RESUMEN
BACKGROUND: Early identification of patients with chronic kidney disease (CKD) and advancing kidney insufficiency, followed by specialist care, can decelerate the progression of the disease. However, awareness of the importance and possible consequences of kidney insufficiency is low among doctors and patients. Since kidney insufficiency can be asymptomatic even in higher stages, it is often not even known to those belonging to risk groups. This study aims to clarify whether, for hospitalised patients with advanced chronic kidney disease, a risk-based appointment with a nephrology specialist reduces disease progression. METHODS: The target population of the study is hospitalised CKD patients with an increased risk of end-stage renal disease (ESRD), more specifically with an ESRD risk of at least 9% in the next 5 years. This risk is estimated by the internationally validated Kidney Failure Risk Equation (KFRE). The intervention consists of a specific appointment with a nephrology specialist after the hospital stay, while control patients are discharged from the hospital as usual. Eight medical centres include participants according to a stepped-wedge design, with randomised sequential centre-wise crossover from recruiting patients into the control group to recruitment to the intervention. The estimated glomerular filtration rate (eGFR) is measured for each patient during the hospital stay and after 12 months within the regular care by the general practitioner. The difference in the change of the eGFR over this period is compared between the intervention and control groups and considered the primary endpoint. DISCUSSION: This study is designed to evaluate the effect of risk-based appointments with nephrology specialists for hospitalised CKD patients with an increased risk of end-stage renal disease. If the intervention is proven to be beneficial, it may be implemented in routine care. Limitations will be examined and discussed. The evaluation will include further endpoints such as non-guideline-compliant medication, economic considerations and interviews with contributing physicians to assess the acceptance and feasibility of the intervention. TRIAL REGISTRATION: German Clinical Trials Register DRKS00029691 . Registered on 12 September 2022.
Asunto(s)
Progresión de la Enfermedad , Tasa de Filtración Glomerular , Fallo Renal Crónico , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal , Insuficiencia Renal Crónica , Humanos , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/diagnóstico , Fallo Renal Crónico/terapia , Factores de Riesgo , Hospitalización , Medición de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Citas y HorariosRESUMEN
OBJECTIVE: The insulin tolerance test (ITT) is regarded as the gold standard for the evaluation of pituitary ACTH and growth hormone reserve. However, the intended critical hypoglycemia results in considerable discomfort and requires close surveillance during the test. DESIGN AND METHODS: In a pilot study, we evaluated whether the ITT could be markedly simplified, made less hazardous and more convenient by routine i.v. low-dose glucose administration after hypoglycemia has been achieved. Sixteen healthy subjects (three females, 13 males) were tested twice in a randomized, single-blinded fashion, receiving 0.15 IU insulin/kg body weight as an i.v. bolus. After hypoglycemia (serum glucose less than 2.2 mmol/l) had been achieved, 500 ml isotonic saline (protocol A (A)), or 500 ml 5% glucose solution (protocol B (B)) were infused over 30 min. RESULTS: Compared with saline, glucose infusion shortened the period of hypoglycemia from 31 + 14 to 17 + 6 min (P < 0.01). In addition, prolonged duration of hypoglycemia (>45 min) was reduced (6 subjects in protocol A vs none in protocol B). Despite shorter duration of hypoglycemia, all subjects had adequate stimulated cortisol (>500 nmol/l) and hGH (>5 microg/l) levels. Mean peak concentrations of plasma ACTH (24 +/- 12 pmol/l (A) vs 21 +/- 8 pmol/l (B)), serum cortisol (690 +/- 83 nmol/l vs 634 +/- 83 nmol/l) and serum hGH (26 +/- 16 microg/l vs 22 +/- 13 microg/l) were slightly, but not significantly lower. In contrast, glucose infusion significantly reduced peak plasma epinephrine levels at 45 min (4.96 +/- 4.91 pmol/l (A) vs 1.53 +/- 1.1 pmol/l (B), P < 0.05) and ameliorated discomfort, as evaluated by a visual analog scale (P < 0.05). CONCLUSIONS: Taken together, our pilot study suggests that, while the duration of hypoglycemia is shortened and acute epinephrine response is reduced, low-dose infusion of glucose does not significantly alter peak cortisol and growth hormone responses during ITT. Studies with a larger number of subjects and patients with suspected hypopituitarism are needed to further evaluate this modified protocol.
Asunto(s)
Glucosa/administración & dosificación , Hipoglucemia/tratamiento farmacológico , Hipoglucemia/fisiopatología , Hipoglucemiantes , Insulina , Hormona Adrenocorticotrópica/sangre , Adulto , Relación Dosis-Respuesta a Droga , Epinefrina/sangre , Femenino , Glucosa/uso terapéutico , Hormona de Crecimiento Humana/sangre , Humanos , Hidrocortisona/sangre , Hipoglucemia/sangre , Hipoglucemia/inducido químicamente , Infusiones Intravenosas , Masculino , Dimensión del Dolor , Proyectos Piloto , Método Simple Ciego , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
Store-operated Ca(2+) entry, stimulated by depletion of intracellular Ca(2+) pools, has not been fully elucidated in vascular smooth muscle cells of pig coronary arteries. Therefore, [Ca(2+)](i) was measured in cultured cells derived from extramural pig coronary arteries using the Fura-2/AM fluorometry. Divalent cation entry was visualized with the Fura-2 Mn(2+)-quenching technique. Ca(2+) stores were depleted either by repetitive stimulation of P2Y purinoceptors with ATP (10 micromol/L), or by the sarcoendoplasmic Ca(2+)-ATPase inhibitor 2,5-Di-(tert-butyl)-1,4-benzohydroquinone (BHQ; 1 micromol/L) in Ca(2+)-free medium (EGTA 1 mmol/L). Addition of Ca(2+)(1 mmol/L) induced refilling of ATP-sensitive Ca(2+) stores and an increase in [Ca(2+)](i) in the presence of BHQ. Both could be significantly diminished by Ni(2+)(5 and 1mmol/L), La(3+)(10 micromol/L), Gd(3+)(10 micromol/L), and Mg(2+)(5.1 mmol/L). In contrast to the BHQ-mediated rise in [Ca(2+)](i), refilling of ATP-depleted stores was affected by neither flufenamate (0.1 mmol/L), nor by nitrendipine, nifedipine, and nisoldipine (each 1 micromol/L). The data suggest that after store depletion in pig coronary smooth muscle cells ATP and BHQ may converge on a common, Ni(2+)-, La(3+)-, Gd(3+)-, and Mg(2+)- sensitive Ca(2+) entry pathway, i.e. on a store-operated Ca(2+) entry. An additional contribution of the Na(+)/Ca(2+) exchanger cannot be excluded. Flufenamate-sensitive non-selective cation channels and dihydropyridine-sensitive L-type Ca(2+) channels are not involved in refilling of Ca(2+) stores after previous depletion by repetitive P2Y purinoceptor stimulation. The store-operated Ca(2+) entry in-between repetitive purinoceptor stimulation, i.e. in the absence of the agonist, may be responsible for the maintenance of agonist-induced rhythmic Ca(2+) responses.
Asunto(s)
Calcio/metabolismo , Músculo Liso Vascular/metabolismo , Receptores Purinérgicos P2/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Bloqueadores de los Canales de Calcio/farmacología , ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Cationes Bivalentes , Células Cultivadas , Vasos Coronarios/citología , Dihidropiridinas/farmacología , Fura-2 , Hidroquinonas/farmacología , Líquido Intracelular/metabolismo , Magnesio , Manganeso , Músculo Liso Vascular/citología , Sarcolema/metabolismo , PorcinosRESUMEN
OBJECTIVE: The insulin tolerance test (ITT) is an established standardized test for the evaluation of the hypothalamic-pituitary-adrenal axis. While a peak cortisol value of >18 microg/dl is usually interpreted as a sufficient response to the ITT, the plasma ACTH response has not yet been standardized. METHODS: We evaluated retrospectively the peak plasma ACTH concentrations during 140 ITTs in 125 patients with suspected pituitary insufficiency and prospectively in 15 healthy subjects. RESULTS: All healthy subjects had a peak cortisol concentration >/=18 microg/dl; 32 of 125 tests in the patients showed an insufficient cortisol response (peak cortisol concentration <18 microg/dl). The peak stimulated ACTH concentration in patients with secondary adrenal insufficiency (SAI) was 49.2+/-37.2 pg/ml (mean+/-s.d.) vs 130.9+/-89.3 pg/ml in patients without SAI, and 110.9+/-55.4 pg/ml in normal subjects (P<0.001). There was a weak, but significantly positive correlation between the peak ACTH and peak cortisol concentrations (rho=0.446, P<0.001), but there was also a very wide spread of the values. Defining a cut-off value for the peak plasma ACTH concentration with a sufficient sensitivity and specificity to identify patients with an impaired hypothalamic-pituitary-adrenal (HPA) axis was not possible. A peak plasma ACTH <20 pg/ml as a cut-off value had a sensitivity of 25% and a specificity of 98% for SAI. A cut-off value of a peak plasma ACTH <140 pg/ml had a sensitivity of 97% but a low specificity of 39%. CONCLUSIONS: Although there is a significant positive correlation between the peak ACTH and the peak cortisol concentrations, we conclude that there is no additional benefit in determining the ACTH concentrations during an ITT. Because of the strong variations of the values, the peak ACTH concentration is a poor parameter for the evaluation of the HPA axis.
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Insuficiencia Suprarrenal/diagnóstico , Hormona Adrenocorticotrópica/sangre , Hipopituitarismo/diagnóstico , Insulina , Pruebas de Función Adreno-Hipofisaria/métodos , Insuficiencia Suprarrenal/sangre , Femenino , Humanos , Hidrocortisona/sangre , Hipopituitarismo/sangre , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Sistema Hipófiso-Suprarrenal/fisiología , Plasma , Valores de Referencia , Estudios RetrospectivosRESUMEN
A 68-year-old man presented with general fatigue, increasing adynamia, weakness, vertigo and recurrent syncope. Six weeks earlier the diagnosis of a macroprolactinoma had been established based on a greatly elevated prolactin concentration (161 170 micro U/l) and MR-evidence of a 3.5 cm measuring pituitary mass. The patient had been started on cabergoline (1.5 mg weekly). Orthostatic hypotension due to the dopamine agonist was considered very likely and carbergoline therapy was stopped. However, there was no relief of the symptoms and further syncopes followed. Testing of blood pressure and heart rate regulation, selective testing of postganglionic cardiac neurons with [ 123 J] metaiodobenzylguanidine scintigraphy provided evidence of grossly impaired neurogenic cardiovascular regulation due to failure of postganglionic efferent sympathetic activity. This is characteristic for pure autonomic failure. The patient was treated symptomatically with high fluid intake, compression stockings, fludrohydrocortisone (0.1 mg o.d.s.), piroxicam (20 mg o.d.s.) and etilephrin (10 mg q.d.s.), which enabled him to cope with daily activities without syncope. This case shows that vertigo in a patient with macroprolactinoma is not always related to drug therapy but may be related to other causes.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedades del Sistema Nervioso Autónomo/etiología , Agonistas de Dopamina/farmacología , Etilefrina/uso terapéutico , Fludrocortisona/uso terapéutico , Piroxicam/uso terapéutico , Neoplasias Hipofisarias/diagnóstico , Prolactinoma/diagnóstico , Vértigo/etiología , Agonistas Adrenérgicos/uso terapéutico , Anciano , Presión Sanguínea , Inhibidores de la Ciclooxigenasa/uso terapéutico , Diagnóstico Diferencial , Disfunción Eréctil/etiología , Hormonas/sangre , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Hipofisarias/sangre , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/fisiopatología , Prolactinoma/sangre , Prolactinoma/tratamiento farmacológico , Prolactinoma/fisiopatología , Maniobra de Valsalva , Vértigo/inducido químicamenteRESUMEN
When the Alzheimer's disease patient is no longer mentally competent to handle his or her legal and personal affairs, a guardianship is the most common solution.
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Enfermedad de Alzheimer/psicología , Tutores Legales , Voluntad en Vida/legislación & jurisprudencia , Competencia Mental/legislación & jurisprudencia , Anciano , Humanos , Estados UnidosRESUMEN
BACKGROUND AND PURPOSE: Combined hormone replacement therapy with oestrogens plus the synthetic progestin medroxyprogesterone acetate (MPA) is associated with an increased risk of thrombosis. However, the mechanisms of this pro-thrombotic effect are largely unknown. The purpose of this study was to: (i) compare the pro-thrombotic effect of MPA with another synthetic progestin, norethisterone acetate (NET-A), (ii) determine if MPA's pro-thrombotic effect can be antagonized by the progesterone and glucocorticoid receptor antagonist mifepristone and (iii) elucidate underlying mechanisms by comparing aortic gene expression after chronic MPA with that after NET-A treatment. EXPERIMENTAL APPROACH: Female apolipoprotein E-deficient mice were ovariectomized and treated with placebo, MPA, a combination of MPA + mifepristone or NET-A for 90 days on a Western-type diet. Arterial thrombosis was measured in vivo in a photothrombosis model. Aortic gene expression was analysed using microarrays; GeneOntology and KEGG pathway analyses were conducted. KEY RESULTS: MPA's pro-thrombotic effects were prevented by mifepristone, while NET-A did not affect arterial thrombosis. Aortic gene expression analysis showed, for the first time, that gestagens induce similar effects on a set of genes potentially promoting thrombosis. However, in NET-A-treated mice other genes with potentially anti-thrombotic effects were also affected, which might counterbalance the effects of the pro-thrombotic genes. CONCLUSIONS AND IMPLICATIONS: The pro-thrombotic effects of synthetic progestins appear to be compound-specific, rather than representing a class effect of gestagens. Furthermore, the different thrombotic responses elicited by MPA and NET-A might be attributed to a more balanced, 'homeostatic' gene expression induced in NET-A- as compared with MPA-treated mice.
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Aorta/efectos de los fármacos , Trombosis de las Arterias Carótidas/genética , Anticonceptivos Femeninos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Acetato de Medroxiprogesterona/farmacología , Noretindrona/análogos & derivados , Animales , Aorta/metabolismo , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Células Cultivadas , Vasos Coronarios/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Ratones Noqueados , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Noretindrona/farmacología , Acetato de Noretindrona , Análisis de Secuencia por Matrices de Oligonucleótidos , Ovariectomía , Reacción en Cadena de la PolimerasaRESUMEN
In primarily cultured pig coronary smooth muscle cells, extracellular adenosine triphosphate (ATP; 10(-9) to 10(-3) M) dose-dependently increases intracellular calcium ([Ca2+]i). The [Ca2+]i transients measured by fura-2 fluorescence consist of peak and plateau phases with [Ca2+]i values of 191.84 +/- 5.67 nM (n = 10) and 91.67 +/- 1.89 nM, respectively. In Ca(2+)-free solution, the peak phases persisted, but there was a loss of the plateau response, indicating an initial ATP-stimulated intracellular Ca2+ release and a subsequent transarcolemmal Ca2+ entry. Various agonists have been used to characterize the P2 purinoceptor subtype involved in the ATP-induced Ca2+ transients. The rank order of potency was uridine triphosphate (UTP) > ATP >> 2-meSATP > beta,gamma-meATP = alpha,beta-meATP = adenosine = 0. To examine the refilling of ATP-sensitive stores, four repetitive 60-s ATP responses were produced throughout with a 5-min recovery period in between. Now the ATP peaks gradually declined in Ca(2+)-free solution, indicating the emptying of the stores. If, however, Ca2+ entry was allowed in the "refilling period" (i.e., between the ATP pulses), the Ca2+ peaks could be maintained or restored, respectively. The data suggest that the ATP-dependent [Ca2+]i transients may be mediated via a UTP > ATP-activated P2Y purinoceptor subtype, mediating both an intracellular Ca2+ release and a transarcolemmal Ca2+ influx. The refilling of Ca2+ stores may occur through the unstimulated membrane after agonist stimulation. A putative pathway may be a "capacitative" Ca2+ entry induced on depletion of intracellular Ca2+ stores.