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      Evaluation of hypothalamic–pituitary function in children following acute bacterial meningitis

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          Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation.

          Circulating IGF-I and -II are bound to specific insulin-like growth factor (IGF)-binding proteins (IGFBPs), of which IGFBP-3 binds the majority of the IGFs. IGFBP-3 levels are regulated by GH and have been suggested to provide additional information on GH secretory capacity compared to IGF-I. However, the diagnostic value of IGFBP-3 is still controversial, perhaps because the quality of the available normative data for IGFBP-3 varies. It has recently been shown that a large number of individuals is required to establish reference ranges for IGF-I that take into account age, sex, body mass index (BMI), and pubertal stage. Therefore, we measured IGFBP-3, IGF-I, IGF-II, IGFBP-1, and IGFBP-2 levels by RIA in 907 healthy children to establish well characterized normative data on IGFBP-3 according to age, sex, and pubertal stage and to study the complex relationship between IGFs and their BPs in puberty. We found that IGFBP-3 levels increase with age in children, with maximal levels in puberty; girls experience peak values approximately 1 yr earlier than boys. Age, sex, height, BMI, and pubertal maturation were all important factors in determining the circulating levels of IGFBP-3, whereas IGF-I levels were unaffected by BMI. Comparison of IGFBP-3 with IGF-1 concentrations revealed that they did not exhibit the same developmental pattern in puberty. IGF-I levels increased to relatively higher levels than IGFBP-3, leading to an increasing molar ratio between IGF-I and IGFBP-3 in puberty, when growth velocity is high. Concomitantly, IGF-II and IGFBP-2 levels were unchanged throughout puberty, whereas IGFBP-1 levels declined with age in prepubertal children, with lowest values in puberty. There was a highly significant correlation between IGF-I and -II and IGFBP-3 on a molar basis (r = 0.84; P < 0.0001). Thus, we speculate that IGFBP-3 is pivotal for circulating IGF bioactivity and that the increase in the molar ratio between IGF-I and IGFBP-3 reflects an increase in free, biologically active IGF-I. In conclusion, we have provided normative data on a large group of healthy individuals and conclude that age, sex, height, BMI, and pubertal maturation have to be taken into account before a single IGFBP-3 value in a growth-retarded child can be evaluated properly.
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            Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis.

            Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.
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              Apoptosis of neurons in the dentate gyrus in humans suffering from bacterial meningitis.

              Apoptosis of granular cells in the dentate gyrus frequently occurs in animal models of bacterial meningitis. In 37 autopsy cases of bacterial meningitis we evaluated, by light microscopy and in-situ tailing, whether this pattern of neuronal damage is of relevance in humans. Neuronal apoptoses in the dentate gyrus (density 1 to 19/mm2) were observed in 26 cases of bacterial meningitis and in none of 10 aged-matched control cases dying from non-neurological diseases. The density of apoptotic neurons depended on the interval between the onset of symptoms of meningitis and death (death within the first 2 days: 1.8+/-2.8 apoptoses/mm2; later than 18 days: 1.8+/-1.7/mm2; compared to death between days 3 and 18: 7.4+/-6.6 apoptoses/mm2, p = 0.007 and 0.004, respectively). Neuronal apoptosis in the dentate gyrus was not linked to neuronal damage in other parts of the brain or previous treatment with corticosteroids. Since learning deficits are frequently observed in survivors of bacterial meningitis, strategies to reduce the density of apoptotic neurons in the dentate gyrus may decrease the frequency of neurological sequela in patients surviving bacterial meningitis.
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                Author and article information

                Journal
                Pituitary
                Pituitary
                Springer Science and Business Media LLC
                1386-341X
                1573-7403
                February 2015
                December 20 2013
                February 2015
                : 18
                : 1
                : 1-7
                Article
                10.1007/s11102-013-0547-4
                6afbcca7-71f3-423d-940a-f6a07db38e79
                © 2015

                http://www.springer.com/tdm

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