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Biomedical subjects

N James

Publications and source records attributed to N James.

At least 19 recordsLinked to original sources
PubMed2006

A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen.

A multicentre phase II trial to determine the efficacy of vinflunine as second-line therapy in patients with advanced transitional cell carcinoma (TCC) of the bladder; secondary objectives were to assess duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients had tumours that failed or progressed after first-line platinum-containing regimens for advanced or metastatic disease, or had progressive disease after platinum-containing chemotherapy given with adjuvant or neoadjuvant intent. Response and adverse events were assessed according to WHO criteria and NCI-CTC (version 2), respectively. Out of 51 patients treated with 320 mg m(-2) of vinflunine, nine patients responded to the therapy yielding an overall response rate of 18% (95% CI: 8.4-30.9%), and 67% (95%CI: 52.1-79.3%) achieved disease control (PR+SD). Of note, responses were seen in patients with relatively poor prognostic factors such as a short (<12 months) interval from prior platinum therapy (19%, including an 11% response rate in those progressing <3 months after platinum treatment), prior treatment for metastatic disease (24%), prior treatment with vinca alkaloids (14%) and visceral involvement (20%). The median duration of response was 9.1 months (95% CI: 4.2-15.0) and the median PFS was 3.0 months (95% CI: 2.4-3.8). The median OS was 6.6 months (95% CI: 4.8-7.6). The main haematological toxicity was grade 3-4 neutropenia, observed in 67% of patients (42% of cycles). Febrile neutropenia was observed in five patients (10%) and among them two were fatal. Constipation was frequently observed (but was manageable and noncumulative) and was grade 3-4 in only 8% of patients. The incidence of grade 3 nausea and vomiting was very low (4 and 6% of patients, respectively). Neither grade 3-4 sensory neuropathy nor severe venous irritation was observed. Moreover, and of importance in this particular study population, no grade 3-4 renal function impairment was observed. Vinflunine is an active agent for the treatment of platinum-pretreated bladder cancer, and these results warrant further investigation in phase III trials, either as monotherapy or in combination with other agents as treatment of advanced/metastatic TCC of the bladder.

Adult↗
PubMed2006

Observational assessment of situation awareness, team differences and training implications.

The two goals were to investigate, first, the practicability and reliability of observational assessment of team situation awareness (SA) and, second, the nature of any team differences, their consistency and training implications. Five shift teams tackled three scenarios, each with three probe events concerning SA, and three observers viewed and rated concurrently each shift. This methodology was found to be practicable and achieved satisfactory rater reliability as indicated by intraclass and inter-rater correlations. Team differences in SA emerged although there was no consistent pattern. A retrospective analysis of individual and team behaviours relating to SA was performed using the Critical Incident Technique. A total of 75 incidents and 20 behavioural dimensions relevant to SA were identified and these were subsumed under planning, problem solving, team coordination, attention, communication and knowledge. These findings are discussed with regard to the nature and measurement of SA, and the content of training to improve SA for control room teams.

Adult↗
PubMed2005

The cost of glucocorticoid-associated adverse events in rheumatoid arthritis.

OBJECTIVE: To estimate the costs of glucocorticoid associated adverse events (GAEs) in patients with rheumatoid arthritis (RA). METHODS: We conducted a literature review of studies reporting GAEs in RA patients, and developed a Markov model with the following GAEs: fractures (vertebral, hip, pelvic), hypertension, diabetes, gastrointestinal complications, pneumonia, urinary tract infection, cataract and, in an extended model, myocardial infarction (MI) and stroke. Two-year total costs were calculated using direct medical costs (2001 US dollars [USD]) and by running 10,000 Monte Carlo simulations with probability values randomly selected from the GAE literature. RESULTS: On average, glucocorticoid users spent USD 445 more than non-users, or USD 0.46 for each dollar spent on purchasing the drug. When adding MI and stroke, users spent on average USD 430 more than non-users, or USD 0.44 for each dollar spent on purchasing the drug; this incremental cost ranged from USD 193 to USD 682 if MI and stroke were excluded, respectively. In 70% of the simulations there were more deaths among users than among non-users, in both the model with and without MI and stroke. CONCLUSIONS: Although results varied depending on attributed GAEs, in general glucocorticoid users spent more than non-users on GAE treatment, and had higher mortality. Patients, providers and policy makers should consider these potential costs of GAEs when making treatment decisions.

Arthritis, Rheumatoid↗
PubMed2004

Is gene therapy the answer for prostate cancer?

Prostate cancer is the third most common cancer, accounting for one in 10 cancer diagnoses in men worldwide during 2000. Despite this high burden of morbidity, there is a lack of curative treatments for locally advanced and metastatic disease. Good anatomical accessibility of the prostate combined with substantial molecular understanding of the disease makes prostate cancer an attractive target for gene therapy. Considerable progress has been made in the development of suitable gene transfer vectors and prostate-targeting strategies. Therapeutic approaches being explored fall into two broad categories: corrective and cytoreductive/cytolytic. There are currently 63 prostate cancer gene therapy clinical trials based on these approaches registered in the United States and United Kingdom. Although significant hurdles remain to be overcome, early clinical trial results are encouraging, suggesting that gene therapy may become an important treatment option for prostate cancer.

Clinical Trials as Topic↗
PubMed2004

The effects of creatine supplementation on cardiovascular, metabolic, and thermoregulatory responses during exercise in the heat in endurance-trained humans.

The effects of creatine (Cr) supplementation on cardiovascular, metabolic, and thermoregulatory responses, and on the capacity of trained humans to perform prolonged exercise in the heat was examined. Endurance-trained males (n = 21) performed 2 constant-load exercise tests to exhaustion at 63 +/- 5 % VO(2max) in the heat (ambient temperature: 30.3 +/- 0.5 C) before and after 7 d of Cr (20 g x d (-1 ) Cr + 140 g x d (-1 ) glucose polymer) or placebo. Cr increased intracellular water and reduced thermoregulatory and cardiovascular responses (e.g., heart rate, rectal temperature, sweat rate) but did not significantly increase time to exhaustion (47.0 +/-4.7 min vs. 49.7 +/- 7.5 min, P =0.095). Time to exhaustion was increased significantly in subjects whose estimated intramuscular Cr levels were substantially increased ("responders" : 47.3 +/- 4.9 min vs. 51.7 +/- 7.4 min, P = 0.031). Cr-induced hyperhydration can result in a more efficient thermoregulatory response during prolonged exercise in the heat.

Adaptation, Physiological↗
PubMed2003

Obituary advice.

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Biographies as Topic↗
PubMed2003

The effect of biological effective dose on time to symptom progression in metastatic renal cell carcinoma.

AIMS: Renal cell carcinoma is commonly thought to be a radioresistant malignancy. Retrospective studies report conflicting results on the effect of radiotherapy dose escalation on response and time to progression in symptomatic metastatic disease; studies using the linear quadratic model have used alpha/beta ratios that are inappropriate for slow growing tumours. We aim to describe our experience with palliative radiotherapy in this context, relating Biological Effective Dose to outcome. MATERIALS AND METHODS: From December 1995 to April 2001, 143 independent palliative radiotherapy treatments were delivered to 78 patients in a single institution. Retrospective data was obtained on the radiotherapy schedule used, symptom response and time to symptom progression. The biological effective dose (BED) was calculated using alpha/beta ratios of 3 and 7 Gy (BED3 and BED7). The Log-Rank test was used to assess any differences in time to progression, and the Cox Proportional Hazards analysis to determine prognostic factors of time to progression. RESULTS: Overall symptomatic response rate was 73%, with most responses being partial (67%). Forty-three (38%) patients had symptomatic progression after a median follow-up of 425 days. BED (BED3 or BED7) was not significantly different across response types (complete, partial or no response; P=0.90 and 0.88, respectively) and was not predictive for time to symptomatic progression (P=0.99 for BED3 and P=0.70 for BED7). Patients with bone metastases received less total dose (P=0.001), less BED (BED3, P=0.0013, and BED7, P=0.0005) and had a significantly longer time to progression than other sites of metastases (hazard ratio (HR) 0.4; 95% confidence interval (CI) 0.2-0.7; P=0.004). Initial treatment with interferon-alpha alone in patients presenting with metastatic disease, before palliative radiotherapy, was also associated with a shorter time to symptom progression (HR 4.6; 95% CI 1.5-14.1; P=0.007). On removal of these criteria, brain metastases became a significant predictor of progression time, with an HR of 2.5 (95% CI 1.0-5.9; P=0.05), showing an increased risk of progression with brain metastases compared with metastases elsewhere. Time from primary diagnosis to development of metastatic disease was not predictive of time to symptom progression (P=0.29). CONCLUSION: Despite the widespread assumption that renal cell carcinoma is radioresistant, retrospective assessment showed high response rates to palliative radiotherapy. On the basis of our data, higher BED does not seem to be a predictor of response or of duration of response in the palliative treatment of renal cell carcinoma. Palliation of bone pain seems to be particularly durable compared with the palliation of symptoms at other sites of metastases. A trend for shorter duration of palliative effect of whole-brain radiotherapy was noted.

Adult↗
PubMed2001

Mouse hepatocyte response to peroxisome proliferators: dependency on hepatic nonparenchymal cells and peroxisome proliferator activated receptor alpha (PPARalpha).

Peroxisome proliferators (PPs) are rodent nongenotoxic hepatocarcinogens that induce peroxisome proliferation and DNA synthesis, and suppress apoptosis in rodent hepatocytes. PPs act through the PP-activated receptor alpha (PPARalpha); tumour necrosis factor alpha (TNFalpha) and hepatic nonparenchymal cells (NPCs), the major source of TNF alpha in the liver, have also been implicated in mediating the rodent hepatic response to PPs. Here we investigate the interaction between PPARalpha and NPCs in regulating the response to PPs. Using normal hepatocyte cultures containing around 20% NPCs, the PP nafenopin (50 microM) induced DNA synthesis and suppressed transforming growth factor beta1-induced apoptosis. However, when the NPCs were removed by differential centrifugation, nafenopin did not induce DNA synthesis or suppress apoptosis in the pure hepatocytes. Reconstitution of the normal hepatocyte cultures by mixing together the pure hepatocytes and the previously separated NPCs in the same proportions as the original cell preparation (17.7+/-8.7% NPCs) restored the response to nafenopin. Interestingly, nafenopin was still able to induce beta-oxidation in the pure hepatocyte cultures, consistent with NPCs being required for PP-induced growth but not for peroxisome proliferation. Next, we evaluated the role of PPARalpha in the hepatocyte dependency upon NPCs. Interestingly, NPCs isolated from PPARalpha-null mice, like those isolated from the wild-type NPCs, restored the hepatocyte response to nafenopin. However, as expected, PPARalpha-null hepatocytes remained non-responsive to PPs, irrespective of the genotype of the added NPCs. These data support a role for NPCs in facilitating a response of hepatocytes to PPs that is ultimately dependent on the presence of PPARalpha in the hepatocyte.

Animals↗
PubMed2001

Educational strategies used in increasing fluid intake and enhancing hydration status in field hockey players preparing for competition in a hot and humid environment: a case study.

The purpose of the present study was to develop a hydration strategy for use by female English field hockey players at the 1998 Commonwealth Games in Malaysia. An additional aim was to initiate the process of acclimation. Fifteen elite players, mean age (+/-SEM) 24.1 +/- 1.19 years, height 1.67 +/- 0.01 m, and body mass 62.8 +/- 1.76 kg, took part in a 5-day training camp immediately prior to departure for the Games. In order to develop the hydration strategy, training took place under similar environmental conditions to those to be experienced in Malaysia (i.e., 32 degrees C, 80% humidity). Acclimation training consisted of 30-50 min of either continuous, low intensity cycling or high intensity intermittent cycling, which more closely replicated the pattern of activity in field hockey. Body mass measures taken each morning, and pre and post training, together with urine color measures, were used to assess hydration status. Pre-loading with up to 1 L of a 3% carbohydrate-electrolyte solution or water immediately prior to acclimation training, as well as regular drinks throughout, ensured that players avoided significant dehydration, with percent body mass changes ranging from -0.34% to +4.24% post training. Furthermore, the protocol used was sufficient to initiate the process of acclimation as demonstrated by a significant reduction in exercising heart rate and core temperature at all time points by days 4 and 5. In conclusion, although labor intensive and time consuming, the camp was successful in developing a hydration strategy that players were able to utilize once at the Games.

Adult↗
PubMed2000

Leptin and IGF-I levels in unconditioned male volunteers after short-term exercise.

We have previously shown that serum gonadotropins, particularly LH, decline after acute exercise in male volunteers. The mechanism for this decline is unknown. Plasma leptin and IGF-I concentrations were measured in seven male volunteers after acute exercise to exhaustion using the Bruce protocol. Leptin concentrations declined following exercise reaching nadir values 30-120 min after exercise. As anticipated, plasma IGF-I concentrations showed a transient rise immediately after exercise falling thereafter to nadir levels 60-90 min after exercise before returning towards baseline levels. In view of the previously described decline in gonadotropin release after acute exercise, the decline in plasma leptin levels, perhaps related to the rise in IGF-I, may play a role in exercise-induced inhibition of gonadotropin release presumably by inhibition of GnRH secretion.

Adult↗
PubMed2000

A common polymorphism acts as an intragenic modifier of mutant p53 behaviour.

The p73 protein, a homologue of the tumour-suppressor protein p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactivate p73. The binding of such mutants is influenced by whether TP53 (encoding p53) codon 72, by virtue of a common polymorphism in the human population, encodes Arg or Pro. The ability of mutant p53 to bind p73, neutralize p73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg. We found that the Arg-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes. Thus, inactivation of p53 family members may contribute to the biological properties of a subset of p53 mutants, and a polymorphic residue within p53 affects mutant behaviour.

Alleles↗
PubMed2000

Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators.

Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocytes, PPs cause cell proliferation, suppression of apoptosis and peroxisome proliferation. We have investigated the role of different families of mitogen-activated protein (MAP) kinases in the mode of action of PPs. Addition of 50 microM nafenopin to primary rat hepatocyte cultures caused weak activation of extracellular signal regulated kinases and p38 MAP kinase. However, incubation of primary hepatocytes with the p38 MAP kinase inhibitor SB203580 or the MAP kinase kinase (MEK) inhibitor PD098059 prevented the induction of DNA synthesis and the suppression of transforming growth factor beta(1)-induced apoptosis by the PP nafenopin. In contrast, in the presence of these MAP kinase inhibitors, nafenopin still induced palmitoyl CoA oxidation, a measure of peroxisome proliferation. We have shown previously that PPs such as nafenopin require tumour necrosis factor alpha (TNF-alpha) to exert their effects on cellular proliferation and apoptosis. Here we show that treatment of primary rat hepatocyte cultures with nafenopin causes an increase in bioactive TNF-alpha and that this process requires p38 MAP kinase activity.

Animals↗