Variants regulating ZBTB4 are associated with age-at-onset of Alzheimer's disease.

The identification of novel genetic modifiers of age-at-onset (AAO) of Alzheimer's disease (AD) could advance our understanding of AD and provide novel therapeutic targets. A previous genome scan for modifiers of AAO among families affected by early-onset AD caused by the PSEN2 N141I variant identified 2 loci with significant evidence for linkage: 1q23.3 and 17p13.2. Here, we describe the fine-mapping of these 2 linkage regions, and test for replication in 6 independent datasets. By fine-mapping these linkage signals in a single large family, we reduced the linkage regions to 11% their original size and nominated 54 candidate variants. Among the 11 variants associated with AAO of AD in a larger sample of Germans from Russia, the strongest evidence implicated promoter variants influencing NCSTN on 1q23.3 and ZBTB4 on 17p13.2. The association between ZBTB4 and AAO of AD was replicated by multiple variants in independent, trans-ethnic datasets. Our results show association between AAO of AD and both ZBTB4 and NCSTN. ZBTB4 is a transcriptional repressor that regulates the cell cycle, including the apoptotic response to amyloid beta, while NCSTN is part of the gamma secretase complex, known to influence amyloid beta production. These genes therefore suggest important roles for amyloid beta and cell cycle pathways in AAO of AD.

Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content.

Large interindividual variability has been observed in the metabolism of CYP2C19 substrates in vivo. The study aimed to evaluate sources of this variability in CYP2C19 activity, focusing on CYP2C19 diplotypes and the cytochrome P450 oxidoreductase (POR). CYP2C19 gene analysis was carried out on 347 human liver samples. CYP2C19 activity assayed using human liver microsomes confirmed a significant a priori predicted rank order for (S)-mephenytoin hydroxylase activity of CYP2C19*17/*17 > *1B/*17 > *1B/*1B > *2A/*17 > *1B/*2A > *2A/*2A diplotypes. In a multivariate analysis, the CYP2C19*2A allele and POR protein content were associated with CYP2C19 activity. Further analysis indicated a strong effect of the CYP2C19*2A, but not the *17, allele on both metabolic steps in the conversion of clopidogrel to its active metabolite. The present study demonstrates that interindividual variability in CYP2C19 activity is due to differences in both CYP2C19 protein content associated with gene diplotypes and the POR concentration.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.58.

The relationship between quality of care and financial performance in dialysis: "doing well by doing good".

Dialysis is an archetype for the application of the principles of continuous quality improvement (CQI) to medicine. Dialysis treatment dosage and hematocrit values are just two examples of data that can be readily obtained for reliable and valid quality analysis and improvement of the dialysis process. A dialysis CQI program should focus on the improvement of care processes to effect improvements in patient outcomes and should function through the teamwork of caregivers at all levels within an organization. By succeeding in the continuous improvement of the multiple processes involved in the delivery of chronic dialysis to patients, dialysis providers can expect to see improvement in patient outcomes and, as a direct result, improvement in financial performance, both in the fee-for-service, as well as in the capitated model of reimbursement.

Meaningful rehabilitation of the end-stage renal disease patient.

In this highly technological age, health care providers are called to attend to the patient as a whole person, with dreams and goals and a desire for purpose and meaning in life. In this article, we propose a broadened definition of rehabilitation and a rehabilitation program designed to effect an improvement in the quality of life of each renal patient by aiming to restore meaningful existence in each of their lives. An individualized plan for rehabilitation can be constructed and implemented with far-reaching success when the focus is on the life goals of the patient, whether physical, social, psychological, or intellectual. These programs not only enhance the quality of life of the patient with end-stage renal disease, but are cost-effective, both at the societal level and at the level of the dialysis clinic.

Safe use of thrombolysis in the elderly.

Elderly individuals with acute myocardial infarction represent a high-risk population that may benefit the most from thrombolytic therapy. To date, studies with streptokinase, tissue plasminogen activator (t-PA), and APSAC have shown improved survival in patients up to age 80, although there was an increased risk for hemorrhagic complications. While a placebo-controlled trial is needed to confirm these findings in even older patients, careful screening of the individual should make thrombolysis safe and effective for selected patients in this age group.