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      Osteoclast imbalance in primary familial brain calcification: evidence for its role in brain calcification

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          Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.

          Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
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            The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update.

            Mitochondrial dysfunction has been shown to participate in the induction of apoptosis and has even been suggested to be central to the apoptotic pathway. Indeed, opening of the mitochondrial permeability transition pore has been demonstrated to induce depolarization of the transmembrane potential (deltapsi(m)), release of apoptogenic factors and loss of oxidative phosphorylation. In some apoptotic systems, loss of deltapsi(m) may be an early event in the apoptotic process. However, there are emerging data suggesting that, depending on the model of apoptosis, the loss of deltapsi(m) may not be an early requirement for apoptosis, but on the contrary may be a consequence of the apoptotic-signaling pathway. Furthermore, to add to these conflicting data, loss of deltapsi(m) has been demonstrated to not be required for cytochrome c release, whereas release of apoptosis inducing factor AIF is dependent upon disruption of deltapsi(m) early in the apoptotic pathway. Together, the existing literature suggests that depending on the cell system under investigation and the apoptotic stimuli used, dissipation of deltapsi(m) may or may not be an early event in the apoptotic pathway. Discrepancies in this area of apoptosis research may be attributed to the fluorochromes used to detect deltapsi(m). Differential degrees of sensitivity of these fluorochromes exist, and there are also important factors that contribute to their ability to accurately discriminate changes in deltapsi(m).
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              Dysregulation of bone remodeling by imatinib mesylate.

              Imatinib mesylate is a rationally designed tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Although the efficacy and tolerability of imatinib are a vast improvement over conventional chemotherapies, the drug exhibits off-target effects. An unanticipated side effect of imatinib therapy is hypophosphatemia and hypocalcemia, which in part has been attributed to drug-mediated changes to renal and gastrointestinal handling of phosphate and calcium. However, emerging data suggest that imatinib also targets cells of the skeleton, stimulating the retention and sequestration of calcium and phosphate to bone, leading to decreased circulating levels of these minerals. The aim of this review is to highlight our current understanding of the mechanisms surrounding the effects of imatinib on the skeleton. In particular, it examines recent studies suggesting that imatinib has direct effects on bone-resorbing osteoclasts and bone-forming osteoblasts through inhibition of c-fms, c-kit, carbonic anhydrase II, and the platelet-derived growth factor receptor. The potential application of imatinib in the treatment of cancer-induced osteolysis will also be discussed.
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                Author and article information

                Journal
                Brain
                Oxford University Press (OUP)
                0006-8950
                1460-2156
                January 2020
                January 01 2020
                November 21 2019
                January 2020
                January 01 2020
                November 21 2019
                : 143
                : 1
                : e1
                Affiliations
                [1 ]Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
                [2 ]Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
                [3 ]DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany
                [4 ]Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
                Article
                10.1093/brain/awz351
                31754706
                81ea33aa-037d-405b-97da-e2a0585d4e87
                © 2019

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