the reactivity of the immune system. Analogous to the situation in the mouse, these various regulatory T cell functions are exerted by lymphocytes residing in distinct T cell subpopulations (1,2). These subsets can be recognized by distinct surface markers such as receptors for Fc fragments of different immunoglobulin isotypes (3) and cell surface structures defined by monoclonal antibodies (4).