Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.
Type I mucopolysaccharidosis (MPS I) IntroductionType I mucopolysaccharidosis (MPS I) is one of the most frequent lysosomal storage disorders (LSDs) and is due to the inherited deficiency of ␣-L-iduronidase (IDUA) activity, which results in the accumulation of its unprocessed substrates (glycosaminoglycans; GAGs) in many organs. 1 The disorder is systemic and clinically heterogeneous. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation. The clinical spectrum ranges from the severe Hurler syndrome (MPS I-H) to the attenuated Scheie syndrome. Mental retardation is distinctive only of MPS I-H, which is fatal in childhood if untreated, thus representing the variant with the most urgent need for new therapies. Enzyme replacement therapy (ie, parenteral administration of exogenous enzyme that can be internalized by tissue cells via the mannosium-6-phosphate receptor) is recommended only for MPS I patients without primary neurologic disease, due to the inability of the enzyme to efficiently cross the blood-brain barrier; moreover, neutralizing antibodies can attenuate its efficacy. 2 When performed at early ages, hematopoietic stem cell (HSC) transplantation (HCT) from healthy donors alleviates most disease manifestations in MPS I-H patients, likely by migration of the transplant-derived leukocytes into organs, where they can clear the storage and secrete the functional enzyme for correction of the metabolic defect in resident cells. 3 However, despite recent improvements in the outcome of HCT, the morbidity and mortality associated with the procedure are still not negligible, mostly due to rejection and graft-versus-host disease. Moreover, the amount of enzyme that transplantation can provide to the organism can be limiting, especially since donors are often heterozygous siblings. Indeed, a relationship between circulating enzyme levels after transplant and urinary GAGs has been shown 4 : the low enzyme levels achieved with heterozygote donor transplant lead to less adequate reduction in GAG levels. Likely due to partial metabolic correction at disease sites, the impact of HCT on central nervous system (CNS) and skeletal disease, despite being substantial in ameliorating patients' phenotype, could still benefit from further improvement. 5 The benefits of different gene therapy approaches were established in MPS I animal models. Intravenous delivery of viral vectors, which can establish a tissue source for systemic enzyme distribution, was effective in controlling disease manifestations in The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From MPS I animal models upon neonatal treatment.  However, residu...
An association between the R990G polymorphism of the CaSR gene, coding for calcium-sensing receptor, and primary hypercalciuria was found in kidney stone formers. To confirm this relationship, we investigated hypercalciuric women without stones and studied the effect of CaSR gene in human embryonic kidney cells (HEK-293). We genotyped for CaSR A986S, R990G, and Q1011E polymorphisms, 119 normocalciuric and 124 hypercalciuric women with negative history of kidney stones. Homozygous (n=2) or heterozygous (n=21) women for the 990G allele considered as one group had an increased risk to be hypercalciuric (odds ratio=5.2; P=0.001) and higher calcium excretion (P=0.005) in comparison with homozygous women for the 990R allele (n=220). HEK-293 cells were transfected with the variant allele at the three CaSR gene polymorphisms and with the most common allele with no variants. The transient increment of intracellular calcium caused by the stepwise increase of extracellular calcium was evaluated in stable transfected cells loaded with fura-2 AM. The extracellular calcium concentration producing the half-maximal intracellular calcium response was lower in HEK-293 cells transfected with the 990G allele than in those transfected with the wild-type allele (P=0.0001). Our findings indicate that R990G polymorphism results in a gain-of-function of the calcium-sensing receptor and increased susceptibility to primary hypercalciuria.
Low serum vitamin D is associated with increased MS risk in patients with CIS.
Objective: To evaluate the potential role of quantitative ultrasound (QUS) investigation in assessing the osteopenia of prematurity. Design: QUS parameters measured at the time of discharge were related to the anthropometric characteristics and age (postnatal and gestational) of 51 (34 female and 17 male) preterm infants fed fortified human milk. Methods: QUS evaluation was performed at the humerus (h) by measuring two parameters: ultrasound velocity (hSOS, in m/s) and bone transmission time (hBTT, in ms). A group of 43 term infants (29 female and 14 male) was also evaluated. Results: In preterm infants, significant correlations were found for hSOS and hBTT vs gestational age (r ¼ 0.504, 0.477, P , 0.0001), length (r ¼ 0.641, 0.594, P , 0.0001) and weight (r ¼ 0.580, 0.562, P , 0.0001) at birth, and length (r ¼ 0.341, 0.332, P , 0.05) and weight (r ¼ 0.331, r ¼ 0.362, P , 0.05) at QUS measurement. In preterm infants, both QUS parameters were negatively correlated with age (r ¼ 2 0.536, P , 0.0001, r ¼ 2 0.443, P , 0.001) and were significantly lower than in the term infants (hSOS: 1664^42 m/s vs 1734^28 m/s, P , 0.0001; hBTT: 0.58^0.24 ms vs 1.06^0.15 ms, P , 0.0001) even when adjusted for body length (P , 0.05). In preterm infants, hSOS was also negatively correlated with postconceptional age (r ¼ 2 0.322, P , 0.05).Conclusions: This study suggests that bone mineral accrual is mainly determined by the development in utero, and that prematurity induces a halt in the bone development process in the early postnatal period. QUS parameters are correlated with the severity of prematurity and might therefore have clinical applications when bone maturation in early life needs to be determined.
Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-B ligand (
The liver is the current site for pancreatic islet transplantation, but has many drawbacks due to immunologic and nonimmunologic factors. We asked whether pancreatic islets could be engrafted in the bone marrow (BM), an easily accessible and widely distributed transplant site that may lack the limitations seen in the liver. Syngeneic islets engrafted efficiently in the BM of C57BL/6 mice rendered diabetic by streptozocin treatment. For more than 1 year after transplantation, these animals showed parameters of glucose metabolism that were similar to those of nondiabetic mice. Islets in BM had a higher probability to reach euglycemia than islets in liver (2.4-fold increase, P ؍ .02), showed a compact morphology with a conserved ratio between ␣ and ␤ cells, and affected bone structure only very marginally. Islets in BM did not compromise hematopoietic activity, even when it was strongly induced in response to a BM aplasia-inducing infection with lymphocytic choriomeningitis virus.
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