Late onset of Wilson's disease in a family with genetic haemochromatosis.

We report the coexistence of Wilson's disease and genetic haemochromatosis in one family. The diagnosis of genetic haemochromatosis was established in a 52-year-old man. Among his siblings, one 57-year-old sister and one 55-year-old brother had decreased copper and ceruloplasmin levels in serum and increased urinary copper excretion. The sister shared the same human leucocyte antigen haplotypes and was homozygous for the HFE mutation C282Y, like the propositus. However, she had normal liver iron content and increased liver copper content. Her dietary copper intake was probably excessive. The association of Wilson's disease and genetic haemochromatosis is rare and has only been described twice. The onset of Wilson's disease after 50 years of age is rare; Wilson's disease should be considered in any patient with unexplained chronic liver disease; an excess in liver copper content might be induced by excessive dietary input in a susceptible individual.

Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats.

UNLABELLED: Strontium ranelate given to intact rats at doses up to 900 mg/kg/day increases bone resistance, cortical and trabecular bone volume, micro-architecture, bone mass, and total ALP activity, thus indicating a bone-forming activity and an improvement of overall bone tissue quality. INTRODUCTION: Various anti-osteoporotic agents are available for clinical use; however, there is still a need for drugs able to positively influence the coupling between bone formation and bone resorption to increase bone mass and bone strength. Strontium ranelate (PROTELOS), a new chemical entity containing stable strontium (Sr), was tested for its capacity to influence bone quality and quantity. MATERIALS AND METHODS: The long-term effects of strontium ranelate on bone were investigated in intact female rats treated with various doses of strontium ranelate (0, 225, 450, and 900 mg/kg/day) for 2 years. In a second series of experiments, the effects of 625 mg/kg/day were evaluated in intact male and female rats for the same period of time. Bone mineral mass and mechanical properties were evaluated at various skeletal sites (vertebra and femur), and bone tissue micro-architecture was evaluated by static histomorphometry at the tibio-fibular junction (cortical bone) and at the tibia metaphysis (trabecular bone). Plasma total alkaline phosphatase (ALP) activity and serum levels of insulin-like growth factor-I (IGF-I) were also assessed. RESULTS: In female rats treated with strontium ranelate over 2 years, dose-dependent increases of bone strength and bone mass of the vertebral body (containing a large proportion of trabecular bone) and of the midshaft femur (containing mainly cortical bone) were detected without change in bone stiffness. Similar effects were observed in males at the level of the vertebra. This increase in mechanical properties was associated with improvements of the micro-architecture as assessed by increases of trabecular and cortical bone volumes and trabecular number and thickness. Finally, plasma total ALP activity and IGF-I were also increased in treated animals, compatible with a bone-forming activity of strontium ranelate. CONCLUSION: A long-term treatment with strontium ranelate in intact rats is very safe for bone and improves bone resistance by increasing bone mass and improving architecture while maintaining bone stiffness.

Noninvasive measurement of bone strontium.

The strontium content of bone has hitherto been impossible to measure noninvasively. A novel dual-photon absorptiometry (DPA) method was developed. 241Am (59.5 keV) and 133Ba (356 keV) were used as radiation sources. The linearity of the DPA method was studied in monkey bones ex vivo after treatment over 52 wk with strontium ranelate. The bone strontium expressed in terms of the percentage molar ratio SrHA/(SrHA + CaHA) x 100%, where HA denotes hydroxyapatite, was measured (1) by the DPA method and (2) by inductively coupled plasma-atomic emission spectrophotometry at the same distal site of the femur. The results correlated significantly: y = 0.33%Sr + 1.086x; r = 0.976; standard error of the estimate (SEE) = 0.57%Sr. In order to measure the accuracy error of Sr%, 30 normal volunteers were measured. Their mean values did not differ significantly from zero and the SD was 0.5%. The radiation dose was small, the equivalent whole-body dose to human subjects being 0.005 micro Sv. This novel DPA method is likely to be successful for bone strontium measurement in humans.

Methylmercury exposure assessment using dietary and biomarker data among frequent seafood consumers in France CALIPSO study.

BACKGROUND: Seafood is considered by toxicologists as the main source of methylmercury (MeHg), but little data is available concerning contamination of seafood and MeHg status of French frequent consumers. OBJECTIVES: The objectives were to assess food exposure and biomarker of exposure of MeHg from a group of frequent consumers of seafood. METHODS: Two approaches to exposure assessment were used: the currently used food intake and the biomarker of exposure. A validated food frequency questionnaire (FFQ) was used to assess seafood consumptions for 80 products of 385 frequent consumers aged 18 and over in four French coastal areas. Seafood samples were collected in each region considering preservation methods and supply habits according to a total diet study sampling. Food samples were analyzed for MeHg. Exposure was assessed by combining consumptions with contamination data. Whole blood samples were collected from the volunteers and analyzed for MeHg. RESULTS: The mean dietary exposure to MeHg or weekly intake (WI FFQ) was 1.51+/-1.17 microg/kg bw/wk. Thirty-five percent of the subjects exceed the Joint Expert Committee on Food Additives (JECFA) provisional tolerable weekly intake (PTWI), whereas the use of the biological results with the JECFA/Environmental Protection Agency (EPA) one-compartment pharmacokinetic model to calculate weekly intake (WI PKM) shows that only 2% of subjects exceed the PTWI. The mean of the individual ratios WI FFQ/WI PKM is 4.3 and the higher the WI FFQ and the blood MeHg level, the lower is the ratio, close to 1-2. CONCLUSIONS: These analyses support the assumption that the calculated dose of methylmercury is overestimated with the FFQ-based method used in this study. Since FFQ are commonly used in risk assessments, the overestimate of dose is public health protective and this finding is somewhat reassuring from a public health point of view, especially since the JECFA or EPA have applied uncertainty factors of 3.2 or 3, respectively, to take into account the inter-individual pharmacokinetic variability.

Fluoride and strontium accumulation in bone does not correlate with osteoid tissue in dialysis patients.

BACKGROUND: Osteomalacia is now a rare disease in dialysis patients in developed countries since the withdrawal of aluminium overload. The involvement of fluoride and strontium in the pathogenesis of the disease has been suggested. The aim of this study was to investigate a possible association between osteomalacia in dialysis patients and the fluoride or strontium contents of bone. METHODS: Of 271 bone biopsies from chronic haemodialysis patients referred to our centre, we studied the nine biopsies from patients with osteomalacia. They were compared with 23 biopsies from patients with hyperparathyroidism and 24 biopsies from patients with adynamic bone disease. Histomorphometric static and dynamic indices were measured. Bone fluoride and strontium contents were measured in biopsies from haemodialysis patients, and were compared with those of control patients. RESULTS: In the nine patients with osteomalacia, we found an absence of double labelled surfaces and increased osteoid thickness. Mild aluminium overload was observed in two of the nine patients. The bone strontium content of the entire dialysis population studied was not significantly different from control values (0.023+/-0.001 vs 0.019+/-0.002% mol/mol, P=0.15). However, bone strontium level was slightly but significantly increased in patients with osteomalacia (0.030+/-0.005%), compared with both controls (0.019+/-0.002%, P<0.05) and the other bone diseases (0.021+/-0.002%, P<0.05). Bone fluoride content was significantly higher in the entire dialysis population than in the controls (0.33+/-0.04 vs 0.13+/-0.018% (g/g ash weight), P=0.04). It was increased in osteomalacic patients compared with controls and with patients having hyperparathyroidism or adynamic bone disease. There was no correlation between formation indices (OV/BV, OS/BS, Ob.S/BS) and bone fluoride or strontium content. CONCLUSIONS: We found a prevalence of osteomalacia of 3.3% in our biopsy series for chronic dialysis patients. However, although bone strontium and fluoride contents were slightly increased, no causal relationship with these individual metals and osteomalacia could be firmly established in this small number of patients. The hypothesis of strontium- or fluoride-induced osteomalacia in renal patients merits further investigation.