Specialisation in oral surgery.
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Humans↗
Biomedical subjects
D Barnard
Publications and source records attributed to D Barnard.
The coevolution of bioethics and the medical humanities with palliative medicine, 1967-1997.
The Department of Humanities that I chair at the Pennsylvania State University College of Medicine was the first such department ever established at any medical school. It opened in 1967. In that same year, St. Christopher's, the first modern hospice, opened in London. Merely a coincidence? I do not think so. The forces that propelled bioethics and the humanities into medical education were the same forces that called the modern hospice movement into being. Over the past three decades, both movements have evolved together, nourishing each other and challenging each other. This essay will sketch three phases in the coevolution of bioethics and the medical humanities on the one hand, and hospice and palliative medicine on the other. The first phase I will call the common matrix of concern. The second phase I will call the elaboration of the concept and practice of "whole person care." The third phase I will call the era of public policy and corporate medicine.
Journal Article↗
Reading and teaching social medicine. [Review of: Henderson GE; King NMP; Strauss RP; Estroff SE; Churchill LR. The social medicine reader. Duke University Press, 1997].
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Education, Medical↗
Heme compounds in dinosaur trabecular bone.
Six independent lines of evidence point to the existence of heme-containing compounds and/or hemoglobin breakdown products in extracts of trabecular tissues of the large theropod dinosaur Tyrannosaurus rex. These include signatures from nuclear magnetic resonance and electron spin resonance that indicate the presence of a paramagnetic compound consistent with heme. In addition, UV/visible spectroscopy and high performance liquid chromatography data are consistent with the Soret absorbance characteristic of this molecule. Resonance Raman profiles are also consistent with a modified heme structure. Finally, when dinosaurian tissues were extracted for protein fragments and were used to immunize rats, the resulting antisera reacted positively with purified avian and mammalian hemoglobins. The most parsimonious explanation of this evidence is the presence of blood-derived hemoglobin compounds preserved in the dinosaurian tissues.
Animals↗
Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling.
Activation of the Raf serine/threonine protein kinases is tightly regulated by multiple phosphorylation events. Phosphorylation of either tyrosine 340 or 341 in the catalytic domain of Raf-1 has been previously shown to induce the ability of the protein kinase to phosphorylate MEK. By using a combination of mitogenic and enzymatic assays, we found that phosphorylation of the adjacent residue, serine 338, and, to a lesser extent, serine 339 is essential for the biological and enzymatic activities of Raf-1. Replacement of S338 with alanine blocked the ability of prenylated Raf-CX to transform Rat-1 fibroblasts. Similarly, the loss of S338-S339 in Raf-1 prevented protein kinase activation in COS-7 cells by either oncogenic Ras[V12] or v-Src. Consistent with phosphorylation of S338-S339, acidic amino acid substitutions of these residues partially restored transforming activity to Raf-CX, as well as kinase activation of Raf-1 by Ras[V12] or v-Src. Two-dimensional phosphopeptide mapping of wild-type Raf-CX and Raf-CX[A338A339] confirmed the presence of a phosphoserine-containing peptide with the predicted mobility in the wild-type protein which was absent from the mutant. This peptide could be quantitatively precipitated by an antipeptide antibody specific for the 18-residue tryptic peptide containing S338-S339 and was demonstrated to contain only phosphoserine. Phosphorylation of this peptide in Raf-1 was significantly increased by coexpression with Ras[V12]. These data demonstrate that Raf-1 residues 338 to 341 constitute a unique phosphoregulatory site in which the phosphorylation of serine and tyrosine residues contributes to the regulation of Raf by Ras, Src, and Ras-independent membrane localization.
Amino Acid Sequence↗
A phase I trial to assess the value of recombinant human granulocyte colony stimulating factor (R-MeTHuG-CSF, filgrastim) in accelerating the dose rate of chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma (NHL). The Central Lymphoma Group.
In a multi-centre phase I study we investigated the possibility of reducing the interval between courses of standard CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mgs day 1, and prednisolone 40 mg/m2 days 1-8) from 21 days to 15 days and then 10 days using granulocyte colony stimulating factor (r-MetHuG-CSF (Amgen)-filgrastim) to accelerate neutrophil recovery. Patients received CHOP followed by G-CSF 5 micrograms/kg s.c. from day 2 to the day before the next course (e.g. days 2-14 for the 15-day interval). A total of 28 patients with newly diagnosed intermediate grade or high grade NHL were studied. Four patients were studied at a 21-day interval, six patients were treated at a 15-day interval and subsequently six patients at a 10-day interval. Following analysis of this initial cohort, a further 12 patients were evaluated; four at the 15-day interval, and eight at the 10-day interval. No dose-limiting toxicity was seen in the four patients receiving 21-day CHOP. Dose-limiting toxicity was seen in 4/10 patients treated at the 15-day interval (M:F 7:3, median age 55.5, range 39-67 years). This consisted of infection in two patients, recurrent infection and debility in a third, and mucositis in a fourth. Seven patients experienced one or more infectious episodes requiring antibiotics (median number of episodes: 2, range 1-4). Fourteen patients (M:F 4:3, median age 47.5, range 25-63 years) were treated at the 10-day interval. Dose-limiting toxicity was seen in six patients. This consisted of severe mucositis in three patients, neutropenia and thrombocytopenia on two separate occasions in one patient, and steroid-induced gastritis in two patients. Nine patients had one or more documented infections (median: 2, range 1-3) requiring antibiotics, of which six were severe (WHO grade 3 or 4). One patient died of Pneumocystis carinii (PCP) pneumonia. In summary, G-CSF (filgrastim) will facilitate the shortening of the dosage interval between cycles of CHOP chemotherapy due to accelerated hematological recovery. However, non-hematological toxicity due to the shorter dosage interval is increased and infective episodes are frequent.
Adult↗
Susceptibility of Actinomyces israelii to antibiotics, sodium hypochlorite and calcium hydroxide.
Actinomyces israelii has been repeatedly implicated as a cause of failure of endodontic therapy. This study investigated the antimicrobial effect of antibiotics as well as intracanal medicaments, sodium hypochlorite solution and calcium hydroxide, on this important pathogen. Growth of A. israelii was inhibited by low concentrations of antibiotics, yet high concentrations were not bactericidal for A. israelii over 1 week. When A. israelii was exposed for 2-6 weeks at concentrations equivalent to clinical serum levels, the antibiotics were lethal. The results reveal a species-specific antibiotic tolerance for A. israelii. Both sodium hypochlorite solution and calcium hydroxide were found to be highly effective in killing A. israelii.
Actinomyces↗
Identification of the sites of interaction between c-Raf-1 and Ras-GTP.
Specific sites of protein-protein interaction were identified in the 51-149 region of c-Raf-1 using contact epitope scanning and site-directed mutagenesis. Nineteen overlapping peptides based upon the primary sequence of the Ras binding domain of c-Raf-1 were tested for the ability to competitively inhibit complex formation between Ras-GTP and the c-Raf-1 N-terminus. A peptide containing c-Raf-1 residues 91-105 as well as five overlapping peptides covering a region extending from residues 118 to 143 interfered with Ras association, defining these sites as potential contact surfaces with Ras. Alanine scanning mutagenesis was used as a second probe for sites of Ras interaction with the c-Raf-1 N-terminus. Raf residues 64-67 and 80-103 were demonstrated as important for association with Ras-GTP with residues 66, 67, 84, 87, 89 and 91 identified as the most critical individual points of contact with the Ras protein. Alanine substitution of residues between 118-143 suggested only one potentially weak site of interaction defined by residues 120-125. The combined results of both peptide and mutagenic analyses suggest that the primary site of c-Raf-1 interaction with Ras maps to Raf residues 80-103, with secondary interactions occurring with residues 66 and 67 and possibly 120-125. Contact epitope scanning of the Ras effector region found maximum inhibition of Ras/Raf association with a peptide corresponding to Ras amino acids 37-51. A model is proposed for the GTP-dependent association of Ras and Raf.
Amino Acid Sequence↗
A Streptococcus mutans mutant that synthesizes elevated levels of intracellular polysaccharide is hypercariogenic in vivo.
We used the streptococcal transposon, Tn916 to identify and isolate mutants of Streptococcus mutans with altered intracellular polysaccharide (IPS) accumulation. We report on the isolation and characterization of S. mutans SMS202, a transposon mutant which accumulated the glycogen-like IPS in excess of wild-type levels. Southern blot analysis confirmed a single Tn916 insertion into the SMS202 chromosome. Moreover, quantitative ultrastructural analysis revealed significantly increased concentrations of IPS in SMS202 relative to those of the wild-type progenitor strain, UA130. The activities of ADPglucose pyrophosphorylase (GlgC) and glycogen synthase (GlgA), enzymes required for the biosynthesis of bacterial IPS, were also elevated in the IPS excess mutant. Furthermore, SMS202 was significantly more cariogenic on the molar surfaces of germ-free rats than the wild type (P < 0.01), thus confirming a central role for IPS in S. mutants-induced caries formation. We propose that the increased cariogenic potential of SMS202 is due to constitutive expression of genes which encode glycogen biosynthesis in this oral pathogen. The coordinate expression of GlgC and GlgA along with the results of ongoing nucleotide sequence analysis and Northern hybridization experiments support an operon-like arrangement for the glg genes of this oral pathogen.
Amino Acid Sequence↗
Toward a person-centered medicine: religious studies in the medical curriculum.
The role of religious studies in the medical curriculum derives from three important aspects of people's engagement with religious belief and practice. These are (1) religion as a source of meaning, (2) religion as a source and framework for values, and (3) religion as an outstanding context for the appreciation of human diversity. By offering separate religious studies courses, or by introducing religious themes and content into students' other learning experiences, the curriculum can foster the student's respect for the individuality of the patient in his or her cultural context; heighten the student's awareness of the patient's--and his or her own--beliefs, values, and faith as resources for dealing with illness, suffering, and death; help students address any of the myriad value-laden aspects of everyday living that are part of the context of many doctor-patient encounters; and strengthen the student's commitment to a person-centered medicine that emphasizes the care of the suffering person rather than the biology of disease. The authors discuss the strengths and limitations of several settings for the teaching of religious issues in medicine, and suggest specific pedagogical approaches, readings, and resources.
Cultural Diversity↗
The promise of intimacy and the fear of our own undoing.
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Emotions↗
Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura.
The most serious complication of childhood acute immune thrombocytopenic purpura (ITP), intracranial haemorrhage, occurs in about 1% of children with platelet counts below 20 x 10(9)/L. We conducted a randomised study to explore three treatment options in this high-risk group. 146 children (> 6 months and < 18 years old) with typical acute ITP and platelet counts of 20 x 10(9)/L or lower were randomised to receive high-dose intravenous immunoglobulin G (IVIgG) 1 g/kg on 2 consecutive days (n = 34), 0.8 g/kg once (n = 35), intravenous anti-D 25 micrograms/kg on 2 consecutive days (n = 38), or oral prednisone 4 mg/kg per day with tapering and discontinuation of prednisone by day 21 (n = 39). The rate of response as reflected by the number of days with platelet counts at 20 x 10(9)/L or lower and the time taken to achieve a platelet count 50 x 10(9)/L or more was significantly faster for both IVIgG groups than for the anti-D group (p < 0.05); the difference between prednisone and IVIgG was significant (p < 0.05) only for the IVIgG 0.8 g/kg group, and responses to the two IgG groups were similar. These differences in response rates were reflected in the percentages of children with platelet counts of 20 x 10(9)/L or lower at 72 hours following the start of treatment: 3% (IVIgG 0.8 g/kg x 1), 6% (IVIgG 1 g/kg x 2), 18% (anti-D), and 21% (oral prednisone 4 mg/kg/day). Treatment-associated toxicities included a fall in haemoglobin with anti-D (to less than 100 g/L in 24% of cases); weight gain with oral prednisone; and fever, nausea, vomiting, and headache with IVIgG. On the basis of these results, intravenous anti-D cannot be recommended as initial therapy for children with acute ITP and platelet counts of 20 x 10(9)/L or lower. A single dose of 0.8 g/kg IVIgG offers the fastest recovery for the least treatment; additional IgG or oral prednisone can be reserved for the one-third of children who continue to have platelet counts of 20 x 10(9)/L or less at 48-72 hours after the start of treatment.
Adolescent↗
The internal compartmentation of rat-liver mitochondria: tomographic study using the high-voltage transmission electron microscope.
The three-dimensional organization of the internal compartments of conventionally fixed and embedded rat-liver mitochondria has been determined by tomographic reconstruction from tilt-series images collected on the Albany high-voltage electron microscope. The results indicate that the inner membranes of these organelles are predominantly tubular in the orthodox (expanded matrix) conformation, as previously suggested by scanning electron microscopy. In the condensed (contracted matrix) conformation, the intracristal space opens up into large irregularly shaped compartments which are connected to each other and to the external (intermembrane) space by tubes with approximately the same diameter (20 nm) as those observed in the orthodox state. These results raise several questions, in particular about the nature of the structural transitions that occur in the cristae during matrix expansion and contraction, and about the influence of inner-membrane shape on the diffusion of ions and metabolites between the intracristal and intermembrane compartments.
Animals↗
Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE.
Deep vein thrombosis (DVT) and pulmonary embolism (PE) occur in pediatric patients; however, the incidence, associated morbidity, and mortality are unknown. A Canadian registry of DVT and PE in children (ages 1 month to 18 years) was established July 1, 1990 in 15 tertiary-care pediatric centers. One-hundred thirty-seven patients were identified prospectively and are the subject of this report. The incidence of DVT/PE was 5.3/10,000 hospital admissions or 0.07/10,000 children in Canada. Infants under 1 year old and teenagers predominated with equal numbers of both sexes. DVT were located in the upper (n = 50) and lower (n = 79) venous system, or as PE alone (n = 8). Central venous lines (CVLs) were present in approximately 33% of children with DVT (n = 45). Associated conditions were present in 96% of children and 90% of children had two or more associated conditions for DVT. DVT was diagnosed by venography (n = 83), duplex ultrasound (n = 37), and other combinations (n = 17). Twenty-two of the 31 ventilation/perfusion scans performed were interpreted as high-probability scans for PE. Therapy consisted of heparin (n = 115), thrombolysis (n = 15), surgical removal of a CVL or thrombus (n = 22), and oral anticoagulant therapy (n = 103). Significant bleeding complications did not occur. However, three (2.2%) children died as a direct consequence of their thromboembolic disease; DVT reoccurred in 23 children and postphlebitic syndrome (PPS) occurred in 26. In conclusion, DVTs occur in a significant number of hospitalized children with a mortality of 2.2%. Complications are not hemorrhagic, but thrombotic, and characterized by PE, recurrent disease, and PPS. In contrast to adults, the upper venous system is frequently affected because of the use of CVLs. The frequency of DVT/PE justifies controlled trials of primary prophylaxis in high-risk groups, and therapeutic trials to determine optimal treatment.
Administration, Oral↗
Citation for the presentation of the 1994 De Puy Surgical Prize to Tony Markus.
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Awards and Prizes↗
Making a place for the humanities in residency education.
The residents' retreat brings the process of medical humanities teaching into closer alignment with some of its most important purposes. The retreat format offers an opportunity to pursue profound and challenging aspects of residency education in more depth than is possible in the usual in-hospital teaching settings. The setting and pace of the retreat foster an attitude of reflection and heightened self-awareness for the residents; expose them to the values, insights, and feelings of their peers and faculty mentors; and lay a foundation for follow-up activities at the medical center that can involve more residents than can be accommodated at the retreat itself.
Faculty, Medical↗
GATA-1 is expressed in acute erythroblastic leukaemia.
Previous studies have demonstrated the expression of GATA-1 (a DNA-binding nuclear protein) in erythrocytes, megakaryocytes, eosinophils, basophils, mast cells, early marrow progenitor cells and in mouse and human erythroid leukaemia cell lines. We studied 31 bone marrow specimens from patients with acute myeloid leukaemia (AML) for GATA-1 expression by reverse transcriptase/polymerase chain reaction (RT/PCR) analysis. GATA-1 expression was detected in all of the patients with erythroleukaemia, and in one of nine patients with megakaryoblastic leukaemia, but absent from 17 patients with French-American-British (FAB) M1-5 leukaemia. In AML, GATA-1 expression is indicative of differentiation to the erythroid and possibly megakaryocytic lineages, analogous to its expression in normal haemopoiesis.
Bone Marrow↗