Childhood hypophosphatasia with homozygous mutation of ALPL.

OBJECTIVE: To describe an unusual phenotype of a case with rare homozygous ALPL gene mutation that results in mild form of hypophosphatasia. METHODS: Case presentation, description of biochemical profiles, genetic testing and a brief review of literature are presented. RESULTS: A 13-year-old male presented with chronic left knee pain. Radiogram of the left knee indicated two oval radiolucent lesions in the femoral metaphysis. Serum alkaline phosphatase activity (17 U/L) was markedly below normal (42 to 362 U/L). Serum pyridoxal 5' phosphate (258 µg/L) was above normal (5 to 50 µg/L). Sequence analysis of ALPL gene indicated a homozygous missense mutation c.1077 C>G (p. I359M). The mutation was previously identified in a case of perinatal hypophosphatasia with severe skeletal abnormalities in contrast to the mild phenotype of the patient we present. CONCLUSION: The case of homozygous mutation of ALPL gene but mild form of hypophosphatasia suggests that functions of the mutated protein may be modified by other factors.

C-peptide reduces pro-inflammatory cytokine secretion in LPS-stimulated U937 monocytes in condition of hyperglycemia.

OBJECTIVE: We investigated C-peptide effects on inflammatory cytokine release and adhesion of monocytes exposed to high glucose and lipopolysaccharide (LPS) in vitro. MATERIALS AND METHODS: Monocytic cells (U-937) were cultured in the presence of 30 mmol/L glucose and stimulated with 0.5 ng/µL LPS in the presence or absence of C-peptide (1 µmol/L) for 24 h to induce inflammatory cytokine secretion. Adhesion of U-937 monocytes to human aortic endothelial cells (HAEC) was also studied in the presence or absence of C-peptide. Concentrations of IL-6, IL-8, macrophage inflammatory protein(MIP)-1α, and MIP-1ß in supernatants from LPS-stimulated U-937 monocytes were assessed by Luminex. To gain insights into potential intracellular signaling pathways affected by C-peptide, we investigated nuclear translocation of nuclear factor(NF)-κB p65/p50 subunits by western blot in LPS-treated U-937 cells. The effect of C-peptide on LPS-induced phosphorylation of the cytoplasmic protein IκB-α was also investigated by immunoblotting. RESULTS: Addition of C-peptide significantly reduced cytokine secretion from LPS-stimulated U-937 monocytes. Adhesion of U-937 cells to HAEC was also significantly reduced by C-peptide. These effects were accompanied by reduced NF-κB p65/p50 nuclear translocation and decreased phosphorylation of IκB-α. CONCLUSIONS: We conclude that, in conditions of hyperglycemia, C-peptide reduces monocytes activation via inhibition of the NF-κB pathway.

Hypercalcemia in Children Using the Ketogenic Diet: A Multicenter Study.

CONTEXT: The ketogenic diet is associated with progressive skeletal demineralization, hypercalciuria, and nephrolithiasis. Acute hypercalcemia has been described as a newly recognized complication of this treatment. OBJECTIVE: To describe the clinical characteristics of acute hypercalcemia in children on the ketogenic diet through analysis of the presentation, response to treatment, and natural history in a large cohort of patients. DESIGN: A multicenter case series was performed including children who developed acute hypercalcemia while treated with the ketogenic diet. Information on clinical presentation, treatment, and course of this complication was collated centrally. RESULTS: There were 14 patients (median (range) age 6.3 (0.9 to 18) years) who developed hypercalcemia 2.1 (range, 0.2-12) years after starting the ketogenic diet. All had low levels of parathyroid hormone and levels of 1,25-dihydroxyvitamin D were low in all except one. Seven (50%) had impaired renal function at presentation. All except the 2 oldest had low alkaline phosphatase levels for age. Once normocalcemia was achieved, hypercalcemia recurred in only 2 of these patients over observation of up to 9.8 years. One patient discontinued the ketogenic diet prior to achieving normocalcemia while 4 more stopped the diet during follow-up after resolution of hypercalcemia. CONCLUSIONS: Ketotic hypercalcemia can occur years after starting the ketogenic diet, especially in the setting of renal impairment. The mechanism is unknown but appears to be due to reduced osteoblast activity and impaired bone formation. We recommend close attention to optimizing bone health in these children, and screening for the development of ketotic hypercalcemia.

Anti-inflammatory properties of C-Peptide.

C-peptide, historically considered a biologically inactive peptide, has been shown to exert insulin-independent biological effects on a number of cells proving itself as a bioactive peptide with anti-inflammatory properties. Type 1 diabetic patients typically lack C-peptide, and are at increased risk of developing both micro- and macrovascular complications, which account for significant morbidity and mortality in this population. Inflammatory mechanisms play a pivotal role in vascular disease. Inflammation and hyperglycemia are major components in the development of vascular dysfunction in type 1 diabetes. The anti-inflammatory properties of C-peptide discovered to date are at the level of the vascular endothelium, and vascular smooth muscle cells exposed to a variety of insults. Additionally, C-peptide has shown anti-inflammatory properties in models of endotoxic shock and type 1 diabetes-associated encephalopathy. Given the anti-inflammatory properties of C-peptide, one may speculate dual hormone replacement therapy with both insulin and C-peptide in patients with type 1 diabetes may be warranted in the future to decrease morbidity and mortality in this population.