Ethical aspects of statistical practice

This paper embodies a personal view of the ethical considerations that the author believes should be continuously in the mind of any applied statistician or biometrician whose work involves extensive collaboration with other persons and organizations. It looks particularly at the contribution of the International Statistical Institute to the codification of principles, the duties of the statistician in relation to data and the interests of his employer or client, his responsibilities to his professional colleagues and towards society as a whole, and, by no means least; the responsibility of the client towards the statistician who works with him.     

Ethical and legal aspects of oncogenomics

The discovery of the genes and cellular pathways that play fundamental roles in several diseases, and the understanding of many diseases at a molecular level due to the advances in the field of genomics, have revolutionized the diagnosis, therapy and prevention of human diseases. Application of genetic testing in numerous medical fields, including pharmacogenomics and oncogenomics, raised numerous ethical questions and introduced legal instruments that are aimed at ensuring the appropriate protection of human research participants. For the effective development of human genomics and translation of novel, validated biomarkers into potentially useful clinical applications in personalized medicine, there is a need for clear ethical standards and principles in all phases of clinical research.     

Ethical aspects of genetic testing.

No research study or significant medical treatment can be done involving patients without their informed consent. In workplaces and environmental settings, individuals are often exposed to mutagenic or carcinogenic substances, usually without their knowledge, and not with their informed consent. Such exposures can lead to evermore easily documentable genetic changes. As genetic testing becomes more widespread, there are significant ethical implications regarding employment, insurance coverage, and confidentiality regarding medical information. With an increased ability to detect genetic changes, or 'unfavorable' genetic polymorphisms, this information should not be used to deny employment or increase insurance rates. Rather, such information should be used to increasingly provide appropriately safe workplaces, and place workers in less hazardous settings.     

Production of precursors for anti-Alzheimer drugs: Asymmetric bioreduction in a packed-bed bioreactor using immobilized D. carota cells

(S)-1-Phenylethanol derivatives, which are the precursors of many pharmacological products, have also been used as anti-Alzheimer drugs. Bioreduction experiments were performed in a batch and packed-bed bioreactor. Then, the kinetics constants were determined by examining the reaction kinetics in the batch system with free and immobilized carrot cells. Also, the effective diffusion coefficient (D_e) of acetophenone in calcium alginate-immobilized carrot cells was investigated. Kinetics constants for free cells, which are intrinsic values, are reaction rate V_max?=?0.052?mmol?L^?1?min^?1, and constants of the Michaelis–Menten K_M?=?2.31?mmol?L^?1. Kinetics constants for immobilized cells, which are considered apparent values, are V_{max, app}?=?0.0407?mmol?L^?1 min^?1, K_{M, app}?=?3.0472?mmol?L^?1 for 2?mm bead diameter, and V_{max, app}?=?0.0453?mmol?L^?1 min^?1, K_{M, app}?=?4.9383?mmol?L^?1 for 3?mm bead diameter. Average value of effective diffusion coefficient of acetophenone in immobilized beads was determined as 1.97?×?10^?6?cm²?s^?1. Using immobilized carrot cells in an up-flow packed-bed reactor, continuous production of (S)-1-phenylethanol through asymmetric bioreduction of acetophenone was performed. The effects of the residence time and concentrations of substrate were investigated at pH 7.6 and 33°C. Enantiomerically pure (S)-1-phenylethanol (ee?>?99%) was produced with 75% conversion at 4-hr residence time.     

Ethical aspects of limiting residents' work hours

DEFINITION OF THE PROBLEM: The regulation of residents' work hours involves several ethical conflicts which need to be systematically analysed and evaluated. ARGUMENTS AND CONCLUSION: The most important ethical principle when regulating work hours is to avoid the harm resulting from the over-work of physicians and from an excessive division of labour. Additionally, other ethical principles have to be taken into account, in particular the principles of nonmaleficence and beneficence for future patients and for physicians. The article presents arguments for balancing the relevant ethical principles and analyses the structural difficulties that occur unavoidably in any regulation of the complex activities of physicians.     

Ethical aspects of human germ-line gene therapy

This presentation remains limited to a survey of the current debate on germ-line gene therapy. Most of the official, often national, reports show great restraint. On the other hand more and more ethicists have taken a positive stance in the matter. Both these viewpoints will be reflected in the overview.     

Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs.

BACKGROUND: Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies, prior to elucidation of the three-dimensional structure of Torpedo californica AChE (TcAChE). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range. RESULTS: Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules. CONCLUSIONS: Our study shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles.     

Anti-Alzheimer drugs: ethical aspects of research and practice

The development and use of drugs that aim at positively influencing the cognitive decline in patients suffering from Alzheimer's disease raises a number of ethical questions. These concern, amongst others, the significance of these drugs for the well-being and quality of life of patients, as well as the informed consent for the use of these medicines, in particular in the context of medical-scientific research. Assessing the value and significance of antidementia drugs not only depends on the positive effect on cognitive decline, but also on the broader meaning for the quality of life of the patient and her primary carer(s). The subjective experiences of those directly involved deserve more attention in research.     

Ethical issues in research on sensitive topics: participants' experiences of distress and benefit

While many studies ask participants to disclose sensitive information or to participate in emotionally arousing tasks, little is known about participants' subjective experiences of discomfort and benefit. Ethics review committees, therefore, have little information about participant experiences to guide their informed decision-making. We asked undergraduate females about their experiences in a study that included an experimental session, interviews, and self-report measures on sensitive topics. We examined results overall, and compared the responses of individuals with and without childhood abuse experiences. Participants who had experienced child abuse were more likely to report distress due to remembering the past, but also more likely to report that participation was helpful. Implications for future research, and recommendations for review boards, are discussed.     

Health care experiences of people with dementia and their caregivers: a meta-ethnographic analysis of qualitative studies

Background:

Understanding the health care experience of people with dementia and their caregivers is becoming increasingly important given the growing number of affected individuals. We conducted a systematic review of qualitative studies that examined aspects of the health care experience of people with dementia and their caregivers to better understand ways to improve care for this population.

Methods:

We searched the electronic databases MEDLINE, Embase, PsychINFO and CINAHL to identify relevant articles. We extracted key study characteristics and methods from the included studies. We also extracted direct quotes from the primary studies, along with the interpretations provided by authors of the studies. We used meta-ethnography to synthesize the extracted information into an overall framework. We evaluated the quality of the primary studies using the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist.

Results:

In total, 46 studies met our inclusion criteria; these involved 1866 people with dementia and their caregivers. We identified 5 major themes: seeking a diagnosis; accessing supports and services; addressing information needs; disease management; and communication and attitudes of health care providers. We conceptualized the health care experience as progressing through phases of seeking understanding and information, identifying the problem, role transitions following diagnosis and living with change.

Interpretation:

The health care experience of people with dementia and their caregivers is a complex and dynamic process, which could be improved for many people. Understanding these experiences provides insight into potential gaps in existing health services. Modifying existing services or implementing new models of care to address these gaps may lead to improved outcomes for people with dementia and their caregivers.The global prevalence of Alzheimer disease and related dementias is estimated to be 36 million people and is expected to double in the next 20 years.¹ Several recent strategies for providing care to patients with dementia have highlighted the importance of coordinated health care services for this growing population.^2–5 Gaps in the quality of care for people with dementia have been identified,^6–8 and improving their quality of care and health care experience has been identified as a priority area.^2–5Incorporating the health care experience of patients and caregivers in health service planning is important to ensure that their needs are met and that person-centred care is provided.⁹ The health care experience of people with dementia and their caregivers provides valuable information about preferences for services and service delivery.¹⁰ Matching available services to patient treatment preferences leads to improved patient outcomes^11,12 and satisfaction without increasing costs.¹³ Qualitative research is ideally suited to exploring the experiences and perspectives of patients and caregivers and has been used to examine these experiences for other conditions.¹⁴ We performed a systematic review and meta-ethnographic synthesis of qualitative studies exploring the health care experience of people with dementia and their caregivers in primary care settings, and we propose a conceptual framework for understanding and improving these health care experiences.     

Steric aspects of dopaminergic drugs.

There are a variety of molecule species of dopamine avaialable at physiological pH. The predominant form available at physiological pH is the phenolic ammonium salt. However, at the present time the molecular form that is optimum for producing dopaminergic activity is unknown. In attempting to delineate the conformational requirements of dopaminergic agonists, a variety of conformationally restricted analogs and complex molecules possessing a dopaminergic segment have been investigated. It appears at this time that the trans extended form of dopamine is the optimum form for binding to dopamine receptors. The rotameric forms of dopamine are also important considerations when examining a molecule for dopaminergic agonist activity. A high degree of stereospecificity has been shown in different dopaminergic systems.     

Ethical aspects of cryobiology: responsible applications in biomedicine and in clinical practice

This paper focuses on ethical issues in applications of cryobiology to humans, more particularly in the field of human reproduction and cryosurgery. The paper also provides essential ingredients for the interface of bioethics and cryobiology. For instance, since the 1970s bioethicists have developed four principles to guide the moral evaluation of the 'new medicine.' These are: respect for persons, non-maleficence, beneficence, and justice. In the field of human reproduction major progress was made by the cryopreservation of reproductive material. Still, ethical issues arise whenever partnerships cease to exist (death) or deteriorate (divorce), and decisions have to be made about the disposition of frozen gametes and embryos. Policy-making becomes, then, a prime concern. Examples of regulation in the United States of America, in the United Kingdom, and across Europe are being offered. Cryosurgery remains a field where cryobiologists struggle in their quest for an optimal technique, thus illustrating the need for assessment of safety, efficacy, and benefit to patients. Increasingly, cryobiologists have been joining in the ethical reflection on the use of cryo-technologies. They may further do so by perfecting their ability to identify ethical aspects, by analysing the norms and values at stake, by learning the skill of making the appropriate choices, and by showing their willingness to justify the choices made be it in the inner circle of pairs or publicly.     

Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs

The 3D structure of a complex of the anti-Alzheimer drug galanthamine with Torpedo californica acetylcholinesterase is reported. Galanthamine, a tertiary alkaloid extracted from several species of Amarylidacae, is so far the only drug that shows a dual activity, being both an acetylcholinesterase inhibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists. The X-ray structure, at 2.5A resolution, shows an unexpected orientation of the ligand within the active site, as well as unusual protein-ligand interactions. The inhibitor binds at the base of the active site gorge, interacting with both the acyl-binding pocket and the principal quaternary ammonium-binding site. However, the tertiary amine group of galanthamine does not directly interact with Trp84. A docking study using the program AUTODOCK correctly predicts the orientation of galanthamine in the active site. The docked lowest-energy structure has a root mean square deviation of 0.5A with respect to the corresponding crystal structure of the complex. The observed binding mode explains the affinities of a series of structural analogs of galanthamine and provides a rational basis for structure-based drug design of synthetic derivatives with improved pharmacological properties. Proteins 2001;42:182-191.     

Enantiomeric resolution of galanthamine and related drugs used in anti-Alzheimer therapy by means of capillary zone electrophoresis employing derivatized cyclodextrin selectors

An analytical assay is presented for the determination of the enantiomeric composition of galanthamine and related synthetic and natural compounds. (−)-Galanthamine is isolated from Galanthus nivalis and is used in this optical pure form in the therapy of Alzheimer’s disease. Recent efforts for a total synthesis of unichiral (−)-galanthamine is connected with the need for a fast and reliable assay for the determination of the optical purity of the end product, as well as for optimizing and controlling the final steps in total synthesis particularly the asymmetric transformation of narwedine. In this paper the enantiomeric resolution of these compounds is reported employing a capillary electrophoretic system with β-cyclodextrin derived chiral selectors. With the proposed system a number of galanthamine and narwedine derived analogous compounds could be separated, including 1-bromo- and N-alkyl-substituted compounds.