RESUMO
BACKGROUND: After kidney transplantation non-adherence and inadequate self-management undermine clinical outcomes and quality of life. Both have been demonstrated to be substantial in all age groups. However, interventions promoting adherence and self-management among kidney transplant recipients that have proven to be effective are scarce. In this study we aim to develop and test an intervention to optimize adherence and self-management. In this article we describe the background and design of the trial entitled 'promoting Medication AdheRence and Self-management among kidney transplant recipients' (MARS-trial)'. METHODS/DESIGN: This is a single-center, parallel arm randomized controlled trial. Nonadherent kidney transplant recipients aged 12 years or older are eligible for inclusion. Patients will be randomly assigned to either the experimental or a control group. The control group will receive care-as-usual. The experimental group will receive care-as-usual plus the MARS-intervention. The MARS-intervention is an outreaching intervention, based on the principles of (multi) systemic therapy which means involving the social network. A standardized intervention protocol is used for consistency but we will tailor the behavior change techniques used to the specific needs and determinants of each patient. The primary outcome of medication adherence will be measured using electronic monitoring. Secondary outcome measures regarding medication adherence and self-management are also assessed. Data is collected at baseline (T0), after a run-in period (T1), at six months post-baseline/end of treatment (T2) and after a six month follow-up period (T3). DISCUSSION: We combined elements of (multi) systemic therapy and evidence-based behavior change techniques to create an outreaching and highly individualized intervention. In this trial we will investigate the impact on medication adherence and self-management after kidney transplantation. TRIAL REGISTRATION: Netherlands Trial Register,trial number NTR7462. Registered 7th September 2018, https://www.trialregister.nl/trial/7264.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Transplante de Rim , Adesão à Medicação , Autogestão/métodos , Humanos , Questionário de Saúde do Paciente , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Rede Social , Apoio Social , TransplantadosRESUMO
Processing of the amyloid precursor protein (APP) leads to the production of amyloid-beta (Abeta), the major component of extracellular plaques in the brains of Alzheimer's disease (AD) patients. Presenilin-1 (PS-1) plays a key role in the final step of Abeta formation, the gamma-secretase cleavage. Previously, we showed that PS-1 is retained in pre-Golgi compartments by incorporation into COPI-coated membranes of the vesicular tubular clusters (VTCs) between endoplasmic reticulum (ER) and Golgi complex. Here, we show that PS-1 also mediates the retention of the beta-cleavage-derived APP-C-terminal fragment (CTFbeta) and/or Abeta in pre-Golgi membranes. Overexpression of PS-1 increased the percentage of CTFbeta and/or Abeta in VTCs as well as their distribution to COPI-coated VTC membranes. By contrast, overexpression of the dominant-negative aspartate mutant PS-1(D257A) or PS-knockout decreased incorporation of these APP derivatives into COPI-coated membranes. Sorting of APP derivatives to COPI-coated VTC membranes was not depending on the APP cytosolic tail. In post-Golgi compartments, PS-1 expression enhanced the association of full-length APP/APPs with endosomal compartments at the expense of plasma membrane-bound APP. We conclude that PS-1, in addition to its role in gamma-secretase cleavage, is also required for the subcellular routing of APP and its derivatives. Malfunctioning of PS-1 in this role may have important consequences for the progress of AD.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Peptídeos beta-Amiloides/ultraestrutura , Precursor de Proteína beta-Amiloide/ultraestrutura , Animais , Células CHO , Complexo I de Proteína do Envoltório/metabolismo , Complexo I de Proteína do Envoltório/ultraestrutura , Cricetinae , Embrião de Mamíferos , Retículo Endoplasmático/ultraestrutura , Endossomos/metabolismo , Endossomos/ultraestrutura , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Complexo de Golgi/ultraestrutura , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/ultraestrutura , Camundongos , Camundongos Knockout , Microscopia Imunoeletrônica , Mutação , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/ultraestrutura , Presenilina-1 , Processamento de Proteína Pós-Traducional , Transporte ProteicoRESUMO
Presenilin-1 is involved in intramembrane proteolysis of various proteins, but its intracellular site of action has remained elusive. Here, we determined by quantitative immunogold-electron microscopy that presenilin-1 in Chinese hamster ovary cells is present in pre-Golgi compartments as well as at the plasma membrane and endosomes. Notably, a high percentage of presenilin-1 resides in COPI-coated membranes between the endoplasmic reticulum and the Golgi complex, indicating significant recycling to the endoplasmic reticulum. By contrast, the inactive aspartate mutant presenilin-1D257A is relatively excluded from COPI-coated membranes, concomitant with increased post-Golgi levels. These data provide critical evidence for the scenario that the complex containing presenilin-1 can serve as gamma-secretase at the plasma membrane or endosomes and suggest a role for COPI-mediated retrograde transport in regulating post-Golgi levels of presenilin-1.