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PURPOSE: To provide evidence-based guidance specific to allied health and nursing practice for the assessment and management of individuals with Duchenne muscular dystrophy (DMD). MATERIALS AND METHODS: Thirteen key focus areas were identified in consultation with health professionals and consumer advocacy groups. A series of systematic literature reviews were conducted to identify assessment and management strategies for each key focus area. A consensus process using modified Delphi methodology, including an Australia-New Zealand expert consensus meeting, was conducted. Recommendations underwent consultative review with key groups before being finalised and prepared for dissemination. RESULTS: This clinical practice guideline (CPG) generated 19 evidence-based recommendations, 117 consensus-based recommendations and five research recommendations across the 13 focus areas to inform allied health assessment and management of individuals with DMD. CONCLUSIONS: The resulting recommendations can be used in conjunction with existing medical CPGs to improve, standardise and advocate for allied health and rehabilitation care in DMD. The process used here may be useful for the development of CPGs in other rare diseases.Implications for rehabilitationImplementation-ready evidence-based statements to guide clinical care of individuals with DMD are provided with the potential to improve participation, function in the community and quality of life.A model for developing best practice statements for other rare neurological diseases is described.Allied health and nursing health professionals should focus research efforts to generate quality evidence to support rehabilitation practice.
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Distrofia Muscular de Duchenne , Consenso , Personal de Salud , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/terapia , Evaluación en Enfermería , Calidad de Vida , Enfermedades RarasRESUMEN
PURPOSE: To develop a consensus statement for the prescription of a Powered Wheelchair Standing Device (PWSD) in young people with Duchenne muscular dystrophy (DMD). MATERIALS AND METHODS: An international multidisciplinary panel comprising clinicians and users (young people with DMD) along with their parents was consulted. A literature review was undertaken and a Delphi method was utilised to generate consensus statements. To supplement limited literature, round one of the Delphi process comprised questions consistent with the International Classification of Functioning, Disability and Health model of disability to generate items based on expert opinion and was completed by 38 clinicians and nine users. Thirty-seven participants completed two further rounds rating the importance of each item with a five-point scale. Agreement of 70% or more participants for items indicated consensus. RESULTS: Consensus was reached for 47 of 80 items. Tolerance and comfort in supported standing for at least 10 min, ankle contracture less than 10 degrees and user goals reflecting motivation to use the standing function were agreed as necessary in guiding the decision to trial a PWSD. Evidence of family, therapist and servicing support were also considered critical in enabling continuity of PWSD use. CONCLUSIONS: PWSD is a mobility option that offers choice, control and opportunity for independence. This consensus statement can assist clinicians with decision-making around factors influencing successful implementation and optimisation of PWSD for young people with DMD.Implications for RehabilitationTolerance and comfort in supported standing for at least 10 minutes, ankle contracture limited to less than 10 degrees and the child's goals reflecting motivation to use the standing position were agreed to be necessary considerations in guiding the decision to trial a PWSD.Trialling a PWSD when the child is predicted to lose the ability to walk within a one to two year period was recommended although a PWSD could be suitable for a child who was unable to walk.Evidence of family, therapist and servicing support was considered critical in enabling continuity of PWSD use.
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Contractura , Distrofia Muscular de Duchenne , Silla de Ruedas , Adolescente , Niño , Técnica Delphi , Humanos , Prescripciones , Posición de PieRESUMEN
The first numerical implementation of a t exp method in 3D using simulated electrode data is presented. Results are compared to Calderón's method as well as more common TV and smoothness regularization-based methods. The t exp method for EIT is based on tailor-made non-linear Fourier transforms involving the measured current and voltage data. Low-pass filtering in the non-linear Fourier domain is used to stabilize the reconstruction process. In 2D, t exp methods have shown great promise for providing robust real-time absolute and time-difference conductivity reconstructions but have yet to be used on practical electrode data in 3D, until now. Results are presented for simulated data for conductivity and permittivity with disjoint non-radially symmetric targets on spherical domains and noisy voltage data. The 3D t exp and Calderón methods are demonstrated to provide comparable quality to their 2D counterparts, and hold promise for real-time reconstructions due to their fast, non-optimized, computational cost.
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Essentials The rs773902 SNP results in differences in platelet protease-activated receptor (PAR4) function. The functional consequences of rs773902 were analyzed in human platelets and stroke patients. rs773902 affects thrombin-induced platelet function, PAR4 desensitization, stroke association. Enhanced PAR4 Thr120 effects on platelet function are blocked by ticagrelor. SUMMARY: Background F2RL3 encodes protease-activated receptor (PAR) 4 and harbors an A/G single-nucleotide polymorphism (SNP) (rs773902) with racially dimorphic allelic frequencies. This SNP mediates an alanine to threonine substitution at residue 120 that alters platelet PAR4 activation by the artificial PAR4-activation peptide (PAR4-AP) AYPGKF. Objectives To determine the functional effects of rs773902 on stimulation by a physiological agonist, thrombin, and on antiplatelet antagonist activity. Methods Healthy human donors were screened and genotyped for rs773902. Platelet function in response to thrombin was assessed without and with antiplatelet antagonists. The association of rs773902 alleles with stroke was assessed in the Stroke Genetics Network study. Results As compared with rs773902 GG donors, platelets from rs773902 AA donors had increased aggregation in response to subnanomolar concentrations of thrombin, increased granule secretion, and decreased sensitivity to PAR4 desensitization. In the presence of PAR1 blockade, this genotype effect was abolished by higher concentrations of or longer exposure to thrombin. We were unable to detect a genotype effect on thrombin-induced PAR4 cleavage, dimerization, and lipid raft localization; however, rs773902 AA platelets required a three-fold higher level of PAR4-AP for receptor desensitization. Ticagrelor, but not vorapaxar, abolished the PAR4 variant effect on thrombin-induced platelet aggregation. A significant association of modest effect was detected between the rs773902 A allele and stroke. Conclusion The F2RL3 rs773902 SNP alters platelet reactivity to thrombin; the allelic effect requires P2Y12 , and is not affected by gender. Ticagrelor blocks the enhanced reactivity of rs773902 A platelets. PAR4 encoded by the rs773902 A allele is relatively resistant to desensitization and may contribute to stroke risk.
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Plaquetas/efectos de los fármacos , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/farmacología , Polimorfismo de Nucleótido Simple , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P2Y12/efectos de los fármacos , Receptores de Trombina/agonistas , Receptores de Trombina/genética , Trombina/farmacología , Ticagrelor/farmacología , Adulto , Animales , Plaquetas/metabolismo , Células COS , Chlorocebus aethiops , Interacciones Farmacológicas , Femenino , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/efectos de los fármacos , Receptores Purinérgicos P2Y12/metabolismo , Receptores de Trombina/metabolismo , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/genética , Adulto JovenRESUMEN
Platelet activation and thrombus formation play a central role in ischemic vascular disease. Thrombin, an especially potent physiologic agonist mediating in vivo activation of platelets, acts via a unique family of G-protein-coupled receptors called protease-activated receptors (PARs) with a broad tissue expression. This review focuses on current antiplatelet therapies as well as innovative approaches to targeting PARs in patients with atherothrombotic vascular disease.
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Plaquetas/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , Receptores de Trombina/antagonistas & inhibidores , Enfermedades Vasculares/tratamiento farmacológico , Drogas en Investigación/farmacología , Drogas en Investigación/uso terapéutico , Humanos , Modelos Biológicos , Inhibidores de Agregación Plaquetaria/farmacologíaRESUMEN
OBJECTIVE: To examine whether distortion product otoacoustic emissions can serve as a replacement for pure tone audiometry in longitudinal screening for occupational noise exposure related auditory deficit. METHODS: A retrospective review was conducted of pure tone audiometry and distortion product otoacoustic emission data obtained sequentially during mandatory screening of brickyard workers (n = 16). Individual pure tone audiometry thresholds were compared with distortion product otoacoustic emission amplitudes, and a correlation of these measurements was conducted. RESULTS: Pure tone audiometry threshold elevation was identified in 13 out of 16 workers. When distortion product otoacoustic emission amplitudes were compared with pure tone audiometry thresholds at matched frequencies, no evidence of a robust relationship was apparent. Seven out of 16 workers had substantial distortion product otoacoustic emissions with elevated pure tone audiometry thresholds. CONCLUSION: No clinically relevant predictive relationship between distortion product otoacoustic emission amplitude and pure tone audiometry threshold was apparent. These results do not support the replacement of pure tone audiometry with distortion product otoacoustic emissions in screening. Distortion product otoacoustic emissions at frequencies associated with elevated pure tone audiometry thresholds are evidence of intact outer hair cell function, suggesting that sites distinct from these contribute to auditory deficit following ototrauma.
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Audiometría de Tonos Puros/métodos , Pérdida Auditiva Provocada por Ruido/diagnóstico , Exposición Profesional/efectos adversos , Salud Laboral , Emisiones Otoacústicas Espontáneas/fisiología , Adulto , Anciano , Umbral Auditivo/fisiología , Bases de Datos Factuales , Femenino , Pérdida Auditiva Provocada por Ruido/epidemiología , Humanos , Incidencia , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Reino Unido , Adulto JovenRESUMEN
3-phosphoinositide-dependent protein kinase 1 (PDK1), a member of the protein A,G and C (AGC) family of proteins, is a Ser/Thr protein kinase that can phosphorylate and activate other protein kinases from the AGC family, including Akt at Thr308, all of which play important roles in mediating cellular responses. The functional role of PDK1 or the importance of phosphorylation of Akt on Thr308 for its activity has not been investigated in human platelets. In this study, we tested two pharmacological inhibitors of PDK1, BX795 and BX912, to assess the role of Thr308 phosphorylation on Akt. PAR4-induced phosphorylation of Akt on Thr308 was inhibited by BX795 without affecting phosphorylation of Akt on Ser473. The lack of Thr308 phosphorylation on Akt also led to the inhibition of PAR4-induced phosphorylation of two downstream substrates of Akt, viz. GSK3ß and PRAS40. In vitro kinase activity of Akt was completely abolished if Thr308 on Akt was not phosphorylated. BX795 caused inhibition of 2-MeSADP-induced or collagen-induced aggregation, ATP secretion and thromboxane generation. Primary aggregation induced by 2-MeSADP was also inhibited in the presence of BX795. PDK1 inhibition also resulted in reduced clot retraction indicating its role in outside-in signalling. These results demonstrate that PDK1 selectively phosphorylates Thr308 on Akt thereby regulating its activity and plays a positive regulatory role in platelet physiological responses.
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Plaquetas/fisiología , Proteína Oncogénica v-akt/metabolismo , Treonina/metabolismo , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenosina Trifosfato/metabolismo , Plaquetas/efectos de los fármacos , Células Cultivadas , Retracción del Coagulo/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Fosforilación/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Pirimidinas/farmacología , Receptores de Trombina/metabolismo , Serina/metabolismo , Transducción de Señal/efectos de los fármacos , Tiofenos/farmacología , Tromboxanos/metabolismoRESUMEN
Recent work by the Encyclopedia of DNA Elements project showed that non-protein-coding RNAs account for an unexpectedly large proportion of the human genome. Among these non-coding RNAs are microRNAs (miRNAs), which are small RNA molecules that modulate protein expression by degrading mRNA or repressing mRNA translation. MiRNAs have been shown to play important roles in hematopoiesis including embryonic stem cell differentiation, erythropoiesis, granulocytopoiesis/monocytopoiesis, lymphopoiesis, and megakaryocytopoiesis. Additionally, disordered miRNA biogenesis and quantitative or qualitative alterations in miRNAs and their targets are associated with hematological pathologies. Platelets contain machinery to process pre-miRNAs into mature miRNAs, and specific platelet miRNA levels have been found to correlate with platelet reactivity. This review summarizes the current state of knowledge of miRNAs in megakaryocytes and platelets, and the exciting possibilities for future megakaryocyte-platelet transcriptome research.
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Plaquetas/citología , MicroARNs/metabolismo , Activación Plaquetaria , Plaquetas/metabolismo , HumanosRESUMEN
BACKGROUND: Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein VI, on platelet function and the risk of cardiovascular disease. METHODS: We performed a population-based case-control study, the Study of Myocardial Infarctions in Leiden, among 547 male patients with a first myocardial infarction (MI) and 646 control subjects, as well as a prospective cohort study in which the same MI patients were followed for recurrent events (fatal and non-fatal MI and unstable angina) and mortality (median follow-up of 12 years). P-selectin expression by platelets induced by crosslinked collagen-related peptide (CRP-XL) was measured by whole blood flow cytometry in 274 MI patients. RESULTS: T13254C was not associated with a first MI, but seemed to be associated with a reduced incidence of recurrent events [per-allele hazard ratio 0.77, 95% confidence interval (CI) 0.56-1.06] and mortality (hazard ratio 0.57, 95% CI 0.37-0.89). Pooling with the Heart and Estrogen/Progestin Replacement Study revealed hazard ratios of 0.81 (95% CI 0.66-0.99) and 0.73 (95% CI 0.55-0.96). The minor C-allele was also strongly associated with a reduced percentage of P-selectin-expressing platelets. The reduction per C-allele was 23% (95% CI 18-28%). In an independent study of 219 healthy volunteers, the per-allele reduction of CRP-XL-induced aggregation was 10% (95% CI 2-18%). CONCLUSION: The minor allele of GP6 T13254C that reduced platelet activation and aggregation also seemed to be associated with a reduced incidence of recurrent cardiovascular events and mortality, but was not associated with first MI.
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Plaquetas/citología , Enfermedades Cardiovasculares/genética , Activación Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/genética , Anciano , Alelos , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Selectina-P/sangre , Polimorfismo Genético , Modelos de Riesgos Proporcionales , Isoformas de Proteínas , RecurrenciaRESUMEN
BACKGROUND: Variation in platelet reactivity contributes to disorders of hemostasis and thrombosis, but the molecular mechanisms are not well understood. OBJECTIVES: To discover associations between interindividual platelet variability and the responsible platelet genes, and to begin to define the molecular mechanisms altering platelet gene expression. SUBJECTS/METHODS: Two hundred and eighty-eight healthy subjects were phenotyped for platelet responsiveness. Platelet RNA from subjects demonstrating hyperreactivity (n=18) and hyporeactivity (n=11) was used to screen the human transcriptome. RESULTS: Distinctly different mRNA profiles were observed between subjects with differing platelet reactivity. Increased levels of mRNA for VAMP8/endobrevin, a critical v-SNARE involved in platelet granule secretion, were associated with platelet hyperreactivity (Q=0.0275). Validation studies of microarray results showed 4.8-fold higher mean VAMP8 mRNA levels in hyperreactive than hyporeactive platelets (P=0.0023). VAMP8 protein levels varied 13-fold among platelets from these normal subjects, and were 2.5-fold higher in hyperreactive platelets (P=0.05). Among our cohort of 288 subjects, a VAMP8 single-nucleotide polymorphism (rs1010) was associated with platelet reactivity in an age-dependent manner (P<0.003). MicroRNA-96 was predicted to bind to the 3'-untranslated regionof VAMP8 mRNA and was detected in platelets. Overexpression of microRNA-96 in VAMP8-expressing cell lines caused a dose-dependent decrease in VAMP8 protein and mRNA, suggesting a role in VAMP8 mRNA degradation. CONCLUSIONS: These findings support a role for VAMP8/endobrevin in the heterogeneity of platelet reactivity, and suggest a role for microRNA-96 in the regulation of VAMP8 expression.
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Plaquetas/metabolismo , MicroARNs/sangre , Agregación Plaquetaria/genética , Polimorfismo de Nucleótido Simple , Proteínas R-SNARE/genética , Regiones no Traducidas 3' , Adulto , Factores de Edad , Sitios de Unión , Epinefrina , Femenino , Perfilación de la Expresión Génica/métodos , Genotipo , Células HCT116 , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Proteínas R-SNARE/sangre , ARN Mensajero/sangre , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Regulación hacia Arriba , Adulto JovenRESUMEN
The presence of amber, the fossil form of the resins produced by many types of higher plants, has been reported from many localities in Mesozoic and Cenozoic rocks. We have found Class I (polylabdanoid) amber in Carboniferous sediments dating to approximately 320 million years ago. This result demonstrates that preconifer gymnosperms evolved the biosynthetic mechanisms to produce complex polyterpenoid resins earlier than previously believed and that the biosynthetic pathways leading to the types of polylabdanoid resins that are now typically found in conifers and those now typically found in angiosperms had already diverged by the Carboniferous.
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Ámbar/química , Evolución Biológica , Cycadopsida/metabolismo , Diterpenos/análisis , Ámbar/clasificación , Cycadopsida/química , Cycadopsida/genética , Diterpenos/metabolismo , Fósiles , Illinois , Magnoliopsida/química , Magnoliopsida/genética , Magnoliopsida/metabolismo , Naftalenos/análisis , Naftalenos/metabolismo , Estereoisomerismo , Terpenos/análisis , Terpenos/metabolismo , Tiempo , Tracheophyta/química , Tracheophyta/genética , Tracheophyta/metabolismoRESUMEN
BACKGROUND AND PURPOSE: The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC. EXPERIMENTAL APPROACH: Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes. KEY RESULTS: We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 +/- 11961) and protein (% control 200 +/- 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-gamma (IFNgamma) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNgamma respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r(2) = 0.545). CONCLUSIONS AND IMPLICATIONS: These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.
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Hidrocarburo de Aril Hidroxilasas/metabolismo , Proteínas Portadoras/metabolismo , Citocromo P-450 CYP3A/metabolismo , Citocinas/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Oxidorreductasas N-Desmetilantes/metabolismo , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/genética , Transporte Biológico , Células Cultivadas , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/genética , Inhibidores del Citocromo P-450 CYP3A , Citocinas/fisiología , Digoxina/farmacocinética , Citometría de Flujo , Humanos , Leucocitos Mononucleares/enzimología , Leucocitos Mononucleares/metabolismo , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Oxidorreductasas N-Desmetilantes/antagonistas & inhibidores , Oxidorreductasas N-Desmetilantes/genética , Receptores de Quimiocina/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Saquinavir/farmacocinéticaRESUMEN
BACKGROUND: Although "aspirin resistance" (AR-inadequate platelet inhibition as suggested by in vitro testing of aspirin-treated patients) has been widely studied in adults and linked to increased risk of adverse outcomes, its prevalence and clinical significance are largely unknown in children. PROCEDURE: To determine AR prevalence in children and its relationship to assay methodology, we undertook a cross-sectional study of 44 children (1-17 years, 24 male) on aspirin for various indications and considered three published definitions of AR in adults: platelet aggregation >/=70% to 10 microM adenosine diphosphate and >/=20% to 0.5 mg/ml arachidonic acid (AA), normal PFA-100(R) closure time and elevated urinary 11-dehydro thromboxane B(2) (11dhTxB(2)) concentration. RESULTS: Six subjects exhibited AR according to at least one of the criteria (5 by PFA-100(R), 1 by aggregometry and 11dhTxB(2) criteria); nearly all subjects had low levels of 11dhTxB(2) compared with controls. Subjects studied prior to therapy showed pronounced changes in AR parameters after aspirin dosing (e.g., mean aggregation to AA decreased from 82% to 6%, P < 0.001), confirming an aspirin effect. Subjects with AR did not differ from aspirin responsive subjects in terms of age, race, platelet count, or aspirin dose, indication or therapy duration. There was minimal correlation between assays. CONCLUSIONS: In this initial prevalence study of a clinically diverse group of pediatric patients, frequencies of AR were assay-dependent; however, the prevalence of true AR is likely low in children (2.3%; 95% CI 0.1-10.7%), in agreement with adult studies. To better define the clinical relevance of AR in children, multicenter, prospective cohort studies are imperative.
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Aspirina , Resistencia a Medicamentos , Adolescente , Aspirina/farmacología , Aspirina/uso terapéutico , Niño , Preescolar , Estudios Transversales , Mediciones Epidemiológicas , Femenino , Humanos , Lactante , Masculino , Agregación Plaquetaria/efectos de los fármacos , Prevalencia , Factores de RiesgoRESUMEN
Terpenoid resin is produced by all families and most genera of the order Coniferales (the conifers), and the distribution of terpenes present in most conifer resins is characteristic of the originating family. Analyses of early Cretaceous (Barremian) amber (fossil resin) from the English Wealden, Isle of Wight, southern England, by pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS), indicate a terpene distribution dominated by abietane- and labdane-type terpenes. Similar distributions are observed in some species of the extant family Pinaceae. The Pinaceae are well represented within the Wealden deposits of southern England, by only one (known) species, Pityites solmsii (Seward) Seward, whereas the macro-fossil record of these deposits is dominated by the extinct conifer family Cheirolepidiaceae, for which no resin chemistry has been reported. By analogy with modern materials, it is probable that the ambers found in these deposits are derived from an extinct member of the Pinaceae, but given the absence of evidence concerning the chemotaxonomy of the Cheirolepidiaceae, this family cannot be excluded a priori as a possible paleobotanical source. These ambers may therefore be assigned to either the Pinaceae or to the Cheirolepidiaceae. These samples are the oldest ambers to date to yield useful chemotaxonomic data.
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BACKGROUND: Variations in platelet function among individuals may be related to differences in platelet-related genes. The major goal of our study was to estimate the contribution of inheritance to the variability in platelet function in unaffected individuals from white and African American families with premature coronary artery disease. METHODS: Platelet reactivity, in the absence of antiplatelet agents, was assessed by in vitro aggregation and the platelet function analyzer closure time. Heritability was estimated using a variance components model. RESULTS: Both white (n = 687) and African American (n = 321) subjects exhibited moderate to strong heritability (h(2)) for epinephrine- and adenosine diphosphate-induced aggregation (0.36-0.42 for white and >0.71 for African American subjects), but heritability for collagen-induced platelet aggregation in platelet-rich plasma was prominent only in African American subjects. Platelet lag phase after collagen stimulation was heritable in both groups (0.47-0.50). A limited genotype analysis demonstrated that the C825T polymorphism of GNB3 was associated with the platelet aggregation response to 2 muM epinephrine, but the effect differed by race. CONCLUSIONS: Considering the few and modest genetic effects reported to affect platelet function, our findings suggest the likely existence of undiscovered important genes that modify platelet reactivity, some of which affect multiple aspects of platelet biology.
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Plaquetas/fisiología , Enfermedad de la Arteria Coronaria/sangre , Adulto , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/etnología , Salud de la Familia , Femenino , Fibrinógeno/metabolismo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria , Polimorfismo Genético , Trombosis/complicaciones , Trombosis/diagnóstico , Tromboxano B2/sangre , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: Although platelet hyperreactivity constitutes an important cardiovascular risk factor, standardized methods for its measurement are lacking. We recently reported that aggregometry using a submaximal concentration of epinephrine identifies individuals with in vitro platelet hyperreactivity; this hyperreactivity was reproducible on multiple occasions over long periods of time. OBJECTIVE AND METHODS: To better understand this aberrant reactivity, we studied in a large group of subjects (n = 386) the relationship between healthy individuals' platelet reactivity to epinephrine and their platelet phenotype as measured by other functional assays. RESULTS: Subjects with hyperreactivity to epinephrine were more likely to exhibit hyperfunction in each major aspect of platelet activity, including adhesion (response to low-dose ristocetin; P < 0.001), activation (surface P-selectin expression and PAC-1 binding after stimulation; P Asunto(s)
Trastornos de las Plaquetas Sanguíneas/genética
, Subunidades beta de la Proteína de Unión al GTP/genética
, Activación Plaquetaria/genética
, Activación Plaquetaria/fisiología
, Adulto
, Epinefrina/farmacología
, Femenino
, Genotipo
, Humanos
, Masculino
, Persona de Mediana Edad
, Adhesividad Plaquetaria/efectos de los fármacos
, Adhesividad Plaquetaria/genética
, Agregación Plaquetaria/efectos de los fármacos
, Agregación Plaquetaria/genética
, Polimorfismo Genético
RESUMEN
INTRODUCTION: The aim of this study was to review our experience of popliteal aneurysms using endovascular techniques. METHODS: Thirty popliteal aneurysms in 25 patients were treated over an 11-year period. Median aneurysm diameter was 26 (16-48) mm. Five were symptomatic and 25 asymptomatic. Patients were treated with the Haemobahn/Viabahn stent-graft (26), Passager (two), Aneurx (one), and PTFE homemade device (one). Data were assessed using life table analysis, and expressed as cumulative patency rates and standard error (SE). RESULTS: Median follow-up was 24 (range 1-95) months. Primary patency was 92.9% (SE 4.5%), 84.7% (SE 6.8%), 80% (SE 8.2%), 74.5% (SE 9.4%) and 74.5% (11.3%) at 1, 6, 12, 24 and 36 months, respectively. Cumulative secondary patency was 96.5% (SE 3.3%), 88.7% (SE 6.0%), 88.7% (SE 8.6%), 83.2% (SE 8.0%) and 83.2% (SE 9.8%) at 1, 6, 12, 24 and 36 months, respectively. CONCLUSION: Endovascular treatment of popliteal aneurysms in this series achieved patency rates similar to open surgery. Aneurysm repair was performed without peroperative deaths and the risks associated with open surgery.