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Biomedical subjects

J C Fletcher

Publications and source records attributed to J C Fletcher.

At least 19 recordsLinked to original sources
PubMed1996

Human fetal gene therapy: moral and ethical questions.

This two-part paper discusses moral and ethical questions raised by future trials of human fetal gene therapy. The first part examines broad moral issues to explore whether fetal gene therapy is a morally praiseworthy goal. Ought it be done at all? These issues include (i) how the concept of fetal gene therapy originally arose as a goal envisioned at the beginning of prenatal diagnosis, (ii) preimplantation genetic diagnosis as a better preconceptual alternative for parents at higher genetic risk, (iii) alternatives to genetic abortions, (iv) the social and economic priority of fetal gene therapy, and (v) whether fetal gene therapy is a "slippery slope" that will end in germ-line gene therapy. This part concludes that far more reasons exist to commend fetal gene therapy than to reject it, given its limits and modest social and economic priority. The second part responds to specific ethical questions that must be raised about any protocol for human gene therapy. These questions and issues are adapted to the prenatal situation: (i) how the previable fetus becomes a "patient," (ii) concern for clinical benefit and minimizing risks to the fetus and pregnant woman, (iii) concern for the voluntary and informed participation of the pregnant woman, the father, and for protection of their privacy, (iv) concern for fair selection of subjects, (v) considerations of harm to germ line cells, and (vi) the role of public oversight of fetal gene therapy. The article concludes by recommending a continuation of the consolidated Recombinant Advisory Committee (RAC) for the near future.

Abortion, Spontaneous↗
PubMed1996

Ethical issues surrounding multifetal pregnancy reduction and selective termination.

MFPR and selective terminations satisfy the criteria of enabling pregnancies to continue with the least harm and most benefits to all involved. The surviving infants can be saved from certain death (abortion) or higher risks of severe harm and death and of an extended stay in neonatal intensive care (premature delivery). In the hands of trained operators, MFPR and selective termination is, in our opinion, the best means to protect the mother's health and well-being, given it is available and approved by the parents. MFPR and selective termination avoid the trauma of abortion of a wanted pregnancy, enable the parents to achieve the goal of having their own child, and avoid the dangers of delivery of multiple premature infants. There is no doubt that any procedure that involves the death of a fetus will be hotly argued despite the potential for greater good. We acknowledge that it will be impossible to convince those who cannot morally accept the taking of any life regardless of the circumstances. We hope, however, that we have shown there is a place for MFPR and selective termination in a very limited number of circumstances and the ethical probity of MFPR and selective termination as an option in such cases.

Congenital Abnormalities↗
PubMed1995

Informed consent in children and adolescents: age, maturation and psychological state.

PURPOSE: The purpose of this investigation was to examine the relationship of understanding of research participation to anxiety, control, and stage of cognitive development. METHODS: Participants included 44 boys and girls ages 7 to 20 years. All were inpatients for the first time in pediatric units of a research hospital. Twenty participants were admitted for experimental treatment of pediatric cancers and 24 were admitted for a 3-week treatment of extreme obesity. An interview was conducted to assess 12 elements of knowledge of research participation of a medical protocol. The interview was coded for: 1) knowledge of research participation score, 2) weighted knowledge of participation in research score (based on physician ratings of what was most-to-least important for children and adolescents to know), and 3) global control (perceived control over life, illness and treatment). A measure of anxiety and one Piagetian task to measure stage of cognitive development also were administered. RESULTS: Pearson correlations, significant at p < or = .05, were as follows: knowledge of participation in research and global control, (r = .40) and weighted knowledge of participation in research score and global control (r = .38). Hierarchical regression showed that the best predictors of knowledge of research participation or the weighted knowledge of research participation score was global control alone or an interaction of global control with anxiety. CONCLUSIONS: Emotional factors were more frequently related to understanding of research participation than age or cognitive development. Providing medical environments that decrease anxiety and increase control may enhance children's and adolescent's understanding of the research process.

Adolescent↗
PubMed1995

The ecdysone-inducible Broad-complex and E74 early genes interact to regulate target gene transcription and Drosophila metamorphosis.

Pulses of the steroid hormone ecdysone initiate Drosophila metamorphosis by inducing widespread changes in gene expression. The Broad-Complex (BR-C) and E74 are induced directly by ecdysone and encode families of transcription factors that regulate ecdysone primary- and secondary-response genes. Genetic analyses have revealed that mutations in the BR-C and E74 are lethal during metamorphosis and that these mutations cause some similar lethal phenotypes and alterations in secondary-response gene transcription. To examine whether the BR-C and E74 function together during development, we have combined representative alleles from each BR-C and E74 complementation group. Analysis of the morphological and molecular phenotypes of the double-mutant animals reveals that BR-C and E74 alleles act together to produce both novel and synergistic effects. We find that the BR-C and E74 share functions in puparium formation, pupation and early gene induction. In addition, our evidence suggests that the BR-C and E74 transcription factors may directly interact to regulate the expression of salivary gland glue and late genes. This data is consistent with current models which propose that combinations of ecdysone primary-response genes regulate common morphogenetic pathways during insect metamorphosis.

Alleles↗
PubMed1995

US public policy on embryo research: two steps forward, one large step back.

This article gives an overview of the final report of the National Institutes of Health (NIH) Embryo Research Panel, which was issued on September 27, 1994 (NIH, 1994). The report was endorsed unanimously by the Advisory Committee to the Director of the NIH, Harold Varmus, on December 2, 1994. A few hours later, President Clinton (Marshall, 1994) issued a statement announcing that he did 'not believe that federal funds should be used to support the creation of human embryos for research purposes', and that he had directed the NIH not to support such research, which was one of the areas of research recommended for Federal funding by the Panel. At present, Dr Varmus is in the process of considering the Panel's report and shaping guidelines to govern the review and conduct of human embryo research. Any guidelines will be published in the Federal Register for comment at a later date. As a result of changes brought about by Congress in 1993, Federal support for research focused on in-vitro fertilization (IVF) could go forward. This represented the first advance in research freedom in the Federal sector to study approaches to IVF. It will involve the NIH in peer review and scientific activities regarding IVF. Assuming that Dr Varmus develops guidelines to support human embryo research limited to use of 'spare' embryos only and perhaps parthenogenotes, a second step will have been taken. My view about the context and meaning of the President's decision, which is nonetheless a decided step to the rear, appears in the final part.

Fertilization in Vitro↗
PubMed1995

The Drosophila E74 gene is required for the proper stage- and tissue-specific transcription of ecdysone-regulated genes at the onset of metamorphosis.

The steroid hormone ecdysone directly induces a small set of early genes, visible as puffs in the larval salivary gland polytene chromosomes, as it signals the onset of Drosophila metamorphorsis. The products of these genes appear to function as regulators that both repress their own expression and induce a large set of secondary-response late genes. We have identified recessive loss-of-function mutations in the early gene E74, a member of the ets protooncogene family that encodes two related DNA-binding proteins, E74A and E74B. These mutations cause defects in pupariation and pupation, and result in lethality during metamorphosis. Here we extend our phenotypic characterization of the E74A and E74B mutant alleles to the molecular level by examining their effects on the transcription of over 30 ecdysone-regulated genes. We show that the transcription of most ecdysone primary-response genes during late larval and prepupal development is unaffected by the E74 mutations. Rather, we find that E74 is necessary for the appropriate regulation of many ecdysone secondary-response genes. E74B is required for the maximal induction of glue genes in mid third instar larval salivary glands, while E74A is required in early prepupae for the proper timing and maximal induction of a subset of late genes. E74 activity is also necessary for the correct regulation of genes expressed predominantly in the fat body, epidermis or imaginal discs. These observations confirm that E74 plays a critical role in regulating transcription during the early stages of Drosophila metamorphosis. In addition, the widespread effects of the E74 mutations on transcription indicate that E74 functions in regulatory hierarchies not only in the larval salivary gland, but throughout the entire organism.

Alleles↗
PubMed1995

The Drosophila E74 gene is required for metamorphosis and plays a role in the polytene chromosome puffing response to ecdysone.

The steroid hormone ecdysone initiates Drosophila metamorphosis by reprogramming gene expression during late larval and prepupal development. The ecdysone-inducible gene E74, a member of the ets proto-oncogene family, has been proposed to play a key role in this process. E74 is encoded within the 74EF early puff and consists of two overlapping transcription units, E74A and E74B. To assess the function(s) of E74 during metamorphosis, we have isolated and characterized recessive loss-of-function mutations specific to each transcription unit. We find that mutations in E74A and E74B are predominantly lethal during prepupal and pupal development, consistent with a critical role for their gene products in metamorphosis. Phenotypic analysis reveals that E74 function is required for both pupariation and pupation, and for the metamorphosis of both larval and imaginal tissues. E74B mutants are defective in puparium formation and head eversion and die as prepupae or cryptocephalic pupae, while E74A mutants pupariate normally and die either as prepupae or pharate adults. We have also investigated the effects of the E74 mutations on gene expression by examining the puffing pattern of the salivary gland polytene chromosomes in newly formed mutant prepupae. Most puffs are only modestly affected by the E74B mutation, whereas a subset of late puffs are sub-maximally induced in E74A mutant prepupae. These observations are consistent with Ashburner's proposal that early puff proteins induce the formation of late puffs, and define E74A as a regulator of late puff activity. They also demonstrate that E74 plays a wide role in reshaping the insect during metamorphosis, affecting tissues other than the salivary gland in which it was originally identified.

Animals↗
PubMed1994

Ethics committees: time to experiment with standards.

Ethics committees now exist in most hospitals. Their recent establishment in many institutions was a response to a 1991 mandate by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). Proposed or new legislation in a few states is elevating the status of these committees, either requiring their use in certain cases, allowing them to substitute for judicial review, or granting immunity to those who follow their advice. Despite these recent JCAHO and legislative developments, it is widely recognized that there is a significant lack of data on the effectiveness of these committees and that committee members often lack the requisite education and skills for effective participation in case consultation. We argue that before granting ethics committees additional authority, there is a need for more research on their performance and a period of experimentation with quality standards governing their membership and operations.

Bioethical Issues↗
PubMed1993

Molecular analysis of the initiation of insect metamorphosis: a comparative study of Drosophila ecdysteroid-regulated transcription.

More than 50 ecdysteroid-regulated Drosophila genes have been described in the literature. These genes were identified using several different ecdysteroid-responsive systems and characterized under a variety of experimental conditions. The diversity of these approaches has made it difficult to compare results and identify common responses to the hormone. As a first step toward characterizing the temporal regulation of these genes by ecdysteroids, we have examined their transcriptional activity throughout third instar larval and prepupal development using a single collection of staged animals. We see four coordinate changes in ecdysteroid-regulated gene activity during third instar larval development, at 78-88 hr, approximately 100 hr, 106-108 hr, and approximately 114 hr after egg laying. A dramatic transition in gene expression occurs at puparium formation, after which the prepupal ecdysteroid pulse induces successive waves of transcription. Our results suggest that several increases in the ecdysteroid titer during third instar larval and prepupal development program a precise temporal progression of gene activity that could direct the appropriate behavioral and developmental changes at the onset of metamorphosis.

Animals↗
PubMed1993

Prenatal diagnosis and sex selection in 19 nations.

As part of a study of ethics and human genetics in 19 nations, we surveyed attitudes of 71 medical geneticists in 4 developing nations (Brazil, Greece, India and Turkey), and 611 geneticists in 15 developed nations, using anonymous questionnaires. Overall, 52% in India, 30% in Brazil, 29% in Greece, and 20% in Turkey would perform prenatal diagnosis to select a male fetus for a couple with 4 daughters and no sons. Sex selection is the major use of prenatal diagnosis in India. The majority in the U.S.A. (62%) and Hungary (60%) would also do sex selection or refer. We discuss possible means of preventing sex selection while avoiding medical paternalism and promoting the autonomy of women.

Attitude↗