Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.     

Differential apoptotic response of J774 macrophages to alumina and ultra-high-molecular-weight polyethylene particles.

We recently identified apoptosis in in vitro wear particle-stimulated macrophages. The recent explosion of interest in apoptosis lies in the fact that it is under positive and negative regulation through evolutionary conserved biochemical pathways. It may also be possible to modulate macrophage apoptosis in the treatment of periprosthetic osteolysis. The purpose of this study was to compare the macrophage response to identically sized particles of alumina ceramic (Al2O3) and ultra-high-molecular-weight polyethylene (UHMWPE) in terms of TNF-alpha release and induction of apoptosis. J774 mouse macrophages were incubated for 0-24 h in the presence of Al2O3 and UHMWPE particles. TNF-alpha release was measured by ELISA; Poly(ADP-ribose)polymerase (PARP) and caspase-3 expression was analyzed by Western blot; DNA fragmentation (DNA laddering) was visualized on agarose gel containing ethidium bromide. Al2O3 particles induced TNF-alpha release after 4 h incubation with concentrations reaching 483 and 800 pg/ml after 24 h with 125 and 250 particles/macrophage, respectively (control = 161 pg/ml) (P < 0.05 vs. control). The same concentrations of UHMWPE particles induced a much larger and significant TNF-alpha release after only 1 h incubation, increasing up to 6250 pg/ml after 24 h (P < 0.05 vs. control). Western blot analysis demonstrated that the active caspase-3 fragment (17 kDa) and the proteolytic PARP fragment (85 kDa) were expressed after 2 h incubation with 125 and 250 Al2O3 particles/macrophage. The active caspase-3 and the PARP fragment had lower expression and appeared after a longer incubation time (8 h) with 125 and 250 UHMWPE particles/macrophage. Finally, DNA fragmentation (DNA laddering) was observed after 16 h with 125 and 250 particles of Al2O3 per macrophage whereas no laddering was induced by UHMWPE particles even after 24 h incubation. This study shows that although both Al2O3 and UHMWPE particles induce TNF-alpha release, this stimulation was much greater (8-10 times higher) with UHMWPE than Al2O3 (P < 0.05 vs. control). As well, the induction of apoptosis, as measured by activation of caspase-3, PARP cleavage and DNA laddering, is different for these two particles, being faster and more important with Al2O3 than UHMWPE. We hypothesize that the ability of Al2O3 to induce macrophage apoptosis may explain the lower TNF-alpha release observed with these particles and explain the differences seen in osteolysis patterns of ceramic-ceramic (CC) vs. metal-polyethylene (Mpe) articulations. In conclusion, apoptosis may be a major internal mechanism to decrease macrophage activity and may be a desired therapeutic endpoint. The identification of an apoptosis-related pathway in the macrophage response to ceramic particles provides crucial data for a rational approach in the treatment and/or prevention of periprosthetic osteolysis.     

Adrafinil-induced orofacial dyskinesia.

We describe the first case of orofacial abnormal movements induced by adrafinil, a vigilance promoting agent of the same pharmacological class as modafinil. The dyskinesias did not spontaneously recover despite adrafinil withdrawal for a 4-month period. They were secondly dramatically improved by tetrabenazine, a presynaptic dopaminergic depleting drug which was introduced after the 4-month adrafinil-free period.     

Ca2+ entry through the apical membrane reduces antidiuretic hormone-induced hydroosmotic response in toad urinary bladder

The role of Ca²⁺ in the regulation of antidiuretic hormone(ADH)-induced water permeability of the apical membrane of the toad urinary bladder was examined. The effects of modifying Ca²⁺ entry through the apical membrane of toad urinary bladders on the hydroosmotic water flow _H2O) and short circuit current (I _sc) were measured. In most experiments the bladders were treated with small amounts of Ag⁺ (10^–7 mol/l) on the apical side. This treatment was used because previous experiments indicate that it markedly increases alkali-earth cation fluxes through an amiloride-insensitive cation channel in the apical membrane of the urinary bladder. Moreover, when Ca²⁺ is the major cation in the apical solution of these Ag⁺-treated bladders, I _sc is mostly due to Ca²⁺ entry through the apical membrane. Ag⁺ increased I _sc and simultaneously inhibited _H2O in bladders perfused with Ca²⁺ solutions on the apical side. Addition of La³⁺ to the apical solution reversed the stimulation of I _sc and the inhibition of _H2O produced by Ag⁺. When bladders were perfused with Ca²⁺-free solutions on the apical side, addition of Ag⁺ did not inhibit _H2O while the stimulation of cation movements through the amiloride-insensitive cation channel persisted. In bladders perfused with apical Ca²⁺ solutions and treated with chlorophenyl thio-cyclic adenosine monophosphate (ClPheS-cAMP) the addition of Ag⁺ did not inhibit _H2O while it still increased I _sc. Finally, addition of Ca²⁺ to the apical solution of bladders not treated with Ag⁺ reduced _H2O. These results taken together with other findings in the literature suggest: (1) Ca²⁺ entry through the Ag⁺-treated amiloride-insensitive cation channel of the apical membrane inhibits _H2O; (2) the effects of Ca²⁺ entry are at a regulatory site that precedes the interaction of cAMP with the water channels; (3) it is also possible that Ca²⁺ entry through the unmodified amiloride-insensitive cation channel may have some inhibitory effect on _H2O.     

Glycosaminoglycan mimetics (RGTA) modulate adult skeletal muscle satellite cell proliferation in vitro

Confocal Raman microspectroscopy (CRM) provides an important and novel means of analyzing the chemical composition of the adhesive/dentin (a/d) interface. The purpose of this study was to develop a method for quantitative determination of the degree of adhesive penetration at the a/d interface using CRM. Three commercial dentin adhesive systems [Scotchbond Multipurpose Plus (SBMP+), Single Bond (SB), and Primer Bond NT (PBNT)] based on the total etch and "wet" bonding technique were examined in this study. Human dentin specimens treated with these adhesives were analyzed with CRM mapping across the a/d interface. Also, Raman spectra were collected on model mixtures of adhesive and type I collagen, and the ratios of the relative intensities of the Raman bands corresponding to adhesive and collagen were used for the construction of calibration curves. By comparing the Raman band ratios of interface specimens to the calibration curves, the percent of adhesive as a function of spatial position across the a/d interface was determined. The results show that there is a gradual decrease in penetration as a function of position for all three adhesive systems while the adhesive concentration gradient decreases in the order of SBMP+ > SB > PBNT. These differences in penetration of the three adhesives at the a/d interface also are discussed relative to the composition and phase segregation in adhesives. Additionally, our results indicate that confocal Raman microspectroscopy is a reliable in situ analytical technique for simple and rapid quantitative determination of adhesive penetration at its interface with prepared dentin.     

Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus

The herpesvirus entry mediator A (HVEM/HveA) and nectin-1 (HveC/CD111) are two major receptors for herpes simplex virus (HSV). Although structurally unrelated, both receptors can independently mediate entry of wild-type (wt) HSV-1 and HSV-2 by interacting with the viral envelope glycoprotein D (gD). Laboratory strains with defined mutations in gD (e.g. rid1) do not use HVEM but use nectin-2 (HveB/CD112) for entry. The relative usage of HVEM and nectin-1 during HSV infection in vivo is not known. In the absence of a defined in vivo model, we used in vitro approaches to address this question. First, we screened HSV clinical isolates from various origins for receptor tropism and found that all used both HVEM and nectin-1. Second, we determined the numbers of surface receptors on various susceptible and resistant cell lines as well as on primary fibroblasts derived from an individual with cleft lip/palate ectodermal dysplasia (CLPED1). Although CLPED1 cells can only express a defective form of nectin-1, they allowed entry of wild type and mutant HSV strains by usage of either HVEM or nectin-2. Finally, we compared the ability of HVEM and nectin-1 to mediate entry when expressed at varying cell surface densities. Both receptors showed a direct relationship between the number of receptors and HSV susceptibility. Direct comparison of receptors suggests that nectin-1 is more efficient at promoting entry than HVEM. Overall, our data suggest that both receptors play a role during HSV infection in vivo and that both are highly efficient even at low levels of expression.     

MECP2 duplication syndrome in a patient from Cameroon

MECP2 duplication syndrome (MDS; OMIM 300260) is an X‐linked neurodevelopmental disorder caused by nonrecurrent duplications of the Xq28 region involving the gene methyl‐CpG‐binding protein 2 (MECP2; OMIM 300005). The core phenotype of affected individuals includes infantile hypotonia, severe intellectual disability, very poor‐to‐absent speech, progressive spasticity, seizures, and recurrent infections. The condition is 100% penetrant in males, with observed variability in phenotypic expression within and between families. Features of MDS in individuals of African descent are not well known. Here, we describe a male patient from Cameroon, with MDS caused by an inherited 610 kb microduplication of Xq28 encompassing the genes MECP2, IRAK1, L1CAM, and SLC6A8. This report supplements the public data on MDS and contributes by highlighting the phenotype of this condition in affected individuals of African descent.     

Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis

Objective

Interstitial lung disease (ILD) is the most severe complication of idiopathic inflammatory myositis (IIM), resulting in significant increase in morbidity and mortality and for which the best treatment remains controversial. We conducted a meta-analysis to evaluate the efficacy of therapies used for the management of IIM-related ILD.

Retinal projections to the lateral posterior-pulvinar complex in intact and early visual cortex lesioned cats

In intact cats, it is generally considered that the lateral posterior-pulvinar complex (LP-pulvinar) does not receive direct retinal terminals, with the exception of the retino-recipient zone known as the geniculate wing. There is, however, some evidence that early lesions of the visual cortex can occasionally induce the formation of novel retinal projections to the LP nucleus. Given the importance of knowing the connectivity pattern of the LP-pulvinar complex in intact and lesioned animals, we used the B fragment of cholera toxin, a sensitive anterograde tracer, to reinvestigate the retinal projections to the LP-pulvinar in normal cats and in cats with early unilateral lesions of the visual cortex (areas 17 and 18). Immunohistochemical localization of the toxin was performed to show the distribution and morphology of retinofugal terminals. A direct bilateral but predominantly contralateral retinal projection reached the caudal portion of LPl and LPm in the form of patches located mainly along its dorsomedial surface and many scattered terminals. The distribution of retinal projections to LP-pulvinar in intact and operated cats did not differ. Contrary to what had been previously reported, we found no evidence for lesion-induced sprouting of retinal axons in these higher-order thalamic nuclei. Retinal input to the LP-pulvinar might modulate visual responses driven by primary visual cortex or superior colliculus.