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Biomedical subjects

L Levitt

Publications and source records attributed to L Levitt.

At least 19 recordsLinked to original sources

Rural origin and rural medical exposure: their impact on the rural and remote medical workforce in Australia.

Australia, like many countries, finds it difficult to recruit enough medical practitioners to live and work in rural and remote communities. Over the last decade the Australian Commonwealth Government has invested in a national strategy to train its medical workforce to encourage recruits to rural and remote general practice. This strategy is based on overseas experience that rural origin students, and those experiencing early and repeated rural exposure during training, are more likely to practise in a rural location. The importance of rural origin as a predictor of rural practice is well documented in the literature. More recent studies have tended to focus on rural exposure during both undergraduate and early postgraduate years, and on developing rural curricula in a multifaceted approach to medical training. All 11 medical schools in Australia have modified their selection criteria to encourage students from rural and remote locations, and have, to a varying degree, encouraged rural exposure in parallel with developing uniquely rural content in their curricula. Many of these initiatives are quite recent and have not yet been thoroughly evaluated against their success in addressing shortages in the rural and remote medical workforce. The aim of the review is to explore how the relationship between rural origin and rural exposure during undergraduate and postgraduate training and choice of practice location has underpinned initiatives in medical education in Australia in the years 1990-2003.

Journal Article↗

Operative treatment of acetabular fractures through the extensile Henry approach.

OBJECTIVE: The purpose of this study was to evaluate the previously unreported application of the extensile Henry approach to the operative treatment of acetabular fractures. METHODS: Thirty-one cases were retrospectively reviewed at an average follow-up of 18.5 months. RESULTS: There were 8 simple and 23 complex associated fracture patterns. The average operative time was 4.5 hours, and the average blood loss was 1,160 mL. Reduction was anatomic in 26 patients (84%), satisfactory in 4 patients (13%), and unsatisfactory in 1 patient (3%). Radiographic results at follow-up were 25 excellent results, 4 good results, and 2 poor results. Twenty-six patients reported no limitation of ordinary activities, whereas five patients had to modify their activities because of pain. No heterotopic ossification occurred in 24 patients (77%). In the seven patients with heterotopic ossification, only one patient had a significant decrease in hip range of motion. Additional complications were two cases of superficial wound infection, one case of hardware failure, and two cases of avascular necrosis of the femoral head. There were no iatrogenic injuries to the sciatic nerve, nor was there any development of flap necrosis. CONCLUSION: The extensile Henry approach is a versatile approach offering an excellent exposure for surgical treatment of acetabular fractures. The rate of complications is comparable with or lower than that of other surgical approaches. By providing a direct exposure of the posterior pelvis, the extensile Henry approach has the advantage of minimizing the risk of iatrogenic injury to the sciatic nerve. In addition, the incidence of clinically significant heterotopic ossification may be reduced through the use of low-dose radiation prophylaxis.

Acetabulum↗

Differential production of interleukin-3 in human T lymphocytes following either CD3 or CD2 receptor activation.

Interleukin-3 (IL-3) is expressed in T lymphocytes and stimulates the growth of multipotent hematopoietic progenitors. Little is known, however, about the stimuli that lead to IL-3 protein release. We examined IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression and protein secretion in human T lymphocytes following activation via the TCR/CD3 complex, the CD2 receptor, and the IL-2 receptor. GM-CSF mRNA expression and protein release were found in CD3 and CD2 activated T cells with maximum GM-CSF release following stimulation with IL-2. IL-3 protein release is regulated via the CD2 receptor with virtually no IL-3 release after T cell stimulation via CD3. In contrast, IL-3 mRNA accumulation is more pronounced after CD3 activation than after CD2 activation. This suggests that upregulation of IL-3 protein release following T cell stimulation via CD-2 occurs largely at the translational or posttranslational level. These data also indicate that differential control of cytokine production can occur in response to activation of the alternative T cell receptor. Interaction of the T cell CD2-receptor with its natural ligand LFA-3 expressed on stromal cells might represent a regulatory mechanism for rapid release of IL-3, facilitating proliferation of multipotent hematopoietic cells.

CD2 Antigens↗

Biology and treatment of adult acute lymphoblastic leukemia.

The molecular analysis of acute lymphoblastic leukemia (ALL) has provided exciting insights into the pathogenesis of this disease. This disease is heterogenous and can be subtyped based on chromosomal, immunophenotypic, and structural criteria. The varying prognostic implications of different ALL subtypes markedly influence the treatment decisions in adults. Many patients with T-cell ALL can be cured with chemotherapy alone. In contrast, patients with early B-lineage ALL with certain chromosomal abnormalities, especially the Philadelphia chromosome, do not have durable responses to chemotherapy and should receive a bone marrow transplantation if an HLA-matched donor is available. Recent reports have shown improved results for adults with B-cell ALL (Burkitt's) after intensive alternating cycles of chemotherapy containing high doses of methotrexate and cyclophosphamide. Future clinical and laboratory investigation should lead to the development of novel and possibly more effective treatments specifically tailored for different subsets of ALL.

Adult↗

The murine interleukin-3 receptor alpha subunit gene: chromosomal localization, genomic structure, and promoter function.

The interleukin-3 receptor (IL-3R) is composed of alpha and beta subunits, members of the class I cytokine receptor family. Here we describe isolation and characterization of the chromosomal gene for the mouse IL-3R alpha subunit (mIL-3R alpha). Whereas the human IL-3R alpha gene is tightly linked with the granulocyte-macrophage colony-stimulating factor receptor alpha subunit (GM-CSFR alpha) gene in the pseudoautosomal region of the X and Y chromosomes, the mIL-3R alpha gene (II3ra) is located in the proximal region of mouse chromosome 14, separated from the mouse GM-CSFR alpha gene, which is on chromosome 19. The mIL-3R alpha gene spans about 10 kb and is divided into 12 exons. All the exon-intron boundaries possess the splicing junction consensus sequences (5'GT-AG3'), and the whole genomic structure is similar to those of the previously reported class I cytokine receptor genes. There are two major transcription initiation sites that are located at 215 and 188 nucleotides upstream of the initiator codon. The promoter region is GC-rich and contains potential binding sites for GATA, Ets, c-myb,, Sp1, Ap-2, and G-C boxes, but not a typical TATA or CAAT sequence. A fusion gene containing 0.8 kb of the 5' noncoding sequence linked to the firefly luciferase gene directed the transcription in mouse mast cells but not in fibroblasts or T cells, suggesting that this promoter functions in a cell type-specific manner. Further sequential deletion of the 5' region suggests two potential regulatory regions for transcription of the mIL-3R alpha gene.

3T3 Cells↗

Overexpression of mitogen-activated protein kinase (ERK1) enhances T-cell cytokine gene expression: role of AP1, NF-AT, and NF-KB.

Transfected Jurkat cells overexpressing extracellular signal-regulated kinase (ERK1), also referred to as mitogen-activated protein (MAP) kinase, were selected by Western blotting assay using anti-ERK1 and antiphosphotyrosine antibodies in combination with a functional MAP kinase assay. We then asked whether enhanced ERK1 expression had any effect on induction of T-cell cytokine genes. The results show that overexpression of ERK1 enhances expression of T-cell interleukin-2 (IL-2), IL-3, and granulocyte-macrophage colony-stimulating factor mRNA; no change was seen in expression of the alpha-actin gene. DNA-binding activities of the transcription factors AP1, NF-AT, and NF-kB were specifically increased twofold to fourfold in ERK1-overexpressing clones relative to nontransformed or vector-transformed cells, whereas no enhancement of CK1-CK2 protein DNA binding activity was detected after ERK1 overexpression. Additionally, increased NF-AT DNA binding activity was associated with functional enhancement of NF-AT transactivating activity in ERK1-overexpressing cells. These results provide direct evidence for the role of MAP kinase in the regulation of cytokine gene expression and indicate that such regulation is likely mediated through the enhanced DNA binding activity of specific nuclear transcription factors.

Base Sequence↗

Transcriptional regulation of interleukin 3 (IL3) in primary human T lymphocytes. Role of AP-1- and octamer-binding proteins in control of IL3 gene expression.

We have investigated the molecular and biochemical basis for activation of interleukin 3 (IL3) gene expression in primary human T lymphocytes following CD3 and CD2 receptor stimulation or activation by phytohemagglutinin plus phorbol 12-myristate 13-acetate. Using transfection and reporter gene assays specifically designed for primary T lymphocytes in conjunction with gel retardation assays, Western blot analyses and UV cross-linking studies, we found that c-Jun, c-Fos, and octamer-binding proteins play a major role in transcriptional activation of the IL3 gene via their interaction with two specific regions contained within the IL3 5'-flanking sequence. Additionally, the region between bases -107 and -59 of the IL3 promoter containing putative AP-2 and Sp1 binding motifs appears necessary for basal level expression of the IL3 gene. The data also indicate that CD2 receptor activation and phytohemagglutinin plus phorbol 12-myristate 13-acetate stimulation augment T cell IL3 gene expression through the same cis- and trans-activating signals. These results should contribute to a better understanding of the regulation of IL3 gene expression in human T lymphocytes.

Antibodies, Monoclonal↗

Microsurgical free bone transfer in the dog.

Bone grafts have been used extensively for the reconstruction of skeletal injury in dogs. Cancellous and corticocancellous chip autografts are used for their osteoinductive and osteoconductive properties. Fresh, fresh-frozen, freeze-dried, and ethylene oxide-sterilized cortical allografts have been recommended for the reconstruction of segmental cortical defects. Donor sites for microsurgical bone transfer have been identified experimentally in the dog, but these remain to be used clinically. This paper reviews the anatomy and structural characteristics of donor sites for microsurgical bone transfer. Potential clinical indications for microsurgical bone transfer in the dog are described.

Animals↗

Differential regulation of lymphokine production by distinct subunits of the T cell interleukin 2 receptor.

Most biologic responses to IL-2 have been attributed to interaction of IL-2 with a high affinity receptor which consists of a heterodimer composed of two distinct IL-2-binding proteins (IL-2R alpha/IL-2R beta). However, both low affinity IL-2R alpha (55 kD) and intermediate affinity IL-2R beta (70-75 kD) also appear to be expressed independently on the cell surface. We investigated the receptor-specific regulatory effects of IL-2 on cytokine production in unstimulated and activated T cells. T cells were activated by stimulation of the antigen receptor complex with anti-CD3 mAb. IL-2 (10(2) U/ml, 1 nM) stimulation of resting cells resulted in a fivefold increase in GM-CSF release but in only minimal IFN-gamma release. IL-2 markedly augmented mRNA expression of GM-CSF but not IFN-gamma in unstimulated T cells. IL-2R beta mAb but not IL-2R alpha mAb decreased IL-2-induced GM-CSF release and mRNA expression from unstimulated T cells. IL-2 concentrations required for GM-CSF release from resting cells suggested ligand binding to an intermediate affinity receptor. GM-CSF and IFN-gamma release from activated T cells increased four- to fivefold in response to 1 nM IL-2 and IL-2 augmented both GM-CSF and IFN-gamma mRNA. IL-2R beta mAb but not IL-2R alpha mAb reduced GM-CSF release and mRNA expression in activated T cells stimulated with 1 nM IL-2. IL-2R alpha blockade markedly decreased IL-2-induced IFN-gamma release and mRNA expression from activated cells, while IL-2R beta blockade had little effect on IFN-gamma production in activated cells. IL-2R alpha blockade altered the affinity of the receptor mediating activated cell GM-CSF release from a high affinity to an intermediate affinity state. These studies indicate an independent role for IL-2R beta in mediating GM-CSF production from T cells. They also suggest that unstimulated and activated T cells, which express distinct IL-2 receptor moieties, mediate release of separate lymphokines and that different subunits of the IL-2 receptor may play an important role in the regulation of cytokine production.

Antibodies, Monoclonal↗

Primary intraosseous fibrosarcoma in a cat.

A primary intraosseous fibrosarcoma was diagnosed in a 1.5-year-old cat. Clinical signs included nonweight-bearing lameness of the right forelimb and signs of pain on palpation of the right elbow. Radiography of the right elbow revealed a well-circumscribed osteolytic lesion of the olecranon. The right fore-limb was amputated, and histologic examination revealed tumor invasion into local veins and metastasis to the axillary lymph nodes. The cat had no signs of tumor redevelopment or pulmonary metastatic disease one year after amputation.

Amputation, Surgical↗

[Lymphokine-induced suppression of erythropoiesis by normal T lymphocytes and retrovirus-associated lymphoproliferative disease].

Activation of genes for interleukin 2 (IL2) and its receptor by the tat gene product of the human retrovirus HTLV-I has been linked to the pathogenesis of adult T cell leukemia. In earlier studies we have demonstrated that IL2-induced inhibition of erythropoiesis is mediated by activated T-Lymphocytes expressing the IL2-receptor. We have now examined the role of activated T cells and interferon-gamma (IF gamma) in inhibition of normal erythropoiesis and in HTLV-I associated lymphoproliferative disease. T cells were activated by triggering of the antigen receptor complex with CD3 monoclonal antibody. Incubation with CD5 antibody recognizing a T cell epitope distinct from the antigen receptor served as a control. Supernatants derived from CD3 activated T cells generated in the presence of IL2 caused a dose-dependent suppression of erythropoiesis. Treatment of supernatant interferon-gamma neutralizing antibody caused a greater than 95% abrogation of inhibition. Next we investigated the mechanisms for acquired pure red cell aplasia in a patient with T gamma-lymphoproliferative disease (T gamma-LPD). Patient marrow erythroid progenitors were 17 +/- 9% of control and increased to 88-102% of control following marrow T cell depletion. Myeloid progenitors were normal. Patient suppressor T cells inhibited growth of autologous and allogeneic marrow erythroid but not myeloid progenitors and produced high titers of IF gamma. The inhibitory factor in patient T cell supernatant was acid labile and sensitive to trypsin, consistent with properties of IF gamma. Prior depletion of activated T cells abrogated the suppressive effect of patient T cell-derived supernatant.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Aplastic↗

Unsuccessful surgical repair of a short soft palate in a dog.

An 8-week-old male Miniature Schnauzer had nasal discharge of milk, food, and water since birth, especially during eating. Examination of the oral cavity revealed a short soft palate. Numerous unsuccessful surgical procedures were performed to construct a shelf of tissue to prevent oronasal reflux. The dog was euthanatized.

Animals↗

The T-cell CD2 determinant mediates inhibition of erythropoiesis by the lymphokine cascade.

We examined the role of the T-cell antigen CD2 in the regulation of erythropoiesis by the lymphokine cascade. T-cell interleukin-2 (IL-2) receptors (p55) were induced via triggering of the antigen receptor-associated CD3 epitope. Before CD3 triggering T cells were preincubated with a CD2-blocking (Leu-5b) or isotype control antibody. T-cell pellets were employed during incubation to facilitate interaction between T-cell LFA-3 and CD2. CD2 blockade caused a 66% to 79% inhibition of p55 expression after three to six days of culture with IL-2. Next we assessed the effect of CD2 blockade on IL-2. Next we assessed the effect of CD2 blockade on IL-2-induced inhibition of BFU-E in autologous cocultures containing CD3-triggered T cells. IL-2 caused a dose-dependent inhibition (52% to 92%) of BFU-E in the presence but not in the absence of CD3-triggered T cells. T-cell CD2 blockade prior to CD3 triggering caused a 65% to 87% abrogation of IL-2-induced inhibition of BFU-E at 10 to 10(2) U/mL IL-2. Preincubation of CD3-triggered T cells with isotype control antibody had no effect on IL-2-induced erythroid inhibition. Day 3 supernatants from CD3-triggered T cells or CD2-blocked, CD3-triggered T cells established in the presence of IL-2 were next assessed for modulation of BFU-E. CD3-triggered T-cell supernatants caused a 77% +/- 9% inhibition of BFU-E. Blockade of CD2 caused a 95% abrogation of T-cell-mediated BFU-E inhibition. In addition, CD2 blockade reduced interferon-gamma (IF gamma) release (84 to 128 U/mL) from CD3-triggered T cells by 81% at day 3 of culture. In control experiments, the addition of IF gamma-neutralizing monoclonal antibody to CD3-triggered T-cell supernatant established in the presence of IL-2 caused 75% abrogation of IL-2 inhibition of BFU-E. We conclude that blockade of the CD2 T-cell determinant induces down modulation of (a) T-cell p55 IL-2 receptor expression, (b) IL-2-induced inhibition of BFU-E, and (c) IL-2-induced marrow T-cell IF gamma release. These data suggest that the T-cell CD2 determinant can exert a regulatory effect on the control of erythropoiesis by the lymphokine cascade.

Antigens, Differentiation↗