Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles

<p>Abstract</p> <p>Background</p> <p>Mild hypophosphatasia (HPP) phenotype may result from <it>ALPL </it>gene mutations exhibiting residual alkaline phosphatase activity or from severe heterozygous mutations exhibiting a dominant negative effect. In order to determine the cause of our failure to detect a second mutation by sequencing in patients with mild HPP and carrying on a single heterozygous mutation, we tested the possible dominant effect of 35 mutations carried by these patients.</p> <p>Methods</p> <p>We tested the mutations by site-directed mutagenesis. We also genotyped 8 exonic and intronic <it>ALPL </it>gene polymorphisms in the patients and in a control group in order to detect the possible existence of a recurrent intronic mild mutation.</p> <p>Results</p> <p>We found that most of the tested mutations exhibit a dominant negative effect that may account for the mild HPP phenotype, and that for at least some of the patients, a second mutation in linkage disequilibrium with a particular haplotype could not be ruled out.</p> <p>Conclusion</p> <p>Mild HPP results in part from compound heterozygosity for severe and moderate mutations, but also in a large part from heterozygous mutations with a dominant negative effect.</p

Case-based reasoning in the care of Alzheimer’s disease patients

Planning the ongoing care of Alzheimer&apos;s Disease (AD) patients is a complex task, marked by cases that change over time, multiple perspectives, and ethical issues. Geriatric interdisciplinary teams of physicians, nurses and social workers currently plan this care without computer assistance. Although AD is incurable, interventions are planned to improve the quality of life for patients and their families. Much of the reasoning involved is case-based, as clinicians look to case histories to learn which interventions are effective, to document clinical ndings, and to train future health care professionals. There is great variability among AD patients, and within the same patient over time. AD is not yet well enough understood for universally effective treatments to be available. The case-based reasoning (CBR) research paradigm complements the medical research approach of finding treatments effective for all patients by matching patients to treatments that were effective for similar patients in the past. The Auguste Project is an effort to provide decision support for planning the ongoing care of AD patients, using CBR and other thought processes natural to members of geriatric interdisciplinary teams. System prototypes are used to explore the reasoning processes involved and to provide the forerunners of practical clinical tools. The first system prototype has just been completed. This prototype supports the decision to prescribe neuroleptic drugs to AD patients with behavioral problems. It uses CBR to determine if a neuroleptic drug should be prescribed and rule-based reasoning to select one of ve approved neuroleptic drugs for a patient. The first system prototype serves as proof of concept that CBR is useful for planning ongoing care for AD patients. Additional prototypes are planned to explore the research issues raised

Identifiability in biobanks: models, measures, and mitigation strategies

The collection and sharing of person-specific biospecimens has raised significant questions regarding privacy. In particular, the question of identifiability, or the degree to which materials stored in biobanks can be linked to the name of the individuals from which they were derived, is under scrutiny. The goal of this paper is to review the extent to which biospecimens and affiliated data can be designated as identifiable. To achieve this goal, we summarize recent research in identifiability assessment for DNA sequence data, as well as associated demographic and clinical data, shared via biobanks. We demonstrate the variability of the degree of risk, the factors that contribute to this variation, and potential ways to mitigate and manage such risk. Finally, we discuss the policy implications of these findings, particularly as they pertain to biobank security and access policies. We situate our review in the context of real data sharing scenarios and biorepositories