The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform
Bruce Patsner - One of the best experts on this subject based on the ideXlab platform.
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riegel v medtronic inc revisiting pre emption for medical devices
Journal of Law Medicine & Ethics, 2009Co-Authors: Bruce PatsnerAbstract:The recent United States Supreme Court decision in Riegel v. Medtronic, Inc. affirmed the doctrine of pre-emption protection only for those medical devices reaching U.S. markets via the PMA (premarketing approval) process and preserved the previous Lohr v. Medtronic decision's lack of preemption protection for those medical devices marketed via the generally more abbreviated 510(k) Clearance Mechanism. This paper reviews the logic and faults of the Riegel decision and discusses the implications of the Riegel decision for pre-emption protection for other classes of FDA-approved medical products.
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Riegel v. Medtronic, Inc.: Revisiting Pre‐emption for Medical Devices
Journal of Law Medicine & Ethics, 2009Co-Authors: Bruce PatsnerAbstract:The recent United States Supreme Court decision in Riegel v. Medtronic, Inc. affirmed the doctrine of pre-emption protection only for those medical devices reaching U.S. markets via the PMA (premarketing approval) process and preserved the previous Lohr v. Medtronic decision's lack of preemption protection for those medical devices marketed via the generally more abbreviated 510(k) Clearance Mechanism. This paper reviews the logic and faults of the Riegel decision and discusses the implications of the Riegel decision for pre-emption protection for other classes of FDA-approved medical products.
Heyu Ni - One of the best experts on this subject based on the ideXlab platform.
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desialylation a novel platelet Clearance Mechanism and a potential new therapeutic target in anti gpib antibody mediated thrombocytopenia
Blood, 2012Co-Authors: June Li, Brian Vadasz, Yougbare Issaka, Sean Lang, John Freedman, Heyu NiAbstract:Abstract 265 Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies directed at patient9s own platelet antigens, primarily glycoprotein (GP)IIbIIIa-integrin (70–80%) and GPIb-complex (20–40%). Current paradigm suggests that Clearance of opsonized platelets through the reticuloendothelial system via Fcγ-receptors results in thrombocytopenia and bleeding disorders. However, evidence from others and our group demonstrated that anti-GPIbα, but not anti-GPIIbIIIa, can induce thrombocytopenia via an Fc-independent pathway, which is resistant to intravenous IgG (IVIG) therapy in murine ITP-models (Blood 2006). These observations are consistent with subsequent IVIG studies in human ITP patients. Interestingly, human anti-GPIb-mediated ITP patients seem also resistant to steroid therapy in our recent retrospective study (American Journal of Hematology 2012). This suggests that binding of anti-GPIbα antibodies may induce platelet Clearance through a different Mechanism which is currently poorly understood. Methods: We developed unique mouse anti-mouse monoclonal antibodies (mAbs) in GPIIIa or GPIba deficient mice. Some of the mAbs have cross-reactivity to both mouse and human GPIIbIIIa and GPIba. Flow cytometry was used to evaluate whether these mAbs were able to induce platelet activation, apoptosis and desialylation. GPIbα is heavily glycosylated and the role of desialylation and exposure of underlying galactose and β-N-acetyl-D-glucosamine (βGN) residues on GPIbα in platelet Clearance was assessed using the sialidase neuraminidase (NA) and it9s inhibitor N-acetyl-2,3-dehydro-2-deoxy neuraminic acid (DANA). Desialyation effects on platelet activation and apoptosis was measured by flow cytometry. We also repeated these experiments with human platelets and plasma from human ITP-patients. We also investigated the effects of anti-GPIbα antibodies on platelet activation, apoptosis and Clearance in vivo. Briefly, BALB/c mice were injected with anti-GPIbαor anti-GPIIIa mAbs and 24 hrs later, platelet desialylation, activation and apoptosis were measured by flow cytometry. The effect of desialylation on platelet Clearance was assessed with DANA. The possible roles of Ashwell-Morell and MAC-1 receptors in GPIbα-mediated platelet Clearance in the liver were examined using immunohistochemistry (anti-CD11b) or blocking of the Ashwell-Morell receptor with asialofetuin. Results and Discussion: We found that anti-GPIbα, but not anti-GPIIbIIIa mAbs, induced significant P-selectin expression and phosphatidylserine (PS)-exposure, and increased inner membrane mitochondrial depolarization (ΔYm). Interestingly, platelets were desialylated in the presence of anti-GPIbα but not anti-GPIIbIIIa mAbs. Moreover, we found that desialylation of GPIbα lies directly upstream of platelet activation and apoptosis, as prior treatment with DANA diminished PS-exposure, and P-selectin expression. Most importantly, incubations of human platelets with ITP-patient plasma showed similar effects. In vivo, we found significant increases in PS-exposure and ΔYm induced by anti-GPIbα, but not by anti-GPIIIa mAbs, independent of IgG subclass. Interestingly, prior injection with DANA rescued platelets numbers in anti-GPIbα, but not in anti-GPIIIa injected mice. A significant role for the Ashwell-Morell and MAC-1 receptors in the Clearance of deglycosylated platelets was observed; blocking of the Ashwell-Morell receptors by asialofetuin, decreased platelet Clearance in anti-GPIbα, but not anti-GPIIbIIIa antibody injected mice, there was also increased staining for MAC-1 on Kupffer cells, exclusively in the presence of an anti-GPIbα mAb tested. Thus, we demonstrate for the first time that anti-GPIbα antibodies induce GPIbα desialyation, leading to platelet activation and apoptosis. Therefore, we identified novel Fc-independent platelet Clearance pathways, more specifically, via Ashwell-Morell and MAC-1 receptors on hepatocytes and liver macrophages. These findings may lead to novel therapeutic regimens including the potential use of sialidase inhibitors as a solution for anti-GPIb-mediated ITP patients previously refractory to both steroid and IVIG therapies. Disclosures: No relevant conflicts of interest to declare.
Karin M. Hoffmeister - One of the best experts on this subject based on the ideXlab platform.
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Clearance Mechanisms for Chilled Platelets
Blood, 2008Co-Authors: Viktoria Rumjantseva, John H Hartwig, Emma C. Josefsson, Hans H. Wandall, Prabhjit K Grewal, Sara Neyeb-hashemi, Goran Larson, Jamey D Marth, Karin M. HoffmeisterAbstract:When platelets are chilled for short times ( 48 h-refrigerated) (Wandall et al. Blood, 2008). Investigating the Clearance Mechanism of 48 h-refrigerated platelets, we now demonstrate macrophage-independent hepatic removal, that is mediated by the Ashwell-Morell asialoglycoprotein receptor (AMR). This conclusion is based on the following evidence: macrophage depletion in mice using clodronate encapsulated liposomes, a procedure that dramatically improves the circulation of 4 h chilled platelets, does not prevent the Clearance of 48 h chilled platelets; streptavidin-POD staining reveals abundant long-term refrigerated and biotinylated platelets in hepatocytes; 48 h-refrigeration increases by ~1.7-fold the binding of the βgalactose-recognizing lectin RCA, but not of the βGlcNAc recognizing lectin sWGA lectin to platelets; KO mice lacking Asgr-1 or Asgr-2 subunits of the AMR support 48 h-refrigerated platelet circulation times comparable to room temperature stored platelets; Co-injection of asialofetuin, a competitive inhibitor of the asialoglycoprotein-receptors, restore the survival of 48 h-refrigerated platelets in WT mice; and hepatocyte HepG2 cells ingest fluorescently labeled long-term refrigerated platelets in culture, and asialofetuin prevents this ingestion. Regarding the platelet target of the Asgr-1/Asgr-2 receptors, circulation of 48 h-refrigerated platelets is markedly improved by removal of GPIbα’s N-T domain using O-sialopeptidase. We conclude that longterm refrigeration exposes galactose residues on GPIbα subunits of platelets to generate ligands recognized by hepatocyte Ashwell-Morell receptors.
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Hepatocytes Ingest Longterm Refrigerated Platelets: A Novel Platelet Clearance Mechanism.
Blood, 2006Co-Authors: Viktoria Rumjantseva, Thomas P Stossel, John H Hartwig, Emma C. Josefsson, Hans H. Wandall, Karin M. HoffmeisterAbstract:We previously reported that the lectin domain of αMβ2 receptors on hepatic macrophages mediates rapid Clearance of washed murine platelets transfused after refrigeration for 2 hours, recognizing exposed βN-acetylglucosamine (βGlcNAc) residues of N-linked glycans on clustered platelet GPIbα molecules and that the same receptors elicit phagocytosis of refrigerated human platelets human macrophages in vitro. A platelet-associated galactosyltransferase catalyzes the covering of βGlcNAc residues with galactose in the presence of UDP-galactose, thereby blocking Clearance of cold mouse platelets in vivo and phagocytosis of human platelets in vitro. These intriguing findings contradicted earlier evidence that refrigeration of human platelets procured for transfusion only promotes their rapid Clearance after prolonged (>8h) incubation and also are inconsistent with the well-known recognition system for exposed galactose residues through asialoglycoprotein (ASGP) receptors. Reconciling these contradictions, we report that the absence of plasma during storage accounts for the differences in time of exposure to cold to promote Clearance and that mouse platelets cold-stored in plasma also only clear rapidly after long-term (48h) storage. We also found that hepatic Clearance of long-term cold-stored (LTCS) mouse platelets occurs in hepatocytes. Streptavidin-POD staining revealed abundant LTCS biotinylated platelets in hepatocyte phagosomes. Furthermore, cells of the hepatocyte HepG2 line avidly ingest fluorescently-labeled LTCS human platelets (7-fold above the baseline of room-temperature-stored platelets), as evidenced by flow cytometry, fluorescent microscopy and by time-laps video microscopy. Long-term cold storage increases by ~1.7-fold platelet binding of the galactose-specific lectin RCA I, implying that with long-term cold storage, exposed galactose residues cluster sufficiently to induce recognition by hepatocyte ASGPR receptors. The results define a new Clearance Mechanism, representing the first example of blood cell removal by a non-myeloid cell. Since we find that human platelets also express a cell surface sialotransferase that adds sialic acid to galactose residues, we suggest that a combination of sialylation and glactosylation, achievable by addition of sugar substrates alone, might accommodate long-term cold storage of platelets for transfusion.
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the Clearance Mechanism of chilled blood platelets
Cell, 2003Co-Authors: Karin M. Hoffmeister, Hervé Falet, Thomas W Felbinger, Cecile V Denis, Wolfgang Bergmeier, Tanya N Mayadas, Ulrich H Von Andrian, Thomas P Stossel, Denisa D Wagner, John H HartwigAbstract:Platelet transfusion is a very common lifesaving medical procedure. Not widely known is the fact that platelets, unlike other blood cells, rapidly leave the circulation if refrigerated prior to transfusion. This peculiarity requires blood services to store platelets at room temperature, limiting platelet supplies for clinical needs. Here, we describe the Mechanism of this Clearance system, a longstanding mystery. Chilling platelets clusters their von Willebrand (vWf) receptors, eliciting recognition of mouse and human platelets by hepatic macrophage complement type 3 (CR3) receptors. CR3-expressing but not CR3-deficient mice exposed to cold rapidly decrease platelet counts. Cooling primes platelets for activation. We propose that platelets are thermosensors, primed at peripheral sites where most injuries occurred throughout evolution. Clearance prevents pathologic thrombosis by primed platelets. Chilled platelets bind vWf and function normally in vitro and ex vivo after transfusion into CR3-deficient mice. Therefore, GPIb modification might permit cold platelet storage.
June Li - One of the best experts on this subject based on the ideXlab platform.
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desialylation a novel platelet Clearance Mechanism and a potential new therapeutic target in anti gpib antibody mediated thrombocytopenia
Blood, 2012Co-Authors: June Li, Brian Vadasz, Yougbare Issaka, Sean Lang, John Freedman, Heyu NiAbstract:Abstract 265 Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies directed at patient9s own platelet antigens, primarily glycoprotein (GP)IIbIIIa-integrin (70–80%) and GPIb-complex (20–40%). Current paradigm suggests that Clearance of opsonized platelets through the reticuloendothelial system via Fcγ-receptors results in thrombocytopenia and bleeding disorders. However, evidence from others and our group demonstrated that anti-GPIbα, but not anti-GPIIbIIIa, can induce thrombocytopenia via an Fc-independent pathway, which is resistant to intravenous IgG (IVIG) therapy in murine ITP-models (Blood 2006). These observations are consistent with subsequent IVIG studies in human ITP patients. Interestingly, human anti-GPIb-mediated ITP patients seem also resistant to steroid therapy in our recent retrospective study (American Journal of Hematology 2012). This suggests that binding of anti-GPIbα antibodies may induce platelet Clearance through a different Mechanism which is currently poorly understood. Methods: We developed unique mouse anti-mouse monoclonal antibodies (mAbs) in GPIIIa or GPIba deficient mice. Some of the mAbs have cross-reactivity to both mouse and human GPIIbIIIa and GPIba. Flow cytometry was used to evaluate whether these mAbs were able to induce platelet activation, apoptosis and desialylation. GPIbα is heavily glycosylated and the role of desialylation and exposure of underlying galactose and β-N-acetyl-D-glucosamine (βGN) residues on GPIbα in platelet Clearance was assessed using the sialidase neuraminidase (NA) and it9s inhibitor N-acetyl-2,3-dehydro-2-deoxy neuraminic acid (DANA). Desialyation effects on platelet activation and apoptosis was measured by flow cytometry. We also repeated these experiments with human platelets and plasma from human ITP-patients. We also investigated the effects of anti-GPIbα antibodies on platelet activation, apoptosis and Clearance in vivo. Briefly, BALB/c mice were injected with anti-GPIbαor anti-GPIIIa mAbs and 24 hrs later, platelet desialylation, activation and apoptosis were measured by flow cytometry. The effect of desialylation on platelet Clearance was assessed with DANA. The possible roles of Ashwell-Morell and MAC-1 receptors in GPIbα-mediated platelet Clearance in the liver were examined using immunohistochemistry (anti-CD11b) or blocking of the Ashwell-Morell receptor with asialofetuin. Results and Discussion: We found that anti-GPIbα, but not anti-GPIIbIIIa mAbs, induced significant P-selectin expression and phosphatidylserine (PS)-exposure, and increased inner membrane mitochondrial depolarization (ΔYm). Interestingly, platelets were desialylated in the presence of anti-GPIbα but not anti-GPIIbIIIa mAbs. Moreover, we found that desialylation of GPIbα lies directly upstream of platelet activation and apoptosis, as prior treatment with DANA diminished PS-exposure, and P-selectin expression. Most importantly, incubations of human platelets with ITP-patient plasma showed similar effects. In vivo, we found significant increases in PS-exposure and ΔYm induced by anti-GPIbα, but not by anti-GPIIIa mAbs, independent of IgG subclass. Interestingly, prior injection with DANA rescued platelets numbers in anti-GPIbα, but not in anti-GPIIIa injected mice. A significant role for the Ashwell-Morell and MAC-1 receptors in the Clearance of deglycosylated platelets was observed; blocking of the Ashwell-Morell receptors by asialofetuin, decreased platelet Clearance in anti-GPIbα, but not anti-GPIIbIIIa antibody injected mice, there was also increased staining for MAC-1 on Kupffer cells, exclusively in the presence of an anti-GPIbα mAb tested. Thus, we demonstrate for the first time that anti-GPIbα antibodies induce GPIbα desialyation, leading to platelet activation and apoptosis. Therefore, we identified novel Fc-independent platelet Clearance pathways, more specifically, via Ashwell-Morell and MAC-1 receptors on hepatocytes and liver macrophages. These findings may lead to novel therapeutic regimens including the potential use of sialidase inhibitors as a solution for anti-GPIb-mediated ITP patients previously refractory to both steroid and IVIG therapies. Disclosures: No relevant conflicts of interest to declare.
Patrick S Daugherty - One of the best experts on this subject based on the ideXlab platform.
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Amyloid β peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Aβ-mediated toxicity in vitro
Biological Chemistry, 2014Co-Authors: Tyler D. Shropshire, Jack Reifert, Sridharan Rajagopalan, Stuart C. Feinstein, David Baker, Patrick S DaughertyAbstract:The gradual accumulation and assembly of β-amyloid (Aβ) peptide into neuritic plaques is a major pathological hallmark of Alzheimer disease (AD). Proteolytic degradation of Aβ is an important Clearance Mechanism under normal circumstances, and it has been found to be compromised in those with AD. Here, the extended substrate specificity and Aβ-degrading capacity of kallikrein 7 (KLK7), a serine protease with a unique chymotrypsin-like specificity, was characterized. Preferred peptide substrates of KLK7 identified using a bacterial display substrate library were found to exhibit a consensus motif of RXΦ(Y/F)↓(Y/F)↓(S/A/G/T) or RXΦ(Y/F)↓(S/T/A) (Φ=hydrophobic), which is remarkably similar to the hydrophobic core motif of Aβ (K 16 L 17 V 18 F 19 F 20 A 21 ) that is largely responsible for aggregation propensity. KLK7 was found to cleave after both Phe residues within the core of Aβ 42 in vitro, thereby inhibiting Aβ fibril formation and promoting the degradation of preformed fibrils. Finally, the treatment of Aβ oligomer preparations with KLK7, but not inactive pro-KLK7, significantly reduced Aβ 42 -mediated toxicity to rat hippocampal neurons to the same extent as the known Aβ-degrading protease insulin-degrading enzyme (IDE). Taken together, these results indicate that KLK7 possesses an Aβ-degrading capacity that can ameliorate the toxic effects of the aggregated peptide in vitro.