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J R Farndon

Publications and source records attributed to J R Farndon.

At least 19 recordsLinked to original sources
PubMed2006

Insulin-like growth factors (IGF) I and II utilize different calcium signaling pathways in a primary human parathyroid cell culture model.

BACKGROUND: In most cell types, influx of calcium (Ca2+) induces a growth or secretory response. The opposite occurs in parathyroid (PTH), cells where there is an inverse relationship between intracellular Ca2+ concentration and PTH secretion. We have examined the effects of calcium channel and metabolism modulators on insulin-like growth factors (IGFs) in a parathyroid cell culture model. METHODS: Cell cultures were prepared from 9 patients undergoing operation for hyperparathyroidism. Following adhesion, the cells were transferred to serum-free medium and dosed with IGF I, II +/- ethyleneglycol-bis(beta-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), nifedipine, nickel, 2-aminoethoxy-diphenylborate (2-APB), or dantrolene. Proliferation (96 hours) was assessed by measuring tritiated thymidine incorporation and PTH release (1 and 3 hours) assayed by IRMA. RESULTS: Both IGF I and II increased DNA synthesis to 162.8% +/- 10.6% (SEM) and 131.1% +/- 7.7%, respectively (P < 0.05). EGTA at 0.2 mmol (ionized Ca2+ 0.2 mmol) did not affect the response to both IGFs. EGTA at 2 mmol (ionized Ca2+ 0 mmol) reduced the DNA synthesis of IGF I and II to 29% and 26%, respectively (P < 0.05). Nifedipine and nickel (nonspecific Ca2+ channel blocker) were equally potent in negating the mitogenic effects of both IGFs. 2-APB (IP3R blocker) reduced the basal DNA synthesis to 51.3% +/- 8.4% but had no effect on either IGF. Dantrolene (ryanodine receptor blocker) negated IGF II induced mitogenisis (74.2% +/- 6.7%) and partially inhibited IGF I mitogenesis (123% +/- 6%) (P < 0.05). The rate of PTH secretion was greater after IGF II stimulation than after IGF I stimulation. CONCLUSIONS: IGFs I and II induce mitogenesis by different calcium signaling pathways. These data suggest that parathyroid cells may utilize different calcium signaling pathways to distinguish growth factors and serum calcium changes.

Analysis of Variance↗
PubMed2001

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol for a controlled clinical trial developed by consensus of an international study group. Part two: design of the study.

GENERAL DESIGN: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). This part describes the design of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). OBJECTIVE: The trial design includes the following elements for a prototype protocol: * The study population is restricted to patients with colorectal cancer, including a left sided resection and an increased perioperative risk (ASA 3 and 4). * Patients are allocated by random to the control or treatment group. * The double blinding strategy of the trial is assessed by psychometric indices. * An endpoint construct with quality of life (EORTC QLQ-C30) and a recovery index (modified Mc Peek index) are used as primary endpoints. Qualitative analysis of clinical relevance of the endpoints is performed by both patients and doctors. * Statistical analysis uses an area under the curve (AUC) model for improvement of quality of life on leaving hospital and two and six months after operation. A confirmatory statistical model with quality of life as the first primary endpoint in the hierarchic test procedure is used. Expectations of patients and surgeons and the negative affect are analysed by social psychological scales. CONCLUSION: This study design differs from other trials on preoperative prophylaxis and postoperative recovery, and has been developed to try a new concept and avoid previous failures.

Clinical Protocols↗
PubMed2000

Changes in cytoplasmic calcium determine the secretory response to extracellular cations in human parathyroid cells: a confocal microscopy study using FM1-43 dye.

Whether activation of the calcium receptor (CaR) modulates secretory events was investigated by real-time fluorescence and confocal microscopy using fura 2 and FM1-43 fluorescent dye. Two paradigms were used: human parathyroid cells, which are stimulated by a step from a high to a low extracellular calcium concentration ([Ca(2+)](ext)), and rMTC6-23 cells, a rat medullary thyroid carcinoma cell line whose secretion is stimulated by an increase in [Ca(2+)](ext). Parathyroid cells were dispersed from parathyroid adenomas removed from 18 patients with primary hyperparathyroidism. In both cell types, incubation with FM1-43 (2 microM) resulted in staining of the plasma membranes, which was rapidly increased following changes in [Ca(2+)](ext) known to stimulate secretion. A high [Ca(2+)](ext) and lanthanum (La(3+)) decreased the membrane-associated FM1-43 fluorescence. Prolonged incubation (5-30 min) in the presence of FM1-43 resulted in accumulation of the dye in the cytoplasm, its granular distribution suggesting targeting of the secretory compartment. These data suggest that FM1-43 fluorescence is determined by: (i) changes in cell membrane surface area associated with secretion-associated events, (ii) displacement/quenching by extracellular cations and (iii) endocytosis of the dye. In parathyroid cells, a rise in FM1-43 fluorescence occurred during incubation in a high (inhibitory) [Ca(2+)](ext) if the cytoplasmic calcium concentration ([Ca(2+)](i)) was decreased by the calcium chelator BAPTA/AM [bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] (10-50 microM). Alternatively, the expected rise in FM1-43 fluorescence did not occur during incubation in a low (stimulatory) [Ca(2+)](ext) if [Ca(2+)](i) was increased by addition of the calcium ionophore A23187 (10-25 microM). These data suggest that [Ca(2+)](i), rather than the absolute value of [Ca(2+)](ext), is the main modulator of secretion from parathyroid cells.

Adult↗
PubMed2000

Insulin-like growth factor binding protein-3 (IGFBP-3) potentiates paclitaxel-induced apoptosis in human breast cancer cells.

Variability in response to chemotherapy is poorly understood. Paclitaxel-induced apoptosis was assessed in human Hs578T breast cancer cells, using the MTT assay, cell counting, morphological features and flow cytometry. Pre-dosing cells with non-glycosylated insulin-like growth factor binding protein-3 (ngIGFBP-3) had no effect on the cells per se but accentuated paclitaxel-induced apoptosis. The apoptotic pathway was further examined by measuring caspase-3 activity in cell lysates at time points over 48 hr after dosing with paclitaxel. Activity increased significantly, and Western immunoblots for caspase-3 in conditioned media showed that the inactive precursor decreased after incubation with paclitaxel. Endogenous production of IGFBP-3 by the cells after incubation with paclitaxel was evaluated using Western ligand blotting, specific IGFBP-3 immunoblotting and radioimmunoassay. Paclitaxel increased endogenous IGFBP-3, which was further increased if the cells had been pre-dosed with ngIGFBP-3. These findings suggest that IGFBP-3 may be an important modulator of paclitaxel-induced apoptosis.

Antineoplastic Agents, Phytogenic↗
PubMed2000

A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma.

BACKGROUND: Quality of life (QL) measurement provides detailed information about outcome from the patient's perspective. This study assessed the impact on short and long term QL of esophagectomy and palliative treatment in patients with esophageal carcinoma. METHODS: Consecutive patients undergoing potentially curative esophagectomy or purely palliative treatment completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the dysphagia scale from the EORTC QLQ-OES24 before treatment and at regular intervals until death or for 3 postoperative years. Median scores were calculated for patients surviving more than 2 years after surgery (n = 17), for patients surviving less than 2 years after esophagectomy (n = 38), and for patients undergoing palliative treatment (n = 37). RESULTS: Baseline functional and symptom QL scores were similar in both groups of patients undergoing esophagectomy, and these were better than scores from patients selected for palliative treatment. Six weeks after esophagectomy, patients reported worse functional, symptom, and global QL scores than before treatment. In patients who survived at least 2 years, QL scores returned to preoperative levels within 9 months, but patients who died within 2 years of surgery never regained their former QL. In both groups, dysphagia improved after surgery and the improvement was maintained until death or for the duration of the study. Patients undergoing palliative treatment reported gradual deterioration in most aspects of QL until death. CONCLUSIONS: Esophagectomy has a negative impact on QL; this effect is transient for patients who survive for 2 or more years. This finding should be considered when selecting patients for surgery.

Aged↗
PubMed2000

C2-Ceramide increases cytoplasmic calcium concentrations in human parathyroid cells.

Effects of extracellular calcium ([Ca(2+)](ext)) on parathyroid cells are mainly due to the activation of a plasma membrane calcium receptor (CaR) coupled with release of intracellular calcium. In addition, high [Ca(2+)](ext) activates the sphingomyelin pathway in bovine parathyroid cells, generating ceramides and sphingosine. This study explored the direct effects of synthetic ceramides on [Ca(2+)](i) in human parathyroid cells. Cells from five parathyroid adenomas removed from patients with primary hyperparathyroidism were dispersed and maintained in primary culture. Intracellular calcium concentration ([Ca(2+)](i)) [Ca(2+)](i) was monitored using standard quantitative fluorescence microscopy in Fura-2/AM-loaded cells. Laser scanning microscopy was used to monitor the intracellular distribution of a fluorescent ceramide analogue (BODIPY-C5). After addition of 10 microM C2-ceramide (N-acetyl-d-erythro-sphingosine), [Ca(2+)](i) increased rapidly (30-60 s) to a peak three times above basal levels in 70% of cells (37/55 cells in four experiments). This effect appeared to be due to release of Ca(2+) from intracellular stores rather than Ca(2+) entry from the extracellular medium. C2-responsive cells had a smaller [Ca(2+)](i) response to subsequent stimulation with the CaR agonist-neomycin (1 mM). These responses were specific to C2 since C6-ceramide (N-hexanoyl-d-erythro-sphingosine) did not affect basal [Ca(2+)](i) nor the responses to an increase in [Ca(2+)](ext) and to neomycin. C5-BODIPY generated intense perinuclear fluorescence, suggesting targeting of the ceramides to the Golgi apparatus. These data demonstrate that endogenous generation of ceramides has the potential to modulate changes in [Ca(2+)](i) and secretion in response to [Ca(2+)](ext) in human parathyroid cells.

Calcium↗
PubMed2000

Quality of life in patients with oesophageal cancer.

There is a growing interest in assessing quality of life in patients with oesophageal cancer because it provides detailed information of the patients' perception of the benefits or harms of treatment. Yet few studies have prospectively measured quality of life using validated appropriate instruments. There are now several questionnaires for patients with cancer, although these are not sufficiently sensitive to small but clinically important changes in quality of life. It is therefore recommended that a disease-specific module is used in conjunction with generic measures. The European Organisation into Research and Treatment of Cancer (EORTC) QLQ-OES24 is currently completing an international validation study. It is used with the EORTC QLQ-C30 core instrument and is designed for patients undergoing potentially curative treatment or palliation of malignant dysphagia. Studies that have assessed quality of life after oesophagectomy have generally found that survivors do regain their former health. Little is known about the effect of neoadjuvant chemoradiation on patients' quality of life. Following endoscopic palliation of dysphagia, quality of life can be maintained and improvement of swallowing is seen. A validated appropriate assessment of quality of life should be included in future palliative trials and in studies of new treatments which may marginally influence survival but cause significant side effects.

Deglutition Disorders↗
PubMed2000

A comparison of reports from referees chosen by authors or journal editors in the peer review process.

The aim was to analyse the peer review process by comparing reports produced by referees selected by journal editors, with those of referees selected by the authors of a scientific manuscript. Some 104 consecutive papers from the UK submitted to the British Journal of Surgery (BJS) were included. Of these, 102 were reviewed blind both by referees chosen by the journal editors, and referees chosen by the paper's principal author. Manuscripts were marked using a standard sheet for four basic aspects: originality, clinical/scientific importance, clarity and analysis; a final overall recommendation about possible publication was given. The time taken and the number of completed referee reports were similar in each group. Referees chosen by the BJS editors were more critical (scored higher) of the submitted articles. Mean scores for all domains were higher than for authors' referees, significantly for scientific importance (p = 0.009) and decision to publish (p = 0.029). In conclusion, reports produced by referees selected by BJS editors were more critical than those chosen by authors of the papers. Authors might argue that this reduced their chance of publication but constructive criticism might improve the final article and assist editors to make decisions about acceptance or rejection.

Authorship↗
PubMed1999

Improving cytological diagnosis and surgical management of parotid adenolymphoma.

BACKGROUND: The role of fine-needle aspiration cytology (FNAC) in the diagnosis and management of discrete parotid swellings remains controversial. Controlled enucleation can be appropriate with accurate preoperative diagnosis. This study (1985-1995) reviewed the role of FNAC in the diagnosis and surgical management of adenolymphoma. METHODS: Review of cytological smears by two observers concentrated on the features of infarction and squamoid metaplasia. Sensitivity, interobserver and intraobserver variation were evaluated statistically in a two-run 'blinded' analysis of 80 cytological slides from a variety of lesions. RESULTS: Of 222 epithelial neoplasms of the parotid, 33 were adenolymphomas. FNAC was performed before operation in 32, producing 34 slides, and a correct cytological diagnosis was made in 21 patients. Retrospective review of the 34 slides, to examine specific features of squamoid metaplasia and infarction, improved diagnostic accuracy. The reliability and reproducibility of cytodiagnosis was confirmed by analysis of interobserver and intraobserver agreement. The sensitivity was high (0.76-0.88). Controlled enucleation was performed in 12 patients and superficial parotidectomy in 11. There were no tumour recurrences. CONCLUSION: Attention to the features of squamoid metaplasia and infarction improves cytological diagnosis and directs appropriate surgical management.

Adenolymphoma↗