Increased levels of Dickkopf-1 are indicative of Wnt/ß-catenin downregulation and lower osteoblast signaling in children and adolescents with type 1 diabetes mellitus, contributing to lower bone mineral density.

Higher levels of Dickkopf-1, which is an inhibitor of Wnt/ß-catenin bone metabolic pathway, could be indicative of downregulated Wnt system, with possible lower osteoblast activation and higher osteoclast signaling in type 1 diabetes mellitus children and adolescents. Dickkopf-1 could significantly contribute to diabetes osteopathy. INTRODUCTION: Increased fracture risk and elevated Dickkopf-1 levels, which is an inhibitor of Wnt/ß-catenin bone metabolic pathway, have been documented in adult patients with type 2 diabetes mellitus (T2D), while no relevant data exist on childhood type 1 diabetes (T1D). Our aim was to study plasma Dickkopf-1 distribution in children and adolescents with T1D and to correlate Dickkopf-1 with metabolic bone markers and bone mineral density (BMD). METHODS: We evaluated 40 children and adolescents with T1D (mean ± SD age 13.04 ± 3.53 years, T1D duration 5.15 ± 3.33 years) and 40 healthy age-matched and gender-matched controls (age 12.99 ± 3.3 years). Dickkopf-1 and bone metabolic markers were measured, while total body and lumbar spine BMD were evaluated with dual-energy X-ray absorptiometry (DXA). RESULTS: Dickkopf-1 demonstrated a Gaussian distribution, with higher levels in T1D patients (13.56 ± 5.34 vs 11.35 ± 3.76 pmol/L, p = 0.024). Higher values were found in boys and in prepubertal children. Dickkopf-1 correlated positively with osteoprotegerin and fasting glucose in patients, while positive correlation with sclerostin and total soluble receptor activator of nuclear factor-kappaB ligand (s-RANKL) was found in controls. Positive correlations with C-telopeptide cross-links (CTX), osteocalcin, alkaline phosphatase, phosphate, and insulin-like growth factor 1 (IGF1) were documented in both groups. Lumbar spine Z-score was positively associated with Dickkopf-1 in controls, while a negative trend was found in patients. CONCLUSIONS: Higher levels of Dickkopf-1 could indicate a downregulated Wnt/ß-catenin system with possible lower osteoblast activation and higher osteoclast signaling in T1D children and adolescents. Dickkopf-1 could possibly be a significant contributor of T1D osteopathy. Future therapies could focus on Wnt/ß-catenin metabolic pathway.

Higher levels of s-RANKL and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signaling and predisposition to lower bone mass: a multivariate cross-sectional analysis.

UNLABELLED: Simultaneous lower bone mineral density, metabolic bone markers, parathyroid hormone (PTH), magnesium, insulin-like growth factor 1 (IGF1), and higher levels of total soluble receptor activator of nuclear factor-kappa B ligand (s-RANKL), osteoprotegerin (OPG), and alkaline phosphatase (ALP) are indicative of lower osteoblast and increased osteoclast signaling in children and adolescents with type 1 diabetes mellitus, predisposing to adult osteopenia and osteoporosis. INTRODUCTION: Type 1 diabetes mellitus (T1DM) is a risk factor for reduced bone mass, disrupting several bone metabolic pathways. We aimed at identifying association patterns between bone metabolic markers, particularly OPG, s-RANKL, and bone mineral density (BMD) in T1DM children and adolescents, in order to study possible underlying pathophysiologic mechanisms of bone loss. METHODS: We evaluated 40 children and adolescents with T1DM (mean ± SD age 13.04 ± 3.53 years, T1DM duration 5.15 ± 3.33 years) and 40 healthy age- and gender-matched controls (aged12.99 ± 3.3 years). OPG, s-RANKL, osteocalcin, C-telopeptide cross-links (CTX), IGF1, electrolytes, PTH, and total 25(OH)D were measured, and total body along with lumbar spine BMD were evaluated with dual energy X-ray absorptiometry (DXA). Multivariate regression and factor analysis were performed after classic inference. RESULTS: Patients had significantly lower BMD, with lower bone turnover markers, PTH, magnesium, and IGF1 than controls, indicating lower osteoblast signaling. Higher levels of total s-RANKL, OPG, and total ALP were observed in patients, with log(s-RANKL) and OPG correlation found only in controls, possibly indicating increased osteoclast signaling in patients. Coupling of bone resorption and formation was observed in both groups. Multivariate regression confirmed simultaneous lower bone turnover, IGF1, magnesium, and higher total s-RANKL, OPG, and ALP in patients, while factor analysis indicated possible activation of RANK/RANKL/OPG system in patients and its association with magnesium and IGF1. Patients with longer disease duration or worse metabolic control had lower BMD. CONCLUSIONS: T1DM children and adolescents have impaired bone metabolism which seems to be multifactorial. Reduced osteoblast and increased osteoclast signaling, resulting from multiple simultaneous disturbances, could lead to reduced peak bone accrual in early adulthood, predisposing to adult osteopenia and osteoporosis.

Risk factors for elevated blood lead levels among children aged 6-36 months living in Greece.

BACKGROUND: Childhood lead poisoning remains a critical environmental health concern because even low blood lead levels (BLLs) can result in permanent adverse health effects. Social factors and living conditions have been correlated with BLLs. There is no recent survey about the prevalence of elevated BLLs among children in Greece. The purpose of this study was to assess BLLs among children aged 6-36 months born and living in Greece and to evaluate their association with demographic, socio-economic and housing conditions. METHODS: In a cross-sectional hospital-based study including 814 randomly selected children aged 6-36 months, BLLs and haematological parameters were evaluated. A questionnaire investigating demographic and socio-economic conditions was completed in all children. Statistical analysis was performed using STATA for Windows v.8.5, and P < 0.05 was considered statistically significant. RESULTS: The mean BLLs of the population were 2.78 (SD = 2.34) µg/dl, and the median was 2.02 µg/dl; 11.7% had BLLs above 5 µg/dl, while 15 children (1.8%) exceeded 10 µg/dl. Being a toddler, being Roma or Asian, living in an industrial/low-income neighbourhood or in an old house, using traditional herbs and/or spices and having a mother with a manual occupation were independent risk factors for elevated BLLs. CONCLUSION: Lead exposure remains a threat for optimal health especially for toddlers and children of socio-economically disadvantaged families living in Greece. A nationwide survey to assess lead exposure in children is necessary to guide prevention governmental policies.

Persistent coagulopathy during Escherichia coli sepsis in a previously healthy infant revealed undiagnosed tyrosinaemia type 1.

Hereditary tyrosinaemia type 1 (HT1) is caused by an enzymatic defect in tyrosine metabolism. It is an autosomal recessive disorder and affects both sexes equally. In young infants HT1 can present as severe liver involvement and in older infants as liver failure and renal tubular dysfunction together with growth failure and rickets. The authors report the case of a 5-month-old, previously healthy, male infant who presented with Escherichia coli sepsis and severe coagulopathy due to liver dysfunction. Despite the early diagnosis of HT1 and treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), the patient died from severe coagulopathy and multi-organ failure.

Clinical and morphological features of paediatric myelodysplastic syndromes: a review of 34 cases.

BACKGROUND: The clinical and morphological spectrum of myelodysplastic syndromes (MDS) during childhood has not yet been completely documented. We herein present the clinical features and morphological data from peripheral blood (PB), bone marrow aspirates (BMA) and bone marrow biopsies (BMB) of a series of paediatric MDS patients, with particular emphasis on their specific morphological characteristics and their diverse underlying genetic background. PATIENTS AND METHODS: Thirty-four patients with MDS (median age 8.45 y) were consecutively diagnosed and treated during a period of 15 y (1988-2002). Diagnosis was based on clinical manifestations, morphology of PB, BMA and BMB, and cytogenetic analysis of BM cells. Clonogenic methylcellulose cell cultures were performed in 23/34 patients. Patients were categorized into group A [26 primary/de novo MDS, i.e. refractory anaemia (RA) 18, RA with excess of blasts (RAEB) 2, RAEB in transformation (RAEB-t) 6] and group B (8 secondary MDS, i.e. RA 4, RAEB 1, RAEB-t 3). Treatment options varied according to protocols active during the period of the study and the availability of a suitable BM donor. Survival probabilities were estimated using the Kaplan-Meier method. RESULTS: Dysplastic features of the erythroid, myeloid and megakaryocytic lineage were detected at BMA in 85%, 50% and 90% of the patients, respectively, while decreased cellularity was found at BMB in 21/34 patients (60%). RA patients of group A presented at BMB significant hypocellularity (14/18) as a prominent finding due to decrease of the myeloid (13/18 patients) and/or the megakaryocytic (14/18 patients) lineage. Hypocellularity in RA was accompanied by dysplasia of the erythroid (17/18 patients) and megakaryocytic (16/18 patients) lineage, the presence of abnormal localization of immature precursors (ALIP, 8/18 patients), fibrosis (5/18) and stromal changes (11/18). Chromosomal aberrations were revealed in 17/34 patients, of which monosomy 7 was present in seven. Cell cultures demonstrated abnormal myeloid and/or erythroid in vitro clonal growth pattern in all the examined patients. An associated disorder or inherited disease, was identified in 14/26 patients (54%) with primary MDS. Cumulative survival of group A patients was 44.2% (RA 66.6%, RAEB/RAEBt 14.6%; p = 0.001), and of the whole group 42.4%, at 14 y. CONCLUSIONS: Hypocellularity of significant degree is a constant and prominent feature among paediatric MDS, especially those with RA. A large variety of associated disorders underlies the clinical appearance of paediatric MDS, reflecting their marked heterogeneity. RA represents the prominent subtype during childhood (69% in this study), and it appears to have the best prognosis, while prognosis of RAEB/RAEBt remains extremely poor.