RESUMEN
INTRODUCTION: Therapeutic goals have been described to monitor achievement, maintenance and continuity of therapeutic response in patients with type 1 Gaucher disease receiving enzyme replacement therapy. AIM: To benchmark the impact of velaglucerase alfa treatment against therapeutic goals for 5 key clinical parameters of type 1 Gaucher disease (anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology). METHODS: In an open-label Phase I/II study, twelve adults with symptomatic type 1 Gaucher disease and intact spleens received velaglucerase alfa for 9 months (60 U/kg infusion every other week [EOW]). Eleven patients completed the study and 10 enrolled in a long-term extension. After 1 year, patients who achieved ≥ 2 hematological or organ goals began step-wise dose reduction from 60 to 45 then 30 U/kg EOW. Data for anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology at baseline and 4 years are available for 8 patients (3 male, 5 female). The proportion of patients at goal for anemia, thrombocytopenia, hepatomegaly and splenomegaly at baseline was compared with the proportion achieving each goal at 4 years. The proportion achieving the skeletal pathology goal was determined on the basis of Z-score improvement from baseline to 4 years. The proportion of patients who achieved all 5 goals at 4 years was compared with the proportion at goal for all 5 parameters at baseline. RESULTS: At baseline, no patient was at goal for all clinical parameters. After 1 year of treatment, all patients maintained goals present at baseline, and all achieved ≥ 2 goals. All 8 patients began step-wise dose reduction from 60 to 30 U/kg EOW between 15 and 18 months. By year 4 of treatment, all patients met goals for all 5 clinical parameters; therefore 100% achievement was seen for each of the 5 long-term, therapeutic goals. DISCUSSION: In this velaglucerase alfa Phase I/II and extension study, clinically meaningful achievement of each long-term, therapeutic goal was observed for each patient, despite dose reduction after 1 year. This is the first report of a cohort where all patients receiving ERT for type 1 Gaucher disease achieved all 5 of these long-term, therapeutic goals within 4 years of starting treatment and after ≥ 2years dose reduction.
Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Enfermedad de Gaucher/patología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Automatisms are commonly seen in epilepsy, either ictally or postictally. However, most automatisms are simple, with hand movements, mouth smacking, nose-rubbing, repetition of a single word, or coughing, grunting, or screeching. Complex automatisms are less common and striking. The authors report two cases of seizure-associated singing where song expression may be recognizable.
Asunto(s)
Automatismo/etiología , Epilepsia Parcial Compleja/fisiopatología , Epilepsia Generalizada/fisiopatología , Música , Adulto , Automatismo/fisiopatología , Electroencefalografía , Epilepsia Parcial Compleja/diagnóstico , Epilepsia Generalizada/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , VozRESUMEN
Dyslipidemia is a major risk factor for coronary heart disease (CHD). While some uncertainty exists about the clinical significance of improving high-density lipoprotein cholesterol and triglyceride levels, large primary- and secondary-prevention studies aimed at lowering low-density lipoprotein cholesterol levels with statins have convincingly reduced CHD events and total mortality. Despite the strong clinical evidence and widely publicized treatment guidelines, many hyperlipidemic patients receive inadequate lipid-lowering treatment. This failure to achieve clinical treatment goals may be due to poor physician adherence to treatment guidelines, patient noncompliance, and the presence of concomitant medical conditions that modify typical hyperlipidemia management. This review considers the challenges and available strategies to optimize lipid management in patients at risk for CHD.
Asunto(s)
Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Adulto , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad Coronaria/sangre , Enfermedad Coronaria/complicaciones , Angiopatías Diabéticas/tratamiento farmacológico , Femenino , Adhesión a Directriz , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/complicaciones , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Posmenopausia , Guías de Práctica Clínica como Asunto , Factores de Riesgo , Triglicéridos/sangreRESUMEN
A case of atrial fibrillation with asystole was diagnosed as ventricular fibrillation because of the autogain feature of the electrocardiographic monitor. Direct current shock therapy was withheld only because the patient regained consciousness.
Asunto(s)
Fibrilación Atrial/complicaciones , Electrocardiografía Ambulatoria , Paro Cardíaco/complicaciones , Fibrilación Ventricular/diagnóstico , Anciano , Fibrilación Atrial/diagnóstico , Errores Diagnósticos , Electrocardiografía , Paro Cardíaco/diagnóstico , Humanos , MasculinoRESUMEN
Insulin resistance, and the compensatory hyperinsulinemia that results, has been linked to a host of defects including glucose intolerance, diabetes, hypertension, dyslipidemia, endothelial dysfunction, impaired fibrinolysis, and subclinical inflammation. Patients with this metabolic syndrome have a markedly increased risk for the development of atherothrombotic cardiovascular disease. The characteristic dyslipidemia of insulin resistance consists of elevated triglyceride and triglyceride-rich lipoprotein levels, low levels of high-density lipoprotein cholesterol, and increased concentrations of small, dense low-density lipoprotein cholesterol. Management of this dyslipidemia typically involves a dual approach. Lifestyle modification is an essential component of any successful treatment plan, but alone is usually insufficient to correct these lipoprotein abnormalities. Medications that diminish insulin resistance and directly alter lipoproteins are also necessary in the majority of cases. Combinations of therapeutic agents are often required to optimize attainment of treatment goals.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Hiperlipidemias/fisiopatología , Hiperlipidemias/terapia , Resistencia a la Insulina , Enfermedades Cardiovasculares/epidemiología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Lactonas/uso terapéutico , Estilo de Vida , Lipasa/antagonistas & inhibidores , Metformina/uso terapéutico , Niacina/uso terapéutico , Orlistat , Factores de RiesgoRESUMEN
A case is presented of an exceptionally good death after discontinuation of dialysis, and the authors trace the evolution of their attempts at measuring quality of dying in patients with end-stage renal disease. The Dialysis Quality of Dying Apgar is based on the pediatric tool for measuring the condition of newborn babies. Previous research with termination of dialysis has revealed that staff, patients, and families characterize a good death as being pain-free, peaceful, and brief. The quality of dying tool has corresponding domains to which it adds advance care planning and non-pain symptoms. Quantification of patient deaths combined with descriptive narratives can be used to establish benchmarks for the provision of terminal care. Very good deaths need to be recognized and valued as goals for palliative medicine.
Asunto(s)
Estado de Salud , Fallo Renal Crónico/psicología , Fallo Renal Crónico/terapia , Calidad de la Atención de Salud , Calidad de Vida , Cuidado Terminal/normas , Directivas Anticipadas , Anciano , Actitud Frente a la Muerte , Actitud Frente a la Salud , Toma de Decisiones , Familia/psicología , Resultado Fatal , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Dolor/diagnóstico , Dolor/etiología , Dimensión del Dolor , Diálisis Peritoneal , Factores de TiempoRESUMEN
We developed a rapid, non-invasive, and inexpensive, assay capable of identifying BRCA1 and BRCA2 (BRCA) mutations in buccal cells. To determine the predictive value of this immunoassay, a double blind study of 13 high risk individuals was conducted by two independent teams. As greater than 90% of BRCA mutations result in protein truncations, a diminished anti-carboxy immunoreactivity relative to anti-amino immunoreactivity was scored as predictive for mutation. Comparison to BRCA DNA analysis was undertaken. The positive and negative predictive values were 90% and 100% respectively (p<0.02), suggesting great promise as an inexpensive and rapid screen for BRCA mutations.
Asunto(s)
Genes BRCA1/genética , Pruebas Genéticas/métodos , Inmunoensayo/métodos , Mucosa Bucal/química , Mutación/genética , Proteínas de Neoplasias/genética , Factores de Transcripción/genética , Proteína BRCA1/análisis , Proteína BRCA1/genética , Proteína BRCA2 , Mejilla , ADN/análisis , ADN/genética , Análisis Mutacional de ADN , Método Doble Ciego , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Mucosa Bucal/citología , Proteínas de Neoplasias/análisis , Polimorfismo Conformacional Retorcido-Simple , Valor Predictivo de las Pruebas , Factores de Riesgo , Sensibilidad y Especificidad , Factores de Transcripción/análisisRESUMEN
The recent publication of the Atorvastatin Versus Revascularization Treatment (AVERT) trial has renewed debate on the optimal management strategy for relatively stable patients with coronary artery disease. Currently, coronary angiography and percutaneous coronary intervention are often performed in stable patients with good exercise tolerance who have not been treated with proven medications such as aspirin, statins and beta-adrenergic blocking agents in conjunction with comprehensive lifestyle modification. We review the results of prior trials comparing medical therapy with angioplasty and assess their strengths and limitations and then make conclusions about the aggregate data. Next, we describe the ongoing Clinical Outcome Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, which will be the largest of the studies comparing optimal medical therapy and percutaneous revascularization. This study will employ intensive medical management in all patients with coronary disease, and the incremental benefit of state of the art revascularization techniques in terms of clinical event reduction, quality of life issues and cost-effectiveness will be addressed. For now, aggressive medical therapy and revascularization should be viewed as complementary rather than opposing strategies. All patients with coronary heart disease should receive proven medical and lifestyle prescriptions to favorably alter the atherosclerotic process. Percutaneous revascularization without comprehensive risk factor modification is a suboptimal therapeutic strategy.
Asunto(s)
Angioplastia Coronaria con Balón , Enfermedad Coronaria/terapia , Anticolesterolemiantes/uso terapéutico , Atorvastatina , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/cirugía , Ácidos Heptanoicos/uso terapéutico , Humanos , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/cirugía , Isquemia Miocárdica/terapia , Revascularización Miocárdica , Pirroles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
We describe a newborn boy one of triplets, whose karyotype was 46,XY, t(8;12)(q22;q21). Prenatal diagnosis of multiple craniofacial anomalies had been made. Following delivery, the patient was thought to exhibit findings consistent with a diagnosis of frontofacionasal dysostosis. We hypothesize that one of the break points of this translocation may involve a gene essential to craniofacial development.
Asunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 8/genética , Anomalías Craneofaciales/genética , Disostosis/genética , Translocación Genética/genética , Humanos , Lactante , Recién Nacido , Cariotipificación , Masculino , Fenotipo , Síndrome , TrillizosRESUMEN
Previously we demonstrated that protein coded by the BRCA1 gene was expressed in normal human buccal cells. The present study confirmed that BRCA2 protein was similarly expressed in these cells. Messenger RNA for BRCA2 was detected with sequential use of two primer sets. Pooled cell samples from healthy donors reacted strongly with two commercially available antibodies, I17 and C15. Immunoreactivity was present in both cytoplasmic and nuclear compartments. We conclude buccal cells will provide a suitable model for exploration of normal BRCA function.
Asunto(s)
Mucosa Bucal/metabolismo , Proteínas de Neoplasias/biosíntesis , Factores de Transcripción/biosíntesis , Adulto , Proteína BRCA1/inmunología , Proteína BRCA1/metabolismo , Proteína BRCA2 , Mejilla , ADN Complementario/genética , ADN Complementario/metabolismo , Femenino , Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Inmunohistoquímica , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genética , Factores de Transcripción/inmunologíaRESUMEN
To determine whether immunohistochemistry can identify BRCA1 mutations, immunohistochemical (IH) analysis was undertaken on paraffin sections of paired ovarian cancer and normal tissue using antibodies against both terminal regions of the BRCA1 protein. Ten patients at risk for BRCA1 mutations were studied. The results of BRCA1 mutation analysis and IH were compared. In tumor, IH correctly identified the presence or absence of loss of heterozygosity in all specimens. In all uninvolved specimens, IH correctly identified the presence or absence of a germline mutation. The sensitivity, specificity, positive and negative predictive values were 100% suggesting promise as a rapid and inexpensive screen.
Asunto(s)
Anticuerpos , Proteína BRCA1/inmunología , Genes BRCA1/genética , Mutación de Línea Germinal , Inmunohistoquímica/métodos , Neoplasias Ováricas/genética , Fragmentos de Péptidos/inmunología , Adulto , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Análisis Mutacional de ADN , Femenino , Humanos , Neoplasias Ováricas/patología , Ovario/metabolismo , Ovario/fisiología , Adhesión en Parafina , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
An increased fetal nuchal translucency detected by first trimester ultrasound has been associated with an elevated risk of aneuploidy. The etiology of the increased nuchal translucency in fetuses with normal chromosomes is uncertain, but it has been associated with poor pregnancy outcome. We report a fetus with increased nuchal translucency and a normal karyotype, in which parvovirus was detected by polymerase chain reaction in the amniotic fluid. Although an ultrasound detected an increased nuchal fold thickness in the second trimester, the pregnancy was otherwise uncomplicated. Parvovirus should be considered as a possible etiology of increased nuchal translucency. The risks to a fetus with first trimester parvovirus infections diagnosed under these conditions are uncertain and require larger studies.
Asunto(s)
Cuello/diagnóstico por imagen , Infecciones por Parvoviridae/diagnóstico por imagen , Parvovirus , Ultrasonografía Prenatal , Adulto , Líquido Amniótico/virología , Femenino , Humanos , Parvovirus/aislamiento & purificación , Embarazo , Resultado del Embarazo , Primer Trimestre del Embarazo , Segundo Trimestre del EmbarazoAsunto(s)
Países en Desarrollo , Oftalmología , Extracción de Catarata , Educación de Postgrado en Medicina , Instituciones de Salud , Humanos , Lentes Intraoculares , Microcirugia , Procedimientos Quirúrgicos Oftalmológicos , Oftalmología/educación , Oftalmología/instrumentación , Resultado del TratamientoRESUMEN
The human breast epithelial cell line, MCF-10A, derived from tissue from a woman undergoing a cutaneous mastectomy for fibrocystic breast disease, is negative for estrogen receptor expression, has undergone minimal genetic changes, retains many of the characteristics of normal breast epithelium and fails to exhibit growth in nude mice. When transfected with a functional copy of the estrogen receptor, both ER and MDM2 expression are negatively regulated by the presence of increasing concentrations of estradiol, as previously reported. We obtained the MCF-10A cell line from the American Type Culture Collection and confirmed that it was negative for ER expression. After approximately 20 passages under differing growth conditions, one subline was determined to be positive for ER expression. Growth of this ER-positive subline in phenol red-free media supplemented with charcoal-dextran stripped serum in the presence of nanomolar concentrations of estradiol failed to modulate ER and MDM2 expression, and induced expression of both pS2 and cathepsin D. Simultaneously with these observations, we observed that this subline, unlike the parent MCF-10A line, overexpressed P53 protein with a nuclear localization. Intermediate levels of the P53-inducible protein p21 WAF1/Cip1 were also detected in the ER-positive subline whereas levels of this protein in the parent subline were barely detectable, as measured by immunohistochemical methods. We conclude from these studies that ER expression and P53 alteration may constitute early steps in progression of malignant potential for breast cancer development.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas Nucleares , Receptores de Estrógenos/biosíntesis , Neoplasias de la Mama/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Epitelio/patología , Epitelio/ultraestructura , Estradiol/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas c-mdm2 , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
OBJECTIVE: To evaluate the utility of the prenatal three-generation pedigree in assessment of the obstetric patient's primary medical risks. STUDY DESIGN: In a case series, 250 charts of patients referred for amniocentesis on the basis of advanced maternal age were reviewed for a significant genetic risk of a primary care disorder. RESULTS: A total of 40 patients (16%) were at significantly increased risk for a primary care disorder. Thirty-eight patients (15.2%) were at increased risk for medical conditions for which early screening, detection and/or intervention are established. CONCLUSION: For the advanced maternal age population, formal genetic risk assessment performed prior to amniocentesis can be beneficial in primary care risk assessment.
Asunto(s)
Asesoramiento Genético , Obstetricia , Atención Primaria de Salud , Adulto , Femenino , Humanos , Edad Materna , Registros Médicos , Linaje , Embarazo , Embarazo de Alto Riesgo , Medición de RiesgoRESUMEN
Prenatal diagnosis and clinical follow up of a patient with mosaicism for anomalies of chromosome 18 are reported. The fetus appeared on ultrasound to have multiple anomalies, including clubbed feet, abnormal hand positioning, edema of the scalp, cleft palate, and polyhydramnios. The karyotype on amniocytes was 47,XY,+i(18p). Postnatally, the peripheral blood karyotype was 46,XY,+i(18q), whereas the skin fibroblast karyotype was 47,XY,+i(18p). The infant had many features consistent with those previously described in cases of tetrasomy 18p and some that were consistent with trisomy 18q.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas/diagnóstico , Cromosomas Humanos Par 18 , Mosaicismo/diagnóstico , Diagnóstico Prenatal , Trisomía/diagnóstico , Anomalías Múltiples/diagnóstico , Adulto , Amniocentesis , Trastornos de los Cromosomas , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Cariotipificación , Masculino , Embarazo , Ultrasonografía PrenatalRESUMEN
A 43-year-old woman with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in acute phase received high-dose chemotherapy followed by transfusion of 12 randomly selected units of umbilical cord blood. HLA analysis showed cells of one donor from day +10 to day +43 post-transfusion. This unit was HLA class II identical with that of the patient.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Femenino , Sangre Fetal/citología , Trasplante de Tejido Fetal , Supervivencia de Injerto , Prueba de Histocompatibilidad , Humanos , Trasplante HomólogoRESUMEN
While tumor suppressor properties of BRCA1 are well documented, less is understood concerning the normal function of this protein in healthy adult tissues. We demonstrate here that BRCA1 protein is expressed in human buccal cells. Expression of BRCA1 mRNA transcripts in buccal cells was confirmed by PCR of reverse transcribed RNA. Three BRCA1 antibodies, D20, MS110 and MS13, reacted positively with cytospin deposited buccal cells, demonstrating apparent cytoplasmic and nuclear distribution of BRCA1 protein. Double antibody immunofluorescent, binding of D20 and MS110 was differentially distributed. We conclude that buccal cells provide a cell source for exploration of BRCA1 protein function in normal human adults.