Heparan sulfates, the carbohydrate chains of heparan sulfate proteoglycans, play an important role in basement membrane organization and endothelial barrier function. We explored whether endothelial cells secrete a heparan sulfate degrading heparanase under inflammatory conditions and what pathways were responsible for heparanase expression. Heparanase mRNA and protein by Western blot were induced when cultured endothelial cells were treated with cytokines, oxidized low-density lipoprotein (LDL) or fatty acids. Heparanase protein in the cell media was induced 2-10-fold when cells were treated with tumor necrosis factor alpha (TNFalpha) or interleukin 1beta (IL-1beta). Vascular endothelial growth factor (VEGF), in contrast, decreased heparanase secretion. Inhibitors to nuclear factor-kappaB (NFkappaB), PI3-kinase, MAP kinase, or c-jun kinase (JNK) did not affect TNFalpha-induced heparanase secretion. Interestingly, inhibition of caspase-8 completely abolished heparanase secretion induced by TNFalpha. Fatty acids also induced heparanase, and this required an Sp1 site in the heparanase promoter. Immunohistochemical analyses of cross sections of aorta showed intense staining for heparanase in the endothelium of apoE-null mice but not wild-type mice. Thus, heparanase is an inducible inflammatory gene product that may play an important role in vascular biology.

Lipoprotein lipase (LPL), the rate-limiting enzyme for hydrolysis of plasma lipoprotein triglycerides, is a normal constituent of the arterial wall. We explored whether LPL affects (a) lipoprotein transport across bovine aortic endothelial cells or (b) lipoprotein binding to subendothelial cell matrix (retention). When bovine milk LPL was added to endothelial cell monolayers before addition of "2'I-labeled LDL, LDL transport across the monolayers was unchanged; but, at all concentrations of LDL tested (1-100 jig), LDL retention by the monolayers increased more than fourfold. '251-labeled LDL binding to extracellular matrix increased when LPL was added directly to the matrix or was added to the basolateral side ofthe endothelial cell monolayers. Increased LDL binding required the presence of LPL and was not associated with LDL aggregation. LPL also increased VLDL, but not HDL, retention. Monoclonal anti-LPL IgG decreased both VLDL and LDL retention in the presence of LPL. Lipoprotein transport across the monolayers increased during hydrolysis of VLDL triglyceride (TG). In the presence of LPL and VLDL, VLDL transport across the monolayers increased 18% and LDL transport increased 37%. High molar concentrations of oleic acid to bovine serum albumin (3:1) in the medium increased VLDL transport 30%.LDL transport increased 42% when oleic acid was added to the media. Therefore, LPL primarily increased retention of LDL and VLDL. A less remarkable increase in lipoprotein transport was found during hydrolysis of TG-containing lipoproteins. We hypothesize that LPL-mediated VLDL and LDL retention within the arterial wall potentiates conversion of these lipoproteins to more atherogenic forms. (J. Clin. Invest. 1992.89:373-380.)

Purpose of ReviewNutritional rickets and osteomalacia are common in dark-skinned and migrant populations. Their global incidence is rising due to changing population demographics, failing prevention policies and missing implementation strategies. The calcium deprivation spectrum has hypocalcaemic (seizures, tetany and dilated cardiomyopathy) and late hypophosphataemic (rickets, osteomalacia and muscle weakness) complications. This article reviews sustainable prevention strategies and identifies areas for future research.Recent FindingsThe global rickets consensus recognises the equal contribution of vitamin D and dietary calcium in the causation of calcium deprivation and provides a three stage categorisation for sufficiency, insufficiency and deficiency. For rickets prevention, 400 IU daily is recommended for all infants from birth and 600 IU in pregnancy, alongside monitoring in antenatal and child health surveillance programmes.SummaryHigh-risk populations require lifelong supplementation and food fortification with vitamin D or calcium. Future research should identify the true prevalence of rickets and osteomalacia, their role in bone fragility and infant mortality, and best screening and public health prevention tools.

BackgroundNutritional rickets is a growing global public health concern despite existing prevention programmes and health policies. We aimed to compare infant and childhood vitamin D supplementation policies, implementation strategies and practices across Europe and explore factors influencing adherence.MethodsEuropean Society for Paediatric Endocrinology Bone and Growth Plate Working Group members and other specialists completed a questionnaire on country-specific vitamin D supplementation policy and child health care programmes, socioeconomic factors, policy implementation strategies and adherence. Factors influencing adherence were assessed using Kendall’s tau-b correlation coefficient.ResultsResponses were received from 29 of 30 European countries (97%). Ninety-six per cent had national policies for infant vitamin D supplementation. Supplements are commenced on day 1–5 in 48% (14/29) of countries, day 6–21 in 48% (14/29); only the UK (1/29) starts supplements at 6 months. Duration of supplementation varied widely (6 months to lifelong in at-risk populations). Good (≥80% of infants), moderate (50–79%) and low adherence (<50%) to supplements was reported by 59% (17/29), 31% (9/29) and 10% (3/29) of countries, respectively. UK reported lowest adherence (5–20%). Factors significantly associated with good adherence were universal supplementation independent of feeding mode (P = 0.007), providing information at neonatal unit (NNU) discharge (P = 0.02), financial family support (P = 0.005); monitoring adherence at surveillance visits (P = 0.001) and the total number of factors adopted (P < 0.001).ConclusionsGood adherence to supplementation is a multi-task operation that works best when parents are informed at birth, all babies are supplemented, and adherence monitoring is incorporated into child health surveillance visits. Implementation strategies matter for delivering efficient prevention policies.

These suppression-release effects of high-dose denosumab on bone remodeling raise questions about safety of fixed dosing and treatment duration. In young people, weight-adjusted dosing and safety monitoring during and after antiresorptive therapy is required.