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Biomedical subjects

D Barnard

Publications and source records attributed to D Barnard.

At least 55 records · Page 3Linked to original sources
PubMed1994

Critical binding and regulatory interactions between Ras and Raf occur through a small, stable N-terminal domain of Raf and specific Ras effector residues.

Genetic and biochemical evidence suggests that the Ras protooncogene product regulates the activation of the Raf kinase pathway, leading to the proposal that Raf is a direct mitogenic effector of activated Ras. Here we report the use of a novel competition assay to measure in vitro the relative affinity of the c-Raf-1 regulatory region for Ras-GTP, Ras-GDP, and 10 oncogenic and effector mutant Ras proteins. c-Raf-1 associates with normal Ras and the oncogenic V12 and L61 forms of Ras with equal affinity. The moderately transforming mutant Ras[E30K31] also bound to the c-Raf-1 regulatory region with normal affinity. Transformation-defective Ras effector mutants Ras[N33], Ras[S35], and Ras[N38] bound poorly. In contrast, the transformation defective Ras[G26I27] and Ras[E45] mutants bound to the c-Raf-1 regulatory region with nearly wild-type affinity. A stable, high-affinity Ras-binding region of c-Raf-1 was mapped to a 99-amino-acid subfragment of the first 257 residues. The smallest Ras-binding region identified consisted of N-terminal residues 51 to 131, although stable expression of the domain and high-affinity binding were improved by the presence of residues 132 to 149. Deletion of the Raf zinc finger region did not reduce Ras-binding affinity, while removal of the first 50 amino acids greatly increased affinity. Phosphorylation of Raf[1-149] by protein kinase A on serine 43 resulted in significant inhibiton of Ras binding. demonstrating that the mechanism of cyclic AMP downregulation results through structural changes occurring exclusively in this small Ras-binding domain.

Cyclic AMP-Dependent Protein Kinases↗
PubMed1993

A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura.

Fifty-three children, aged 7 months to 14.4 years and with typical acute immune thrombocytopenic purpura and platelet counts < or = 20 10(9)/L, were randomly assigned to receive intravenously administered immune globulin G (IVIG), 1 gm/kg per day for 2 consecutive days (n = 19); orally administered prednisone, starting at a dose of 4 mg/kg per day, with tapering and discontinuation of corticosteroids by day 21 (n = 18); or no therapy (n = 16). Both IVIG and prednisone resulted in significantly fewer days with platelet counts < or = 20 x 10(9)/L in comparison with no therapy (median, 1 and 2 days vs 4 days; corresponding ranges, 1 to 20 and 1 to 11 days vs 1 to 132 days; p < 0.01). Reversal of clinically important thrombocytopenia assessed by the number of days taken to achieve a platelet count of > or = 50 x 10(9)/L was significantly faster in children randomly assigned to receive IVIG (median, 2 days; range, 1 to 34 days) than in those receiving prednisone (median, 4 days; range, 2 to 13 days; p < 0.001) or no therapy (median, 16 days; range, 2 to 132 days; p < 0.001). Because the risk of intracranial hemorrhage in children with acute immune thrombocytopenic purpura is highest in the group with severe thrombocytopenia, and appears to be restricted to children with platelet counts < or = 20 x 10(9)/L, these results support the use of IVIG or high doses of prednisone as initial therapy in children with acute immune thrombocytopenic purpura and severe thrombocytopenia (platelet counts < or = 20 x 10(9)/L).

Administration, Oral↗
PubMed1993

Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study.

PURPOSE: Childrens Cancer Group (CCG) protocol 2861 was designed to test the feasibility of aggressively timed induction therapy followed by autologous or allogeneic bone marrow transplantation (BMT) as the sole postremission therapy for newly diagnosed children with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Between April 1988 and October 1989, 142 patients were eligible for study. All patients entered received a timing-intensive five-drug induction of dexamethasone, cytarabine (Ara-C), thioguanine, etoposide, and daunorubicin (DCTER) over 4 days with a second cycle administered after 6 days of rest, irrespective of hematologic status at that time. Most patients subsequently received a second two-cycle induction course. Those who achieved remission were eligible for bone marrow ablative therapy with busulfan and cyclophosphamide, followed by 4-hydroperoxy-cyclophosphamide (4-HC)-purged autologous or allogeneic BMT rescue. RESULTS: One hundred eight (76%) patients achieved remission: 19 (13%) died of complications of the leukemia and/or chemotherapy, and 15 (11%) failed to achieve remission. Seventy-four patients subsequently underwent BMT with either autologous (n = 58) or allogeneic (n = 16) rescue. For patients who received autologous rescue with 4-HC-purged grafts, the actuarial disease-free survival (DFS) rate at 3 years from the day of transplant is 51%, compared with 55% for patients who received allogeneic grafts (P = .92). At 3 years, the overall actuarial survival rate for all 142 patients entered on this study is 45%, with an event-free survival (EFS) rate of 37%. Adverse prognostic factors for outcome included an elevated WBC count or the presence of CNS leukemia at the time of AML diagnosis. CONCLUSION: Results suggest that aggressively timed induction therapy followed by marrow ablation and BMT rescue with either autologous or allogeneic grafts for children with newly diagnosed AML or MDS is both feasible and effective.

Actuarial Analysis↗
PubMed1992

Reflections of a reluctant clinical ethicist: ethics consultation and the collapse of critical distance.

The obvious appeal and growing momentum of clinical ethics in academic medical centers should not blind us to a potential danger: the collapse of critical distance. The very integration into the clinical milieu and the processes of clinical decision making, that clinical ethics claims as its greatest success, carries the seeds of a dilution of ethics' critical stance toward medicine and medical education. The purpose of this paper is to suggest how this might occur, and what potential contributions of ethics to medicine might be sacrificed as a result. Medical sociology will be used for comparison. Sociologists have found that they may function either as students and critics of established medical practices and educational philosophies, or as collaborative participants in them--but rarely both. It may be that professional ethics is most effective when it plays the role of 'stranger' rather than insider, and is continually able to question the most basic assumptions and values of the enterprise with which it is associated. As with medical sociology, ethics and humanities must ask to what extent their desire for acceptance in the clinic requires their acceptance of the clinic: specifically, acceptance of basic assumptions about optimal ways of organizing medical education, socializing physicians-in-training, providing care, and even of defining medical ethics itself. The paper concludes by recommending that ethics reassert its 'strangeness' in the medical milieu even as it assumes a more prominent role within the medical center.

Clinical Medicine↗
PubMed1992

A multicenter study of the treatment of childhood chronic idiopathic thrombocytopenic purpura with anti-D.

We evaluated the effects of the intravenous administration of anti-D, an immune globulin directed at the D antigen on erythrocytes that is purified from plasma from sensitized persons, on patients with idiopathic thrombocytopenic purpura. To determine the most effective dose, the duration of response, and the side effects of this therapy in children, we performed a multicenter cohort study of escalating doses of intravenously administered anti-D in children aged 1 to 18 years with chronic idiopathic thrombocytopenic purpura, defined as idiopathic thrombocytopenic purpura persisting for more than 6 months with a platelet count of less than 50 x 10(9) cells/L. Twenty-five Rh-positive children received increasing doses of anti-D as follows: day 1, 25 micrograms/kg; day 2, 25 micrograms/kg; day 7, 35 micrograms/kg; day 14, 45 micrograms/kg; and day 21, 55 micrograms/kg. Administration of anti-D was stopped after day 21 or when the platelet count rose to greater than 150 x 10(9) cells/L or the hemoglobin level was 100 gm/L. Platelet count was less than 50 x 10(9) cells/L in all children before treatment. A response was defined as an increase in the platelet count to more than 50 x 10(9)/L and a doubling of the pretreatment platelet count. Of 25 children, 23 (92%) had responses by day 7 of the initial treatment protocol. Eighteen children (72%) had platelet counts greater than 150 x 10(9) cells/L by day 7 after two doses of anti-D. Median duration of response was 5 weeks (range 1 to 24 weeks). Average drop in hemoglobin level was 13.7 gm/L; in one child (a nonresponder) hemoglobin value fell to less than 100 gm/L. No other untoward side effects were seen. Of the 23 children who responded, 21 were retreated with one dose of anti-D when platelet counts returned to baseline values of less than 50 x 10(9) cells/L; all but three of the children who underwent retreatment showed a response the second time. Sixteen children continued to receive intermittent anti-D therapy after completion of the study, and all continued to have excellent responses. We conclude that anti-D is a safe, effective, and relatively inexpensive therapy for childhood chronic idiopathic thrombocytopenic purpura.

Adolescent↗
PubMed1990

Scope and limitations of orthognathic surgery.

Modern orthognathic surgical procedures allow correction of bony disproportion in almost any part of the face, but are limited in the fine tuning of tooth position and occlusion. However, carefully planned combined surgical and orthodontic treatment can produce dental and skeletal results of a high standard. If a GDP is presented with a malocclusion beyond the scope of normal orthodontic treatment, then referral to an oral surgery/orthodontic clinic is indicated. This article provides an overview of what the team on such a clinic can achieve.

Adult↗
PubMed1989

Serum cholinesterase isoenzymes and the WHHL rabbit: the relationship between the activity of cholinesterase not bound to low-density-lipoprotein and lipoprotein titer.

Serum cholinesterase has been previously shown to complex with beta-lipoprotein in the plasma. Since serum cholinesterase exists as isoenzymes in plasma, the relationship between the activity of these isoenzymes (unbound to beta-lipoprotein) and lipoprotein titer was investigated. The results indicated that the total of C2, C3, and C4 isoenzyme activities were expressed within a narrow range and independent of low density lipoprotein titer. These findings may indicate that unbound plasma cholinesterase may undergo autoregulation independent of cholinesterase bound to beta-lipoprotein.

Animals↗
PubMed1989

Teaching medical ethics in its contexts: Penn State College of Medicine.

Ethics teaching at The Pennsylvania State University College of Medicine began when the medical school accepted its first students in 1967. The ethics program co-evolved with the school and the Department of Humanities without guidelines or models, since neither medical ethics nor medical humanities had yet been invented as fields of study. The focus of the article is on two key differences between the Penn State ethics program and most other such programs: the teaching of medical ethics within the context of other issues of value and meaning in medicine, and the fact that the humanities faculty is involved in the activities and structures of the medical center of which the medical school is a part. The authors close with a description of successful factors in their program that they maintain could apply to other programs.

Bioethical Issues↗
PubMed1988

Mandibular pathology presenting as a parotid tumour.

Swelling in the parotid region is often the presenting sign of a tumour of salivary gland origin. However, the possibility of disease involving adjacent structures must always be considered. Three cases are presented where pathology of the mandibular ramus presented as swelling in the parotid region. A clinical diagnosis of a parotid tumour was made, parotidectomy scheduled, and in two cases carried out before the correct diagnosis was reached. Difficulties of differential diagnosis are discussed, and imaging techniques reviewed. The value of plain radiographs of the adjacent hard tissues is emphasised. Careful interpretation should be based on a sound understanding of pathology of the jaws.

Aged↗
PubMed1988

Love and death: existential dimensions of physicians' difficulties with moral problems.

Physicians often appear more troubled by moral dilemmas than would seem justified given the present social and professional consensus on many of the questions involved. Their discomfort arises not only at ethical, technical, and behavioral levels (the most commonly identified sources of difficulty), but also at an existential level, that is, as the manifestation of conflicts rooted in the processes and conditions of our coming-to-be as persons. Analysis of this level of physicians' moral difficulties requires renewed attention to the physician as a person, and suggests new perspectives on the interpersonal environment of medical practice.

Bioethical Issues↗
PubMed1988

The apparent reversal of a wasting syndrome by nutritional intervention in Saguinus mystax.

One hundred eighty sexually mature Saguinus mystax were imported from Peru in six lots over a period of 1 year. Within 1 year after arrival, the mortality was 60% and the majority of the tamarins showed signs similar to "wasting marmoset syndrome" (WMS). In an effort to improve the survival rate, an open formula diet replaced the commercial closed formula diet that had been fed since arrival of the tamarins. The open formula diet contained 26.2% crude protein, 12.3% ether extract, 43.3% nitrogen free extract and 5.9% crude fiber on a dry matter basis. The diet was evaluated on the basis of palatability, weight gain, mortality, digestibility, nitrogen balance, serum biochemical parameters and blood counts. The mean daily consumption on an as-is basis was 44.8g or 335 Kcal gross energy/Kg of body wt./day. During the 3 month open formula diet evaluation period average weight increased by 56g (p less than .05), mortality decreased demonstratively, and alopecia and chronic diarrhea were nearly eliminated. Mean daily gross energy intake for S. mystax (335 Kcal/Kg of body wt/day) was substantially greater than previously reported values for callitrichids. WMS signs observed in the S. mystax colony were controlled by providing what appears to be an adequate diet.

Animal Feed↗
PubMed1988

Residency ethics teaching. A critique of current trends.

There is a growing effort to formalize ethics teaching for medical residents. Currently, this effort is overemphasizing a single approach--the clinical ethics consultation or ethics case conference--at the expense of several other important options. While the clinical ethics approach has many benefits, it also has harmful side effects when it is made the single method for residency ethics teaching: it constricts ethics teaching within too narrow a view of medical ethics, and it forfeits an opportunity for ethics to challenge some problematic features of residency education itself.

Clinical Clerkship↗
PubMed1987

The viability of the concept of a primary health care team: a view from the medical humanities.

To question the viability of the concept of a primary health care team implies at least the possibility that something about the nature of primary care, and about the nature of giving care in teams, places the two in conflict. In fact, a number of interesting and provocative questions concerning primary health care teams are in the areas of ethics and professional values. Primary care is inherently a 'moral notion', and when the concept of the health care team is yoked to that of primary care, the team takes on the normative coloration of primary care. This occurs at two levels. At a societal and professional level, the concept of a primary health care team depends on extra-professional values (e.g. a society's understanding of the requirements of social justice, funding priorities for health services, or the perceived worth of particular patient populations), and professional values such as autonomy and authority. At the level of face-to-face clinical encounters, questions arise as to a team's ability to maintain interpersonal and moral accountability to patients and society. Future research on the functioning of health care teams should focus more on these normative issues, rather than on the bureaucratic and logistical dimensions of team care that currently predominate in the professional literature.

Behavioral Research↗