RESUMEN
We are exploring the concept of adaptive multimodality imaging, a form of non-linear optimization where the imaging configuration is automatically adjusted in response to the object. Preliminary studies suggest that substantial improvement in objective, task-based measures of image quality can result. We describe here our work to add motorized adjustment capabilities and a matching CT to our existing FastSPECT II system to form an adaptive small-animal SPECT/CT.
RESUMEN
Yersinia pseudotuberculosis was isolated from mastitis cases in nine dairy cows in Israel. Six cases occurred on one farm (three instances of two cows, 2 months apart) and three cases on one farm each. Seven cows suffered from clinical and two from subclinical mastitis. All but two of the cows were culled. The literature describing cases of bovine mastitis caused by Y. pseudotuberculosis is reviewed and the human public health implications are discussed.
Asunto(s)
Mastitis Bovina/microbiología , Salud Pública , Infecciones por Yersinia pseudotuberculosis/veterinaria , Yersinia pseudotuberculosis/aislamiento & purificación , Animales , Bovinos , Recuento de Colonia Microbiana , Femenino , Contaminación de Alimentos/prevención & control , Microbiología de Alimentos , Humanos , Israel , Mastitis Bovina/epidemiología , Mastitis Bovina/transmisión , Infecciones por Yersinia pseudotuberculosis/epidemiología , Infecciones por Yersinia pseudotuberculosis/microbiología , ZoonosisRESUMEN
AIMS: To examine baseline characteristics of patients recruited into ADOPT, a multinational trial comparing three oral glucose-lowering monotherapies. METHODS: Between April 2000 and June 2002, 4360 patients aged 30-75 years with Type 2 diabetes diagnosed for < 3 years and remaining on diet therapy alone with fasting plasma glucose levels (FPG) between 7.0 and 10.0 mmol/l were enrolled by 488 North American and European centres. Medical histories, anthropometric data and laboratory measurements were determined using common methodologies. RESULTS: The mean (SD) age of the patients was 57 (10) years, body mass index 32.2 (6.4) kg/m(2), HbA(1c) 7.4 (0.9)%; 58% were male, 88% Caucasian and 15% smoked. North American Caucasians (NAC) were younger, more obese, and more insulin resistant than European Caucasians (EUC), but had better pancreatic B-cell function. NAC had lower total, low-density lipoprotein- and high-density liporpotein-cholesterol concentrations with higher triglyceride concentrations and were more often on lipid-lowering treatment. They had lower blood pressure levels but were equally likely to be on antihypertensive treatment. Metabolic syndrome was more frequent and microalbuminuria less frequent in NAC. Within North America, NAC had lower HbA(1c) concentrations than Blacks, Hispanics and Asians despite similar or higher FPG and 30-min postchallenge glucose concentrations. CONCLUSIONS: Caucasian North American and European ADOPT patients differ with respect to adiposity, insulin resistance and metabolic syndrome prevalence. North American Blacks, Hispanics and Asians had lower HbA(1c) concentrations than NAC despite similar or higher glucose concentrations. These phenotypic differences may influence the progression of Type 2 diabetes and the response to initial oral glucose-lowering monotherapy.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gliburida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Tiazolidinedionas/uso terapéutico , Adulto , Distribución por Edad , Anciano , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Europa (Continente)/epidemiología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Resistencia a la Insulina/genética , Masculino , Síndrome Metabólico/genética , Persona de Mediana Edad , América del Norte/epidemiología , Grupos Raciales , Rosiglitazona , Distribución por SexoRESUMEN
AIM: To compare the efficacy, safety and tolerability of adding rosiglitazone (RSG) vs. sulphonylurea (SU) dose escalation in older type 2 diabetes mellitus (T2DM) patients inadequately controlled on SU therapy. METHODS: A total of 227 T2DM patients from 48 centres in the USA and Canada, aged > or =60 years, were randomized to receive RSG (4 mg) or placebo once daily in combination with glipizide 10 mg twice daily for 2 years in a double-blind, parallel-group study. Previous SU monotherapy was (1/4) to (1/2) maximum recommended dose for > or =2 months prior to screening with fasting plasma glucose (FPG) > or =7.0 and < or =13.9 mmol/l. Treatment options were individualized, and escalation of study medication was specifically defined. RESULTS: Disease progression (time to reach confirmed FPG > or =10 mmol/l while on maximum doses of both glipizide and study medication or placebo) was reported in 28.7% of patients uptitrating SU plus placebo compared with only 2.0% taking RSG and SU combination (p < 0.0001). RSG + SU significantly decreased HbA(1c), FPG, insulin resistance, plasma free fatty acids and medical care utilization and improved treatment satisfaction compared with uptitrated SU. CONCLUSIONS: Addition of RSG to SU in older T2DM patients significantly improved glycaemic control and reduced disease progression compared with uptitrated SU alone but without increasing hypoglycaemia. These benefits were associated with increased patient treatment satisfaction and reduced medical care utilization with regards to emergency room visits and length of hospitalization. Early addition of RSG is an effective treatment option for older T2DM patients inadequately controlled on submaximal SU monotherapy.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glipizida/administración & dosificación , Hipoglucemiantes/administración & dosificación , Tiazolidinedionas/uso terapéutico , Factores de Edad , Glucemia/análisis , Colesterol/sangre , Diabetes Mellitus Tipo 2/metabolismo , Progresión de la Enfermedad , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Glipizida/efectos adversos , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , Resistencia a la Insulina , Hígado/enzimología , Masculino , Persona de Mediana Edad , Rosiglitazona , Tiazolidinedionas/efectos adversos , Volumetría , Resultado del Tratamiento , Triglicéridos/sangreRESUMEN
This study examines the effect of rosiglitazone on urinary albumin excretion (UAE) in patients with type II diabetes. Urinary albumin: creatinine ratio (ACR) was measured in a 52-week, open-label, cardiac safety study comparing rosiglitazone and glyburide. Patients were randomised to treatment with rosiglitazone 4 mg b.i.d. or glyburide. ACR was measured at baseline and after 28 and 52 weeks of treatment. Statistically significant reductions from baseline in ACR were observed in both treatment groups at week 28. By week 52, only the rosiglitazone group showed a significant reduction from baseline. Similar results were observed for the overall study population and for the subset of patients with baseline microalbuminuria. For patients with microalbuminuria at baseline, reductions in ACR did not correlate strongly with reductions in glycosylated haemoglobin, or fasting plasma glucose, but showed strong correlation with changes in mean 24-h systolic and diastolic blood pressure for rosiglitazone-treated patients (deltaACR vs deltamean 24-h systolic blood pressure, r=0.875; deltaACR vs deltamean 24-h diastolic blood pressure, r=0.755; P < 0.05 for both). No such correlation was observed for glyburide-treated patients. In conclusion, rosiglitazone treatment was associated with a decrease in urinary albumin excretion. These findings suggest a potential beneficial effect of rosiglitazone in the treatment or prevention of renal and vascular complications of type II diabetes.
Asunto(s)
Albuminuria/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Nefropatías Diabéticas/prevención & control , Hipoglucemiantes/administración & dosificación , Tiazoles/administración & dosificación , Tiazolidinedionas , Administración Oral , Anciano , Diabetes Mellitus Tipo 2/diagnóstico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Valores de Referencia , Rosiglitazona , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
The pharmacokinetics and tolerability of a single 8-mg oral dose of rosiglitazone, an anti-diabetic agent, were compared in 10 long-term haemodialysis patients and 10 healthy volunteers. Haemodialysis patients received rosiglitazone 4 h after haemodialysis (non-dialysis day) and 3 h before haemodialysis (dialysis day). Haemodialysis did not influence rosiglitazone pharmacokinetics, and dialytic clearance was low (0.10 1/h). The mean area under the concentration-time curve (AUC(0-infinity)), the maximum observed plasma concentration (Cmax) and the half-life for rosiglitazone were similar in haemodialysis patients (non-dialysis day) and healthy individuals (2192 +/- 598 ng.h/ml versus 2388 +/- 494 ng.h/ml, 338 +/- 114 ng/ml versus 373 +/- 95 ng/ml, and 3.70 +/- 0.75 h versus 3.81 +/- 0.86 h, respectively). AUC(0-infinity) and Cmax were not markedly influenced by haemodialysis. Rosiglitazone dose adjustments are not warranted in patients with type 2 diabetes with end-stage renal failure on haemodialysis.
Asunto(s)
Hipoglucemiantes/farmacocinética , Fallo Renal Crónico/metabolismo , Tiazoles/farmacocinética , Tiazolidinedionas , Adulto , Anciano , Femenino , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Diálisis Renal , Rosiglitazona , Tiazoles/sangre , Tiazoles/uso terapéuticoRESUMEN
The effect of rosiglitazone (Avandia [BRL 49653C]) on the pharmacokinetics of ethinylestradiol and norethindrone was evaluated after repeat dosing of rosiglitazone with an oral contraceptive (OC; Ortho-Novum 1/35 containing norethindrone 1 mg and ethinylestradiol 0.035 mg) in a randomized, double-blind, placebo-controlled crossover study. Thirty-four healthy female volunteers received oral rosiglitazone (RSG) 8 mg + OC or matched placebo (P) + OC daily on days 1 to 14 of a 28-day OC dosing cycle; the alternate regimen was administered during a second cycle. Ethinylestradiol and norethindrone pharmacokinetics were determined from plasma concentrations on day 14. Lack of pharmacokinetic effect was prospectively defined as 90% CI for the point estimate (PE) of the ratio (RSG + OC):(P + OC) contained within a 20% equivalence range for both ethinylestradiol and norethindrone (analyzed by ANOVA). For RSG + OC and P + OC, respectively, mean ethinylestradiol AUC(0-24) was 1126 and 1208 pg.h/mL (PE: 0.92; 90% CI: 0.88-0.97), and mean norethindrone AUC(0-24) was 178 and 171 ng.h/mL (PE: 1.04; 90% CI: 1.00-1.07). Thus, rosiglitazone had no significant effects on the pharmacokinetics of ethinylestradiol or norethindrone. Coadministration of rosiglitazone with OCs does not induce metabolism of these synthetic sex steroids and is not expected to impair the efficacy of OCs or hormone replacement therapy.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Anticonceptivos Orales Combinados/farmacocinética , Etinilestradiol/farmacocinética , Hipoglucemiantes/farmacología , Noretindrona/farmacocinética , Tiazoles/farmacología , Tiazolidinedionas , Adulto , Anticonceptivos Orales Combinados/farmacología , Anticonceptivos Sintéticos Orales/farmacocinética , Estudios Cruzados , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Método Doble Ciego , Interacciones Farmacológicas , Congéneres del Estradiol/farmacocinética , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Oxidorreductasas N-Desmetilantes/metabolismo , Placebos , Rosiglitazona , Tiazoles/administración & dosificaciónRESUMEN
OBJECTIVES: To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. METHODS: Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. RESULTS: Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-h (23%) reduction in terminal elimination half-life t1/2 (4.9 h versus 3.8 h). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and t1/2 are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. CONCLUSION: Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.
Asunto(s)
Acarbosa/farmacología , Hipoglucemiantes/farmacología , Hipoglucemiantes/farmacocinética , Tiazoles/farmacocinética , Tiazolidinedionas , Adulto , Análisis de Varianza , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , RosiglitazonaRESUMEN
OBJECTIVE: To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy. RESEARCH DESIGN AND METHODS: After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA(1c) > or = 7.5% (8.9 +/- 1.1 to 9.1 +/- 1.3) on twice-daily insulin therapy (total daily dose > or = 30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be down- titrated only for safety reasons. The primary end point was reduction of HbA(1c) from baseline. RESULTS: RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA(1c) of 1.2% (P < 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA(1c) > or = 1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups. CONCLUSIONS: The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Tiazoles/uso terapéutico , Tiazolidinedionas , Adulto , Anciano , Glucemia/efectos de los fármacos , Índice de Masa Corporal , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Etnicidad , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Persona de Mediana Edad , Placebos , Rosiglitazona , Seguridad , Tiazoles/efectos adversos , Triglicéridos/sangre , Estados UnidosRESUMEN
Wegener's Granulomatosis is an autoimmune disease characterized by a rare form of systemic vasculitis which can result in damage to vital organs of the body by restricting blood flow to those organs. It affects various systems of the body including the central nervous system and cranial nerves. To our knowledge, there are no previous described cases of oropharyngeal dysphagia in these patients. This paper describes and discusses a case of oropharyngeal dysphagia in a patient with Wegener's Granulomatosis.
Asunto(s)
Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Granulomatosis con Poliangitis/complicaciones , Anciano , Trastornos de Deglución/fisiopatología , Humanos , Masculino , Orofaringe/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: An estimated 15 million adults in the United States are affected by dysphagia (difficulty swallowing). Severe dysphagia predisposes to medical complications such as aspiration pneumonia, bronchospasm, dehydration, malnutrition, and asphyxia. These can cause death or increased health care costs from increased severity of illness and prolonged length of stay. Existing modalities for treating dysphagia are generally ineffective, and at best it may take weeks to months to show improvement. One common conventional therapy, application of cold stimulus to the base of the anterior faucial arch, has been reported to be somewhat effective. We describe an alternative treatment consisting of transcutaneous electrical stimulation (ES) applied through electrodes placed on the neck. OBJECTIVE: Compare the effectiveness of ES treatment to thermal-tactile stimulation (TS) treatment in patients with dysphagia caused by stroke and assess the safety of the technique. METHODS: In this controlled study, stroke patients with swallowing disorder were alternately assigned to one of the two treatment groups (TS or ES). Entry criteria included a primary diagnosis of stroke and confirmation of swallowing disorder by modified barium swallow (MBS). TS consisted of touching the base of the anterior faucial arch with a metal probe chilled by immersion in ice. ES was administered with a modified hand-held battery-powered electrical stimulator connected to a pair of electrodes positioned on the neck. Daily treatments of TS or ES lasted 1 hour. Swallow function before and after the treatment regimen was scored from 0 (aspirates own saliva) to 6 (normal swallow) based on substances the patients could swallow during a modified barium swallow. Demographic data were compared with the test and Fisher exact test. Swallow scores were compared with the Mann-Whitney U test and Wilcoxon signed-rank test. RESULTS: The treatment groups were of similar age and gender (p > 0.27), co-morbid conditions (p = 0.0044), and initial swallow score (p = 0.74). Both treatment groups showed improvement in swallow score, but the final swallow scores were higher in the ES group (p > 0.0001). In addition, 98% of ES patients showed some improvement, whereas 27% of TS patients remained at initial swallow score and 11% got worse. These results are based on similar numbers of treatments (average of 5.5 for ES and 6.0 for TS, p = 0.36). CONCLUSIONS: ES appears to be a safe and effective treatment for dysphagia due to stroke and results in better swallow function than conventional TS treatment.
Asunto(s)
Trastornos de Deglución/terapia , Terapia por Estimulación Eléctrica , Accidente Cerebrovascular/complicaciones , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Deglución , Trastornos de Deglución/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no ParamétricasRESUMEN
This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A(1c); other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A(1c) relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ss-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Tiazoles/uso terapéutico , Tiazolidinedionas , Anciano , Anciano de 80 o más Años , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Método Doble Ciego , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/fisiopatología , Masculino , Persona de Mediana Edad , Rosiglitazona , Método Simple Ciego , Tiazoles/efectos adversosRESUMEN
Rosiglitazone is a potent oral antidiabetic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator-activated nuclear receptor. It improves insulin sensitivity in peripheral tissues and effectively lowers blood glucose in patients with type 2 diabetes. Metformin is a dimethyl-biguanide, also used in type 2 diabetes, that lowers fasting blood glucose primarily by decreasing hepatic glucose output. Rosiglitazone and metformin reduce plasma glucose concentrations via different mechanisms and thus could potentially be used in combination to optimize glycemic control. This study evaluated the effects of the coadministration of these two agents on the pharmacokinetics of both rosiglitazone and metformin. Sixteen male volunteers (22-55 years old) received oral metformin (500 mg every 12 hours), rosiglitazone (2 mg every 12 hours), or the combination each for 4 days. Plasma collected on day 4 of each regimen was assayed for rosiglitazone and metformin concentrations. Oral doses of rosiglitazone and metformin were safe and well tolerated when administered alone or in combination. There were no clinically significant episodes of hypoglycemia or increased blood lactic acid levels following treatment with any regimen. Coadministration of rosiglitazone and metformin had no significant effects on the steady-state pharmacokinetics (AUC(0-12 h), Cmax, tmax, or t1/2) of either drug. The authors conclude that rosiglitazone can be safely administered with metformin and, due to the different mechanisms of action of these agents, may offer a therapeutic advantage in patients with type 2 diabetes mellitus.
Asunto(s)
Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Tiazoles/farmacocinética , Tiazolidinedionas , Acidosis Láctica/inducido químicamente , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Masculino , Metformina/administración & dosificación , Persona de Mediana Edad , Rosiglitazona , Tiazoles/administración & dosificaciónRESUMEN
OBJECTIVE: Our purpose was to describe the outcome of the Rastelli repair in D -transposition of the great arteries and to determine the risk factors associated with unfavorable events. METHODS: From March 1973 to April 1998, 101 patients with D -transposition of the great arteries and ventricular septal defect underwent a Rastelli type of repair. Median age and weight were 3.1 years (10th to 90th percentiles 0.3-9.9 years) and 12.8 kg (5.9-28.2). Pulmonary stenosis was present in 73 patients and pulmonary atresia in 18; 10 patients had no left ventricular outflow tract obstruction. RESULTS: There were 7 early deaths (7%) and no operative deaths in the last 7 years of the study. Risk factors for early death, by univariable analysis, included straddling tricuspid valve (P =.04) and longer aortic crossclamping times (P =.04). At a median follow-up of 8.5 years, there were 17 late deaths and 1 patient had undergone heart transplantation. Forty-four patients had reoperations for conduit stenosis, 11 for left ventricular outflow tract obstruction, and 28 had interventional catheterization to relieve conduit stenosis. Nine patients had late arrhythmias, and there were 5 sudden deaths. Overall freedom from death or transplantation (Kaplan-Meier) was 82%, 80%, 68%, and 52% at 5, 10, 15, and 20 years, respectively. Freedom from death or reintervention (catheterization or surgical treatment) was 53%, 24%, and 21% at 5, 10, and 15 years of follow-up, respectively. CONCLUSIONS: The Rastelli repair can be performed with low early mortality. However, substantial late morbidity and mortality are associated with conduit obstruction, left ventricular outflow tract obstruction, and arrhythmia.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Transposición de los Grandes Vasos/cirugía , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Lactante , Modelos Logísticos , Masculino , Complicaciones Posoperatorias/epidemiología , Modelos de Riesgos Proporcionales , Reoperación , Factores de Riesgo , Estadísticas no Paramétricas , Análisis de Supervivencia , Transposición de los Grandes Vasos/complicaciones , Resultado del TratamientoRESUMEN
To determine the rate and statistics of light-evoked transmitter release from bipolar synapses, intracellular recordings were made from ON-alpha ganglion cells in the periphery of the intact, superfused, cat retina. Sodium channels were blocked with tetrodotoxin to prevent action potentials. A light bar covering the receptive field center excited the bipolar cells that contact the alpha cell and evoked a transient then a sustained depolarization. The sustained depolarization was quantified as change in mean voltage (Deltav), and the increase in voltage noise that accompanied it was quantified as change in voltage variance (Deltasigma(2)). As light intensity increased, Deltav and Deltasigma(2) both increased, but their ratio held constant. This behavior is consistent with Poisson arrival of transmitter quanta at the ganglion cell. The response component attributable to glutamate quanta from bipolar synapses was isolated by application of 6-cyano-7-nitroquinoxaline (CNQX). As CNQX concentration increased, the signal/noise ratio of this response component (Deltav(CNQX)/Deltasigma(CNQX)) held constant. This is also consistent with Poisson arrival and justified the application of fluctuation analysis. Two different methods of fluctuation analysis applied to Deltav(CNQX) and Deltasigma(CNQX) produced similar results, leading to an estimate that a just-maximal sustained response was caused by approximately 3,700 quanta s(-1). The transient response was caused by a rate that was no more than 10-fold greater. Because the ON-alpha cell at this retinal locus has approximately 2,200 bipolar synapses, one synapse released approximately 1.7 quanta s(-1) for the sustained response and no more than 17 quanta s(-1) for the transient. Consequently, within the ganglion cell's integration interval, here calculated to be approximately 16 ms, a bipolar synapse rarely releases more than one quantum. Thus for just-maximal sustained and transient depolarizations, the conductance modulated by a single bipolar cell synapse is limited to the quantal conductance ( approximately 100 pS at its peak). This helps preserve linear summation of quanta. The Deltav/Deltasigma(2) ratio remained constant even as the ganglion cell's response saturated, which suggested that even at the peak of sensory input, summation remains linear, and that saturation occurs before the bipolar synapse.
Asunto(s)
Potenciales Evocados Visuales/fisiología , Células Ganglionares de la Retina/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/fisiología , Aminobutiratos/farmacología , Animales , Gatos , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Glicinérgicos/farmacología , Técnicas In Vitro , Modelos Neurológicos , Estimulación Luminosa , Distribución de Poisson , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Tetrodotoxina/farmacologíaRESUMEN
The cone signal reaches the cat's On-beta (X) ganglion cell via several parallel circuits (bipolar cell types b1, b2, and b3). These circuits might convey different regions of the cone's temporal bandwidth. To test this, I presented a step of light that elicited a transient depolarization followed by a sustained depolarization. The contribution of bipolar cells to these response components was isolated by blocking action potentials with tetrodotoxin and by blocking inhibitory synaptic potentials with bicuculline and strychnine. Stationary fluctuation analysis of the sustained depolarization gave the rate of quantal bombardment: approximately 5100 quanta sec(-1) for small central cells and approximately 45,000 quanta sec(-1) for large peripheral cells. Normalizing these rates for the vastly different numbers of bipolar synapses (150-370 per small cell vs 2000 per large cell), quantal rate was constant across the retina, approximately 22 quanta synapse(-1) sec(-1). Nonstationary fluctuation analysis gave the mean quantal EPSP amplitude: approximately 240 microV for the transient depolarization and 30 microV for the sustained depolarization. The b1 bipolar cell is known from noise analysis of the On-alpha ganglion cell to have a near-maximal sustained release of only approximately two quanta synapse(-1) sec(-1). This implies that the other bipolar types (b2 and b3) contribute many more quanta to the sustained depolarization (>/=46 synapse(-1) sec(-1)). Type b1 probably contributes large quanta to the transient depolarization. Thus, bipolar cell types b1 and b2/b3 apparently constitute parallel circuits that convey, respectively, high and low frequencies.
Asunto(s)
Células Fotorreceptoras Retinianas Conos/fisiología , Células Ganglionares de la Retina/fisiología , Vías Visuales/fisiología , Algoritmos , Animales , Gatos , Dendritas/fisiología , Electrofisiología , Potenciales Postsinápticos Excitadores/fisiología , Glutamatos/fisiología , Microelectrodos , Estimulación Luminosa , Distribución de Poisson , Teoría Cuántica , Sinapsis/fisiología , Vías Visuales/citologíaRESUMEN
AIMS/HYPOTHESIS: The short-term efficacy, safety and tolerability of rosiglitazone were compared with placebo in patients with Type II (non-insulin-dependent) diabetes mellitus in a dose-ranging study. METHODS: After a 2-week placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone. RESULTS: All rosiglitazone doses significantly reduced fasting plasma glucose compared with baseline. All rosiglitazone treatment groups showed significantly reduced peak postprandial glucose concentrations compared with baseline (p < 0.001) and with placebo (p < 0.0001) and reduced postprandial glucose excursion, without an increase in the area under the postprandial insulin concentration-time curve. Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA1c observed in the placebo group. C peptide and serum insulin concentrations were significantly reduced from baseline in all rosiglitazone treatment groups. In all rosiglitazone treatment groups, nonesterified fatty acids decreased significantly (p < 0.0001) and triglycerides did not change. Although total LDL and HDL cholesterol increased significantly in the rosiglitazone treatment groups, total cholesterol/HDL ratios did not change significantly. The proportion of patients with one or more adverse event was similar in all four treatment groups. No patient showed evidence of hepatotoxicity. CONCLUSION/INTERPRETATION: Rosiglitazone given twice daily significantly reduced fasting and postprandial glucose concentrations, C peptide, insulin and nonesterified fatty acids in Type II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice daily should be the maximum clinical dose.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ingestión de Alimentos/fisiología , Ayuno/sangre , Hipoglucemiantes/administración & dosificación , Tiazoles/administración & dosificación , Tiazolidinedionas , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Fructosamina/sangre , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Lípidos/sangre , Masculino , Persona de Mediana Edad , Rosiglitazona , Tiazoles/efectos adversos , Tiazoles/uso terapéutico , Factores de TiempoRESUMEN
BACKGROUND: Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration. METHODS: One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration. RESULTS: The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.
Asunto(s)
Medios de Contraste/envenenamiento , Angiografía Coronaria , Antagonistas de los Receptores de Endotelina , Indanos/uso terapéutico , Enfermedades Renales/inducido químicamente , Fallo Renal Crónico/diagnóstico por imagen , Anciano , Creatinina/sangre , Femenino , Humanos , Hipotensión/inducido químicamente , Inyecciones Intravenosas , Enfermedades Renales/prevención & control , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Cloruro de Sodio/uso terapéutico , Factores de TiempoRESUMEN
Rosiglitazone is a potent insulin-sensitizing oral hypoglycemic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) nuclear receptor and improves glycemic control in patients with non-insulin-dependent diabetes mellitus. The potential for a drug-drug interaction with oral digoxin was investigated. Subjects received both of the study regimens in a random sequence: digoxin 0.375 mg plus matching placebo for rosiglitazone orally each morning for 14 days or digoxin 0.375 mg plus 8 mg rosiglitazone orally each morning for 14 days. There was a 14-day washout period between sessions. Blood and urine were collected over 24 hours beginning on the morning of day 14 for measurement of digoxin concentrations. An equivalence statistical approach was used, with rosiglitazone considered to have no effect on the pharmacokinetics of digoxin if the 90% confidence interval (CI) for the ratio of digoxin plus rosiglitazone relative to digoxin plus placebo was completely contained within the range (0.80, 1.25) for the primary end points, AUC(0-24), and C24. Digoxin AUC(0-24) and C24 values were similar for digoxin 0.375 mg plus matching placebo (18.5 ng.h/mL and 0.579 ng/mL, respectively) and digoxin 0.375 mg plus rosiglitazone (19.1 ng.h/mL and 0.594 ng/mL, respectively). Point estimates were 1.05 (90% CI: 1.01, 1.10) for AUC(0-24) and 1.04 (90% CI: 0.98, 1.11) for C24. Oral and renal clearance were also similar between regimens. Digoxin alone or in combination with rosiglitazone was safe and well tolerated. The most common adverse experience was headache. Coadministration of digoxin with rosiglitazone had no significant effect on the safety or steady-state pharmacokinetics of digoxin.