Correction of vitamin D status by calcidiol: pharmacokinetic profile, safety, and biochemical effects on bone and mineral metabolism of daily and weekly dosage regimens.

RATIONALE: Calcidiol can be employed to correct vitamin D deficiency. MAIN RESULTS: Calcidiol administered at daily and weekly regimens over a period of 3 months was able to successfully raise 25-hydroxyvitamin D levels without altering other markers related to bone and mineral metabolism. SIGNIFICANCE: Calcidiol supplementation is effective and safe. INTRODUCTION: The correction of vitamin D status is necessary to maintain an optimal mineral and skeletal homeostasis. Despite cholecalciferol (vitamin D3) is the most commonly used drug for vitamin D supplementation, the more hydrophilic compound calcidiol (25-hydroxyvitamin D3) can be employed at daily, weekly, and monthly regimens to reach in the short term the target levels of serum 25-hydroxyvitamin D [25(OH)D]. In the administration of different doses of calcidiol pharmacokinetic study (ADDI-D study), the efficacy and safety of daily and weekly dosages of calcidiol were tested. METHODS: A total of 87 Caucasian, community-dwelling, postmenopausal women, aged 55 years or older, with vitamin D inadequacy (serum 25(OH)D levels <30 ng/ml, with mean 25(OH)D below 20 ng/ml, namely 16.5 ± 7.5 ng/ml) were randomized to receive three different dosages of calcidiol: 20 µg/day, 40 µg/day, and 125 µg/week for 3 months. The attained level of serum 25(OH)D was selected as primary endpoint to assess efficacy, while other parameters of mineral metabolism, (serum calcium, parathyroid hormone, phosphate, FGF23, urinary calcium, and markers of bone turnover) were assessed as secondary endpoints to establish safety. RESULTS: In all the three groups, serum 25(OH)D values significantly and promptly rose and plateaued above the 30 ng/ml threshold remaining within safety interval after 14 days of treatment, with similar efficacy for the similar daily and weekly dose regimens. The different dosages were also equally effective in controlling secondary hyperparathyroidism. No significant changes in calcium and phosphate metabolism and in bone turnover markers were observed for any of the treatments, confirming the safety of this compound. CONCLUSIONS: The results of this study demonstrate the short- and mid-term efficacy and safety on core parameters of mineral metabolism of different daily or weekly dosages of calcidiol when used to treat vitamin D inadequacy or deficiency in postmenopausal women. Further studies are needed to assess falls as primary outcome of calcidiol supplementation.

Changing patterns of prescription in vitamin D supplementation in adults: analysis of a regional dataset.

UNLABELLED: Scientific interest in vitamin D has greatly risen during the last 10 years. The analysis of the changes in vitamin D prescriptions and related costs in a regional prescription dataset has revealed a profound increase in the period 2006-2013. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed. INTRODUCTION: The aim of this study was to analyze the changes in population-based prescription patterns of vitamin D supplements in the general population in an Italian regional setting during an 8-year period (2006-2013). METHODS: Data have been retrieved from the database of reimbursed prescriptions of the Region of Tuscany containing all of the medical reimbursements for the whole regional population (total of 3,619,872 and 3,692,828 inhabitants in 2006 and 2013, respectively). Data referring to adult population (age 20-90+ years) have been considered for this analysis (3,033,530 in 2006 and 3,066,741 in 2013). Two different flows (pharmaceutical distribution dataset and general data flow) were taken into account, using the ATC5 coding system for vitamin D supplements alone or in combination with calcium or alendronate. The number of boxes dispensed was retrieved, the number of patients receiving a specific treatment was calculated, and a cost analysis was performed. RESULTS: An upsurge in the prescriptions of vitamin D compounds was disclosed, mainly sustained by a 75.3-fold increase in cholecalciferol, in all age groups and both sexes. This occurred in parallel to a 4.3-fold rise in prescriptions of oral alendronate in combination with cholecalciferol, a slight decrease in dispensed alendronate alone, and a modest increase in the prescription of the combination of calcium salts and cholecalciferol, and calcium alone. The total cost for reimbursement by the Regional Health System for vitamin D-related compounds rose from €3,242,100 euros in 2006 to €8,155,778 in 2013. CONCLUSION: The huge increase in vitamin D prescriptions and related costs in the last decade, as revealed by the analysis of a regional pharmaceutical dataset, reflects the increased awareness of the possible consequences of a poor vitamin D status. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed.

Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization.

Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.

Variations in polychlorinated biphenyl congener composition in eggs of Mediterranean water birds in relation to their position in the food chain.

The concentrations of the principal PCB congeners and the SigmaPCB were determined in eggs of eight species of water birds collected in two areas of the Mediterranean region. The results for SigmaPCB levels indicate statistically significant differences between the species; in the Po delta the higher values are for those species which feed mainly on fish. Differences exist between the congeners and their percentages when compared with the total residue. Tetrachlorobiphenyls constitute a larger proportion of the SigmaPCB in Avocet and Black-winged Stilt, two species whose diet consists mainly of invertebrates. The main component in all the species is 22'44'55' and its presence varies between 11.4% in Avocet and 21.2% in Audouin's Gull. It is suggested that there is a link between the uptake of PCBs and the position of the species in the food chain.

Lead, mercury, cadmium and selenium in two species of gull feeding on inland dumps, and in marine areas.

The influence of the foraging area on the intake of trace elements was evaluated in tissues of two species of gull: the black-headed gull (Larus ridibundus) and the herring gull (Larus argentatus). Mercury levels were higher in birds from the coastal environment than in those caught on inland dumps; birds found at one dump site showed high levels of lead. Interspecific differences in the levels of mercury and cadmium are discussed.

Heavy metals and selenium in stranded dolphins of the northern Tyrrhenian (NW Mediterranean).

Heavy metal (Hg, Cd, Pb and Zn) and selenium levels were determined in striped (Stenella coeruleoalba) and bottle-nosed dolphins (Tursiops truncatus) stranded along the coast of Tuscany and Latium, Italy in the period 1987-1989. Lead and zinc concentrations were quite low and there was modest accumulation of cadmium in the kidney of both species. Mercury levels were very high, especially in the liver where they reached peaks of 4400 ppm (dry weight) in the striped dolphin and 13,150 ppm (dry weight) in the bottle-nosed dolphin. Selenium levels were also high and were significantly correlated with mercury levels in some organs and tissues. The toxicological significance of the selenium-mercury interaction is discussed.

An assessment of pollutants in eggs of Audouin's gull (Larus audouinii), a rare species of the Mediterranean sea.

Audouin's gull (Larus audouinii) is a very rare species endemic to the Mediterranean basin. A sub-population of an estimated 130 pairs is breeding in the Tuscan Archipelago, an area heavily polluted by mercury and chlorinated hydrocarbons. Here we present the data from 5 years spent monitoring the contaminant levels in the eggs of this species. Mercury, selenium, polychlorobiphenyls (PCBs) and DDE concentrations are two to five times higher than in similar species, such as the yellow-legged herring gull, nesting in the same area. The annual trends in these contaminant levels are discussed. In view of the endangered status of Audouin's gull, there is a need to observe closely the developing trend of contamination in this species.

Trace elements and chlorinated hydrocarbons in eggs of Pelecanus crispus, a world endangered bird species nesting at Lake Mikri Prespa, North-western Greece.

Eggs of the Dalmatian pelican, Pelecanus crispus, collected from 1984 to 1986 at Lake Mikri Prespa, north-western Greece, contained residues of trace elements and PCBs at low concentrations, and of DDE at rather high concentrations. DDE is negatively related to eggshell thickness. Eggshell thickness was reduced by 12-20% in comparison with the pre-1947 (before DDT use) eggshell thickness. However, this decrease did not affect the reproductive success of this species. The main fish species eaten by the Dalmatian pelican at Lake Mikri Prespa were analyzed for pollutants. All the fish contained low concentrations of residues. The contribution of the diet while the birds are on the wintering grounds is unknown. Recommendations for a monitoring programme of pollutants in eggs of the Dalmatian pelican, a world-endangered species, are proposed.

Chlorinated hydrocarbons in the tissues of South Polar Skuas (Catharacta maccormicki) and Adélie Penguins (Pygoscelis adeliea) from Ross Sea, Antarctica.

High rates of egg infertility and embryo death in a colony of South Polar Skuas breeding in the Antarctic were similar to those in polluted North Atlantic populations of the Great Skua. Such loss could not be linked to factors such as organochlorine pollutants, as levels of DDE and PCBs in the contents of skua eggs from the population were only a small fraction of those in polluted skua populations from the Northern Hemisphere. Average eggshell thickness for skuas nesting on Ross Island has shown no significant change since the introduction of DDT. Concentrations of DDE and PCBs in South Polar Skuas were 13 and 22 times higher, respectively, than those in the eggs of sympatric Adélie Penguins, and this probably reflects the greater exposure of skuas to pollution when they migrate north of the Antarctic Convergence in winter. Residues in liver tissue showed a similar trend, and a higher rate of mixed function oxidase induction in skua liver compared to that of penguins is consistent with the trends seen in pollutant levels. The same PCB congener predominated in both skua and penguin samples. Comparisons with historical residue data suggest that global levels of DDT residues are declining.

Monitoring the impact of litter in large vertebrates in the Mediterranean Sea within the European Marine Strategy Framework Directive (MSFD): constraints, specificities and recommendations.

In its decision (2010/477/EU) relating to the European Marine Strategy Framework Directive (MSFD, 2008/56/EC), the European Commission identified the following points as focuses for monitoring: (i) 10.1.1: Trends in the amount, source and composition of litter washed ashore and/or deposited on coastlines, (ii) 10.1.2: Trends in the amount and composition of litter in the water column and accumulation on the sea floor, (iii) 10.1.3: Trends in the amount, distribution and composition of micro-particles (mainly microplastics), and (iv) 10.2.1: Trends in the amount and composition of litter ingested by marine animals. Monitoring the impacts of litter will be considered further in 2014. At that time, the strategy will be discussed in the context of the Mediterranean Sea, providing information on constraints, protocols, existing harm and research needed to support monitoring efforts. The definition of targets and acceptable levels of harm must take all factors into account, whether entanglement, ingestion, the transport and release of pollutants, the transport of alien species and socio-economic impacts. It must also reflect on the practical deployment of "ingestion" measures (10.2.1). The analysis of existing data will reveal the potential and suitability of some higher trophic level organisms (fish, turtles, birds and mammals) for monitoring the adverse effects of litter. Sea turtles appear to be useful indicator species, but the definition of an ecological quality objective is still needed, as well as research on alternative potential indicator species.

Regulatory detoxication responses in Gobiidae experimentally exposed to PCBs.

In order to investigate interspecific responses to pollutants, physiological and biochemical parameters were studied in two species of Gobiidae under both natural and experimental conditions. Gobius niger, collected in a polluted area, had higher mixed function oxidases activity and polychlorobiphenyl (PCB) residues than another species, Zosterisessor ophiocephalus, collected from a relatively clean lagoon. After acclimatization to clean water and exposure to PCBs (Aroclor 1260), both species showed responses similar to those observed in the field and all biochemical parameters related to detoxication were much higher in G. niger. This suggests that this species undergoes metabolic or genetic adaptation.

Persistent organochlorine residues in fish and water birds from the Biobio river, Chile.

Concentrations of polychlorinated biphenyls (PCBs), DDT and its metabolites, HCH isomers and hexachlorobenzene (HCB) were determined in fish and birds from different locations in the Biobio river basin (central Chile). Samples collected near the mouth of the river contained high concentrations of PCBs, reflecting the massive use of these xenobiotics in the urban and industrial areas of Concepcion and Talcauano. Samples collected in the central part of the basin contained very high concentrations of lindane that coincide with the widespread use of lindane-based pesticides (purified γ-HCH) in this area. DDT was distributed homogeneously throughout the basin, except at Laguna Icalma, the source of the river in the Andes. Most PCB residues in fish and birds consisted of congeners between penta- and hepta-chlorobiphenyls. In fish, the predominant congeners were the pentachlorobiphenyl 23'44'5 (IUPAC number 118) and the hexachlorobiphenyl 22'344'55' (PCB-153); in birds 22'44'55' (PCB-180) prevailed.

Long term monitoring of pollutants in eggs of Yellow-legged Herring Gull from Capraia island (Tuscan Archipelago).

Chlorinated hydrocarbons (hexachlorobenzene, lindane, pp'DDE, polychlorinated biphenyls) and trace elements (Hg, Se, Cd, Pb) were determined in eggs of Yellow-legged Herring Gull (Larus cachinnans) collected in an island of the Tyrrhenian Sea during the period 1981-1986. PCBs levels vary on the average between 30.4µg g(-1) d.w. in 1981 to 56.1 µg g(-1) d.w. in 1983. The capillary chromatograms revealed the presence of about 30 somers of PCBs without significant variations in the eggs of the same year; more than 50% of the residues is made up only three isomers: the 22'44'55', the 22'344'5' and the 22'344'55'. Average DDE residues were 7-8 times lower than those of PCBs and declined during the period (from 9.2 µg g(-1) d.w. in 1981 to 4.5 µg g(-1) d.w. in 1986). Cadmium and lead are present in low concentrations. The average levels of mercury and selenium are around 2-2.5 µg g(-1) d.w., and a cumulative correlation, on a molar basis, exists between these two elements.

Multi response biomarker approach in the crab Carcinus aestuarii experimentally exposed to benzo a pyrene, polychlorobiphenyls and methyl mercury.

The aim of this study was to test a multi response biomarker approach for evaluating toxicological risk due to some of the main contaminants in the Mediterranean benzo a pyrene, polychlorobiphenyls and methyl mercury, using the Mediterranean crab Carcinus aestuarii as bioindicator organism. Forty crabs were injected with different doses of these contaminants. Several molecular, biochemical and genotoxic biomarkers were tested in different tissues and biological materials. The main conclusions were: 1 hepatopancreas, gills, haemolymph and excreta seem to be useful for biomarker studies in this species; 2 several biochemical, molecular and genotoxic biomarkers were found suitable for testing in these tissues; 3 several biomarkers were found suitable for evaluating chemical stress due to different Mediterranean contaminants.