RESUMEN
ABSTRACT: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease's recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.
Asunto(s)
Trombosis , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Trombosis/etiología , Trombosis/genética , Trombosis/epidemiología , Adolescente , Enzimas Activadoras de Ubiquitina/genética , Adulto Joven , Factores de Riesgo , Anciano , Niño , Trombosis de la Vena/etiología , Trombosis de la Vena/epidemiología , Trombosis de la Vena/genética , Incidencia , Mutación , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , PreescolarRESUMEN
ABSTRACT: Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Trombocitopenia , Adulto , Humanos , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Estudios Longitudinales , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/complicaciones , Trombocitopenia/genética , Trastornos Mieloproliferativos/complicaciones , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/complicacionesRESUMEN
Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.).
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Cobicistat/farmacocinética , Dabigatrán/farmacocinética , Mucosa Intestinal/metabolismo , Ritonavir/farmacocinética , Adulto , Antitrombinas/administración & dosificación , Antitrombinas/farmacocinética , Antivirales/administración & dosificación , Antivirales/farmacocinética , Área Bajo la Curva , Cobicistat/administración & dosificación , Dabigatrán/administración & dosificación , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Intestinos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Ritonavir/administración & dosificación , Tiempo de TrombinaRESUMEN
PURPOSE: Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. RESULTS: The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions. CONCLUSIONS: This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient with Hermansky-Pudlak syndrome subtype 6.
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Albinismo Oculocutáneo/genética , Hemofilia B/genética , Síndrome de Hermanski-Pudlak/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Adulto , Albinismo Oculocutáneo/patología , Exoma , Femenino , Hemofilia B/patología , Síndrome de Hermanski-Pudlak/patología , Humanos , Masculino , Mutación , FenotipoRESUMEN
Ibrutinib is associated with bleeding-related adverse events of grade ≤ 2 in severity, and infrequently with grade ≥ 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤ 2 bleeding-related adverse events in 55% of 85 patients. No grade ≥ 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤ 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733.
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Hemorragia , Leucemia Linfocítica Crónica de Células B , Agregación Plaquetaria/efectos de los fármacos , Pirazoles , Pirimidinas , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Factor VIII/metabolismo , Femenino , Estudios de Seguimiento , Hemorragia/sangre , Hemorragia/inducido químicamente , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piperidinas , Pruebas de Función Plaquetaria , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Factores de Riesgo , Factor de von Willebrand/metabolismoRESUMEN
The present study tests a refined first component of the Patient-Centered Culturally Sensitive Health Care (PC-CSHC) Model-the evidence supported component that links perceived provider cultural sensitivity to patient satisfaction with provider care and identifies trust of provider as the mediator of this linkage. The refined first component of the PC-CSHC Model tested in the present study is novel in that it includes the three dimensions of provider cultural sensitivity and includes perceived provider impartiality (fairness), a core aspect of perceived health care justice, as a mediator in addition to trust of provider (the other core aspect of perceived health care justice). Study participants were 298 African American/Black primary care clinic patients with low household incomes. Mediation analyses revealed that the three dimensions of patients' perceived provider cultural sensitivity were significant predictors of the participating patients' reported satisfaction with their provider, and that some of these predictive relationships were partially mediated by (1) patients' perceived provider impartiality (fairness), and (2) patients' trust of their provider. Implications of these findings for providers' interactions with patients, development of the PC-CSHC Model, and the roles of psychologists in facilitating patient-provider interactions are discussed.
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Negro o Afroamericano/psicología , Competencia Cultural/psicología , Satisfacción del Paciente/estadística & datos numéricos , Relaciones Médico-Paciente , Adolescente , Adulto , Negro o Afroamericano/estadística & datos numéricos , Anciano , Femenino , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Atención Dirigida al Paciente/métodos , Pobreza , Justicia Social , Encuestas y Cuestionarios , Confianza/psicología , Adulto JovenAsunto(s)
Fármacos Anti-VIH/administración & dosificación , Antitrombinas/administración & dosificación , Antitrombinas/farmacocinética , Coagulación Sanguínea/efectos de los fármacos , Cobicistat/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Dabigatrán/administración & dosificación , Dabigatrán/farmacocinética , Administración Oral , Fármacos Anti-VIH/efectos adversos , Antitrombinas/efectos adversos , Cobicistat/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Dabigatrán/efectos adversos , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Tiempo de TrombinaRESUMEN
BACKGROUND: Spray-drying techniques are commonly utilized in the pharmaceutical, dairy, and animal feed industries for processing liquids into powders but have not been applied to human blood products. Spray-dried protein products are known to maintain stability during storage at room temperature. STUDY DESIGN AND METHODS: Plasma units collected at the donor facility were shipped overnight at room temperature to a processing facility where single-use spray drying occurred. After 48 hours' storage at room temperature, the spray-dried plasma product was split in two and rehydrated with 1.5% glycine or deionized water and assayed for chemistry analytes and coagulation factors. Matched fresh-frozen plasma was analyzed in parallel as controls. RESULTS: Reconstitution was achieved for both rehydration groups within 5 minutes (n = 6). There was no significant intergroup difference in recovery for total protein, albumin, immunoglobulin (Ig)G, IgA, and IgM (96% or higher). With the exception of Factor VIII (58%), the recovery of clotting factors in the glycine reconstituted products ranged from 72% to 93%. Glycine reconstitution was superior to deionized water. CONCLUSION: We documented proteins and coagulation activities were recovered in physiologic quantities in reconstituted spray-dried plasma products. Further optimization of the spray-drying method and reconstitution fluid may result in even better recoveries. Spray drying is a promising technique for preparing human plasma that can be easily stored at room temperature, shipped, and reconstituted. Rapid reconstitution of the microparticles results in a novel plasma product from single donors.
Asunto(s)
Donantes de Sangre , Conservación de la Sangre , Plasma , Liofilización , Humanos , TemperaturaRESUMEN
OBJECTIVE: Circulating endothelial cells (CEC), von Willebrand factor (vWF) antigen, P-selectin, and thrombomodulin are released from damaged endothelium, while decreases in circulating endothelial progenitor cells (CEPC) have been associated with poor vascular outcomes. We examined these markers in the peripheral blood of patients with juvenile dermatomyositis (JDM) and their correlations with disease assessments. METHODS: Peripheral blood endothelial cells and biomarkers were assessed in 20 patients with JDM and matched healthy controls. CEC and CEPC were measured by flow cytometry, while vWF antigen and activity, factor VIII, P-selectin, and thrombomodulin were measured in plate-based assays. Disease activity and damage, nailfold capillary density, and brachial artery flow dilation were assessed. Serum cytokines/chemokines were measured by Luminex. RESULTS: CEC, vWF antigen, factor VIII, and thrombomodulin, but not vWF activity, CEPC, or P-selectin, were elevated in the peripheral blood of patients with JDM. CEC correlated with pulmonary activity (rs = 0.56). The vWF antigen correlated with Patient's/Parent's Global, cutaneous, and extramuscular activity (rs = 0.47-0.54). CEPC negatively correlated with muscle activity and physical function (rs = -0.52 to -0.53). CEPC correlated inversely with endocrine damage. The vWF antigen and activity correlated with interleukin 10 and interferon-gamma inducible protein-10 (rs = 0.64-0.82). CONCLUSION: Markers of endothelial injury are increased in patients with JDM and correlate with extramuscular activity. CEPC correlate inversely with muscle activity, suggesting a functional disturbance in repair mechanisms.
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Dermatomiositis , Células Progenitoras Endoteliales , Biomarcadores , Endotelio Vascular , Humanos , Factor de von WillebrandRESUMEN
AIM/BACKGROUND: Research suggests that patient-perceived culturally sensitive health care encompasses multiple components of the health care delivery system including the cultural sensitivity of front desk office staff. Despite this, research on culturally sensitive health care focuses almost exclusively on provider behaviors, attitudes, and knowledge. This is due in part to the paucity of instruments available to assess the cultural sensitivity of front desk office staff. Thus, the objective of the present study is to determine the psychometric properties of the pilot Tucker-Culturally Sensitive Health Care Office Staff Inventory-Patient Form (T-CSHCOSI-PF), which is an instrument designed to enable patients to evaluate the patient-defined cultural sensitivity of their front desk office staff. METHODS: A sample of 1648 adult patients was recruited by staff at 67 health care sites across the United States. These patients anonymously completed the T-CSHCOSI-PF, a demographic data questionnaire, and a patient satisfaction questionnaire. Findings Confirmatory factor analyses of the TCSHCOSI-PF revealed that this inventory has two factors with high internal consistency reliability and validity (Cronbach's αs=0.97 and 0.95). CONCLUSIONS: It is concluded that the T-CSHCOSI-PF is a psychometrically strong and useful inventory for assessing the cultural sensitivity of front desk office staff. This inventory can be used to support culturally sensitive health care research, evaluate the job performance of front desk office staff, and aid in the development of trainings designed to improve the cultural sensitivity of these office staff.
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Competencia Cultural , Personal de Salud/estadística & datos numéricos , Atención Dirigida al Paciente , Adolescente , Adulto , Análisis Factorial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente/estadística & datos numéricos , Relaciones Médico-Paciente , Consultorios Médicos , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Estados Unidos , Adulto JovenRESUMEN
The purpose of this study was to determine the factor structure, internal consistency reliability, and validity of the Tucker Culturally Sensitive Health Care Clinic Environment Inventory-Patient Form (T-CSHCCEI-PF), a novel instrument designed to assess an aspect of health care often ignored in health care quality research: the cultural sensitivity of health care center policies and environment as perceived by adult, racially/ethnically diverse patients. Using ratings on this inventory by a culturally diverse national sample of adult patients (N = 1,639) from 67 health care sites across the United States, a confirmatory factor analysis of the T-CSHCCEI-PF was conducted, and its reliability and validity were determined. The T-CSHCCEI-PF was shown to be a reliable and valid inventory for culturally diverse patients to provide feedback to the administrators at their health care centers regarding the degree to which these centers have characteristics that are reflective of patient-centered culturally sensitive health care.
Asunto(s)
Asistencia Sanitaria Culturalmente Competente , Ambiente de Instituciones de Salud , Atención Dirigida al Paciente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Estados Unidos , Adulto JovenRESUMEN
The purpose of the present study was to test the effects of a culturally sensitive, health empowerment-focused, community-based health promotion program tailored to adult patients with type 2 diabetes on these patients' body mass index (BMI), blood pressure, and self-reported blood glucose levels, treatment adherence, and stress levels. Study participants (N = 130) consisted mostly of African Americans (70%) and Hispanic/Latinos (22.3%) who were divided almost evenly between an intervention group and wait-list control group. The tested health promotion program is informed by Health Self-Empowerment Theory. At post-test, program participants in the intervention group as compared to those in the control group demonstrated significantly lower levels of BMI, diastolic blood pressure, and physical stress. Implications of these study findings for future similar programs and research are discussed.
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Diabetes Mellitus Tipo 2/terapia , Conductas Relacionadas con la Salud , Promoción de la Salud/organización & administración , Adulto , Diabetes Mellitus Tipo 2/etnología , Femenino , Florida , Educación en Salud , Humanos , Masculino , Grupos RacialesRESUMEN
OBJECTIVE: The Tucker-Culturally Sensitive Health Care Provider Inventory - Patient Form (T-CSHCPI-PF) is an inventory for culturally diverse patients to evaluate provider cultural sensitivity in the health care process. The T-CSHCPI-PF is novel in that it assesses provider cultural sensitivity as defined by culturally diverse patients. The purpose of the present study was to determine the factor structure and internal consistency reliability of the T-CSHCPI-PF. METHOD: A sample of 1648 adult patients was recruited by staff at 67 health care sites across the United States. These patients anonymously completed the T-CSHCPI-PF, a demographic data questionnaire, and a patient satisfaction questionnaire. RESULTS: Confirmatory factor analyses of the TCSHCPI-PF revealed that it has three factors with high internal consistency and validity. CONCLUSION: It is concluded that the T-CSHCPI-PF is a psychometrically strong and useful inventory for assessing the cultural sensitivity of health care providers. PRACTICAL IMPLICATIONS: The T-CSHCPI-PF may be a useful inventory for obtaining patients' feedback on their providers' cultural sensitivity and for assessing the effectiveness of trainings to promote patient-centered cultural sensitivity among providers.
Asunto(s)
Competencia Cultural , Diversidad Cultural , Control de Formularios y Registros/normas , Satisfacción del Paciente/estadística & datos numéricos , Atención Dirigida al Paciente , Adolescente , Adulto , Anciano , Análisis Factorial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Relaciones Médico-Paciente , Reproducibilidad de los Resultados , Factores Socioeconómicos , Encuestas y Cuestionarios , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: A high incidence of nontraumatic osteonecrosis has been reported in HIV-infected patients. We investigated the levels of D-dimer and C-reactive protein (CRP) in a cohort of HIV-infected adults with and without osteonecrosis of the femoral head. METHODS: Forty-three HIV-infected patients with osteonecrosis of the femoral head and a comparison group of 50 HIV-infected patients with negative MRI of the hips and for whom serial plasma samples were available were included. D-dimer and CRP levels were measured prior to and at the time of diagnosis for osteonecrosis patients, at the time of negative MRI of the hips for controls, and at least 6 months later for both groups. RESULTS: Biomarker levels were elevated at the time of diagnosis in the osteonecrosis cohort compared with controls. Median D-dimer value was 0.32âµg/ml in the osteonecrosis group compared with less than 0.22âµg/ml in the control group (Pâ=â0.016). For CRP, the corresponding values were 2.52âmg/l and 1.23âmg/l (Pâ=â0.003). Postdiagnosis, D-dimer and CRP levels were also elevated in the osteonecrosis patients compared with controls. Linear regression demonstrated a rise in D-dimer levels from prediagnosis to diagnosis in the osteonecrosis patients whereas CRP levels did not change significantly over time. CONCLUSION: Compared to controls, patients who developed osteonecrosis had elevated levels of D-dimer and CRP at diagnosis. D-dimer levels increased whereas CRP levels did not change significantly from prediagnosis to diagnosis. These data suggest that patients with higher levels of inflammation are at an increased risk of osteonecrosis.
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Proteína C-Reactiva/metabolismo , Necrosis de la Cabeza Femoral/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Seropositividad para VIH/metabolismo , Inflamación/metabolismo , Adulto , Anciano , Biomarcadores/metabolismo , Recuento de Linfocito CD4 , Femenino , Necrosis de la Cabeza Femoral/inmunología , Necrosis de la Cabeza Femoral/fisiopatología , Seropositividad para VIH/inmunología , Seropositividad para VIH/fisiopatología , Humanos , Incidencia , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Resultado del Tratamiento , Carga ViralRESUMEN
Intraclot tissue plasminogen activator (tPA) has been shown to be an effective treatment for deep vein thrombosis (DVT) (Radiology 2008;246:619 and J Vasc Interv Radiol 2011;22:1107). We sought to correlate pharmacokinetics of tPA, fibrinogen, fibrinolytic inhibitors, and D-dimers with the safety and efficacy of intraclot tPA. Thirty subjects received intraclot tPA for lower extremity DVT by infiltrating the thrombus with ≤10 mg doses tPA in an open-label study, using a pulse-spray catheter. We measured various parameters over 8 h following a first dose of tPA. Mean tPA levels of 75 units per mL (95% confidence interval 19-131 units/mL) were seen immediately after administration of a mean tPA dose of 8.0 mg (SD 1.5 mg). tPA levels returned to baseline within 2 h of completion of treatment. Plasminogen activator inhibitor-1 (PAI-1) was consumed following tPA treatment, but rose to levels significantly greater than baseline (P < 0.001). Fibrinogen decreased slightly, but remained >125 mg/dL for all subjects. α2-antiplasmin decreased from a mean of 115 units/mL to 56 units/mL after tPA administration (P < 0.001) and remained decreased for 8 h. Plasminogen at baseline (112 units/mL) decreased to 89 units/mL immediately after tPA administration (P < 0.001) and was unchanged thereafter. D-dimer levels were >20 µg/mL in all but 4 subjects, one of whom was the only one to fail to achieve clot lysis. The safety of low-dose, intraclot tPA is due to its short persistence in the circulation, lack of hypofibrinogenemia, and a reflexive rise of PAI-1. Subjects whose D-dimers remain <20 µg/mL are at risk of not achieving thrombolysis.
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Fibrinolíticos/uso terapéutico , Activador de Tejido Plasminógeno/uso terapéutico , Trombosis de la Vena/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Inhibidor 1 de Activador Plasminogénico/sangre , Activador de Tejido Plasminógeno/administración & dosificación , Activador de Tejido Plasminógeno/sangreRESUMEN
Participants studied sentences describing two different characters and then were told to forget the sentences about only one of the characters. A second list contained sentences attributed to a third character. Subsequently, they received a recall test on the sentences about the original two characters. When the sentences could be thematically integrated, participants showed no directed forgetting relative to a control group that was never told to forget. However, with unrelated sentences, participants selectively forgot the target character's sentences without forgetting the other character's sentences. This selective directed forgetting effect is a novel empirical result. We interpret the results as consistent with Radvansky's (1999) ideas about inhibition with textual materials.
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Aprendizaje por Asociación/fisiología , Atención/fisiología , Formación de Concepto/fisiología , Trastornos de la Memoria/fisiopatología , Recuerdo Mental/fisiología , Análisis de Varianza , Señales (Psicología) , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Reconocimiento Visual de Modelos , Psicolingüística , Tiempo de Reacción/fisiología , VocabularioRESUMEN
OBJECTIVE: To determine the effects of interleukin (IL)-2 treatment on inflammatory and thrombotic biomarkers in chronically HIV-infected adults receiving antiretroviral therapy. METHODS: Cryopreserved plasma was evaluated retrospectively for C-reactive protein (CRP) and D-dimer at baseline, end of an IL-2 cycle, and long-term follow up from two randomized, controlled trials: 57 IL-2-naive adults receiving either three to six cycles of IL-2 as well as antiretroviral therapy (nucleoside analogues) or antiretroviral therapy alone for 12 months, and 40 IL-2-experienced adults on highly active antiretroviral therapy who either interrupted or continued therapy for 6 months after a baseline IL-2 cycle. High-sensitivity CRP (hsCRP) was measured by immunonephelometry (detection limit 0.175 mg/l) and D-dimer by latex agglutination (detection limit 0.20 mg/l). Median within-group differences and pre and post-IL-2 changes between groups were assessed via nonparametric Wilcoxon signed-rank and Mann-Whitney U-tests. Spearman's rank test was used to assess correlations between changes in hsCRP, D-dimer, and HIV-RNA viral load. RESULTS: Significant increases in hsCRP (study 1: 138.6 mg/l; study 2: 58.9 mg/l) and D-dimer (study 1: 3.1 mg/l; study 2: 0.4 mg/l, all P < 0.0001) occurred by the end of the initial IL-2 cycle, returning to baseline by the end of study. No correlations were seen between changes in hsCRP or D-dimer and HIV-RNA, CD4 T-cell count, or proliferation (Ki67 expression). No thrombotic or cardiovascular serious adverse events occurred during these study periods. CONCLUSION: IL-2 dosing caused transient increases in plasma hsCRP and D-dimer levels, regardless of HIV-RNA viral load, suggesting the possibility of increased risk for thrombotic events.
Asunto(s)
Proteína C-Reactiva/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Interleucina-2/uso terapéutico , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Biomarcadores/sangre , Recuento de Linfocito CD4 , Esquema de Medicación , Estudios de Seguimiento , Infecciones por VIH/sangre , Infecciones por VIH/virología , VIH-1/genética , Humanos , Mediadores de Inflamación/sangre , Interleucina-2/administración & dosificación , ARN Viral/sangre , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Carga ViralRESUMEN
Selective serotonin reuptake inhibitors (SSRIs) reduce platelet serotonin and are associated with increased gastrointestinal bleeding, an effect that is enhanced when taken with NSAIDs or aspirin. The best method to evaluate hemorrhagic events in patients taking SSRIs has not been determined. Platelet aggregation, which is not widely available, shows SSRI inhibition of platelet function; we tested whether a platelet function analyzer could detect SSRI inhibition of platelet function. Two groups of outpatients with mood disorders were recruited; each patient was taking a stable dose of either an SSRI or bupropion for at least 6 weeks. They were tested using the platelet function analyzer-100 (PFA-100; Dade International Inc, Miami, Fla) concomitantly with platelet aggregation. Fifty-eight patients were analyzed. We detected significant differences between the groups using aggregation methods with arachidonic acid (aggregation, P = 0.00001; release, P = 0.009) and collagen (aggregation, P = 0.016; release, P = 0.006). The PFA-100 did not detect differences between the groups or results outside the reference range. The PFA-100 does not detect the inhibitory effects of SSRIs on platelet function, but it can be used to direct evaluation of bleeding in a patient taking an SSRI. Abnormal PFA-100 results suggest additional evaluation for von Willebrand disease, other platelet inhibitory medications, or underlying intrinsic platelet dysfunction.
Asunto(s)
Plaquetas/efectos de los fármacos , Bupropión/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Anciano , Plaquetas/fisiología , Colágeno/farmacología , Epinefrina/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/efectos de los fármacos , Trombina/farmacologíaRESUMEN
We studied the blood coagulation system of 14 patients with metastatic malignancies before and after they had undergone major surgery. In addition to measuring a battery of coagulation factors, we assessed the function of the system with assays of whole blood thrombin generation. With the exceptions of factor VIII (fVIII), which increased, and fibrinogen and fIX, which did not change, the activities of all the pro- and anticoagulant proteins were significantly lower postoperatively. However, the thrombin generating capacity of the system was relatively preserved. Although the integral of thrombin activity over time was lower after surgery, the mean peak thrombin concentration was unchanged and the time to clot formation was shortened. Similar changes could be reproduced by lowering the concentrations of pro- and anticoagulant factors together in control blood samples. Therefore, simultaneous reductions in pro- and anticoagulant proteins postoperatively worked to maintain the functional integrity of the blood coagulation system.