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Biomedical subjects

J Sugarman

Publications and source records attributed to J Sugarman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Retinoic acid receptor alpha suppresses transformation by v-myb.

Retinoic acid (RA) is capable of inducing the differentiation of various myelomonocytic cell lines. During this differentiation process, the levels of c-myb expression decline, suggesting that the RA receptor (RAR) may act in part by down-regulating this proto-oncogene. We have now investigated whether the RAR can also inhibit the function of Myb proteins themselves. We have found that transcriptional activation of a Myb-responsive reporter gene can be inhibited by RA in a human monocytic cell line. This inhibition could not be overcome by the expression of exogenous Myb. The RAR did not interfere with DNA binding by Myb proteins in vitro, suggesting that the functional inhibition occurs at the level of transcriptional activation. To determine the biological relevance of the inhibition of Myb proteins by the RAR, we have used v-myb-transformed monoblasts. These cells differentiate into macrophages in the presence of phorbol ester (tetradecanoyl phorbol acetate [TPA]) but are normally unresponsive to RA treatment. The introduction of an inducible, exogenous RAR alpha into v-myb-transformed monoblasts permitted an RA-dependent differentiation into macrophage-like cells similar to those induced by TPA. These results demonstrate that transformation by v-myb is recessive to RAR alpha and imply that many types of non-RA-responsive leukemia cells may become responsive following the introduction of the RAR.

Animals↗
PubMed1994

Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding.

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) regulate transcription by binding to response elements in target genes that generally consist of two direct repeat half-sites of consensus sequence AGGTCA (ref. 1). RAR/RXR heterodimers activate transcription in response to all-trans or 9-cis retinoic acid by binding to direct repeats spaced by five base pairs (DR5 elements), such that RAR occupies the downstream half-site. RXR homodimers activate transcription in response to 9-cis retinoic acid by binding to direct repeats spaced by one base pair (DR1 elements). Although RXR/RAR heterodimers bind to DR1 elements with higher affinity than RXR homodimers, in most contexts they are unable to activate transcription in response to either all-trans or 9-cis retinoic acid. As a result, RARs inhibit RXR-dependent transcription from these sites. We report that the switching of the RAR from an activator to an inhibitor of retinoid-dependent transcription requires that it be bound to the upstream half-site of DR1 elements and that it allosterically block the binding of ligand to the RXR.

Allosteric Regulation↗
PubMed1994

Are withholding and withdrawing therapy always morally equivalent?

Many medical ethicists accept the thesis that there is no moral difference between withholding and withdrawing life-sustaining therapy. In this paper, we offer an interesting counterexample which shows that this thesis is not always true. Withholding is distinguished from withdrawing by the simple fact that therapy must have already been initiated in order to speak coherently about withdrawal. Provided that there is a genuine need and that therapy is biomedically effective, the historical fact that therapy has been initiated entails a claim to continue therapy that cannot be attributed to patients who have not yet received therapy. This intrinsic difference between withholding and withdrawing therapy is of moral importance. In many instances, patients will waive this claim. But when one considers withdrawing therapy from one patient to help another in a setting of scarce resources, this intrinsic moral difference comes into sharp focus. In an era of shrinking medical resources, this difference cannot be ignored.

Ethical Analysis↗
PubMed1993

Brn-5 is a divergent POU domain factor highly expressed in layer IV of the neocortex.

We have identified rat cDNA clones that encode a POU domain protein, referred to as brain-5 (Brn-5). During embryogenesis in the rat, Brn-5 is widely expressed with highest levels in the developing brain and spinal cord from embryonic day 12.5. In the adult, Brn-5 mRNA is most abundant in the brain, where it is diffusely expressed with the exception of an enrichment in layer IV of the neocortex. However, Brn-5 is also found in multiple adult tissues outside the central nervous system, including kidney, lung, heart, adrenal, skin, testis, and anterior pituitary. This expression pattern contrasts with that of most other POU domain genes that are expressed predominantly in the developing nervous system and are progressively restricted to discrete regions of the brain. The predicted amino acid sequence of Brn-5 is considerably divergent from previously described POU domains and thus defines a new POU domain subclass (class VI). Consistent with its divergent sequence, the DNA-binding characteristics of Brn-5 overlap with, but are clearly distinct from, that of Oct-2. Although Brn-5 can bind to non-octamer sites, a random site selection indicates that its preferred binding site contains a variant octamer core motif. Finally, we show that the amino terminus of Brn-5 contains a transactivation domain.

Amino Acid Sequence↗
PubMed1993

The cost of ethics legislation: a look at the Patient Self-Determination Act.

The Patient Self-Determination Act (PSDA) requires hospitals to ask patients upon admission whether they have an advance directive. Although the PSDA has received extensive criticism, little attention has been paid to the cost of the law, either during its legislative course or following its implementation. Nonetheless, several tangible and intangible costs are associated with the PSDA. Such costs may be incurred by different parties. This paper examines the costs and benefits of the PSDA and illustrates the extent of some of its tangible costs. The incremental start-up cost for one institution's response to the PSDA is estimated to be $49,304 ($1.31 per admission) and the total implementation cost of the program to be $114,528. In addition, the national incremental start-up cost for hospitals to implement the PSDA is estimated to be between $43,625,114 and $101,569,922. Finally, the potential implications of the PSDA for future governmental health care ethics regulation are discussed.

Advance Directives↗
PubMed1992

Severe cutaneous hypersensitivity reactions during treatment of tuberculosis in patients with HIV infection in Tanzania.

Concurrent infection with HIV-1 and Mycobacterium tuberculosis is increasingly common in East Africa. In the past, a drug regimen consisting of 2 months of intramuscular streptomycin plus 12 months of isoniazid and thiacetazone has been used in tuberculosis control programs with acceptable efficacy and low incidence of adverse reactions. Anecdotal reports of increasing cases of Stevens-Johnson syndrome prompted a 2 month prospective search for cases of severe cutaneous hypersensitivity reactions at Muhimbili Medical Centre in Dar es Salaam, Tanzania. Five such patients were admitted to a single ward during this time, 4 of whom were HIV-seropositive and all of whom were being treated with isoniazid and thiacetazone. These findings have implications for the management of tuberculosis in East Africa and perhaps other countries with high prevalence of both HIV-1 and tuberculosis.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Simultaneous patient-side measurement of hemoglobin, glucose, and cholesterol in finger-stick blood.

We describe a multianalyte assay system for patient-side use comprising single-use plastic cartridges and a small monitor. Hemoglobin, glucose, and cholesterol can be simultaneously measured in 3 min in an unmeasured volume of blood. The sample is drawn by capillary action into four channels for delivery to assay-specific stacks containing a set of closely apposed layers. The distal layer is a membrane that acts as the optical surface for reflectance optics. For glucose and cholesterol assays, erythrocytes are removed by a fibrous filter layer and oxidase-peroxidase chemical reactions contained in the optical membrane generate a colored product. For hemoglobin measurement, blood is lysed by detergent contained in a porous disk. The amount of color reaching the optical membrane is measured by fiber optics. To ensure fail-safe operation, sensors verify sample sufficiency and degree of hemolysis. The assays perform comparably with laboratory methods.

Blood Glucose↗
PubMed1992

Factors associated with veterans' decisions about living wills.

Most states have adopted legislation that allows patients to designate by advance directives the type of health care they would like to receive if they should become incompetent while suffering from a terminal illness. The living will is one of the most common of these legal instruments. Unlike most studies that have examined very sick or hospitalized patients' preferences regarding life-sustaining treatments, our study explores the concerns of 70 ambulatory veterans from a general medical clinic regarding living wills. Before the interview, 43% of patients reported never having heard of living wills. At interview, 4% of the patients had a living will, 33% intended to sign a living will but had not done so (INTEND), 54% were undecided about living wills (UNDECIDED), and 9% did not want a living will. Compared with UNDECIDED patients, all other patients did not differ in the use of health care services during the previous year or in diagnoses. INTEND patients, however, were significantly more likely to be white, to express poorer health status, to know someone with a living will, and to have previously discussed the topic. UNDECIDED patients were more likely than INTEND patients to report that religious beliefs about living wills affected their decision. Virtually all (91%) of the respondents believed that signing a living will would not affect their treatment. These data suggest that many patients may not know that they can have a living will and that discussions with those who already have a living will may be helpful in educational programs designed to promote informed patient decision-making.

Aged↗