Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic renal insufficiency (CRI). We proposed that changes in serum PTH and FGF23 levels might be associated with changes in serum phosphorus levels caused by the phosphate binder sevelamer hydrochloride (sevelamer, i.e. crosslinked poly[allylamine hydrochloride]). Rats were fed a diet containing adenine for 4 weeks to establish CRI. Animals were then offered either a normal diet or a diet containing 1 or 3% sevelamer for 8 weeks continuously, or intermittently with sevelamer diet or a normal diet offered for alternating 2-week periods. Changes in the serum levels of phosphorus, calcium, PTH, FGF23, and 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) were monitored over time. Adenine-treated rats developed severe CRI, with markedly elevated serum levels of phosphorus, PTH and FGF23, and reduced levels of serum 1,25(OH)(2)D(3). Continuous treatment with sevelamer suppressed these increases throughout the study period. Serum phosphorus, PTH, and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, the changes in serum FGF23 levels began after the onset of changes in serum phosphorus and PTH levels. In conclusion, circulating PTH, and FGF23 levels can be promptly manipulated through the control of serum phosphorus levels. Moreover, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CRI.
The electronic structure of a family comprising tetrahedral (R-diimine)iron dichloride, and tetrahedral bis(R-diimine)iron compounds has been investigated by Mo ¨ssbauer spectroscopy, magnetic susceptibility measurements, and X-ray crystallography. In addition, broken-symmetry density functional theoretical (B3LYP) calculations have been performed. A detailed understanding of the electronic structure of these complexes has been obtained. A paramagnetic (S t ) 2), tetrahedral complex [Fe II ( 4 L) 2 ], where ( 4 L) 1represents the diamagnetic monoanion N-tert-butylquinolinylamide, has been synthesized and characterized to serve as a benchmark for a Werner-type complex containing a tetrahedral Fe II N 4 geometry and a single high-spin ferrous ion. In contrast to the most commonly used description of the electronic structure of bis(R-diimine)iron(0) complexes as low-valent iron(0) species with two neutral R-diimine ligands, it is established here that they are, in fact, complexes containing two (R-diiminato) 1-• π radical monoanions and a high-spin ferrous ion (in tetrahedral N 4 geometry) (S Fe ) 2). Intramolecular antiferromagnetic coupling between the π radical ligands (S rad ) 1 / 2 ) and the ferrous ion (S Fe ) 2) yields the observed S t ) 1 ground state. The study confirms that R-diimines are redox noninnocent ligands with an energetically low-lying antibonding π* lowest unoccupied molecular orbital which can accept one or two electrons from a transition metal ion. The (R-diimine)FeCl 2 complexes (S t ) 2) are shown to contain a neutral R-diimine ligand, a high spin ferrous ion, and two chloride ligands.
Dystrophic epidermolysis bullosa (DEB) is an inherited blistering skin disorder caused by mutations in the type VII collagen gene (COL7A1). Therapeutic introduction of COL7A1 into skin cells holds significant promise for the treatment of DEB. The purpose of this study was to establish an efficient retroviral transfer method for COL7A1 into DEB epidermal keratinocytes and dermal fibroblasts, and to determine which gene-transferred cells can most efficiently express collagen VII in the skin. We demonstrated that gene transfer using a combination of G protein of vesicular stomatitis virus-pseudotyped retroviral vector and retronectin introduced COL7A1 into keratinocytes and fibroblasts from a DEB patient with the lack of COL7A1 expression. Real-time polymerase chain reaction analysis of the normal human skin demonstrated that the quantity of COL7A1 expression in the epidermis was significantly higher than that in the dermis. Subsequently, we have produced skin grafts with the gene-transferred or untreated DEB keratinocytes and fibroblasts, and have transplanted them into nude rats. Interestingly, the series of skin graft experiments showed that the gene-transferred fibroblasts supplied higher amount of collagen VII to the new dermal-epidermal junction than the gene-transferred keratinocytes. An ultrastructural study revealed that collagen VII from gene-transferred cells formed proper anchoring fibrils. These results suggest that fibroblasts may be a better gene therapy target of DEB treatment than keratinocytes.
SummaryEpidermolysis bullosa acquisita (EBA) is an acquired subepidermal bullous disease characterized by IgG autoantibodies to type VII collagen, a major component of anchoring fibrils. Most patients with EBA are adult and develop autoantibodies to the non-collagenous 1 (NC-1) domain of type VII collagen.In this report, we describe a 4-year-old Japanese boy presenting pruritic vesicles and tense blisters over his whole body.Immunofluorescence studies revealed linear IgG/C3 deposits along the dermal-epidermal junction of the patient's skin, and circulating IgG autoantibodies mapping to the dermal side of 1M NaCl-split skin. By immunoblotting analysis using dermal extracts as a substrate, the patient's IgG antibodies labeled a 290 kD protein corresponding to type VII collagen.Immunoblotting studies using recombinant proteins demonstrated that the patient's circulating autoantibodies recognized not only the NC-1 but also the non-collagenous 2 (NC-2) domain of type VII procollagen.Review of the previously reported cases and the present case suggested that EBA cases with autoantibodies to regions other than the NC-1 domain are all children younger than 10 years of age with clinical features of an inflammatory phenotype.2
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