Objective. To identify the mediator responsible for the impact of chronic inflammation on skeletal development in children (bone loss, defective peak bone mass accrual, stunted growth), we evaluated the effects of chronic interleukin-6 (IL-6) overexpression on the skeletons of growing prepubertal mice.Methods. We studied IL-6-transgenic mice that had high circulating IL-6 levels since birth. Trabecular and cortical bone structure were analyzed by microcomputed tomography. Epiphyseal ossification, growth plates, and calvariae were studied by histology/ histomorphometry. Osteoclastogenesis, osteoblast function/differentiation, and the effects of IL-6 on bone cells were studied in vitro. Osteoblast gene expression was evaluated by reverse transcriptase-polymerase chain reaction. The mineral apposition rate was evaluated dynamically in cortical bone by in vivo double fluorescence labeling.Results. In prepubertal IL-6-transgenic mice, we observed osteopenia, with severe alterations in cortical and trabecular bone microarchitecture, as well as uncoupling of bone formation from resorption, with decreased osteoblast and increased osteoclast number and activity. Increased osteoclastogenesis and reduced osteoblast activity, secondary to decreased precursor proliferation and osteoblast function, were present. IL-6-transgenic mice also showed impaired development of growth plates and epiphyseal ossification centers. Intramembranous and endochondral ossification and the mineral apposition rate were markedly affected, showing the presence of defective ossification.Conclusion. Chronic overexpression of IL-6 alone induces a skeletal phenotype closely resembling growth and skeletal abnormalities observed in children with chronic inflammatory diseases, pointing to IL-6 as a pivotal mediator of the impact of chronic inflammation on postnatal skeletal development. We hypothesize that IL-6-modifying drugs may reduce skeletal defects and prevent the growth retardation associated with these diseases.
Frequent mutations of coding nucleotide repeats are thought to contribute significantly to carcinogenesis associated with microsatellite instability (MSI). We have shown that shortening of the poly(T) 11 within the polypyrimidine stretch/accessory splicing signal of human MRE11 leads to the reduced expression and functional impairment of the MRE11/NBS1/RAD50 complex. This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI. Here, we examined 70 microsatellite unstable primary human cancers and we report that MRE11 mutations occur in 83.7 and 50% of the colorectal and endometrial cancers, respectively. In the colorectal cancer series, mutated MRE11 is more frequently associated with advanced age at diagnosis and A/B stages. Biallelic mutations were present in 38.8% of the cases and more frequently associated with lower (G1/G2) grade tumors. Impaired MRE11 expression was prevalent in primary colorectal tumors with larger and biallelic shortening of the poly(T)11. Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers. Together with the observation that perturbation of the MRE11/NBS1/RAD50 complex predisposes to cancer, our work highlights MRE11 as a new common target in the MMR deficient tumorigenesis and suggests its role in colorectal carcinogenesis
Sclerostin, the secreted protein product of the SOST gene, which is mainly expressed by osteocytes, has recently been proposed as a negative regulator of bone osteoblastogenesis. Chronic elevation of PTH reduces SOST expression by osteocytes, while controversial results have been obtained by intermittent PTH administration. We have investigated the effects of intermittently administered PTH on SOST expression and sclerostin localization, comparing them with those of controls, as they appeared in three different bone segments of rat tibia: secondary trabecular metaphyseal and epiphyseal bone, and cortical diaphyseal bone. The histomorphometric results demonstrate that PTH enhances bone turnover through anabolic effects, as shown by the association of increased bone resorption variables with a significant rise in BV/TV, Tb.Th and Tb.N and a fall in Tb.Sp. PTH induces a SOST mRNA and protein fall in secondary metaphyseal trabeculae, diaphyseal bone and in epiphyseal trabeculae. Numbers of sclerostin immunopositive osteocytes/mm(2) show no change, compared with controls; there are fewer sclerostin-positive osteocytes in secondary metaphyseal trabeculae than in the other two bone areas, both in the control and PTH groups. The low numbers of sclerostin-positive osteocytes in the metaphyseal trabecular bone seem to be directly related to the fact that this area displays a high remodeling rate. The anabolic effects of PTH are in line with the fall of SOST mRNA and protein in all the three bone segments examined; the rise of bone turnover supports a negative role of SOST in bone formation.
Determinations of erythrocyte enzyme scavengers of oxygen radicals (glutathione-peroxidase, superoxide-dismutase and catalase) and determinations of erythrocyte age-dependent glycolytic activities (glucose-6-phosphate-dehydrogenase, pyruvate-kinase and glucose-phosphate-isomerase) were carried out in cord blood and in the blood taken on the 4th day of life in 152 newborn infants with different peak bilirubin levels. The enzyme activities scavenging oxygen radicals, glutathione-peroxidase and superoxide-dismutase were significantly lower in infants with peak bilirubinemia higher than 214 mumol/l, compared to less-jaundiced neonates, both at birth and on the 4th day of life; their values correlated negatively with peak bilirubinemia at birth and on the 4th day of life. Glycolytic age-dependent enzyme activities were significantly higher in more jaundiced newborn infants only on the 4th day of life, when their values correlated positively with peak bilirubinemia. The results of this investigation suggest that a deficiency of factors protecting from oxygen toxicity, may play a role in the development of neonatal hemolysis and jaundice.
The aim of the present study was to determine and compare plasma and erythrocyte concentrations of magnesium in 12 autistic children (10 boys, 2 girls), 17 children with other autistic spectrum disorders (14 boys, 3 girls), 5 girls with classic Rett syndrome, and 14 normal children (7 boys, 7 girls) of the same age. No differences in intracellular Mg were found between controls and pathological subjects; however, autistic children and children with other autistic spectrum disorders had significantly lower plasma concentrations of Mg than normal subjects (p=0.013 and p=0.02, respectively). Although our study population was small, we conclude that children with autistic spectrum disorders require special dietary management. If these cases are diagnosed at an early stage, they can be helped through diet.
Anti-synthetase syndrome is an autoimmune disease characterized by autoantibodies toward amino acyl-tRNA synthetases (ARS), anti-Jo 1 being the most commonly detected. Muscle damage develops in up to 90% of ARS-positive patients, characterized by a necrotizing myositis restricted to the perifascicular region. This topographic distribution of muscle damage may lead to a misdiagnosis of dermatomyositis (DM) at muscle biopsy. We compared morphological, immunohistochemical, and histoenzymatic features of muscle from ARS-positive patients (n = 11) with those of DM (n = 7) providing clues for their differential diagnosis. In addition, we evaluated markers of mitochondrial damage to provide a further distinction between these two entities. Necrosis occurred in the majority of ARS patients, mainly located in the perifascicular region. It was often limited to small foci of fibers, always associated with myocyte regeneration. This last often overwhelmed necrosis, representing occasionally the main finding. In DM, necrosis/regeneration was scarce while the peculiar feature was a diffuse atrophy of perifascicular fibers. These last showed decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion, consistent with mitochondrial dysfunction. In contrast to DM, ARS displayed scattered COX-deficient fibers, not restricted to the perifascicular region. This feature occurred in up to 91% of patients, being prominent only in two.
Bracci, R., Buonocore, G., Garosi, G., Bruchi, S. and Berni, S. (Division of Neonatology, University of Siena, Siena, Italy). Epidemiologic study of neonatal jaundice. A survey of contributing factors. Acta Paediatr Scand Suppl 360: 87, 1989.In the attempt to detect factors influencing bilirubinemia in healthy full-term or nearterm newborn infants, a statistical analysis was carried out on a population of 1126 neonates to study the variables possibly associated with maximum bilirubin values reached in the first days of life. The following variables were studied: maximum bilirubin level (maxBIL), sex, mode of delivery, gestational age, birthweight, ratio of birthweight/weight on 5th day, Apgar score, Rh and ABO incompatibility. Blood glucose and calcium levels, haematocrit, intake of breast milk, formula and glucose solution were also evaluated during the first 5 days of life. Higher maxBIL was found in males compared to females, after spontaneous delivery vs. emergency caesarean section, after caesarean section without fetal distress vs. emergency caesarean section, and in ABO incompatibility vs. no ABO incompatibility. Statistically significant inverse correlations were observed between maxBIL and gestational age, birth weight, blood glucose, and SE-calcium. Significant positive correlations were found between maxBIL and haematocrit and breast milk intake. A multiple regression analysis between maxBIL and the significantly correlated parameters showed that only gestational age and birth weight remained significantly correlated with maxBIL. The results of the present investigation confirm that the factors most commonly reported as being responsible for neonatal hyperbilirubinemia do in fact play a role, although it can be considered almost negligible with the exception of gender, mode of delivery, ABO incompatibility, birthweight and gestational age. Key words: newborn infant, hyperbiliru binemiu.
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