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AIMS: To explore perceptions of useful routine consultations with diabetologists from the perspective of adults with type 1 diabetes, including preferences for discussing psychosocial issues. METHODS: We conducted semi-structured interviews in 2018/2019 with 33 people with type 1 diabetes (age 22-75 years, 20 men and 13 women, median diabetes duration 25 years) recruited from two diabetes clinics in the capital region of Denmark. Interviews were audio recorded, transcribed verbatim and analysed using thematic text condensation. RESULTS: Achieving a useful consultation was perceived as a shared responsibility between people with diabetes and diabetologists. Participants' perspectives of what constitutes a useful consultation and expectations for both consultation and diabetologist varied in relation to perceptions of (1) the interaction between the person with diabetes and diabetologist, including being prepared, being honest, experiencing good rapport and preferring a partnership with the diabetologist or 'keeping it clinical' and (2) the diabetologist's approach to diabetes care, including providing up-to-date knowledge and listening and showing understanding. CONCLUSIONS: Both content and style of diabetes consultations need to be adapted to the individual person with type 1 diabetes. People with diabetes have an important role in expressing their needs and preferences related to both content and style. Diabetologists need to be aware of and attentive to the many individual needs and expectations among people with diabetes, including the desire and need to discuss psychosocial issues. Dialogue tools for preparation and in consultations may enable people with diabetes to voice their needs and expectations and diabetologists to juggle these diversities.
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Diabetes Mellitus Tipo 1/terapia , Relaciones Médico-Paciente , Médicos , Investigación Cualitativa , Derivación y Consulta/organización & administración , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIM: Angiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3-deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d-lactate, reflecting greater methylglyoxal flux. METHODS: We analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs and d-lactate using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA. RESULTS: There was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907-1509) nmol/l vs. irbesartan 300 mg 1053 (820-1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d-lactate levels at either 1 or 2 years. CONCLUSION: Irbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs or d-lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915).
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Albuminuria/tratamiento farmacológico , Desoxiglucosa/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glioxal/sangre , Irbesartán/uso terapéutico , Piruvaldehído/sangre , Albuminuria/sangre , Albuminuria/etiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Biomarcadores/sangre , Cromatografía Liquida , Desoxiglucosa/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Espectrometría de Masas en Tándem , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: To investigate, in a large population in primary care, the relationship between fasting plasma glucose and HbA1c measurements, as well as the clinical implications of anaemia or chronic kidney disease for the interpretation of HbA1c values. METHODS: From a primary care resource, we examined HbA1c and fasting plasma glucose as well as haemoglobin and estimated GFR. We stratified observations by chronic kidney disease stage and anaemia level. The estimation of the mean fasting plasma glucose level from HbA1c alone, and from HbA1c , haemoglobin and estimated GFR, respectively, was evaluated. RESULTS: In 198 346 individuals, the fasting plasma glucose-HbA1c relationship mimicked the regression described in the A1c-Derived Average Glucose (ADAG) study, which was based on average capillary and interstitial glucose. The fasting plasma glucose-HbA1c relationship was unaffected in mild to moderate chronic kidney disease and in mild to moderate anaemia. The correlation changed only in severe hyperglycaemia and concurrent severe anaemia or when estimated GFR was <45 ml/min/1.73m², so that glucose concentration was underestimated by HbA1c in anaemia and overestimated in chronic kidney disease. The prevalence of estimated GFR <30 ml/min/1.73m² was 0.82%, while the prevalence of haemoglobin <81 g/l (5.0 mmol/l) was 0.11%. CONCLUSIONS: The relationship between fasting plasma glucose and HbA1c mimics that of the people with diabetes included in the ADAG study. Mild to moderate anaemia and CKD do not have a significant impact on the interpretation of HbA1c as a marker of retrograde glycaemia. Hence, it seems justified to use HbA1c without adjustment in primary care.
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Anemia/sangre , Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada/análisis , Atención Primaria de Salud , Insuficiencia Renal Crónica/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/complicaciones , Anemia/epidemiología , Glucemia/análisis , Interpretación Estadística de Datos , Bases de Datos como Asunto , Dinamarca/epidemiología , Complicaciones de la Diabetes/sangre , Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Errores Diagnósticos/estadística & datos numéricos , Femenino , Médicos Generales/estadística & datos numéricos , Humanos , Laboratorios/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina/normas , Pautas de la Práctica en Medicina/estadística & datos numéricos , Atención Primaria de Salud/estadística & datos numéricos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Adulto JovenRESUMEN
AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/prevención & control , Nefropatías Diabéticas/orina , Hipoglucemiantes/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Proteoma/análisis , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Proteoma/metabolismo , Proteómica/métodos , Medición de Riesgo , Urinálisis/métodos , Adulto JovenAsunto(s)
Albuminuria/tratamiento farmacológico , Alopurinol/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Fármacos Renales/uso terapéutico , Ácido Úrico/metabolismo , Creatinina/orina , Estudios Cruzados , Método Doble Ciego , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To compare consultation rate for knee osteoarthritis (OA) after meniscus repair, arthroscopic partial meniscectomy (APM), and in general population, respectively. METHOD: We identified patients aged 16-45 years having had meniscus surgery due to traumatic meniscus tear in 1998-2010 in southern Sweden by a healthcare register. Patients were followed from surgery until a diagnosis of knee OA, relocation, death, or December 31st, 2015. We studied the consultation rate for knee OA compared to the general population. RESULTS: We identified 2,487 patients diagnosed with traumatic meniscus tear (mean [SD] age 30.5 [8.6] years); 229 (9.2%) of them had had meniscus repair. The absolute risk of having consulted for knee OA during the study was 17% after APM, 10.0% after meniscus repair, and 2.3% in the general population. Hazard ratio (HR) (95% confidence interval (CI)) for knee OA after repair vs APM was: 0.74 (0.48, 1.15). Excluding cases with OA within 2 years post-surgery, yielded the HR of 0.51 (0.27, 0.96). The consultation rate for knee OA standardized to the general population was then 42 per 10,000 person-years (95% CI 12, 71) in the meniscus repair group, 118 per 10,000 person-years (95% CI 101, 135) after APM, and 20 per 10,000 person-years (95% CI 19.9, 20.1) in the general population. CONCLUSION: The point estimates suggests about 25-50% lower risk of consultation for knee OA after meniscus repair as compared to APM. However, the consultation rate for knee OA after repair was still at least two times higher as compared to the general population.
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Artroscopía/efectos adversos , Meniscectomía/efectos adversos , Osteoartritis de la Rodilla/etiología , Complicaciones Posoperatorias/etiología , Lesiones de Menisco Tibial/cirugía , Adolescente , Adulto , Artroscopía/métodos , Femenino , Estudios de Seguimiento , Humanos , Traumatismos de la Rodilla/cirugía , Masculino , Meniscectomía/métodos , Meniscos Tibiales/cirugía , Persona de Mediana Edad , Osteoartritis de la Rodilla/epidemiología , Complicaciones Posoperatorias/epidemiología , Sistema de Registros , Medición de Riesgo/métodos , Suecia/epidemiología , Adulto JovenRESUMEN
AIMS: To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. METHODS: In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. RESULTS: The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). CONCLUSIONS: The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.
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Albuminuria/prevención & control , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Hipertensión/tratamiento farmacológico , Insuficiencia Renal Crónica/prevención & control , Renina/antagonistas & inhibidores , Anciano , Albuminuria/complicaciones , Albuminuria/epidemiología , Amidas/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biomarcadores/orina , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Estudios de Cohortes , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Fumaratos/uso terapéutico , Humanos , Hipertensión/complicaciones , Hipertensión/orina , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Factores de RiesgoRESUMEN
The contiguity and phase of sequence information are intrinsic to obtain complete understanding of the genome and its relationship to phenotype. We report the fabrication and application of a novel nanochannel design that folds megabase lengths of genomic DNA into a systematic back-and-forth meandering path. Such meandering nanochannels enabled us to visualize the complete 5.7 Mbp (1 mm) stained DNA length of a Schizosaccharomyces pombe chromosome in a single frame of a CCD. We were able to hold the DNA in situ while implementing partial denaturation to obtain a barcode pattern that we could match to a reference map using the Poland-Scheraga model for DNA melting. The facility to compose such long linear lengths of genomic DNA in one field of view enabled us to directly visualize a repeat motif, count the repeat unit number, and chart its location in the genome by reference to unique barcode motifs found at measurable distances from the repeat. Meandering nanochannel dimensions can easily be tailored to human chromosome scales, which would enable the whole genome to be visualized in seconds.
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AIMS: Glucagon-like peptide-1 receptor agonist studies have revealed clinically significant reductions in systolic blood pressure (SBP). The aim was to investigate the time course of the anti-hypertensive effect of liraglutide treatment and potential underlying mechanisms. METHODS: We used an open-label, single-centre trial; 31 participants with Type 2 diabetes and hypertension completed the study. All participants were treated with liraglutide escalated to a maximum dose of 1.8 mg/day for 7 weeks, followed by a 21-day washout period. The primary outcome was a change in 24-h SBP. RESULTS: Twenty-four-h SBP increased by 10 mmHg on day 3 (P = 0.008) and 7 mmHg on day 7 (P = 0.033, 0.6 mg/day). On day 29, (1.8 mg/day), 24-h SBP was 7 mmHg lower compared with baseline (P = 0.11). Following the treatment period (day 49) and after washout (day 70), 24-h BP was equivalent to baseline. In addition, extracellular volume (ECV) was reduced by 2.0 l [95% confidence interval (CI) = 1.0-3.1 l, P < 0.001] and midregional-pro-atrial natriuretic peptide (MR-proANP) was reduced by 20% (95% CI = 12-28%, P < 0.001). Also, urinary albumin excretion declined by 30% (95% CI = 12-44%, P = 0.003), GFR by 11 ml/min/1.73 m(2) (95% CI = 7.2-14.4 ml/min/1.73 m(2) , P < 0.001) and fractional albumin excretion by 29% (95% CI = 3-48%, P = 0.032). CONCLUSIONS: Liraglutide treatment was associated with an initial increase in 24-h SBP, followed by a 7 mmHg reduction after escalation to 1.8 mg/day. This effect subsided after 4 weeks of maximum dose. Reductions in ECV and MR-proANP may explain the anti-hypertensive potential. Liraglutide treatment was associated with reversible reductions in albuminuria and GFR, which has to be confirmed in randomized trials.
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Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipertensión/prevención & control , Riñón/efectos de los fármacos , Liraglutida/farmacología , Liraglutida/uso terapéutico , Adulto , Anciano , Albuminuria/epidemiología , Albuminuria/orina , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Comorbilidad , Diabetes Mellitus Tipo 2/epidemiología , Relación Dosis-Respuesta a Droga , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Incidencia , Riñón/fisiología , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted. METHODS: We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change. RESULTS: Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint. CONCLUSIONS: PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.
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Amidas/uso terapéutico , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Técnicas de Apoyo para la Decisión , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Fumaratos/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Anciano , Algoritmos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS/HYPOTHESIS: Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria. METHODS: We conducted a prospective case-control study. Cases (n = 44) and controls (n = 44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides. RESULTS: The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p = 0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p = 0.002; integrated discrimination index [IDI]: 0.105, p = 0.002). Fragments of collagen and α-2-HS-glycoprotein showed significantly different expression between cases and controls. CONCLUSIONS/INTERPRETATION: Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes.
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Albuminuria/orina , Biomarcadores/orina , Diabetes Mellitus Tipo 2/orina , Péptidos/orina , Anciano , Albuminuria/patología , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteómica/métodosRESUMEN
We study how the orientational correlations of DNA confined to nanochannels depend on the channel diameter D by means of Monte Carlo simulations and a mean-field theory. This theory describes DNA conformations in the experimentally relevant regime where the Flory-de Gennes theory does not apply. We show how local correlations determine the dependence of the end-to-end distance of the DNA molecule upon D. Tapered nanochannels provide the necessary resolution in D to study experimentally how the extension of confined DNA molecules depends upon D. Our experimental and theoretical results are in qualitative agreement.
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Biofisica/métodos , ADN/química , Nanoestructuras/química , Algoritmos , Biopolímeros/química , Simulación por Computador , Iones , Luz , Modelos Estadísticos , Conformación Molecular , Método de Montecarlo , Nanotecnología/métodos , Conformación de Ácido Nucleico , Polímeros/químicaRESUMEN
AIMS: Adding aldosterone receptor blockade to standard renoprotective treatment may provide additional renoprotection in patients with overt nephropathy. We expected an impact of spironolactone in early diabetic nephropathy, and for this hypothesis we studied the effect on markers of glomerular and tubular damage in patients with Type 1 diabetes and persistent microalbuminuria. METHODS: A double-blind, randomized, placebo-controlled crossover study in 21 patients with Type 1 diabetes and microalbuminuria using spironolactone 25 mg or placebo once daily, for 60 days added to standard antihypertensive treatment. After each treatment period, the primary endpoint were evaluated: urinary(u)-albumin excretion/24 hour(h) and secondary endpoints; 24 h blood pressure, glomerular filtration rate (GFR) and markers of tubular damage: urinary liver-type fatty-acid binding protein (LFABP), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1). RESULTS: All patients completed the study. During spironolactone treatment, urinary albumin excretion rate was reduced by 60% (range 21-80%), from 90 mg/24 h to 35 mg/24 h (P=0.01). Blood pressure (24 h) did not change during spironolactone treatment (P>0.2 for all comparisons). The GFR (SD) decreased from 78 (6) mL/min/1.73 m(2) to 72 (6) mL/min/1.73 m(2) (P=0.003). Urinary liver-type fatty-acid binding protein, neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 did not change during treatment (P>0.3 for all comparisons). Treatment was well-tolerated, but two patients had severe hyperkalaemia (plasma potassium = 5.7 mmol/l), which was sufficiently treated with diuretics and dietary intervention. CONCLUSIONS: Spironolactone treatment in addition to standard renoprotective treatment lowers urinary albumin excretion in microalbuminuric patients with Type 1 diabetes, and thus may offer additional renoprotection independent of blood pressure.
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Albuminuria/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Diuréticos/uso terapéutico , Espironolactona/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Albuminuria/orina , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Estudios Cruzados , Diabetes Mellitus Tipo 1/orina , Nefropatías Diabéticas/orina , Método Doble Ciego , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: The optimal antiproteinuric dose of aliskiren is unknown. This study compared the effect of placebo and increasing doses of aliskiren on urinary albumin excretion rate (UAER). METHODS: The trial was a double-blind crossover design. Twenty-six patients with type 2 diabetes mellitus, hypertension and albuminuria were randomised to 2-month treatments with placebo or aliskiren 150 mg, 300 mg or 600 mg once daily, in random order. Primary endpoint was change in UAER; secondary endpoints included changes in 24-h BP, GFR, biomarkers and components of the renin-angiotensin-aldosterone system. RESULTS: Placebo geometric mean UAER was 350 mg/day, mean 24-h BP was 137/81 (SD 12/9) mmHg, GFR was 85 (SD 26) ml min(-1) 1.73 m(-2). Aliskiren 150, 300 and 600 mg daily reduced UAER significantly by 36% (95% CI 17-51), 48% (33-60) and 52% (38-63) respectively (p < 0.001) compared with placebo. UAER reduction during the 600 mg dose was not significantly different from the 300 mg dose. Twenty-four-hour systolic BP was reduced by 4.5, 8.0 and 9.2 mmHg versus placebo, significant for 300 and 600 mg (p < or = 0.001). Twenty-four-hour diastolic BP was reduced by 3.0, 4.1 and 4.4 mmHg, significant versus placebo (p = 0.019, p = 0.001 and p < 0.001). GFR was reduced by 3.0, 5.1 and 6.5 ml min(-1) 1.73 m(-2). hsPRA was reduced by 63%, 70%, and 82% (p < 0.001 for all). Adverse events, most frequently dizziness and fatigue, occurred during all doses. CONCLUSIONS: In patients with type 2 diabetes mellitus, hypertension and albuminuria there is no improved antiproteinuric effect when using 600 mg aliskiren daily compared with the maximal recommended antihypertensive dose of 300 mg. TRIAL REGISTRATION: Clinicaltrials.gov NCT00464776 FUNDING: Novartis Pharma AG.
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Albuminuria/tratamiento farmacológico , Amidas/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fumaratos/administración & dosificación , Hipertensión/tratamiento farmacológico , Adulto , Albuminuria/complicaciones , Amidas/uso terapéutico , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Estudios Cruzados , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Esquema de Medicación , Fumaratos/uso terapéutico , Humanos , Hipertensión/complicaciones , Renina/antagonistas & inhibidoresRESUMEN
AIM: To better define the indications for adrenalectomy for adrenal metastasis we have analysed factors predicting survival in our institutional series. METHODS: A consecutive series of 30 patients undergoing adrenalectomy for metastasis (1996-2007), excluding patients with simultaneous ipsilateral renal cell carcinoma (RCC), was studied. Metastases were regarded as synchronous (<6 mo), or metachronous (>6 mo), depending on the interval after primary surgery. Survival was calculated from time of adrenalectomy and factors influencing survival were identified. RESULTS: The tumour diagnoses were RCC n = 9, malignant melanoma n = 5, non-small-cell lung cancer n = 5, colorectal carcinoma n = 4, foregut carcinoid n = 2, adrenocortical carcinoma, breast cancer, hepatocellular carcinoma, urothelial carcinoma, and liposarcoma (one each); nine adrenal metastases were synchronous and 21 metachronous. Ten patients had undergone previous surgery for extra-adrenal metastases. Out of 30 adrenalectomies 10 were laparoscopic (LAdx) and 20 open (OAdx) procedures without surgical complications. The local recurrence rate was low: LAdx 1/10, OAdx 1/20, and the median survival was 23 months. Independent prognosticators of favourable survival were adrenalectomy for potential cure (p = 0.01), no previous metastasis surgery (p = 0.02), and tumour type (p = 0.043), with better prognosis for patients with adrenal metastasis from colorectal carcinoma and RCC and worse prognosis in non-small-cell lung cancer and malignant melanoma. CONCLUSIONS: Surgery for adrenal metastasis is safe and the indication for this procedure in an individual patient can be supported by several prognostic factors. The survival benefit in patients with adrenalectomy for potential cure indicates a therapeutic value of adrenalectomy in selected patients.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/mortalidad , Neoplasias de las Glándulas Suprarrenales/secundario , Adrenalectomía/mortalidad , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Estimación de Kaplan-Meier , Laparoscopía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
We present measurements of the ac response of a single-electron box (SEB). We apply a radio frequency signal with a frequency larger than the tunneling rate and drive the system out of equilibrium. We observe much more dissipation in the SEB then one would expect from a simple circuit model. We can explain this in terms of a mechanism that we call the Sisyphus resistance. The Sisyphus resistance has a strong gate dependence which can be used for electrometery applications.
Asunto(s)
Conductometría/instrumentación , Modelos Teóricos , Simulación por Computador , Impedancia Eléctrica , Transporte de Electrón , Transferencia de Energía , Dispersión de RadiaciónRESUMEN
We report the observation of photon generation in a microwave cavity with a time-dependent boundary condition. Our system is a microfabricated quarter-wave coplanar waveguide cavity. The electrical length of the cavity is varied by using the tunable inductance of a superconducting quantum interference device. It is measured at a temperature significantly less than the resonance frequency. When the length is modulated at approximately twice the static resonance frequency, spontaneous parametric oscillations of the cavity field are observed. Time-resolved measurements of the dynamical state of the cavity show multiple stable states. The behavior is well described by theory. Our results may be considered a preliminary step towards demonstrating the dynamical Casimir effect.
RESUMEN
AIMS/HYPOTHESIS: The purpose of this study was to evaluate the optimal renoprotective effect of ultrahigh doses of lisinopril, as reflected by short-term changes in urinary albumin excretion rate (UAER), in type 1 diabetic patients with diabetic nephropathy. METHODS: At the Steno Diabetes Center, 49 type 1 diabetic patients with diabetic nephropathy completed this double-masked randomised crossover trial consisting of an initial washout period followed by three treatment periods each lasting 2 months, where all patients received lisinopril 20, 40 and 60 mg once daily in randomised order in addition to slow-release furosemide. Allocation was concealed by sequentially numbered opaque sealed envelopes. UAER, 24 h ambulatory blood pressure (ABP) and estimated GFR were determined at baseline and after each treatment period. RESULTS: All 49 patients completed all three treatment periods. Baseline values were: UAER (geometric mean [95% CI]) 362 (240-545) mg/24 h, 24 h ABP (mean [SD]) 142 (14)/74 (8) mmHg and estimated GFR 75 (29) ml min(-1) 1.73 m(-2). Reductions in UAER from baseline were 63%, 71% and 70%, respectively, with the increasing doses of lisinopril (p < 0.001). Compared with lisinopril 20 mg there was a further reduction in UAER of 23% with lisinopril 40 mg and 19% with 60 mg, p < 0.05. ABP was reduced from baseline by 10/5, 13/7 and 12/7 mmHg (p < 0.001 vs baseline, p < 0.05 for diastolic ABP 20 vs 40 mg, otherwise NS between doses). The difference in UAER between 20 and 40 mg lisinopril was significant after adjustment for changes in ABP (p < 0.01). Two patients were excluded from the study because of an increase in plasma creatinine and one because of high BP; otherwise the study medication was well tolerated with few, mild, dose-independent adverse effects. CONCLUSIONS/INTERPRETATION: Lisinopril 40 mg once daily is generally safe and offers additional reductions in BP and UAER in comparison with the currently recommended dose of 20 mg. Lisinopril 60 mg offers no further beneficial effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT00118976.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Lisinopril/uso terapéutico , Adulto , Albuminuria/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Estudios Cruzados , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/fisiopatología , Angiopatías Diabéticas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Sustancias Protectoras/uso terapéuticoRESUMEN
Inhibition of renin with an active site inhibitor, aliskiren, lowers blood pressure (BP) in diabetic patients. Here, we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/creatinine ratios (UACRs) to check whether aliskiren can decrease proteinuria. After a 4-week washout of previous medications, patients received aliskiren and furosemide daily for 28 days followed by a 4-week withdrawal period. Twenty-four-hour BPs were measured at baseline throughout treatment and withdrawal periods. The UACR was significantly reduced after 2-4 days of treatment with another significant reduction after 28 days. Systolic blood pressure (SBP) was significantly lower after 7 days with no further reduction after 28 days. The BP returned toward baseline 3 days after withdrawal, whereas the UACR was still significantly reduced compared with baseline 12 days after withdrawal. Our study shows that aliskiren reduced 24 h SBP, and this was associated with a reduction in albuminuria in type 2 diabetic patients.