RESUMEN
Memory and cognitive decline are the product of numerous physiological changes within the aging brain. Multiple theories have focused on the oxidative, calcium, cholinergic, vascular, and inflammation hypotheses of brain aging, with recent evidence suggesting that reductions in insulin signaling may also contribute. Specifically, a reduction in insulin receptor density and mRNA levels has been implicated, however, overcoming these changes remains a challenge. While increasing insulin receptor occupation has been successful in offsetting cognitive decline, alternative molecular approaches should be considered as they could bypass the need for brain insulin delivery. Moreover, this approach may be favorable to test the impact of continued insulin receptor signaling on neuronal function. Here we used hippocampal cultures infected with lentivirus with or without IRß, a constitutively active, truncated form of the human insulin receptor, to characterize the impact continued insulin receptor signaling on voltage-gated calcium channels. Infected cultures were harvested between DIV 13 and 17 (48 h after infection) for Western blot analysis on pAKT and AKT. These results were complemented with whole-cell patch-clamp recordings of individual pyramidal neurons starting 96 h post-infection. Results indicate that while a significant increase in neuronal pAKT/AKT ratio was seen at the time point tested, effects on voltage-gated calcium channels were not detected. These results suggest that there is a significant difference between constitutively active insulin receptors and the actions of insulin on an intact receptor, highlighting potential alternate mechanisms of neuronal insulin resistance and mode of activation.
Asunto(s)
Canales de Calcio/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Receptor de Insulina/biosíntesis , Animales , Células Cultivadas , Expresión Génica , Humanos , Ratas , Ratas Sprague-Dawley , Receptor de Insulina/genéticaRESUMEN
Major surgery in persons with haemophilia A and inhibitors is increasingly being performed. Both recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC) are used to cover surgery but it remains unclear what the optimal dosing schedules are. We describe the use of a hybrid regimen in four inhibitor patients undergoing eight major surgical procedures using rFVIIa in the initial 2-6 postoperative days followed by FEIBA for the remaining period. All patients were also treated with tranexamic acid while receiving rFVIIa. We performed six major orthopaedic procedures, one emergency orchidectomy and one open appendectomy. The dosing schedules were at the higher end of those described in the literature but within the recommendations of the summary of product characteristics. Despite this, we encountered non-surgical bleeding in four of eight episodes. Three of these occurred in one individual suggesting a patient factor. The overall outcome was good for all episodes. The hybrid regimen combines flexibility of dose and dosing frequency of rFVIIa in the immediate postoperative setting with the advantage of a reduced dosing frequency with FEIBA in the subsequent days. This study also emphasizes that surgical procedures in this patient group remain a challenge.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Factores de Coagulación Sanguínea/inmunología , Factores de Coagulación Sanguínea/uso terapéutico , Factor VIIa/inmunología , Factor VIIa/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemofilia A/cirugía , Adulto , Apendicectomía , Quimioterapia Combinada , Hemofilia A/inmunología , Humanos , Masculino , Persona de Mediana Edad , Orquiectomía , Periodo Posoperatorio , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéuticoRESUMEN
INTRODUCTION: An isolated prolongation to the activated partial thromboplastin time (APTT) can be caused by the presence of the lupus anticoagulant or an intrinsic or contact factor deficiency, of which only deficiencies of factors VIII, IX or XI are associated with bleeding. Our local protocol states that further investigation of a prolonged APTT by specific assays of FVIII, FIX and FXI should only be undertaken where the APTT with one reagent (Synthasil) is more than 3 s prolonged, and further investigation by an APTT with a second reagent (Actin FS) is also prolonged, unless there is a history of bleeding in the patient, in which case assays are indicated irrespective of the APTT. METHODS: We retrospectively reviewed the results of all APTTs performed over a 36-month period to evaluate whether strictly applying our protocol would reduce the number of unnecessary clotting factor assays performed, without leaving patients with potentially significant bleeding disorders undiagnosed. RESULTS: Of a total number of 587 samples tested for coagulation factors VIII, IX and XI, only 117 samples yielded an abnormal result. Thus, 80% of all the assays requested in the 3-year period audited gave a result within the reference range for factors VIII, FIX and XI. Three quarters of the abnormal results revealed mild FXI deficiency. CONCLUSION: This review has demonstrated that no significant coagulation factor deficiency would be left undiagnosed if the protocol was followed. This would have considerably reduced the cost and time spent performing these assays.
Asunto(s)
Actinas , Tiempo de Tromboplastina Parcial , Actinas/sangre , Algoritmos , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/diagnóstico , Factores de Coagulación Sanguínea , HumanosRESUMEN
Haemoperitoneum secondary to ruptured corpus luteum is a rare complication for women on anticoagulants and with certain congenital bleeding disorders. A surgical approach is often taken, leading to oophorectomy in many cases. We describe three patients presenting with haemoperitoneum in association with factor VII deficiency, factor X deficiency and sitosterolaemia. In two of the patients, recurrent episodes occurred prior to introduction of the oral contraceptive pill. Conservative management with blood product and factor concentrate support was successful in avoiding surgery in three of the five episodes of bleeding. These cases demonstrate that preservation of ovarian function is possible with a conservative approach and recurrent episodes may be prevented by suppression of ovulation.
Asunto(s)
Trastornos de la Coagulación Sanguínea/complicaciones , Anticonceptivos Hormonales Orales/uso terapéutico , Hemoperitoneo/prevención & control , Ovulación/efectos de los fármacos , Adulto , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Cuerpo Lúteo/lesiones , Deficiencia del Factor VII/complicaciones , Deficiencia del Factor X/complicaciones , Femenino , Hemoperitoneo/tratamiento farmacológico , Hemoperitoneo/etiología , Humanos , Rotura Espontánea , Sitoesteroles/sangreRESUMEN
This eighth best practice review examines four series of common primary care questions in laboratory medicine: (i) sodium abnormalities; (ii) faecal occult blood testing; (iii) warfarin management; and (iv) sputum cytology in diagnosis of bronchopulmonary malignancy. The review is presented in question-answer format, referenced for each question series. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus rather than evidence-based. They will be updated periodically to take account of new information.
Asunto(s)
Anticoagulantes/administración & dosificación , Sangre Oculta , Patología Clínica/métodos , Atención Primaria de Salud/métodos , Sodio/sangre , Monitoreo de Drogas/métodos , Medicina Basada en la Evidencia , Humanos , Hipernatremia/diagnóstico , Hiponatremia/diagnóstico , Neoplasias Pulmonares/diagnóstico , Esputo/citologíaAsunto(s)
Enfermedades de la Conjuntiva/etiología , Hemorragia del Ojo/etiología , Facoemulsificación , Hemorragia Posoperatoria/etiología , Trombastenia/complicaciones , Anciano , Enfermedades de la Conjuntiva/terapia , Hemorragia del Ojo/terapia , Femenino , Humanos , Hemorragia Posoperatoria/terapiaRESUMEN
We describe a case in which an elderly woman is hospitalised for acute medical illness and ask how this patient's risk of venous thromboembolism should be assessed and managed. Venous thromboembolism was previously regarded as a surgical problem, but occurs at least as frequently among medical patients. The risk of venous thromboembolism varies, but recent studies have provided detailed data on the risk in patients with acute medical illness, in particular those patients with acute heart failure, respiratory failure and acute infectious disease. As the evidence has accumulated, specific guidelines recommend provision of thromboprophylaxis to patients at risk. An approach to venous thromboembolic risk assessment and prevention in acutely ill medical patients is presented.
Asunto(s)
Anticoagulantes/uso terapéutico , Enoxaparina/uso terapéutico , Tromboembolia/prevención & control , Trombosis de la Vena/prevención & control , Enfermedad Aguda , Anciano , Gasto Cardíaco Bajo/terapia , Femenino , Hospitalización , Humanos , Infecciones/terapia , Enfermedad Pulmonar Obstructiva Crónica/terapia , Factores de RiesgoAsunto(s)
Riñón/anomalías , Vena Cava Inferior/anomalías , Trombosis de la Vena/complicaciones , Adolescente , Femenino , Humanos , Riñón/diagnóstico por imagen , Síndrome , Tomografía Computarizada por Rayos X , Vena Cava Inferior/diagnóstico por imagen , Trombosis de la Vena/diagnóstico por imagenRESUMEN
BACKGROUND: Glycoprotein (GP) VI plays a crucial role in platelet activation and aggregation. We investigated whether polymorphic variation at the GP VI locus confers an increased risk of myocardial infarction (MI). METHODS AND RESULTS: Coding and 5' and 3' non-coding regions of the GP VI gene were analyzed by polymerase chain reaction and conformation sensitive gel electrophoresis in 21 healthy subjects. Ten dimorphisms, 5 of which predicted amino acid substitutions (T13254C, A19871G, A21908G, A22630T, C22644A), were identified. Two core haplotypes involving 7 dimorphisms (C10781A and G10873A and all those predicting amino acid substitutions) were apparent. The contribution of the T13254C dimorphism, which predicted the substitution of serine 219 by proline, to risk of MI was assessed in 525 patients with acute MI and 474 controls, all aged <75 years. The allelic odds ratio (OR) for MI associated with the 13254C allele was 1.16 (95% CI, 0.91 to 1.46; P=0.23). Compared with corresponding control subgroups, the 13254CC genotype was more common among cases who were female (OR, 4.52; 95% CI, 1.23 to 16.64; P=0.029), nonsmokers (OR, 2.50; 95% CI, 0.98 to 6.38; P=0.048), aged >/=60 years (OR, 6.48; 95% CI, 1.47 to 28.45; P=0.009) or carried the beta-fibrinogen -148T allele associated with increased fibrinogen levels (OR, 10.49; 95% CI, 1.32 to 83.42; P=0.02). In logistic regression analysis that took other cardiovascular risk factors into account, the interactions of GP VI genotype with age (P=0.005) and beta-fibrinogen genotype (P=0.035) remained significant. CONCLUSIONS: The GP VI 13254CC genotype increases the risk of MI, particularly in older individuals, and the interaction of the GP VI 13254C allele with other candidate risk alleles may accentuate this risk.
Asunto(s)
Infarto del Miocardio/genética , Glicoproteínas de Membrana Plaquetaria/genética , Anciano , Alelos , Sustitución de Aminoácidos , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Glicoproteínas de Membrana Plaquetaria/análisis , Polimorfismo Genético , Factores de Riesgo , Análisis de Secuencia de ADNAsunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Factor VIIa/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemorragia Posoperatoria/tratamiento farmacológico , Abdomen , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/inmunología , Transfusión Sanguínea , Femenino , Hematoma/cirugía , Hemofilia A/complicaciones , Hemofilia A/inmunología , Humanos , Enfermedades Renales/cirugía , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Hemorragia Posoperatoria/etiología , Tiempo de Protrombina , Proteínas Recombinantes/uso terapéutico , Insuficiencia del TratamientoRESUMEN
There is a recognized association between von Willebrand's disease and gastrointestinal angiodysplasia. Most previous publications have been reports of the association itself and there is little published on the management and long-term follow-up of affected patients. We report our experience and follow-up of six patients, and review the previous literature.
Asunto(s)
Angiodisplasia/terapia , Enfermedades Gastrointestinales/terapia , Enfermedades de von Willebrand/complicaciones , Adulto , Anciano , Anemia Ferropénica/etiología , Angiodisplasia/complicaciones , Angiodisplasia/diagnóstico , Angiografía , Transfusión Sanguínea , Colectomía , Colonoscopía , Sistema Digestivo/irrigación sanguínea , Femenino , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/diagnóstico , Hemorragia Gastrointestinal/etiología , Hemostáticos/uso terapéutico , Humanos , Hierro/uso terapéutico , Masculino , Enfermedades de von Willebrand/diagnósticoRESUMEN
Venous thromboembolism remains an important cause of morbidity and mortality for surgical and non-surgical patients, and its pathophysiology in acutely ill, non-surgical patients is not well understood. The clinically silent nature of thromboembolism makes it a significant threat to hospital patients.
Asunto(s)
Tromboembolia/etiología , Trombosis de la Vena/etiología , Muerte Súbita/etiología , Femenino , Humanos , Complicaciones Intraoperatorias/etiología , Neoplasias/complicaciones , Embarazo , Complicaciones Cardiovasculares del Embarazo/etiología , Factores de Riesgo , Tromboembolia/mortalidad , Trombosis de la Vena/mortalidad , Heridas y Lesiones/complicacionesRESUMEN
Prothrombin complex concentrates (PCCs) and, more recently, activated prothrombin complex concentrates (APCCs), are widely used for the treatment of active bleeding in haemophiliacs with inhibitors. Myocardial infarction (MI), associated with the use of these concentrates, is a well-recognized, but uncommon, complication. We review the 14 previous cases published in the literature and describe two additional patients. MI related to the use of activated and non-activated PCCs predominantly affects young patients who often have no preceding history of, or risk factors for, MI and tends to be associated with large cumulative doses of concentrate. The most frequent pathological finding is myocardial haemorrhage, with no evidence of coronary artery atheroma or thrombosis. The management of further bleeding in these patients is difficult. We have safely used recombinant factor VIIa to treat bleeding in the immediate and long-term period following PCC-related MI.
Asunto(s)
Factores de Coagulación Sanguínea/efectos adversos , Factor VIIa/uso terapéutico , Hemartrosis/tratamiento farmacológico , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Infarto del Miocardio/etiología , Abdomen , Adulto , Anciano , Inhibidores de Factor de Coagulación Sanguínea/sangre , Factores de Coagulación Sanguínea/uso terapéutico , Factor VIII , Hematoma/tratamiento farmacológico , Hemofilia A/sangre , Humanos , Articulación de la Rodilla , Masculino , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéuticoRESUMEN
Recent clinical studies have confirmed that acutely ill medical patients are at substantial risk of venous thromboembolism, which can be reduced by thromboprophylaxis with low molecular weight heparin. These studies have resulted in approval of a low molecular weight heparin (enoxaparin) for the prophylaxis of venous thromboembolism in medical patients bedridden as a result of acute illness.
Asunto(s)
Anticoagulantes/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Tromboembolia/prevención & control , Enfermedad Aguda , Humanos , Factores de RiesgoRESUMEN
Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1. 5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons with PROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency. (Blood. 2000;95:1935-1941)
Asunto(s)
Deficiencia de Proteína S/genética , Trombosis de la Vena/genética , Adulto , Factores de Edad , Alelos , Anticoagulantes/farmacología , Southern Blotting , Exones , Factor V/genética , Femenino , Haplotipos , Humanos , Intrones , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Fenotipo , Mutación Puntual , Deficiencia de Proteína S/complicaciones , Protrombina/genética , Factores de Riesgo , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/etiología , Warfarina/farmacologíaRESUMEN
OBJECTIVES: To compare a new low-dose warfarin induction regimen with the Fennerty regimen in elderly inpatients. DESIGN: Age-stratified, randomized prospective study. SUBJECTS: 120 age-stratified elderly inpatients. INTERVENTIONS: Each patient was randomized to either the new induction regimen or to a modified Fennerty regimen. MAIN OUTCOMES MEASURES: Days to therapeutic International Normalized Ratio (INR >2); days in the therapeutic range (INR 2-3) during induction; number of patients with INR >4.5; ability of day 4 INR to predict day 8 warfarin dose. RESULTS: The mean time to therapeutic INR was longer for the new induction regimen than modified Fennerty regimen in patients aged 65-75 years [4.6 (mean) +/- 1.6 (SD) days vs 3.8 +/- 0.8 days; P = 0.03] and in patients aged >75 years (4.5 +/- 1.4 days vs 3.5 +/- 0.7 days; P = 0.003). Patients spent more time in the therapeutic INR range with the new induction regimen [3.0 +/- 1.3 days vs 2.7 +/- 1.3 days (P = 0.03) for those aged 65-75 years and 2.9 +/- 1.1 days vs 2.4 +/- 1.3 days (P = 0.04 for those aged >75 years]. Fewer patients using the new regimen had INRs >4.5 in the first 8 days [1 (3%) vs 6 (20%) for 65-75 years (P < 0.05) and 1 (3%) vs 11 (37%) for >75 years (P < 0.01)]. The ability to predict the maintenance dose to within 1 mg was 55% for both regimens. CONCLUSION: The low-dose regimen has important clinical advantages over the Fennerty regimen for anticoagulating elderly inpatients.
Asunto(s)
Anticoagulantes/administración & dosificación , Tromboembolia/tratamiento farmacológico , Warfarina/administración & dosificación , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Hemorragia/inducido químicamente , Humanos , Relación Normalizada Internacional , Estudios Prospectivos , Factores de Riesgo , Tromboembolia/etiología , Warfarina/efectos adversosRESUMEN
The prothrombin gene mutation, 20210A, a guanine to adenine substitution at nucleotide position 20210, has recently been described as an additional risk factor for venous thromboembolic disease. We describe the case of a patient with combined heterozygous prothrombin 20210A mutation and type 1 protein C deficiency who presented with massive mesenteric venous infarction of his small bowel and survived following the use of protein C concentrate and extensive small bowel resection.