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Biomedical subjects

K Arthur

Publications and source records attributed to K Arthur.

At least 19 recordsLinked to original sources
PubMed2005

Phenotypic changes in mitochondrial membrane potential (Delta psi(m)) during valinomycin-induced depolarisation and apoptosis.

A large body of evidence has implicated mitochondria in control of cell death, where key apoptotic mechanisms involve change in mitochondrial membrane permeability and depolarisation of mitochondrial membrane potential (Delta psi(m)). Assessment of Delta psi(m) is traditionally conducted using the lipophilic cation JC-1 on the flow cytometer or by fluorescent microscopy. Here we assess JC-1 aggregation using the novel tool of digital texture analysis to establish mitochondrial phenotypic changes induced by the K+ ionophore, valinomycin in a unique model comprising SW480 and SW620 cell lines. This provides an opportunity to study these phenomena in the context of colorectal cancer. Valinomycin-induced apoptosis was detected using morphology and analysis of DNA content. Cells were treated with valinomycin, images digitally recorded on a calibrated video photometer and subjected to high resolution digital texture analysis. This demonstrated that the HARAM texture features (Mean of the Haralick texture features) were highly valuable in describing the transition of Delta psi(m) as the cell undergoes apoptosis. In conclusion this study illustrates the potential of texture analysis as a novel and additional technique for quantifying JC-1 aggregation and revealing the spectrum of collapse of Delta psi(m) during apoptosis.

Apoptosis↗
PubMed2000

Management of aggressive histologic variants of endometrial carcinoma at the Tom Baker Cancer Centre between 1984 and 1994.

OBJECTIVE: The aim of this study was to determine the patient characteristics and outcome of patients with aggressive histologic variants (AV) of endometrial carcinoma, including uterine papillary serous carcinoma (UPSC), uterine clear cell carcinoma (UCCC), and mixed type. METHODS AND MATERIALS: All cases with AV histological type of endometrial carcinoma from January 1984 to December 1994 at the Tom Baker Cancer Centre were identified using the Alberta Cancer Registry. Relevant data from the charts of these patients were entered into a study database (Microsoft Excel) and analyzed for presentation, demography, treatment parameters, and outcome of treatment. All pathology was reviewed at the time of diagnosis. Statistical analysis was performed using the S-plus statistics computer program. Univariate and multivariate analyses were used to assess independent prognostic factors using the Cox proportional hazards model. RESULTS: A total of 103 patients with AV histological type were identified and analyzed; there were 61, 31, and 11 cases of UPSC, CCC, and mixed tumors, respectively. Sixty-three patients had Stage I, 11 had Stage II, 15 had Stage III, and 14 had Stage IV disease. The median age of patients was 67 years with a range of 36 to 86 years. Median follow-up was 60 months with a range of 36 to 156 months. The Cox proportional hazards model showed that lymphvascular space invasion and stage are the two independent prognostic factors affecting recurrence and survival. Forty six percent of all cases underwent surgery alone, 39% underwent treatment which included pelvic RT, and 17% underwent treatment which included chemotherapy. Pelvic recurrence was reduced significantly by radiotherapy in Stages I, II, and III (19% recurrence with no RT vs 7% recurrence with RT, P < 0.005). Chemotherapy improved overall survival, but made little difference in distant relapse rates. CONCLUSIONS: Stage Ia cases treated by surgery alone have a low risk of relapse and need not be offered adjuvant systemic therapy or pelvic radiation. Patients with Ib, Ic, II, and III have significantly lower pelvic failure rates if treated with pelvic radiation, but still have a high distant failure rate. Systemic therapy did not significantly improve distant relapse-free survival, but did extend overall survival. Stage IV patients usually died within 6 months with a few responding to systemic chemotherapy. These results suggest that there is a need for randomized trials for these patients.

Adenocarcinoma, Clear Cell↗
PubMed1998

The utility of chest radiography in the follow-up of pneumonia.

AIM: We conducted this study to determine whether chest radiography was clinically useful in the follow-up of uncomplicated pneumonia affecting children aged between 6 weeks and 15 years. METHOD: We examined the case records of all 78 paediatric admissions for pneumonia to our hospital over one year. Thirteen children were excluded on account of age or other complicating factors. RESULTS: Of the 65 study cases, the mean age was 3.5 years (range 0.4-13 years). On admission 51 (79%) had cough, 53 (82%) fever, 53 (82%) tachypnoea and 50 (77%) had abnormal chest signs. Elevation of C reactive protein was recorded in 43 (66%) cases and leukocytosis in 42 (65%). All children received initial chest radiographs which showed unilobular/lobar changes in 34 (53%), bilobar changes in 19 (29%) and diffuse abnormalities in 7 (11%). Forty-one patients were followed up both clinically and radiologically, usually (31 cases) between four and six weeks after discharge. Thirty-seven children had no abnormal symptoms or signs and had normal chest radiographs. The remaining four had symptoms and signs, their radiographs showed either slight resolution or no change from the admission films. CONCLUSION: In cases of uncomplicated pneumonia, follow-up chest radiography should be deferred until at least four weeks after discharge and is not indicated if symptoms and signs are absent.

Adolescent↗
PubMed1998

The FGF receptor-1 tyrosine kinase domain regulates myogenesis but is not sufficient to stimulate proliferation.

Ligand-stimulated activation of FGF receptors (FGFRs) in skeletal muscle cells represses terminal myogenic differentiation. Skeletal muscle cell lines and subsets of primary cells are dependent on FGFs to repress myogenesis and maintain growth. To understand the intracellular events that transduce these signals, MM14 skeletal muscle cells were transfected with expression vectors encoding chimeric receptors. The chimeras are comprised of the PDGF beta receptor (PDGFbetaR) extracellular domain, the FGFR-1 intracellular domain, and either the PDGFbetaR or FGFR-1 transmembrane domain. The chimeric receptors were autophosphorylated upon PDGF-BB stimulation and are capable of stimulating mitogen-activated protein kinase activity. Activation of the tyrosine kinase domain of either chimera repressed myogenesis, suggesting intracellular responses regulating skeletal muscle differentiation are transduced by activation of the FGFR-1 tyrosine kinase. Unexpectedly, we found that activation of either chimeric receptor failed to stimulate cellular proliferation. Thus, it appears that regulation of skeletal muscle differentiation by FGFs requires only activation of the FGFR tyrosine kinase. In contrast, stimulation of proliferation may require additional, as yet unidentified, signals involving the receptor ectodomain, the FGF ligand, and heparan sulfate either alone, or in combination.

Animals↗
PubMed1998

Cell proliferation studies in primary synovial chondromatosis.

Primary synovial chondromatosis (PSC) is thought to be a cartilaginous metaplasia, but it may recur locally and malignant change has been reported. Histologically, the cartilage is usually cellular, with binucleate forms. These findings suggest that the disease is not simply a metaplasia but imply a proliferative component. In this study, immunohistochemical detection of Ki-67 protein using an antigen retrieval microwave heating technique and DNA image cytometry (VIDAS image analysis system) has been used to assess the proliferative activity in 20 cases of PSC and the results have been compared with those obtained in other cartilage tissues: ten enchondromas, ten chondrosarcomas, and ten samples of normal articular cartilage. There was no detectable staining for Ki-67 protein in cases of PSC or in benign tissues, but there was a significant association between Ki-67 labelling index and grade in the chondrosarcomas (P < 0.01). The absence of mitotic figures and the lack of Ki-67 protein in PSC are consistent with a metaplasia. All enchondromas gave diploid DNA histograms but non-diploid histograms were obtained i eight cases (40 per cent) of PSC, with significant populations of hyperdiploid and DNA aneuploid cells. The mean DNA content, the percentage of hyperdiploid cells, the percentage of DNA aneuploid cells, and the 2c deviation index were all significantly higher in PSC than in enchondromas (P < 0.01). These findings with image cytometry suggest a proliferative process in the development of at least some cases of PSC. In terms of cell proliferative activity, PSC appears to occupy a position which is intermediate between benign enchondromas and malignant chondrosarcomas, which may explain the aggressive clinical behaviour occasionally seen in this condition.

Bone Neoplasms↗
PubMed1998

Comparison of p53 and DNA content abnormalities in adenocarcinoma of the oesophagus and gastric cardia.

This study examined the association between 17p allelic loss, p53 gene mutation, p53 protein expression and DNA aneuploidy in a series of adenocarcinomas arising in the oesophagus and gastric cardia. 17p allelic loss was detected in 79% (15 of 19) of oesophageal and in 83% (29 of 35) of gastric adenocarcinomas. p53 mutations were detected in 70% (14 of 20) and 63% (26 of 41) of oesophageal and of gastric adenocarcinomas respectively. Both tumour types were associated with a predominance of base transitions at CpG dinucleotides. In five cases of oesophageal adenocarcinoma, the same mutation was detected both in tumour and in adjacent dysplastic Barrett's epithelium. Diffuse p53 protein expression was detected in 65% (13 of 20) and 59% (24 of 41) of oesophageal and of gastric tumours, respectively, and was associated with the presence of p53 missense mutation (Chi-squared, P < 0.0001). DNA aneuploidy was detected in 80% (16 of 20) of oesophageal and in 70% (28 of 40) of gastric tumours. No association was found between p53 or DNA content abnormalities and tumour stage or histological subtype. In conclusion, this study detected a similar pattern of p53 alterations in adenocarcinoma of the oesophagus and gastric cardia--molecular data consistent with the observation that these tumours demonstrate similar clinical and epidemiological features.

Adenocarcinoma↗
PubMed1998

Benefit of aggressive multimodality therapy with autologous stem cell support for intra-abdominal desmoplastic small round cell tumor.

A case is described of a 19-year-old man with poor prognosis intra-abdominal desmoplastic small round cell tumor, who achieved a durable complete remission after aggressive multimodality treatment. He was diagnosed with a large peri-rectal mass and bulky metastases to the peritoneum, omentum and liver. He achieved a partial response to six courses of chemotherapy with VAC (vincristine, adriamycin, actinomycin, cyclophosphamide) and VIP (VP-16, ifosfamide, cisplatin). This was followed by resection of the omentum and cryotherapy to six of the liver lesions. He then achieved a complete response following high-dose busulfan 16 mg/kg and melphalan 140 mg/m2 with autologous stem cell support. Finally, pelvic radiotherapy was given to consolidate the remission. Twenty-six months following his diagnosis, and 19 months after the transplant, he remains well with no clinical or radiologic evidence of recurrent disease. This case report suggests a role for autologous stem cell transplantation as part of multimodality therapy for this unusual and aggressive malignancy.

Abdominal Neoplasms↗
PubMed1998

Cellular proliferation and nuclear ploidy assessments augment established prognostic factors in predicting malignancy in testicular Leydig cell tumours.

AIMS: Testicular Leydig cell tumours are rare. Although most behave benignly approximately 10% are malignant. Clinicopathological features have been described which have some value in predicting malignant behaviour, although as with other endocrine tumours uncertainties remain in many individual cases. Our aim was to determine the clinicopathological features of 20 testicular Leydig cell tumours. We wished to investigate whether, in addition to established clinicopathological features, the MIB1 index and/or flow cytometric analysis of nuclear DNA content are of value in predicting malignancy. We also wished to investigate the frequency of p53 protein accumulation in these neoplasms. METHODS AND RESULTS: Twenty testicular Leydig cell tumours were studied and the clinical case notes examined. Histological sections were assessed by pathologists involved in the study. Pathological features evaluated included: tumour size, extratesticular extension, nuclear pleomorphism, mitotic activity, necrosis and vascular invasion. Immunohistochemical staining was performed with the anti-p53 monoclonal antibody DO-7 and the cell proliferation marker MIB1. A flow cytometric analysis of nuclear DNA content was also performed. Three tumours behaved in a malignant fashion with the development of metastases. Another had morphological features of malignancy but the patient died a short time after diagnosis from unrelated causes. These four neoplasms were larger than benign tumours, often contained areas of necrosis and sometimes exhibited vascular invasion. They generally exhibited greater nuclear pleomorphism and a higher mitotic rate than benign tumours. Three of the four malignant tumours had a high MIB1 index (20-50%) and the fourth exhibited DNA aneuploidy by flow cytometry. Two malignant tumours showed increased expression of p53 protein, with approximately 50% of nuclei staining with DO-7. All benign tumours had a low MIB1 index (0-2%) and a diploid DNA profile, except for one case where there was DNA aneuploidy. There was little or no staining of benign tumours with DO-7. CONCLUSIONS: The study confirms that large size, marked nuclear pleomorphism, high mitotic rate, necrosis and vascular invasion are important factors in predicting malignant behaviour in testicular Leydig cell tumours. Additional prognostic value may be derived from the MIB1 index and flow cytometry. Accumulation of p53 protein, through mutational or other events, may be important in malignant progression in these tumours.

Adult↗
PubMed1996

p53 mutation, allele loss on chromosome 17p, and DNA content in ovarian carcinoma.

The aim of this investigation was to explore the relationships between p53 mutation, DNA aneuploidy, 17p deletions, and clinical stage in ovarian cancer. Nuclear suspensions were obtained by tissue disaggregation, stained with propidium iodide, and analysed on a Coulter EPICS Elite flow cytometer. DNA cell cycle analysis was performed using Multicycle software (Phoenix Flow Systems). DNA extracted from paraffin-embedded archival carcinomas/non-tumour tissue was used as template for PCR amplification of the microsatellite dinucleotide repeat polymorphism D17S513, a locus telomeric to p53 on 17p13.1. Allele loss at D17S513 was detected in 64.5 per cent of carcinomas (20 of 31 informative cases). DNA aneuploidy was detected in 20 of 54 (37 per cent) carcinomas. Eight of ten cases previously shown to harbour p53 mutations showed aneuploid DNA content. Although ten other DNA aneuploid cases had shown no p53 mutations, the results show a statistically significant association between p53 mutation and DNA aneuploidy (P < 0.01). Furthermore, the mean DNA index of the DNA aneuploid cases was significantly higher in p53 mutant cases compared with those showing no p53 mutation (P = 0.02). There was also a significant association between p53 mutations and stage, between ploidy and stage, and between allelic deletions at D17S513 or p53 and stage, but not between these allelic deletions and ploidy. p53 mutations appear to be associated with DNA aneuploidy in ovarian cancer independently of 17p deletions. p53 mutations, DNA aneuploidy, and 17p deletions are associated with late stage.

Alleles↗
PubMed1996

Flow cytometric analysis does not reliably differentiate benign from malignant phaeochromocytoma.

BACKGROUND AND OBJECTIVE: The differentiation of benign from malignant phaeochromocytoma is difficult. We have examined whether the use of flow cytometric determination of nuclear DNA content would be useful as a predictor of malignant behaviour in patients with phaeochromocytoma as some previous studies had suggested that a diploid cytometric DNA pattern indicated benign disease. DESIGN AND PATIENTS: DNA flow cytometry was performed on phaeochromocytoma tissue from 36 patients (19 female, 17 male; mean age at presentation 39.5 years). The results were correlated with clinical outcome after prolonged follow-up. MEASUREMENTS: DNA histograms were constructed following nuclear suspension analysis. RESULTS: Of 26 patients followed up for more than 5 years after initial removal of primary phaeochromocytoma, three have died from malignant recurrence. In these patients a diploid DNA cytometric pattern was observed in two and an aneuploid pattern in one. Twenty-one patients are still alive. DNA cytometry showed a diploid pattern in the one patient who developed recurrent phaeochromocytoma 4 years after removal of a primary tumour. CONCLUSION: In this study, three of nine patients with an apparently benign diploid cytometric pattern subsequently developed recurrent disease. Routine use of DNA flow cytometry did not reliably differentiate benign from malignant phaeochromocytoma. Prolonged clinical and biochemical follow-up is still necessary for all patients with this condition.

Adult↗
PubMed1996

High-dose melphalan +/- total body irradiation and autologous hematopoietic stem cell rescue for adult patients with Ewing's sarcoma or peripheral neuroectodermal tumor.

The role of high-dose therapy and autologous stem cell transplantation (ASCT) in the treatment of patients with Ewing's sarcoma (EWS) remains uncertain. From November 1985 to September 1994, 13 patients aged 16-30 years (median 20.5) received high-dose melphalan (HDM) 140-200 mg/m2 +/- 500 cGy TBI followed by ASCT for relapsed/refractory (n = 4), metastatic (n = 2), or non-metastatic (n = 6) EWS, or for peripheral neuroectodermal tumor (PNET) (n = 1). This regimen was well tolerated with no transplant-related mortality and no toxicity requiring life sustaining measures. Three of the four patients treated for relapsed/refractory EWS had progression-free survivals (PFS) less than 5 months. The only long-term survivor of these four patients received HDM while in complete remission following pulmonary irradiation. Both patients with pulmonary metastases at presentation died just 5 and 6 months post-ASCT. All four patients with non-metastatic, bulky (> 8 cm) osseous EWS progressed at a median of 11 months (range 7-22 months) while the two patients with non-bulky EWS remain progression-free 25+ and 28+ months post-HDM/TBI + ASCT. The 19-year-old patient with a PNET of the thoracoabdominal wall relapsed 4 months post-ASCT. Overall, only three of these 13 patients remain progression-free at 25+, 28+, and 108+ months following HDM +/- TBI and ASCT. In conclusion, HDM +/- TBI did not obviously improve the outcome of these 13 patients relative to that expected following conventional dose therapy alone.

Adolescent↗
PubMed1995

Simple isotope dilution assay for propionic acid and isovaleric acid.

A gas chromatographic-mass spectrometric method is described for the assay of propionic acid and of isovaleric acid in physiological fluids by isotope dilution. The acids are derivatized to the pentafluorobenzyl esters to decrease volatility to render them suitable for GC-MS analysis. The following reference values were found. Propionic acid: plasma 0.54 +/- 0.38 mumol/l (n = 13, range 0.03-1.38 mumol/l), urine 1.7 +/- 1.6 mumol/mmol creatinine (n = 9, range 0.1-4.9 mumol/mmol creatinine). Isovaleric acid: plasma 0.89 +/- 0.93 mumol/l (n = 10, range 0.01-3.03 mumol/l), urine 0.38 +/- 0.51 mumol/mmol creatinine (n = 10, range 0.01-1.70 mumol/mmol creatinine).

Creatinine↗
PubMed1995

Phase II study to evaluate the toxicity and efficacy of concurrent cisplatin and radiation therapy in the treatment of patients with locally advanced squamous cell carcinoma of the cervix.

Sixty patients presenting with poor prognosis squamous cell cancer of the cervix have been studied in a phase II clinical trial. Patients were treated with radiotherapy and concurrent cisplatin chemotherapy every 10 days. Treatment was well tolerated with all patients completing radiotherapy as prescribed. There was one case of grade 4 acute bowel toxicity. Significant late morbidity was acceptable for this group of patients being restricted to two cases (3.3%) of grade 4 toxicity to the bowel. Pelvic control rates of 78% have been observed. There have been no pelvic recurrences after 26 months, although recurrences beyond the pelvis have occurred up to 4 years later. Actuarial 4-year survival is encouraging at 60%.

Actuarial Analysis↗
PubMed1994

Role of FGFs in skeletal muscle and limb development.

Fibroblast growth factors (FGFs) are a family of nine proteins that bind to three distinct types of cell surface molecules: (i) FGF receptor tyrosine kinases (FGFR-1 through FGFR-4); (ii) a cysteine-rich FGF receptor (CFR); and (iii) heparan sulfate proteoglycans (HSPGs). Signaling by FGFs requires participation of at least two of these receptors: the FGFRs and HSPGs form a signaling complex. The length and sulfation pattern of the heparan sulfate chain determines both the activity of the signaling complex and, in part, the ligand specificity for FGFR-1. Thus, the heparan sulfate proteoglycans are likely to play an essential role in signaling. We have recently identified a role for FGF in limb bud development in vivo. In the chick limb bud, ectopic expression of the 18 kDa form of FGF-2 or FGF-2 fused to an artificial signal peptide at its amino terminus causes skeletal duplications. These data, and the observations that FGF-2 is localized to the subjacent mesoderm and the apical ectodermal ridge in the early developing limb, suggest that FGF-2 plays an important role in limb outgrowth. We propose that FGF-2 is an apical ectodermal ridge-derived factor that participates in limb outgrowth and patterning.

Animals↗
PubMed1994

Therapy with recombinant human erythropoietin in patients with myelodysplastic syndromes.

We conducted a Phase I-II trial of recombinant human erythropoietin-beta (rhEPO) in patients with myelodysplastic syndrome (MDS). Patients with anemia and pathologically confirmed MDS were eligible for the study. Treatment consisted of rhEPO by subcutaneous injection thrice weekly for 6 weeks at one of three dose levels (100 U/kg (three patients), 200 U/kg (three patients) and 400 U/kg (14 patients)). Ferrous sulfate (325 mg po tid) was also administered if the transferrin saturation was below 30% (two patients). Patients were monitored with weekly CBC, white cell differential, and reticulocyte counts. Bone marrow examinations were performed at the conclusion of the treatment period and after a 2 week washout period. Patients who responded to therapy were continued on rhEPO at the same dose for 6 additional months. Response criteria included: 50% reduction in transfusion requirements compared with the 6 week pre-study period; doubling of reticulocyte count that was maintained on two determinations at least 1 week apart; or an increase in hemoglobin by at least 1.2 gm/dl without transfusions. Pre-treatment factors potentially predictive of response were analyzed by univariate analysis and in a multivariate fashion by classification and regression trees. Seven of the twenty patients sustained an untransfused rise in serum hemoglobin > or = 1.2 gm/dl. Four of the sixteen patients (including three of seven patients experiencing a rise in serum hemoglobin) who were transfusion-dependent prior to the study achieved a reduction or elimination of their transfusion requirements. Five of thirteen patients who received rhEPO during the extension phase had a continued response. A low baseline erythropoietin level (< 50 mU/ml) was the best predictor of hemoglobin response when controlling for other variables. rhEPO has a role in the treatment of certain patients with MDS, particularly in those whose endogenous serum erythropoietin levels are not markedly elevated.

Adult↗
PubMed1994

Intraosseous infusion: success of a standardized regional training program for prehospital advanced life support providers.

STUDY OBJECTIVE: To evaluate a standardized training program in intraosseous (IO) infusion for prehospital providers. DESIGN: Prospective multicenter 24-month study. SETTING: IO infusions were performed by prehospital providers from eight advanced life support units serving 14 hospitals within nine counties. PARTICIPANTS: Field advanced life support providers (paramedics and registered nurses). INTERVENTIONS: All providers participated in a one-hour standardized training session and supervised hands-on simulation. Providers completed a data sheet on all IO infusions performed. Data sheets were collected and summarized. RESULTS: One hundred thirty-four prehospital providers completed the training session and were approved to perform the procedure. Fifteen patients requiring IO infusion were encountered during the study period. Thirteen (87%) had IO infusion completed successfully. Clinical indications included 11 patients in cardiac arrest, two trauma resuscitations, one seizure, and one toxic ingestion. Patient ages ranged from 1 to 24 months. Seven patients were initially resuscitated. Four survived to hospital discharge. Procedural complications included one incidence of local fluid extravasation and one IO line that became dislodged en route. There were no complications at time of discharge in the four survivors. All procedures were performed in less than two minutes. CONCLUSION: A one-hour standardized training session was successfully used to train prehospital providers in the procedure of IO infusion. IO infusion then was implemented into their clinical practice with a satisfactory success rate and few complications.

Child, Preschool↗
PubMed1994

Three-dimensional computerised analysis of epithelial cell proliferation in the gastrointestinal tract.

This study describes a new technique for the visualisation and quantitation of glandular epithelial cell proliferation in gastrointestinal mucosa using computerised three-dimensional reconstruction. The tissue used in this study was colorectal biopsy tissue infiltrated in vitro with bromodeoxyuridine (BrdU), although the method could be applied to any gastrointestinal site labelled with any specific marker for cell proliferation. The method is as follows. Five-micron-thick serial sections (> 100) were cut from colorectal biopsies infiltrated in vitro with BrdU. After labelling all the sections for BrdU-positive cells using standard immunohistochemistry, colorectal glands were identified which were completely sectioned within the series. Each microscopic image of the sectioned gland was orientated, digitised and stored using a Kontron image analyser. On each of the stored images, the crypt profile, the positive cells and the negative cells were interactively marked and digitally stored. Using three-dimensional (3-D) reconstruction software, the outer surface of the crypt, the total positive and the total negative fractions could be viewed in three dimensions. The total BrdU-positive cell number could be automatically calculated for the complete crypt or, alternatively, compartmental analysis of the labelling pattern within the crypt could be obtained. This represents a powerful technique: it does not require orientation, it can be carried out on complex glandular structures and is not affected by the biases involved in measuring labelling indices from single tissue sections.

Bromodeoxyuridine↗