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Biomedical subjects

T M Walker

Publications and source records attributed to T M Walker.

At least 19 recordsLinked to original sources
PubMed2002

Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer.

Nineteen breast cancer patients with measurable metastatic disease who were starting an initial or new line of therapy were evaluated for circulating epithelial cells (CECs) a minimum of 4 times over the course of treatment. In 7 of the 10 CEC+ patients, HER-2 expression was detected on the CECs. CECs expressing HER-2 varied among patients and in serial samples from the same patient including a shift from HER-2- to HER-2+ CECs. These results demonstrate that it is possible to quantify receptors essential for rationally designed therapy using CECs and that reliance on the immunophenotype of the primary tumor can be misleading.

Breast Neoplasms↗
PubMed2001

Cytochrome P450 activity in control and induced long-term cultures of rat hepatocyte spheroids.

Long-term events such as enzyme induction or chronic toxicity require long-term liver culture models that maintain activity of xenobiotic metabolising enzymes. The levels of these enzyme activities and their responsiveness to chemical induction was studied in rat hepatocyte spheroids, a potential long-term hepatocyte culture model. In comparison with other long-term liver culture models, the basal metabolic activity of spheroids has not been well studied. Additionally, no existing data on the induction of CYP3A activity in spheroids could be found. The basal xenobiotic metabolising activity of rat hepatocyte spheroids was monitored over 14 days in culture, using testosterone as a probe substrate. When spheroids from days 2-14 in culture were compared to 24-h control spheroids, there was a differential maintenance of basal CYP activity. CYP2A and CYP3A activities were maintained over the culture period, while there were time-related decreases in CYP2C11 and CYP2C/CYP2B1/2 activities. The responsiveness of rat hepatocyte spheroids to chemical induction was studied following treatment with phenobarbitone (PB) or dexamethasone (DEX). PB treatment induced CYP2A, CYP2C, CYP2B1/2 and CYP3A activities. DEX treatment resulted in an induction of CYP3A and CYP2C11 activities. The results demonstrate that rat hepatocyte spheroids retained some of the liver-specific functions essential in a long-term hepatocyte culture model, thus making spheroids comparable to other long-term culture models available.

Animal Testing Alternatives↗
PubMed2000

Gallstones in sickle cell disease: observations from The Jamaican Cohort study.

The prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones were studied in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort study from birth. Gallstones developed in 96 patients with homozygous sickle cell disease and 18 patients with sickle cell-hemoglobin C disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous sickle cell disease.

Adolescent↗
PubMed2000

The differential cytotoxicity of methotrexate in rat hepatocyte monolayer and spheroid cultures.

It is important to assess the usefulness of long-term in vitro liver models for studying chronic toxicity, since acute assays may not reflect the in vivo situation. A potential long-term hepatocyte culture (i.e. liver spheroids) was investigated and compared to primary rat hepatocyte monolayer cultures following exposure to methotrexate (MTX), a well-documented chronic hepatotoxin. Following up to 7 days' treatment with MTX, cultures were morphologically assessed and assayed for enzyme leakage, intracellular reduced glutathione (GSH) and adenosine triphosphate (ATP). Spheroids maintained higher concentrations of GSH over the 14-day culture and ATP was maintained, but at a concentration not significantly different from monolayer cultures. Treatment of monolayer cultures resulted in concentration-related decreases in GSH and ATP, accompanied by enzyme leakage. In contrast, only ATP was affected following treatment of spheroids for 7 days. Spheroids appeared to be less sensitive to exposure to MTX, when compared with monolayer cultures. This may result from the maintenance of cellular functions, or from the lack of compound penetration into the three-dimensional spheroid structure. Therefore, the usefulness of spheroids to chronic in vitro toxicity testing may be limited.

Adenosine Triphosphate↗
PubMed1999

The neurotoxic effects of methylenedioxymethamphetamine (MDMA) and its metabolites on rat brain spheroids in culture.

Rat whole-brain spheroids were used to assess the intrinsic neurotoxicity of methylenedioxy-methamphetamine (MDMA, Ecstasy) and two of its metabolites, dihydroxymethamphetamine (DHMA) and 6-hydroxy-MDMA (6-OH MDMA). Exposure of brain spheroids to MDMA or the metabolite 6-OH MDMA (up to 500 micromol/L) for 5 days in culture did not alter intracellular levels of glutathione (GSH), glial fibrillary acidic protein (GFAP) or serotonin (5-HT). In contrast, exposure to the metabolite DHMA, which can deplete intracellular thiols, significantly increased GSH levels (up to 170% of control) following exposure to 50 and 100 micromol/L DHMA. There was also a significant reduction in the levels of glial fibrillary acidic protein (GFAP) and GSH by DHMA at the highest concentration tested (500 micromol/L) but there was no effect on 5HT. This may constitute a sublethal neurotoxic compensatory response to DHMA in an attempt to replenish depleted intraneural GSH levels following metabolite exposure. Rat whole-brain spheroids may thus be a useful in vitro model to delineate mechanisms and effects of this class of neurotoxin.

3,4-Methylenedioxyamphetamine↗
PubMed1998

The identification and differential expression of calcium-binding proteins associated with ocular melanoma.

Calcium-binding proteins may endow tumor cells with properties related to their malignancy and metastatic phenotype. Chromatographic procedures and amino acid sequence analysis were used in this study to identify seven calcium-binding proteins, annexin VI, cap g, annexin V, calmodulin, S100A11, S100B and S100A6, associated with uveal melanoma, the primary ocular tumor of adults. This series of calcium-binding proteins was identified in both primary tumors and cell lines of uveal melanoma. Several of the proteins were shown by immunochemical methods to be differentially expressed between normal uveal melanocytes and malignant melanomas of the uvea. In addition, the expression of S100A6 may correlate with the malignant properties of the tumor.

Adult↗
PubMed1998

A redefined type of elbow dysplasia in the dog--2 cases.

Two dogs with calcified masses on the medial aspect of the elbow, resembling those previously reported as ununited medial humeral epicondyle, support proposed ideas that these masses arise due to calcification of flexer tendons at their origin, and that different pathogeneses are likely involved in their development.

Animals↗
PubMed1997

Taxol-mediated changes in fibrosarcoma-induced immune cell function: modulation of antitumor activities.

The anticancer drug taxol (paclitaxel) inhibits tumors through multiple cytotoxic and cytostatic mechanisms. Independently of these mechanisms, taxol induces distinct immunological efficacy when it acts as a second signal for activation of tumoricidal activity by interferon gamma (IFN gamma)-primed murine normal host macrophages. We reported that tumor-distal macrophages, which mediate immunosuppression through dysregulated nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha) production, are differentially regulated by taxol. Because taxol influences tumor cell growth dynamics and activates immune cell populations, we assessed the ex vivo immunosuppressive and antitumor activities of taxol-treated normal host and tumor-bearing host (TBH) macrophages. Pretreatment of such cells with taxol partly reconstituted T cell alloantigen reactivity, suggesting that taxol mediates a limited reversal of TBH macrophage immunosuppressive activity. Taxol-treated TBH macrophages significantly suppressed the growth of fibrosarcoma cells (Meth-KDE) through soluble effector molecules and promoted direct cell-mediated cytotoxicity, indicating that taxol enhanced tumor-induced macrophage antitumor activities. Tumor-induced helper T cells, however, showed a higher sensitivity to direct taxol-induced suppression. These data demonstrate that taxol exerts pleiotropic effects on antitumor immune responses with the capacity to abate the immunosuppressive activities of macrophages and promote macrophage-mediated antitumor activities simultaneously, but also directly modulating T cell reactivity. Collectively, these studies suggest that the antineoplastic drug taxol may impart antitumor activity through an immunotherapeutic capacity.

Animals↗
PubMed1997

Uncomplicated pregnancy following total bilateral rectus harvest: a case report.

Muscle-sparing rectus abdominis muscle harvest has been advocated to preserve abdominal wall integrity and to reduce postoperative complications and functional loss. In previous cases of pregnancy following single and bilateral rectus muscle harvest, muscle-sparing techniques were used to fortify the abdominal wall. We report a case of uncomplicated gestation and delivery following total bilateral rectus muscle harvest. While abdominal wall strength is greatly affected by rectus harvest, the fascial and tendonous components of the abdominal wall contribute substantial static integrity and elasticity. Careful repair of the donor site makes complete rectus muscle harvest an option even for women contemplating pregnancy.

Adult↗
PubMed1996

Biliary sludge in sickle cell disease.

Biliary sludge was observed in the gallbladder in 17 of 429 patients in a cohort study of sickle cell disease. Discrete gallstones later developed in 12 patients, but no stones developed in five patients; one patient with biliary sludge had no change in his condition for 5 years. None of the patients with biliary sludge had any symptoms referable to the biliary tract, and cholecystectomy has not been performed. The Jamaican experience suggests that biliary sludge may be treated conservatively, similar to our approach to asymptomatic gallstones.

Adolescent↗
PubMed1996

Renal length in sickle cell disease: observations from a cohort study.

Renal length has been measured by ultrasound in 237 subjects with homozygous sickle cell (SS) disease, 147 with sickle cell-hemoglobin C (SC) disease, and in 78 age-matched controls with a normal hemoglobin (AA) genotype. As expected, renal length increased with age in all genotypes but mean length was significantly greater in SS disease compared with SC disease (mean difference 4.3 mm after adjustment for height) and significantly greater in both genotypes than in AA controls (SS/AA difference 9.2 mm, SC/AA difference 5.0 mm after adjustment for height). Examination of relationships between renal length and some hematological indices (hemoglobin, fetal hemoglobin, reticulocyte counts, alpha thalassemia status) in SS or SC disease showed only a significant negative correlation with hemoglobin and positive correlation with reticulocyte count in SS disease. Further analysis suggested that the stronger relationship was between renal length and high reticulocyte count. The mechanism of renal enlargement is unknown although glomerular hypertrophy and increased renal blood volume are likely contributors.

Adolescent↗
PubMed1995

Induction of macrophage suppressor activity by fibrosarcoma-derived transforming growth factor-beta 1: contrasting effects on resting and activated macrophages.

Tumor-derived transforming growth factor-beta 1 (TGF-beta 1) suppresses several immune responses. Because tumor growth induces macrophage (m phi) suppressor activity, we determined whether murine fibrosarcoma-derived TGF-beta 1 contributed to m phi-mediated suppression of autoantigen- and alloantigen-stimulated T cell proliferation. The murine fibrosarcoma Meth-KDE cell line constitutively produced TGF-beta 1. Meth-KDE tumor-bearing host (TBH) syngeneic splenic m phi s suppressed autoantigen- and alloantigen-stimulated normal host (NH) CD4+ T cell proliferation. Pretreatment with Meth-KDE supernatants induced NH m phi s to suppress T cell proliferation as much as TBH m phi s. Anti-TGF-beta 1 antibody treatment reversed Meth-KDE-induced NH m phi-mediated suppression. Recombinant TGF-beta 1-induced m phi-mediated suppression was not blocked during inhibition of prostaglandin E2 (PGE2), nitric oxide (NO), or TGF-beta 1 production. However, Meth-KDE-induced m phi-mediated suppression was partly reduced when PGE2 production was inhibited. Pretreatment with tumor cell-derived TGF-beta 1, but not recombinant TGF-beta 1, increased activated m phi PGE2 production. These results show that additional tumor-derived molecules aid in TGF-beta 1-enhanced PGE2 production. Also, TGF-beta 1 alone up-regulates m phi synthesis of suppressor molecules that are different from PGE2, NO, and TGF-beta 1. Although TGF-beta 1 has direct suppressor activity on lymphocytes, these results show that release of tumor cell TGF-beta 1 also induces m phi suppressor activity.

Animals↗
PubMed1995

Increased renal reflectivity in sickle cell disease: prevalence and characteristics.

Renal ultrasound appearances have been examined in 315 patients with sickle cell disease aged 10-20 years, followed in a cohort study from birth. There were three different echo patterns. A normal appearance (type 1) occurred in 235 (75%) of all subjects, and in 159/179 (89%) with homozygous sickle cell (SS) disease. A diffuse increase in reflectivity throughout the kidney (type 2), similar to that of adjacent liver, occurred in 17 patients (5%). Widespread confluent or focal increase in reflectivity confined to the renal medulla (type 3) occurred in 63 (20%) of the total group, and was much more common in the mild genotypes of sickle cell-haemoglobin C disease (41/111, 37%) and sickle cell-beta+ thalassaemia (15/19, 79%) than in SS disease (5/179, 3%). We speculate that type 2 changes may reflect diffuse glomerular and interstitial fibrosis, and that type 3 resembles changes seen in sub-clinical nephrocalcinosis, and could be due to iron deposition.

Adolescent↗
PubMed1995

Potential neurotoxicity of a novel aminoacridine analogue.

1. A class of compounds, 9-aminoacridines, have long been known to be reversible inhibitors of acetylcholinesterase (AChE-EC 3.1.1.7), the most familiar of which is 9-amino-1,2,3,4-tetrahydroacridine (Tacrine). 2. A novel aminoacridine was synthesised: -2-tertiary-butyl-9-amino-1,2,3,4- tetrahydroacridine (2tBuTHA). 3. In vitro comparisons of the acetylcholinesterase inhibitory potential and neurotoxicity compared to Tacrine were performed using a chemically differentiated neuroblastoma cell line (Neuro 2A). 2tBuTHA, but not Tacrine, was cytotoxic to the neural cell following 20 h exposure, despite being the least potent AChE inhibitor (IC80 AChE 12.53 microM +/- 1.14 s.e.m., Neutral Red Uptake IC50 9.53 microM +/- 0.98 s.e.m., MTT Reduction IC80 14.6 microM +/- 1.43 s.e.m.). 4. In vivo studies used a novel application of a five arm radial maze to assess neuropharmacological effects on working memory in control and Scopolamine (1 mg kg-1 i.p.) treated mice. There was an impairment of short term cognitive function with 2tBuTHA (15 mg kg-1 i.p.), but not Tacrine (10 mg kg-1 i.p.) which improved the Scopolamine deficit as expected. 5. This combined in vitro and in vivo data infers a neurotoxic property for the novel compound 2tBuTHA, a close structural analogue of Tacrine.

Aminoacridines↗
PubMed1994

Tumor growth alters T cell and macrophage production of and responsiveness to granulocyte-macrophage colony-stimulating factor: partial dysregulation through interleukin-10.

Tumor growth induces phenotypic and functional changes among splenic T cells and macrophages (M phi) that contribute to the immunosuppression observed in tumor-bearing hosts (TBH). These changes partly arise through alterations in immune cell production of and responsiveness to cytokines. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important T cell- and M phi-derived cytokine that is produced during normal host immunogenic challenge, but it's involvement during cancer is poorly defined. In contrast, interleukin-10 (IL-10) is an inhibitory cytokine that is produced by immune cells as a deactivation factor. IL-10 can disrupt GM-CSF synthesis and may be associated with tumor-induced changes in cytokine synthesis. We determined if tumor growth alters T-cell and M phi synthesis of and responsiveness to GM-CSF, and if these alterations occur because tumor growth heightens immune cell sensitivity to IL-10. Tumor growth significantly decreased T-cell synthesis of GM-CSF during activation by concanavalin A, and TBH T cells were more susceptible to GM-CSF synthesis inhibition by IL-10 than their normal host (NH) counterparts. This suppression was observed using both unseparated splenic lymphocyte preparations and purified CD4+ and CD8+ T cells. Similarly, TBH M phi (both splenic and peritoneal) produced less GM-CSF than NH M phi during activation by lipopolysaccharide. Tumor growth also altered major histocompatibility complex (MHC) class II- M phi GM-CSF synthesis. TBH M phi were more susceptible to GM-CSF synthesis inhibition by IL-10 than their NH counterparts. Although TBH T cells demonstrate less proliferation than NH T cells during activation, tumor growth did not compromise T-cell responsiveness to GM-CSF. However, tumor growth did increase TBH T-cell susceptibility to inhibition of proliferation by IL-10. Tumor growth suppressed M phi responsiveness to GM-CSF, and IL-10 further decreased M phi responsiveness to GM-CSF. Collectively, these results suggest that T cell and M phi production of and responsiveness to GM-CSF is disrupted during tumor growth, and that TBH T cells and M phi are more susceptible to the suppressor activity of IL-10 than their NH counterparts.

Animals↗
PubMed1993

An assessment of Gd-DTPA as a CT contrast agent in the renal tract.

Intravenous gadolinium diethylene triamine penta-acetic acid (Gadopentetate dimeglumine, Gd-DTPA) is visualized as a radiographic contrast agent in the renal tract on computed tomography (CT). In this study the CT appearance of this contrast agent within the renal collecting systems of 12 patients is described following a Gd-DTPA enhanced magnetic resonance imaging (MRI) study. The CT appearances are variable and not predictable on the basis of time from injection, age, sex or indices of renal function.

Adult↗
PubMed1993

Focal echogenic lesions in the spleen in sickle cell disease.

Focal echogenic lesions in the spleen were observed in 11 patients aged 9-17 years with sickle cell disease. All lesions were spherical and could be single or multiple. No patient had symptoms related to the spleen at the time of ultrasound examination, and the lesions had not changed when re-examined after 1 year. Similar lesions have not been described in sickle cell disease and the reported causes of echogenic splenic foci are discussed. It is suggested that, when seen in sickle cell disease, these foci are likely to have a benign cause, and that further investigation, especially for malignant disease, is not necessary.

Adolescent↗