ABSTRACT
Essentials von Willebrand factor (VWF) is synthesized in endothelial cells and platelet precursors. Type 3 patients with Pro2808Leufs*24 have lower bleeding scores than other type 3s. The Pro2808Leufs*24 variant was examined in patient platelets and endothelial cells. Type 3s with this variant contain releaseable VWF, possibly reducing bleeding. SUMMARY: Background A novel variant, p.Pro2808Leufs*24, in the von Willebrand factor (VWF) gene was previously identified in the Canadian von Willebrand disease (VWD) patient population. Clinical observations of type 3 VWD patients with this variant indicate a milder bleeding phenotype compared with other type 3 patients. Objective To assess the effect of the Pro2808Leufs*24 variant on the molecular pathogenesis of VWD and correlate this with the phenotype observed in patients. Patients/Methods Phenotypic data from individuals in the Canadian type 3 VWD study were analyzed. VWF expression in platelets and plasma was assessed via immunoblotting. Cellular expression of VWF in platelets and blood outgrowth endothelial cells (BOEC) was examined via immunofluorescence microscopy and biochemical analysis in a type 3 index case and family member with Pro2808Leufs*24. Results Twenty-six individuals with the Pro2808Leufs*24 variant (16 type 3 VWD homozygous or compound heterozygous and 10 heterozygous family members) were studied. Bleeding scores were lower in type 3 patients with Pro2808Leufs*24 compared with type 3 patients with other variants, confirming a milder bleeding phenotype. Immunoblotting of platelet lysates detected VWF in the platelets of type 3 patients with Pro2808Leufs*24. Examination of an index case detected VWF within platelets via immunofluorescence microscopy, and in vitro experiments showed that this VWF was released upon platelet activation. Patient BOECs showed decreased VWF synthesis and secretion, although some VWF-containing granules were observed. Conclusion Type 3 VWD patients with the Pro2808Leufs*24 have bioavailable platelet-derived VWF that may produce a milder bleeding phenotype than other type 3s.
Subject(s)
Blood Platelets/metabolism , Endothelial Cells/metabolism , Hemorrhage , Plasma/metabolism , von Willebrand Disease, Type 3/blood , von Willebrand Factor/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Canada , Cells, Cultured , Female , Genetic Variation , Heterozygote , Homozygote , Humans , Leucine , Male , Microscopy, Fluorescence , Middle Aged , Pedigree , Phenotype , Proline , Young AdultABSTRACT
von Willebrand disease (VWD) is the most common bleeding disorder. Type 1 VWD represents the majority of cases and results from a partial quantitative deficiency of von Willebrand factor (VWF). The diagnosis of Type 1 VWD presents many challenges, despite there being three established diagnostic criteria: a personal history of mucocutaneous bleeding, a family history and low VWF levels. These criteria do not always coexist, and there is great overlap of clinical phenotypes and laboratory parameters between healthy individuals and those with VWD. Mild bleeding symptoms can have any number of causes and bleeding is commonly reported in the general population. VWF levels do not always correlate with bleeding symptoms and can be variable between affected family members. Additionally, VWF levels vary widely as a result of both genetic and non-genetic influences. Perhaps the greatest current controversy in the diagnosis of Type 1 VWD is that there is no consensus laboratory cut-off for the diagnosis, raising concern about both over- and under-diagnosis. Ongoing studies are addressing these issues by clarifying the underlying pathogenesis of the disease, as well as the natural history and the risk of future bleeding in those with the diagnosis.
Subject(s)
von Willebrand Disease, Type 1/diagnosis , Hemorrhage/blood , Hemorrhage/diagnosis , Hemorrhage/genetics , Humans , Phenotype , von Willebrand Disease, Type 1/blood , von Willebrand Disease, Type 1/geneticsABSTRACT
Ninety-four workers completed the Minnesota Multiphasic Personality Inventory--2 (MMPI-2) on 2 separate occasions, with an average lag of 21.3 months (SD = 14.1, range = 2-75), within the context of a psychological assessment after suffering an injury due to crime or accident. MMPI-2 profiles were moderately consistent, with correlation coefficients ranging from .61 to .73 for clinical scales, from .52 to .80 for supplementary scales, from .65 to .78 for content scales, and from .32 to .73 for the Personality Psychopathology Five scales (A. R. Harkness, J. L. McNulty, & Y. S. Ben-Porath, 1995). The results suggest that the MMPI-2 provides consistent and stable results across time in injured workers.
Subject(s)
Accidents, Occupational/psychology , Crime/psychology , MMPI/statistics & numerical data , Stress Disorders, Post-Traumatic/diagnosis , Wounds and Injuries/psychology , Adult , Brain Injury, Chronic/psychology , Brain Injury, Chronic/rehabilitation , Female , Follow-Up Studies , Humans , Male , Middle Aged , Psychometrics , Rehabilitation, Vocational , Reproducibility of Results , Stress Disorders, Post-Traumatic/psychology , Wounds and Injuries/rehabilitationABSTRACT
OBJECTIVE: To evaluate the evidence concerning the role of threatening life events in accounting for clinically significant posttraumatic stress responses. METHOD: Research was examined to review the epidemiology, evidence of dose-response relations, and individual difference factors in accounting for variations in conditions, including posttraumatic stress disorder, after exposure to threatening events. RESULTS: The evidence is significantly discrepant from the clinical Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) model. Greater distress arises from individual differences than from event characteristics. Important individual differences that interact with threat exposures include trait negative affectivity (neuroticism); beliefs about emotions, the self, the world, and the sources and consequences of danger; and prevent acts, disorders, and intelligence. Reasons for the discrepancies between the evidence and the current model of posttraumatic distress are proposed. CONCLUSION: In accounting for responses to threatening life events, the relatively minor contribution of event qualities compared with individual differences has significant treatment implications. Treatment approaches assuming that toxic event exposure creates a posttraumatic disorder fail to consider individual differences that could improve treatment efficacy.
Subject(s)
Individuality , Life Change Events , Manuals as Topic/standards , Psychiatry/standards , Stress Disorders, Post-Traumatic/classification , Terminology as Topic , Adaptation, Psychological , Disease Susceptibility , Emotions/physiology , Humans , Models, Psychological , Neurotic Disorders/etiology , Risk Factors , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/etiology , Stress Disorders, Post-Traumatic/physiopathology , Stress Disorders, Post-Traumatic/therapy , Stress, Psychological/classification , Stress, Psychological/etiology , United States/epidemiologyABSTRACT
Maternal thyrotoxicosis complicates approximately 0.2% of pregnancies. Simultaneous occurrence of maternal and fetal thyrotoxicosis during labor is rare, and control of maternal tachycardia and hypertension, as well as fetal manifestations of thyrotoxicosis, are cornerstones of management. An 18-year-old nulliparous female at 33 weeks gestational age presented in labor with thyrotoxicosis. Fetal tachycardia was present as well. Labetalol therapy resulted in a decrease in maternal pulse and blood pressure, and resolution of fetal tachycardia. Vaginal delivery occurred. Subsequent evaluation demonstrated neonatal thyrotoxicosis and high maternal titers of thyroid-stimulating immunoglobulin. In conclusion, labetalol was beneficial in the treatment of maternal and fetal thyrotoxicosis during labor.
