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Biomedical subjects

T Preston

Publications and source records attributed to T Preston.

At least 55 records · Page 3Linked to original sources
PubMed2000

Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement.

Weight-losing patients with advanced cancer often fail to gain weight with conventional nutritional support. This suboptimal response might be explained, in part, by an increased metabolic response to feeding. It has been suggested that eicosapentaenoic acid (EPA) can modify beneficially the metabolic response to cancer. The aim of the present study was to examine the metabolic response to feeding in cancer and the effects of an EPA-enriched oral food supplement on this response. A total of 16 weight-losing, non-diabetic patients with unresectable pancreatic adenocarcinoma and six healthy, weight-stable controls were studied by indirect calorimetry in the fasting and fed states. Body composition was estimated by bioimpedence analysis. Cancer patients were then given a fish-oil-enriched nutritional supplement providing 2 g of EPA and 2550 kJ daily, and underwent repeat metabolic study after 3 weeks of such supplementation. At baseline, resting energy expenditure whether expressed per kg body weight, lean body mass or body cell mass was significantly greater in the cancer patients compared with controls. Fat oxidation was significantly higher in the fasting state in cancer patients [median 1.26 g.kg(-1).min(-1) (interquartile range 0.95-1.38)] than in controls [0.76 g.kg(-1). min(-1) (0.62-0.92); P<0.05]. Over the 4 h feeding period, changes in insulin and glucose concentrations in cancer patients suggested relative glucose intolerance. In response to oral meal feeding, the percentage change in the area under the curve of energy expenditure was significantly lower in the cancer patients [median 7.9% (interquartile range 3.4-9.0)] than in controls [12.6% (9.9-15.1); P<0.01]. After 3 weeks of the EPA-enriched supplement, the body weight of the cancer patients had increased and the energy expenditure in response to feeding had risen significantly [9.6% (6. 3-12.4)], such that it was no different from baseline healthy control values. Similarly, fasting fat oxidation fell to 1.02 g. kg(-1).min(-1) (0.8-1.18), again no longer significantly different from baseline healthy control values. While weight-losing patients with advanced pancreatic cancer have an increased resting energy expenditure and increased fat oxidation, the energy cost of feeding is, in fact, reduced. Provision of a fish-oil-enriched nutritional supplement results in some normalization of the metabolic response in both the fasted and fed states, in association with an improvement in nutritional status.

Aged↗
PubMed1999

Measurement of urinary total 13C and 13C urea by isotope ratio mass spectrometry after administration of lactose [13C]-ureide.

A method of measuring total 13C excreted in urine after oral administration of lactose [13C]-ureide was developed using isotope ratio mass spectrometry. Furthermore, a method to measure 13C urea excreted in the urine was developed. Each urine sample collected over a 24 hour period, after administration of the tracer dose, was analysed for both total 13C and 13C urea. Combustion of the dried urine samples allowed measurement of the total 13C content. Treatment of urine samples with urease (EC 3.5.1.5) and analysis by isotope ratio mass spectrometry of the CO2 evolved allowed measurement of 13C urea in the urine sample. The total 13C and 13C urea content of each urine sample, obtained throughout the protocol, were compared to total 13C and 13C urea contents of a urine sample taken before the test. This allowed calculation of the fraction of tracer incorporated into urea and the fraction of tracer excreted in total. Analyses showed that approximately 15% of the dose administered, in terms of 13C, was recovered in the urine over the sampling period. Further analysis for urinary 13C urea showed that less than 1% of the label was incorporated into urea excreted over the sampling period.

Carbon Isotopes↗
PubMed1999

Pancreatic cancer as a model: inflammatory mediators, acute-phase response, and cancer cachexia.

Patients with pancreatic cancer frequently develop the syndrome of cancer cachexia. Pro-inflammatory cytokines have been strongly implicated in the pathogenesis of this syndrome. In patients with pancreatic cancer an acute-phase response (an index of pro-inflammatory cytokine activity) is associated with accelerated weight loss, hypermetabolism, anorexia, and a shortened duration of survival. However, little is known about the primary significance of the acute-phase response in terms of altered hepatic export protein synthesis rates and its potential impact on the body's nitrogen economy. In a recent series of studies on weight-losing pancreatic cancer patients with hypoalbuminemia we have demonstrated albumin synthesis to be unaltered whereas fibrinogen synthesis is increased two- to threefold compared with healthy controls. Because of the mismatch in amino acid composition between the body's main labile amino acid reserve (skeletal muscle) and that of acute-phase proteins, these results lend support to the concept that in pancreatic cancer the reprioritization of body protein metabolism during an acute-phase response may well be a significant factor in the loss of lean tissue in these patients.

Acute-Phase Proteins↗
PubMed1999

Characterization of p80, a novel nuclear and cytoplasmic protein in dinoflagellates.

The presence of myosin in dinoflagellates was tested using an anti-Acanthamoeba castellanii myosin II polyclonal antibody on the heterotrophic dinoflagellate Crypthecodinium cohnii Seligo. Western blots revealed the presence of a unique band of 80 kDa in total protein extracts and after immunoprecipitation. Expression of this 80 kDa protein appeared constant during the different phases of the cell cycle. In protein extracts from various other dinoflagellates, this 80 kDa protein was detected only in the autotrophic species Prorocentrum micans Ehr. Screening of a C. cohnii cDNA expression library with this antibody revealed a cDNA coding for an amino acid sequence without homology in the databases. However, particular regions were detected: - a polyglutamine repeat domain in the N-terminal part of the protein, - four peptide sequences associated with GTP-binding sites, - a sequence with slight homology to the rod tail of Caenorhabditis elegans myosin II, -a sequence with homology to a human kinesin motor domain. Immunocytolocalization performed on C. cohnii thin sections with a polyclonal antibody raised against the recombinant protein showed p80 to be present both within the nucleus and in the cytoplasm. Labelling was widespread in the nucleoplasm and more concentrated at the periphery of the permanently condensed chromosomes. In the cytoplasm, labelling appeared in a punctate region close to the nucleus and in the flagellum. Potential functions of this novel protein are discussed.

Amino Acid Sequence↗
PubMed1999

Fish oil-enriched nutritional supplement attenuates progression of the acute-phase response in weight-losing patients with advanced pancreatic cancer.

The presence of an acute-phase protein response (APPR) has been suggested to shorten survival and contribute to weight loss in patients with pancreatic cancer. Fatty acids derived from fish oil have been shown to alter proinflammatory cytokine production and acute-phase protein synthesis in vitro. The present study was designed to determine the effects of a fish oil-enriched nutritional supplement on the concentrations of a range of individual acute-phase proteins (APP) in patients with advanced pancreatic cancer. In a sequential series, 18 patients with pancreatic cancer received the supplement (providing 2 g eicosapentaenoic acid and 1 g docosahexaenoic acid/d) for 3 wk while another 18 received full supportive care alone. Six healthy subjects served as additional controls. Acute-phase proteins were measured before and after the 3-wk intervention period in cancer patients. At baseline, albumin, transferrin and pre-albumin were significantly reduced and fibrinogen, haptoglobin, alpha-1-acid glycoprotein, alpha-1-antitrypsin, ceruloplasmin and C-reactive protein (CRP) were significantly elevated in the cancer patients compared with healthy controls, reflecting their roles as negative and positive acute phase proteins, respectively. In the supplemented cancer group, the only significant change in APP concentrations over the 4-wk study period was an increase in transferrin. In the control cancer group there were further significant reductions in albumin, transferrin and pre-albumin, and a significant increase in CRP concentration. These results suggest that many positive and negative APP are altered in advanced pancreatic cancer. The APPR tends to progress in untreated patients but may be stabilized by the administration of a fish oil-enriched nutritional supplement. This may have implications for reducing wasting in such patients.

Acute-Phase Proteins↗
PubMed1998

Analysis of tert.-butyldimethylsilyl [1-13C]palmitic acid in stool samples by gas chromatography-mass spectrometry with electron impact ionisation: comparison with combustion isotope-ratio mass spectrometry.

The use of 13C-labelled compounds to study lipid metabolism is increasing. Typically less than 40% of the orally administered label is recovered in breath CO2. The remainder must be either absorbed and not oxidised or not absorbed and remain in the faeces. Two methods of determining how much tracer passes through the body, and is present in the stool, were compared. Compound specific analysis of tert.-butyldimethylsilyl [13C]hexadecanoic acid by gas chromatography-mass spectrometry (GC-MS) with electron impact ionisation was compared with bulk analysis of whole stool and lipid extract by continuous flow isotope ratio mass spectrometry (CF-IRMS) with a combustion interface. The mean difference between the IRMS and GC-MS methods was -0.02 mmol 13C d(-1) with a mean excretion of 14.2 mmol 13C d(-1). Combustion IRMS is both simpler and cheaper, when the objective is to determine how much administered dose appears in stool, and information about the form of the label is not required.

Adult↗
PubMed1998

Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test.

AIMS: Carbamazepine is a known enzyme inducer. The aim of this study was to determine whether carbamazepine induces the metabolism of caffeine in children. METHODS: Children due to receive carbamazepine for epilepsy were recruited into the study. The caffeine breath test was carried out prior to the administration of carbamazepine and after a minimum of 2-3 weeks therapy. Five children were studied and they received 200-600 mg carbamazepine daily. RESULTS: The mean values of the 2 h cumulative labelled carbon dioxide were 3.47% before and 7.65% during carbamazepine. There was a significant increase in the percentage labelled caffeine exhaled as carbon dioxide during the administration of carbamazepine (Student's paired t-test, P < 0.05). CONCLUSIONS: The results suggest that carbamazepine induces the metabolism of caffeine by the CYP1A2 pathway in the children studied.

Adolescent↗
PubMed1998

Longitudinal study of body cell mass depletion and the inflammatory response in cancer patients.

There is recent evidence that the inflammatory response may be important in the disproportionate loss of body cell mass in cancer patients. To examine this further, 18 male patients with lung or gastrointestinal cancer were studied over a 12-week period. In addition to weight, anthropometry, C-reactive protein (marker of the inflammatory response), albumin, and total body potassium were measured at baseline and 12 weeks. When those patients who lost total body potassium were compared with those who had not, there was a significant increase in the baseline and 12-week C-reactive protein concentrations (p < 0.05). The reduction in total body potassium was also associated with a reduction in triceps skinfold thickness (p < 0.05). There were significant correlations between the mean C-reactive protein concentration and the relative (r = -0.846, p < 0.001) and absolute (r = -0.806, p < 0.001) change in total body potassium over the follow-up period. This study demonstrates the association of a chronic inflammatory response with the rate of loss of body cell mass observed in cancer patients.

Aged↗
PubMed1998

Fibrinogen synthesis is elevated in fasting cancer patients with an acute phase response.

The unusual amino acid composition of acute phase proteins may be relevant to our understanding of the mechanism of tissue wasting in chronic inflammatory disease. During periods in which demand for amino acids outstrips dietary supply, skeletal muscle protein may be mobilized to meet this demand. An imbalance in the amino acid composition of these proteins may thus be detrimental to the body's nitrogen economy. To address this problem, we have measured the synthetic rate of fibrinogen (perhaps the major acute phase protein) and plasma amino acid profiles in a group of patients with adenocarcinoma of the pancreas and an ongoing inflammatory response (serum C-reactive protein >10 mg/L in the absence of any other obvious infective or inflammatory cause). These were also measured in a control group with no evidence of inflammation. Fibrinogen synthesis was measured after an overnight fast, using a flooding dose of 2H5-phenylalanine. The fractional rate of fibrinogen synthesis was significantly elevated in the cancer group compared with healthy controls [39.3 (20.0-49.9) and 21.9 (13.2-37.7) %/d, respectively; median (range), P < 0.05]. The absolute rate of fibrinogen synthesis was also elevated [84 (33-143) and 26 (15-43) mg/(kg.d), respectively; median (range), P < 0.01]. We calculated that, in cancer patients with anorexia-cachexia (i.e., documented ongoing weight loss in the absence of an obvious cause such as obstruction or malabsorption), aromatic amino acid supply (predominantly tryptophan) most limits fibrinogen synthesis from skeletal muscle reserves. Demand for the nonessential amino acids serine and glycine was elevated. Assuming that tryptophan is limiting, up to 2.6 g muscle protein ( approximately 12 g skeletal muscle tissue) may be wasted to synthesize 1 g fibrinogen. Interpretation of the observation that circulating free tryptophan concentrations were significantly reduced in the cancer patients will have to await flux measurements. The metabolic changes accompanying the inflammatory response suggest that down-regulation of this process may be beneficial.

Acute-Phase Reaction↗
PubMed1998

Albumin synthesis rates are not decreased in hypoalbuminemic cachectic cancer patients with an ongoing acute-phase protein response.

OBJECTIVE: To determine whether suppression of albumin synthesis contributes to the hypoalbuminemia observed in weight-losing cancer patients with evidence of an ongoing acute-phase protein response (APPR). BACKGROUND DATA: Proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) are known to downregulate albumin synthesis and increase acute-phase protein production in isolated hepatocytes. However, whether albumin synthesis is suppressed in hypoalbuminemic cancer patients with evidence of an ongoing acute-phase response is unknown. METHODS: Albumin synthesis rates were determined in six healthy controls and in six weight-losing pancreatic cancer patients with an ongoing APPR using a flooding dose technique with [2H5]-phenylalanine. The presence of an APPR was defined as a serum C-reactive protein concentration >10 mg/L. Serum cytokines (TNF, IL-6) and soluble TNF receptors (sTNF-R 55 and 75), along with serum cortisol and insulin, were also measured in both groups. RESULTS: Cancer patients had reduced serum albumin (median 32 [range, 23-36] vs. 42 g/L [40-45]; p < 0.01) and increased serum C-reactive protein concentrations (72 [23-126] vs. <5 mg/L; p < 0.01) when compared with controls. TNF was not detected in either group. sTNF-R 55 levels were significantly elevated in the cancer patients (3.8 [1.9-8.1] vs. 1.2 pg/mL [0.9-2.2]; p < 0.01). Circulating IL-6, insulin, and cortisol concentrations were not significantly different between the groups. The intravascular albumin mass was lower (88 [56-93] vs. 133 g [105-177]; p < 0.01), but the intravascular albumin fractional synthetic rate was higher (13.9 [13.5-18.5] vs. 10.3%/d [71-11.3]; p < 0.01) in the cancer patients compared with the controls. The total intravascular albumin synthetic rate was, however, similar between the two groups (12.7 [7.7-15.7] vs. 11.7 g/d [8.5-18.7]; p NS). CONCLUSIONS: In weight-losing pancreatic cancer patients with evidence of an ongoing APPR, hypoalbuminemia is not caused by a decreased rate of albumin synthesis.

Acute-Phase Proteins↗
PubMed1997

v-Ras and v-Raf block differentiation of transformable C3H10T1/2-derived preadipocytes at lower levels than required for neoplastic transformation.

To investigate the functional relationship between the transforming ability of Ras and its role as an integral component of the differentiative insulin signaling pathway, we introduced a leu61-activated ras gene into a Ras-transformable, C3H10T1/2-derived preadipocytic cell line. The results demonstrate that rasleu61 expression in this line blocks differentiation and that this block appears at lower levels than required for full neoplastic transformation. In addition, to examine whether the inability of Rasleu61 to induce differentiation by replacing the insulin signal could be attributed to its transforming effect in this system, we examined the effect of Rasleu61 at levels below the baseline, by expressing rasleu61 in a series of preadipocytes which were rendered deficient in endogenous c-Ras activity. The results show that even very low Rasleu61 levels, insufficient to restore the growth rate of these cells to normal, blocked rather than enhanced differentiation, indicating that rasleu61 expression alone is not sufficient to promote adipocytic differentiation in this system, even in the absence of neoplastic transformation. Consistent with its established role as a downstream effector of Ras, v-Raf expression mirrored the v-Ras effects upon adipocytic differentiation and transformation.

Adipocytes↗
PubMed1997

The timing of insulin/c-Ras signal is critical for its effect upon the differentiation of C3H10T1/2-derived preadipocytes.

The effect of the peptide hormone insulin upon the differentiation of a 10T1/2-derived preadipocytic line was found to display a potent time-dependence. Insulin addition before cell confluence strongly enhanced differentiation, while addition after confluence had no effect. In keeping with the role of c-Ras as a downstream effector of insulin, c-ras downregulation before confluence abolished differentiation, while it was ineffective once the process of differentiation was underway. These data suggest that the insulin signal is effective during an early window of time before cell confluence, while normal c-Ras levels are required for its transmission.

Adipocytes↗
PubMed1997

Cerebrospinal fluid findings in children with Lyme disease-associated facial nerve palsy.

OBJECTIVE: To determine the relative frequency of abnormal cerebrospinal fluid (CSF) findings in children with Lyme disease-associated facial nerve palsy. DESIGN: A clinical series. A prospective evaluation was undertaken of the condition of children seen between 1988 and 1996 at a single medical center in a Lyme disease endemic area. PATIENTS: Forty children (24 boys and 16 girls, aged 3-19 years) with new onset facial nerve palsy who met the Centers for Disease Control and Prevention case definition of Lyme disease. INTERVENTIONS: Neurologic examinations. Cerebrospinal fluid analysis. MAIN OUTCOME MEASURES: Rates of abnormal CSF findings: white blood cell count, protein level, and Borrelia burgdorferi-specific CSF assays. RESULTS: Cerebrospinal fluid white blood cell count, protein level, or both were abnormal in 27 (68%) of the children. Thirty-six (90%) of the 40 children had a CSF abnormality consistent with central nervous system infection or immune involvement by B burgdorferi. Of the 22 children with CSF pleocytosis, only 7 (32%) had headache and none had meningeal signs. CONCLUSIONS: Most children with Lyme disease-associated facial nerve palsy have CSF abnormalities. Our studies indicate that, in endemic areas, facial nerve palsy in children may be a marker of Lyme disease and occult meningitis. When Lyme disease is suspected, CSF should be examined; in some cases, it may be helpful to expand beyond routine CSF studies to look at a battery of B burgdorferi-specific assays.

Adolescent↗
PubMed1997

Lack of inhibitory effect of cimetidine on caffeine metabolism in children using the caffeine breath test.

AIMS: To study the potential drug interaction between cimetidine and caffeine in a group of children who received cimetidine for gastritis. METHODS: The caffeine breath test was carried out prior to the administration of cimetidine and after 2-3 weeks therapy. The children (n = 1) received 300-800 mg cimetidine daily (11-36 mg kg(-1) day(-1)). RESULTS: There was no significant change in the 2 h cumulative labelled CO2 following the administration of cimetidine (mean values 5.61% before and 4.87% during cimetidine; Student's t-test P > 0.2). CONCLUSIONS: Cimetidine did not have an inhibitory effect on the metabolism of caffeine in this group of children studied.

Adolescent↗
PubMed1997

Enhanced drug metabolism in young children with cystic fibrosis.

The effect of cystic fibrosis on caffeine metabolism was studied in young children using the caffeine breath test. Eight children with cystic fibrosis aged 2-6 years and nine age matched controls were studied on a single occasion, and the cumulative percentage of labelled caffeine exhaled as carbon dioxide measured over two hours. This was significantly higher in the patients with cystic fibrosis than in controls, suggesting an increase in the CYP1A2 metabolic pathway in the former. The fact that these were young children with minimal lung and liver disease suggests that enhanced drug metabolism in children with cystic fibrosis is hereditary rather than secondary to lung and liver damage.

Breath Tests↗
PubMed1997

Ras(leu61) blocks differentiation of transformable 3T3 L1 and C3H10T1/2-derived preadipocytes in a dose- and time-dependent manner.

To investigate the functional relationship between the transforming ability of Ras and its role as an integral component of the differentiation-promoting insulin signaling pathway, we introduced a leu61-activated ras gene into the Ras-transformable 3T3 L1 (ATCC CCL92.1) and a number of C3H10T1/2-derived preadipocytic cell lines. The results demonstrate a quantitative reciprocal regulation of differentiation and several transformation-associated properties in response to graded levels of ras gene expression, with the loss of differentiative capacity, morphological transformation, stimulation of proliferation, and anchorage-independent growth requiring increasing levels of Ras(leu61) protein. Furthermore, using novel, tightly regulatable 3T3 L1 transfectants, we demonstrated that Ras(leu61) effectiveness in blocking adipocytic differentiation is strictly dependent on the timing of its expression relative to cell growth arrest, with ras(leu61) expression being ineffective at inhibiting differentiation or inducing morphological transformation once the differentiative process has commenced. Moreover, rasleu61 induction failed to substitute for or enhance the c-Ras-dependent differentiative insulin signal, even under conditions in which it did not induce transformation. Therefore, although necessary for insulin signal transduction, the Ras signal alone is not sufficient to induce adipocytic differentiation in this system. Consistent with its established role as a downstream effector of Ras, v-Raf expression mirrored the Rasleu61 effects on adipocytic differentiation and transformation.

3T3 Cells↗