What’s Past Is Prologue Simsek, Zeki; Fox, Brian Curtis; Heavey, Ciaran
Journal of management,
01/2015, Letnik:
41, Številka:
1
Journal Article
Recenzirano
Organizational researchers have long used imprinting as a theoretical lens for a historically embedded understanding of diverse, significant phenomena for explanatory, evaluative, and managerial ...purposes. The intuitive appeal of imprinting has facilitated its widespread diffusion throughout numerous disciplines and research fields, but the growing fragmentation of associated theory and evidence has blurred our understanding of the nature, sources, and mechanisms of imprinting as well as the context in which imprinting shapes the behavior and outcomes of distinct entities. To address these issues, we begin by developing a framework for generalizing theoretical constructs, statements, and relationships across levels of analysis, contexts, and disciplinary boundaries. Using the core themes of this framework, we next provide a systematic review of 119 imprinting studies allowing for more definitive statements about what we know, do not know, and should know about imprinting. Finally, by building on the review, together with the proposed framework, we chart a focused course for future inquiry and applications for organizational research on imprinting.
Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per ...million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 10
neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.
Summary
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs in c. 1 in 1000 births and is caused by maternal antibodies against human platelet alloantigens that bind incompatible fetal ...platelets and promote their clearance from the circulation. Affected infants can experience bleeding, bruising and, in severe cases, intracranial haemorrhage and even death. As maternal screening is not routinely performed, and first pregnancies can be affected, most cases are diagnosed at delivery of a first affected pregnancy. Unlike its erythrocyte counterpart, Haemolytic Disease of the Fetus and Newborn, there is no prophylactic treatment for FNAIT. This report will review recent advances made in understanding the pathogenesis of FNAIT: the platelet alloantigens involved, maternal exposure and sensitization to fetal platelet antigens, properties of platelet Immunoglobulin G antibodies, maternal‐fetal antibody transport mechanisms and efforts to develop an effective FNAIT prophylaxis.
Heparin-induced thrombocytopenia (HIT) complicated by severe thrombocytopenia and thrombosis can pose significant treatment challenges. Use of alternative anticoagulants in this setting may increase ...bleeding risks, especially in patients who have a protracted disease course. Additional therapies are lacking in this severely affected patient population.
We describe three patients with HIT who had severe thromboembolism and prolonged thrombocytopenia refractory to standard treatment but who achieved an immediate and sustained response to IVIg therapy. The mechanism of action of IVIg was evaluated in these patients and in five additional patients with severe HIT. The impact of a common polymorphism (H/R 131) in the platelet IgG receptor FcγRIIa on IVIg-mediated inhibition of platelet activation was also examined.
At levels attained in vivo, IVIg inhibits HIT antibody-mediated platelet activation. The constant domain of IgG (Fc) but not the antigen-binding portion (Fab) is required for this effect. Consistent with this finding, IVIg had no effect on HIT antibody binding in a solid-phase HIT immunoassay (platelet factor 4 enzyme-linked immunoassay). The H/R131 polymorphism in FcγRIIa influences the susceptibility of platelets to IVIg treatment, with the HH131 genotype being most susceptible to IVIg-mediated inhibition of antibody-induced activation. However, at high doses of IVIg, activation of platelets of all FcγRIIa genotypes was significantly inhibited. All three patients did well on long-term anticoagulation therapy with direct oral anticoagulants.
These studies suggest that IVIg treatment should be considered in patients with HIT who have severe disease that is refractory to standard therapies.
Background Almost without exception, patients with heparin-induced thrombocytopenia/thrombosis (HIT) have antibodies that recognize platelet factor 4 (PF4) in a complex with heparin; however, many ...heparin-treated patients without HIT are also antibody-positive. A platelet activation test, the serotonin release assay (SRA), is useful for identifying a subset of antibodies that are platelet-activating and most likely to cause HIT. However, this “gold standard” assay for HIT diagnosis is technically demanding and is routinely available only through referral laboratories, limiting its availability for timely diagnosis and management. Methods We compared the diagnostic performance of the SRA with that of a technically simple platelet activation assay, the PF4-dependent P-selectin expression assay (PEA), which uses platelets pretreated with PF4 as targets for antibody detection. Archived serum samples from 91 patients for whom clinical information (HIT 4Ts thrombocytopenia, timing of platelet count fall, thrombosis, and other causes of thrombocytopenia score) was available were used. Patients with an intermediate 4Ts score and a PF4 ELISA (enzyme-linked immunosorbent assay) optical density ≥ 2.0, or a high 4Ts score and a PF4 ELISA optical density ≥ 1.0, were considered HIT positive; others were designated HIT negative. Results The PEA had higher diagnostic accuracy (area under the curve, 0.92 vs 0.82; P = .02) than the SRA, using this definition of HIT. Eleven of 16 serum samples that were PEA positive and SRA negative were HIT positive. Studies done with identical target platelets and serially diluted samples from patients with HIT showed that the PEA is inherently more sensitive than the SRA for the detection of platelet-activating antibodies. Conclusions The PEA is technically less demanding than the SRA and may be more accurate for the diagnosis of HIT.
Summary
Neonatal alloimmune thrombocytopenia, (NAIT) is caused by maternal antibodies raised against alloantigens carried on fetal platelets. Although many cases are mild, NAIT is a significant cause ...of morbidity and mortality in newborns and is the most common cause of intracranial haemorrhage in full‐term infants. In this report, we review the pathogenesis, clinical presentation, laboratory diagnosis and prenatal and post‐natal management of NAIT and highlight areas of controversy that deserve the attention of clinical and laboratory investigators.
Sialic acids occupy the terminal position of glycan chains and have the potential to influence the antigenicity of glycoproteins (GP). The polymorphisms of human platelet alloantigens (HPA)-3 and ...HPA-9, located near the C-terminus of the extracellular domain of platelet membrane GPIIb, are adjacent to sialyl-core 1 O-glycans emanating from serines 845 and 847. Whether the nearby O-glycans affect the antigenicity of HPA-9b or influence the binding of anti-HPA-9b alloantibodies in clinically significant cases of neonatal alloimmune thrombocytopenia is unknown. To address this issue, we generated a series of O-glycan mutant HPA-9 allele-specific induced pluripotent stem cell lines, differentiated them to megakaryocytes (MKs), and examined their ability to bind HPA-9b-specific alloantibodies. We found that both wild-type MKs treated with neuraminidase and those genetically modified to lack the sialidases ST3GAL1 and ST3GAL2 dramatically increased anti-HPA-9b alloantibody binding, indicating that the HPA-9b epitope is partially masked by terminal sialic acids on nearby O-glycans of GPIIb. Interestingly, mutating the serine residues that carry these glycan chains to alanine actually reduced the binding of anti-HPA-9b alloantibodies, indicating that these 2 O-glycan chains contribute to the presentation of the HPA-9b epitope-perhaps by stabilizing the conformation of the GP in this region. Collectively, our data suggest that detection of anti-HPA-9b alloantibodies may be enhanced through the use of HPA-9b-specific MKs that have been genetically altered to lack nearby terminal sialic acid residues but retain the glycan chains to which they are attached.
(1) Examine performance on an objective measure of reward-related cognitive impulsivity (delay discounting) among self-reported habitual short sleepers and medium (i.e. recommended 7-9 hours) length ...sleepers either reporting or not reporting daytime dysfunction; (2) Inform the debate regarding what type and duration of short sleep (e.g. 21 to 24 hours of total sleep deprivation, self-reported habitual short sleep duration) meaningfully influences cognitive impulsivity; (3) Compare the predictive utility of sleep duration and perceived dysfunction to other factors previously shown to influence cognitive impulsivity via delay discounting performance (age, income, education, and fluid intelligence).
We analyzed data from 1190 adults from the Human Connectome Project database. Participants were grouped on whether they reported habitual short (≤6 hours) vs. medium length (7-9 hours) sleep duration and whether they perceived daytime dysfunction using the Pittsburgh Sleep Quality Index.
All short sleepers exhibited increased delay discounting compared to all medium length sleepers, regardless of perceived dysfunction. Of the variables examined, self-reported sleep duration was the strongest predictor of delay discounting behavior between groups and across all 1190 participants.
Individuals who report habitual short sleep are likely to exhibit increased reward-related cognitive impulsivity regardless of perceived sleep-related daytime impairment. Therefore, there is a reason to suspect that these individuals exhibit more daytime dysfunction, in the form of reward-related cognitive impulsivity, than they may assume. Current findings suggest that assessment of sleep duration over the prior month has meaningful predictive utility for human reward-related impulsivity.
PDF
