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BACKGROUND: Discontinuation of antidepressant medication can be difficult due to withdrawal symptoms and relapse risk. Scientific evidence on the questions of who, when, and how to stop antidepressants is limited. In Amsterdam a multidisciplinary outpatient clinic was started to provide advice and guidance. AIM: To substantiate the design of the clinic. Central questions relate to knowing which patients are referred, the background of their request, and their experiences with the outpatient clinic. METHOD: The first 51 patients of the clinic were described on the basis of file research, in addition a survey was conducted into patient experiences. RESULTS: Half of the patients (55%) actually started discontinuation, 39% were advised not to do so (yet). Patients at the clinic had used antidepressants for an average of 10 years, and 76% had previously attempted to stop. 21% had now successfully stopped and 25% were satisfied with a lower dose. One patient relapsed during tapering. CONCLUSION: So far, patients with long-term antidepressant use and multiple quit attempts have been referred. Our experiences are aimed at helping individual patients but can also result in more knowledge about who can stop at what moment, and how this should be done.
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Antidepresivos , Síndrome de Abstinencia a Sustancias , Humanos , Antidepresivos/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Recurrencia , Instituciones de Atención AmbulatoriaRESUMEN
INTRODUCTION: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. METHODS: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. RESULTS: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. CONCLUSION: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Toma de Decisiones Clínicas , Guías de Práctica Clínica como Asunto/normas , Algoritmos , Consenso , Técnica Delphi , Humanos , Países BajosRESUMEN
BACKGROUND: The prevalence of antipsychotic drug use in people with intellectual disability (id) is high and largely off-label for challenging behaviour (cb), while evidence for their efficacy lacks. Side-effects frequently occur. Guidelines recommend appropriate psychotropic drug use by monitoring of effects and side-effects and discontinuing off-label use for cb. However, they are insufficiently adhered to. Discontinuation often fails due to behavioural worsening by largely unknown causes.
AIM: To offer an overview of results of off-label antipsychotic drug discontinuation and determinants for success or failure.
METHOD: Literature search in Medline, embase and Psycinfo.
RESULTS: Prospective open-label studies show that discontinuation in selected populations is possible in 33-40% and in placebo-controlled studies in 55-82%. Challenging behaviours, as measured with a standardized scale, mostly remained similar in those who succeeded as well as in those who failed to discontinue. Health problems, extrapyramidal symptoms, higher antipsychotic drug dosage, more severe cb, autism and male gender in participants, negative emotions towards cb, less knowledge on psychotropic drugs and male gender of support professional were related to less chance of successful discontinuation.
CONCLUSION: To improve results of antipsychotic drug discontinuation, proper diagnostics of underlying causes for cb, involvement of all stakeholders and enhancement of treatment opportunities for psychopathology in people with id are needed. Integrative care and knowledge development of id- and mental health care may be helpful.
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Antipsicóticos , Enfermedades de los Ganglios Basales , Discapacidad Intelectual , Antipsicóticos/uso terapéutico , Humanos , Discapacidad Intelectual/tratamiento farmacológico , Masculino , Estudios Prospectivos , Psicotrópicos/uso terapéuticoRESUMEN
AIM: The ability of patients with poor pudendal nerve function to voluntarily contract their external anal sphincter is limited. However, it is not known whether the condition of the pudendal nerve influences voluntary puborectal muscle contraction. Recently, we described the puborectal continence reflex that maintains faecal continence by involuntary contractions of the puborectal muscle. We aim to investigate whether both voluntary and involuntary contractions of the puborectal muscle are influenced by the condition of the pudendal nerve. METHOD: We retrospectively analysed 129 adult patients who underwent anorectal function tests at the Anorectal Physiology Laboratory. Anal electrosensitivity was used as a measurement of the pudendal nerve function. Voluntary and involuntary contractions of the puborectal muscle were defined as maximum puborectal muscle contractility and maximum pressure at the level of the puborectal muscle during the balloon retention test. RESULTS: Voluntary contraction of the puborectal muscle was significantly decreased in patients with pudendal nerve damage (P = 0.002). Involuntary contractions, however, were not associated with the condition of the pudendal nerve (P = 0.63). Multiple linear regression analysis showed that the condition of the pudendal nerve and patients' sex significantly predicted voluntary contraction but not involuntary contraction. CONCLUSION: Voluntary contractions of the puborectal muscle are significantly decreased in patients with pudendal nerve damage, while involuntary contractions of the puborectal muscle are comparable to those of patients without nerve damage. We conclude that the puborectal continence reflex, which controls involuntary contractions of the puborectal muscle, is not regulated by the pudendal nerve.
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Canal Anal/fisiopatología , Incontinencia Fecal/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Nervio Pudendo/fisiopatología , Reflejo Anormal/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Canal Anal/inervación , Defecación/fisiología , Incontinencia Fecal/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Presión , Reflejo , Estudios Retrospectivos , Adulto JovenRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Benzodiazepines are widely consumed in prisons, despite the iatrogenic risks associated with this therapeutic class. A multidisciplinary pharmacotherapy programme was therefore initiated by pharmacists in 2001. The aim of this study was to demonstrate the efficacy of teamwork between psychiatrists and pharmacists in benzodiazepine dose adjustment, with 15 years of hindsight. METHOD: In this retrospective study, daily prescribed benzodiazepine doses were compared between a reference group of patients in prisons in Lyon, France, in 2000, and four groups after psychiatrist-pharmacist teamwork in 2004, 2008, 2012 and 2016. RESULTS AND DISCUSSION: A number of 1249 patients were included. Prescribed doses of benzodiazepine decreased in the intervention groups, to a mean of 29-35 mg diazepam equivalent per day, compared to the control group (42 mg/day) (P < .001). The first 4-year period (2000-2004) demonstrated that monthly meetings and systematic pharmaceutical medication review had an impact on prescribed benzodiazepines, limiting consumed doses. The others (2004-2008, 2008-2012 and 2012-2016) confirmed that physicians' adherence to prescription guidelines and the efficacy of pharmacotherapy programme was maintained, particularly in those inmates taking high doses. WHAT IS NEW AND CONCLUSION: A continuous quality programme conducted by psychiatrists and pharmacists showed positive impact in reducing doses of benzodiazepine prescribed to prisoner patients and contributing to reduce risk of benzodiazepine-related problems.
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Benzodiazepinas/administración & dosificación , Farmacéuticos/organización & administración , Pautas de la Práctica en Medicina/normas , Prisioneros , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Francia , Adhesión a Directriz , Humanos , Masculino , Grupo de Atención al Paciente/organización & administración , Guías de Práctica Clínica como Asunto , Psiquiatría/organización & administración , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity. SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health. RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner. CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in human obesity.
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Tejido Adiposo/metabolismo , Hipotálamo/metabolismo , Obesidad , Proteínas , Proteínas Adaptadoras Transductoras de Señales , Frecuencia de los Genes/genética , Humanos , Metaboloma/genética , Metaboloma/fisiología , Metabolómica , Obesidad/epidemiología , Obesidad/genética , Obesidad/metabolismo , Proteínas/análisis , Proteínas/genética , Proteínas/metabolismoRESUMEN
BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 ± 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 ± 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).
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Pueblo Asiatico , Restricción Calórica , Sistema Cardiovascular/metabolismo , Sobrepeso/sangre , Población Blanca , Tejido Adiposo/metabolismo , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Superficie Corporal , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Hemoglobina Glucada/metabolismo , Humanos , Insulina/sangre , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Estudios Prospectivos , Análisis de la Onda del Pulso , Triglicéridos/sangreRESUMEN
BACKGROUND: Older patients with breast cancer are often not treated in accordance with guidelines. With the emergence of endocrine therapy, omission of surgery can be considered in some patients. The aim of this population-based study was to investigate time trends in surgical treatment between 1995 and 2011, and to evaluate the effects of omitting surgery on overall and relative survival in older patients with resectable breast cancer. METHODS: Patients aged 75 years and older with stage I-III breast cancer diagnosed between 1995 and 2011 were selected from the Netherlands Cancer Registry. Time trends of all treatment modalities were evaluated using linear regression models. Changes in overall survival were calculated by Cox regression. Relative survival was calculated using the Ederer II method. RESULTS: Overall, 26 292 patients were included. The proportion of patients receiving surgical treatment decreased significantly, from 90·8 per cent in 1995 to 69·9 per cent in 2011 (P < 0·001). Multivariable analysis showed that overall survival did not change over time (hazard ratio 1·00 (95 per cent confidence interval (c.i.) 0·99 to 1·00) per year); nor did relative survival (relative excess risk 1·00 (0·98 to 1·02) per year). CONCLUSION: Omission of surgery has become more common in older patients with breast cancer during the past 15 years in the Netherlands, but this has not altered overall or relative survival.
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Neoplasias de la Mama/mortalidad , Distribución por Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/cirugía , Femenino , Mortalidad Hospitalaria , Humanos , Países Bajos/epidemiología , Pronóstico , Análisis de SupervivenciaRESUMEN
To identify ways to improve cancer care for older patients, we set out to examine how older patients in the Netherlands are currently being evaluated prior to oncological treatment and to explore the potential obstacles in the incorporation of a geriatric evaluation, using a web-based survey sent to Dutch medical oncology specialists and oncology nursing specialists. The response rate was 34% (183 out of 544). Two-thirds of respondents reported that a geriatric evaluation was being used, although primarily on an ad hoc basis only. Most respondents expressed a desire for a routine evaluation or more intensive collaboration with the geriatrician and 86% of respondents who were not using a geriatric evaluation expressed their interest to do so. The most important obstacles were a lack of time or personnel and insufficient availability of a geriatrician to perform the assessment. Thus, over 30% of oncology professionals in the Netherlands express an interest in geriatric oncology. Important obstacles to a routine implementation of a geriatric evaluation are a lack of time, or insufficient availability of geriatricians; this could be overcome with policies that acknowledge that quality cancer care for older patients requires the investment of time and personnel.
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Atención a la Salud/normas , Evaluación Geriátrica/métodos , Oncología Médica/métodos , Neoplasias/terapia , Enfermería Oncológica/normas , Especialización , Adulto , Anciano , Actitud del Personal de Salud , Competencia Clínica , Conducta Cooperativa , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/enfermería , Países Bajos , Enfermeras Clínicas/psicología , Satisfacción del PacienteRESUMEN
The storage of triglyceride (TG) droplets in nonadipose tissues is called ectopic fat storage. Ectopic fat is associated with insulin resistance and type 2 diabetes mellitus (T2DM). Not the triglycerides per se but the accumulation of intermediates of lipid metabolism in organs, such as the liver, skeletal muscle, and heart seem to disrupt metabolic processes and impair organ function. We describe the mechanisms of ectopic fat depositions in the liver, skeletal muscle, and in and around the heart and the consequences for each organs function. In addition, we systematically reviewed the literature for the effects of diet-induced weight loss and exercise on ectopic fat depositions.
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OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures and thiazolidinediones (TZDs) increase this risk. TZDs stimulate the expression of sclerostin, a negative regulator of bone formation, in vitro. Abnormal sclerostin production may, therefore, be involved in the pathogenesis of increased bone fragility in patients with T2DM treated with TZDs. METHODS: We measured serum sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in 71 men with T2DM treated with either pioglitazone (PIO) (30 mg once daily) or metformin (MET) (1000 mg twice daily). Baseline values of sclerostin and P1NP were compared with those of 30 healthy male controls. RESULTS: Compared with healthy controls, patients with T2DM had significantly higher serum sclerostin levels (59.9 vs 45.2 pg/ml, P<0.001) but similar serum P1NP levels (33.6 vs 36.0 ng /ml, P=0.39). After 24 weeks of treatment, serum sclerostin levels increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P=0.018). Changes in serum sclerostin were significantly correlated with changes in serum CTX in all patients (r=0.36, P=0.002) and in PIO-treated patients (r=0.39, P=0.020), but not in MET-treated patients (r=0.17, P=0.31). CONCLUSIONS: Men with T2DM have higher serum sclerostin levels than healthy controls, and these levels further increase after treatment with PIO, which is also associated with increased serum CTX. These findings suggest that increased sclerostin production may be involved in the pathogenesis of increased skeletal fragility in patients with T2DM in general and may specifically contribute to the detrimental effect of TZDs on bone.
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Biomarcadores/sangre , Proteínas Morfogenéticas Óseas/sangre , Remodelación Ósea/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Metformina/farmacología , Tiazolidinedionas/farmacología , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Biomarcadores/análisis , Biomarcadores/metabolismo , Proteínas Morfogenéticas Óseas/análisis , Remodelación Ósea/fisiología , Huesos/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Marcadores Genéticos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Masculino , Metformina/administración & dosificación , Metformina/efectos adversos , Persona de Mediana Edad , Pioglitazona , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/efectos adversosRESUMEN
BACKGROUND: Ingestion of high doses of casein hydrolysate stimulates insulin secretion in healthy subjects and patients with type 2 diabetes. The effects of low doses have not been studied. The aim of this study was to assess the effect of lower doses of a casein hydrolysate on the glucose and insulin responses to an oral glucose tolerance test in patients with type 2 diabetes. METHODS: In this randomized, placebo-controlled, double-blind study, thirteen patients with type 2 diabetes (age: 58±1 years) were studied. Glucose, insulin and C-peptide responses were determined after the oral administration of 0 (control), 6 or 12 g protein hydrolysate in combination with 50 g carbohydrate. RESULTS: Twelve grams of casein hydrolysate, but not 6g, elevated insulin levels and decreased glucose levels post-challenge. These changes over time were not large enough to also affect the total area under the curve of glucose and insulin. C-peptide levels did not change after both treatments. CONCLUSION: Ingestion of six grams of casein hydrolysate did not affect glucose or insulin responses. Intake of 12 g of casein hydrolysate has a small positive effect on post-challenge insulin and glucose levels in patients with type 2 diabetes.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/sangre , Glucemia/metabolismo , Péptido C/sangre , Caseínas/administración & dosificación , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Hiperglucemia/diagnóstico , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
CONTEXT: Peroxisome proliferator-activated receptor-gamma agonists are involved in fat cell differentiation. OBJECTIVE: The objective of the study was to investigate the effect of pioglitazone vs. metformin on pericardial fat volume in type 2 diabetic (T2DM) patients. Furthermore, we aimed to assess the relationship between pericardial fat volume, other fat compartments, and myocardial function at baseline and after treatment. DESIGN: This was a prospective, randomized, double-blind, intervention study. SETTING: The study was conducted at a university hospital. PATIENTS: Patients included 78 men with T2DM (aged 56.5 +/- 0.6 yr; glycosylated hemoglobin 7.1 +/- 0.1%) without structural heart disease. INTERVENTION: Patients were randomly assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo during 24 wk. MAIN OUTCOME MEASURES: Pericardial and abdominal fat volumes and myocardial left ventricular function were measured by magnetic resonance imaging and hepatic and myocardial triglyceride content by proton magnetic resonance spectroscopy. RESULTS: Pioglitazone increased pericardial fat volume [30.5 +/- 1.7 ml (baseline) vs. 33.1 +/- 1.8 ml], whereas metformin did not affect pericardial fat volume (29.2 +/- 1.5 ml vs. 29.6 +/- 1.6 ml, between groups P = 0.02). After correction for body mass index and age, only visceral fat volume correlated with pericardial fat volume at baseline (r = 0.55, P < 0.001). The increase in pericardial fat volume induced by pioglitazone was not associated with a decrease in left ventricular diastolic function. CONCLUSION: In T2DM patients, pioglitazone increases pericardial fat volume. This increase in pericardial fat volume did not negatively affect myocardial function after 24 wk. These observations question the notion of an inverse causal relationship between pericardial fat volume and myocardial function.
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Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Diabetes Mellitus Tipo 2/patología , Metformina/farmacología , Pericardio/efectos de los fármacos , Tiazolidinedionas/farmacología , Grasa Abdominal/efectos de los fármacos , Grasa Abdominal/patología , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacos , Pericardio/patología , Pioglitazona , Placebos , Tiazolidinedionas/uso terapéuticoRESUMEN
OBJECTIVE: To determine the extent to which Dutch patients with a history of cardiovascular disease and high cholesterol levels, treated in specialised care, are achieving low-cholesterol targets as defined by national guidelines. DESIGN: Hospital-based cohort study. SETTING: Practices of 41 hospital-based cardiologists and internists in the Netherlands. SUBJECTS: 7377 patients. RESULTS: Forty-one percent of the patients with an indication for secondary cardiovascular prevention by lipid-lowering drug treatment were receiving medication and were achieving cholesterol targets, 42% were receiving lipid-lowering medication but had cholesterol levels above target, 11% were not receiving treatment, and 5% had no recent lipid measurements. CONCLUSION: Compared with previous studies, the SOLID study shows that a relatively large percentage of the Dutch patients under specialised care with a history of cardiovascular disease and an indication for cholesterol-reducing therapy are currently being treated. A considerable proportion of the patients, however, are still not receiving optimal treatment and more than 10% are not being treated at all.
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ABC transporter proteins may protect haematopoietic progenitor cells from chemotherapy-induced toxicity. By using an in vitro colony-forming assay, we found that bone marrow of Mdr1ab, Mrp1, Mdr1ab/Mrp1 knockout (KO) mice was two-, five- to 10- and 25-fold, respectively, more sensitive to vincristine than wild-type mice bone marrow. To study the impact of ABC transporters on in vivo bone marrow sensitivity without the added complication of altered pharmacokinetics, we created chimeras of wild-type mice transplanted with bone marrow from wild-type, Mrp1, Mdr1ab or Mdr1ab/Mrp1 KO donor mice. Following a single bolus injection of vincristine, the chimeras transplanted with wild-type or Mdr1ab KO marrow cells showed no reductions in WBC. A significant reduction was observed in Mrp1 KO chimeras, but the most pronounced effect was observed in mice receiving bone marrow from Mdr1ab/Mrp1 KO mice. A pharmacokinetic analysis in wild-type and KO mice showed that the absence of P-gp reduced the body clearance of vincristine, but that no further reduction occurred when Mrp1 was also absent. However, the tissue accumulation of vincristine in tissues of these Mdr1ab/Mrp1 KO mice was further increased. This study demonstrates that the presence of multiple drug transporters protects the bone marrow, and probably other tissues as well, against chemotherapeutic insults.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos Fitogénicos/toxicidad , Médula Ósea/efectos de los fármacos , Vincristina/toxicidad , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacocinética , Trasplante de Médula Ósea , Masculino , Ratones , Ratones Noqueados , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Reacción en Cadena de la Polimerasa , Distribución Tisular , Quimera por Trasplante , Vincristina/sangre , Vincristina/farmacocinéticaRESUMEN
AIMS: A double-blind randomised study was performed to compare the dose-effect and dose-tolerability relationships between the alpha-glucosidase inhibitor miglitol in doses of 25 mg, 50 mg, 100 mg and 200 mg all t.i.d. vs placebo t.i.d. in patients with Type 2 diabetes mellitus on diet only. METHODS: After a 6-week placebo run-in period 468 patients with a fasting blood glucose > or = 7 mmol/l as well as a HbA1c between 6.1% and 10.4% were randomised for a 24-week treatment period. RESULTS: The results of 465 patients were valid for safety analysis and of 384 patients for the efficacy analysis. In the placebo group the HbA1c level increased by 0.40+/-1.46% as compared with baseline. The decrease in the mean HbA1c values (corrected for differences in baseline values) was significant and dose-dependent for all miglitol groups compared with placebo, being -0.46% (95% CI: -0.91%, -0.01%) in the 25 mg group, -0.45% (95% CI: -0.90%, -0.003%) in the 50 mg group, -0.84% (95% CI: -1.31%, -0.37%) in the 100 mg group and -1.26% (95% CI: -1.76%, -0.76%) in the 200 mg group. Blood glucose levels following a standardised breakfast tolerance test were significantly and dose-dependently lower for all the miglitol doses at 12 and 24 wk of treatment compared to baseline: in comparison with baseline maximum blood glucose increased by 4% with placebo and decreased by 7%, 14%, 24% and 33% with miglitol 25 mg, 50 mg, 100 mg and 200 mg t.i.d. respectively. The same pattern was seen with postprandial maximal serum insulin levels which decreased by 8% under placebo and by 17%, 26%, 25% and 35% with the 25 mg to 200 mg doses of miglitol. The adverse events reported were mainly of gastrointestinal nature, mostly being flatulence, diarrhoea and abdominal pain and the incidence increased with increasing dose. Although the side effects were not serious, they were troublesome, leading to a considerable drop-out rate increasing with dose. CONCLUSIONS: The alpha-glucosidase inhibitor miglitol in Type 2 diabetic patients on diet alone decreases both HbA1c levels and postprandial glucose and insulin levels in a dose-dependent manner. Gastrointestinal side effects also showed dose-dependency. Combination of efficacy and safety results leads to the conclusion that the optimal dose of miglitol will be in the range of 50 to 100 mg t.i.d.
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Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosamina/análogos & derivados , Glucosamina/administración & dosificación , Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes/administración & dosificación , 1-Desoxinojirimicina/análogos & derivados , Anciano , Glucemia/análisis , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Inhibidores Enzimáticos/administración & dosificación , Femenino , Alimentos , Enfermedades Gastrointestinales/inducido químicamente , Glucosamina/efectos adversos , Hemoglobina Glucada/análisis , Humanos , Iminopiranosas , Insulina/sangre , Masculino , Persona de Mediana Edad , PlacebosRESUMEN
Improving the efficiency of feed N utilization by dairy cattle is the most effective means to reduce nutrient losses from dairy farms. The objectives of this study were to quantify the impact of different management strategies on the efficiency of feed N utilization for dairy farms in the Chesapeake Bay Drainage Basin. A confidential mail survey was completed in December 1998 by 454 dairy farmers in PA, MD, VA, WV, and DE. Nitrogen intake, urinary and fecal N, and efficiency of feed N utilization was estimated from survey data and milk analysis for each herd. Average efficiency of feed N utilization for milk production by lactating dairy cows (N in milk/N in feed x 100) was 28.4% (SD = 3.9). On average, farmers fed 6.6% more N than recommended by the National Research Council, resulting in a 16% increase in urinary N and a 2.7% increase in fecal N. Use of monthly milk yield and component testing, administration of bovine somatotropin (bST), and extending photoperiod with artificial light each increased efficiency of feed N utilization by 4.2 to 6.9%, while use of a complete feed decreased efficiency by 5.6%. Increased frequency of ration balancing and more frequent forage nutrient testing were associated with higher milk production, but not increased N utilization efficiency. Feeding protein closer to recommendations and increasing production per cow both contributed to improving efficiency of feed N utilization.
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Fenómenos Fisiológicos Nutricionales de los Animales , Bovinos/fisiología , Industria Lechera/métodos , Nitrógeno/metabolismo , Animales , Dieta , Heces/química , Femenino , Hormona del Crecimiento/administración & dosificación , Lactancia , Nitrógeno/administración & dosificación , Nitrógeno/análisis , Política Nutricional , Necesidades Nutricionales , Fotoperiodo , Estaciones del Año , Urea/análisisRESUMEN
The hypothesis of this field study was that providing farmers with information regarding their herd's milk urea nitrogen (MUN) would result in more accurate feed management and a change in MUN toward target values. All dairy herd bulk tanks (n = 1156) in the Maryland and Virginia Milk Producers' Cooperative were tested for MUN each month for six months ending in May 1999. Farmers (n = 454) who returned a survey were provided with the results of their MUN analysis each month along with interpretive information. Survey results indicated that most (89.5%) dairy farmers did not routinely use MUN prior to participating in the project, but most (88%) extension agents and nutritionists in the region recommended it. The average MUN across all farms in the study increased in the spring, but the increase was 0.52 mg/dl lower for farmers receiving MUN results than for those who did not participate in the program. Farmers who indicated they increased dietary crude protein (CP) due to low MUN started with MUN values that were 3 mg/dl below target but ended with target values. Farmers who indicated that they decreased CP due to high MUN began the project with high MUN but decreased it by 1 mg/dl compared to non-participating farmers. At the end of the project, 30% of farmers responding to a follow-up survey indicated they would use MUN analysis in the future. Providing MUN results and interpretive information to farmers was documented to change feeding practices and subsequent MUN results.