bluuebunny/crossref_metadata_2025 huggingface dataset:
Discontinuation and switching of therapy after initiation of lipid‐lowering drugs: the effects of comorbidities and patient characteristics
Authors: Yang Chen‐Chang , Jick Susan S. , A. Testa Marcia
Published: July 2003

Aims  To evaluate the effects of comorbidities and patient characteristics on treatment continuation among patients starting their first course of lipid‐lowering drug (LLD) therapy.

Methods  Within the UK General Practice Research Database (GPRD), we identified 22 408 patients who started LLD therapy due to coronary heart disease, hyperlipidaemia, or other atherosclerotic diseases, and who received ≥ two prescriptions for LLD between January 1 1990 and December 31 1997. Differences in potential predictors of treatment continuation between patients who continued, and patients who discontinued/switched lipid‐lowering therapy within 1 year after treatment initiation were compared by fitting multivariate logistic regression models. The effects of baseline characteristics on treatment continuation after switching of LLDs were also analysed.

Results  Discontinuation/switching of lipid‐lowering therapy was common during the study period, especially among patients who received nonstatin, nonfibrate LLDs (log‐rank test P = 0.0001). Statin use, more frequent physician visits, more concurrent cardiovascular medications, diabetes, and fewer noncardiovascular medications were associated with treatment continuation of LLDs. Among patients who switched therapy, prescribing of a statin as the substituted LLD, more concurrent cardiovascular medications, and later treatment switching were related to a higher probability of treatment continuation after switching LLDs.

Conclusions  Treatment continuation after initiation or switching of lipid‐lowering therapy largely increased with concomitant cardiovascular comorbidities, and more health care utilization, and is more common for statins than for other LLDs. Practice guidelines, patient education, and quality of care assessment for lipid‐lowering therapy should emphasize factors that predispose patients to discontinuation/switching, in an effort to optimize the choice of therapeutic regimens and to improve patient adherence.
Pseudoephedrine: effects on milk production in women and estimation of infant exposure via breastmilk
Authors: Aljazaf Khalidah , Hale Thomas W. , Ilett Kenneth F. , Hartmann Peter E. , Mitoulas Leon R. , Kristensen Judith H. , Hackett L. Peter
Published: July 2003

Aims  To assess the effects of pseudoephedrine on breast blood flow, temperature and milk production, and to estimate the likely infant dose during breastfeeding.

Methods  Eight lactating women (mean age 35 years and weight 69 kg) participated in a single‐blind randomized crossover study of 60 mg pseudoephedrine hydrochloride vs placebo. Breast blood flow and surface temperature were measured from 0 to 4 h following the dose, and change in plasma prolactin was measured as the difference between predose and 1 h postdose concentrations. Milk production was measured for 24 h following placebo and pseudoephedrine. Infant dose of pseudoephedrine for a 60‐mg dose administered four times daily to the mother was quantified as the product of average steady‐state drug concentration in milk and an estimated milk production rate of 0.15 l kg−1 day−1 and expressed relative to the maternal weight‐adjusted dose.

Results  There were no physiologically significant changes in breast blood flow or temperature between the placebo and pseudoephedrine periods. The mean change in plasma prolactin was slightly (13.5%), but not significantly lower (t = 1.245, P = 0.253) after pseudoephedrine (1775 mU l−1) compared with placebo (2014 mU l−1). However, the mean milk volume was reduced by 24% from 784 ml day−1 in the placebo period to 623 ml day−1 in the pseudoephedrine period (difference between means 161 ml day−1 (95% CI: 63, 259 ml day−1); t = 3.9, P = 0.006). Assuming maternal intake of 60 mg pseudoephedrine hydrochloride four times daily, the estimated infant dose of pseudoephedrine was 4.3% (95% CI, 3.2, 5.4%) of the weight‐adjusted maternal dose.

Conclusions  A single dose of pseudoephedrine significantly reduced milk production. This effect was not attributable to changes in blood flow, but depression of prolactin secretion may be a contributing factor. At the maximum recommended pseudoephedrine doses, the calculated infant dose delivered via milk was < 10% of the maternal dose, and is unlikely to affect the infant adversely. The ability of pseudoephedrine to suppress lactation suggests a novel use for the drug.
Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin–clarithromycin interaction
Authors: Rengelshausen Jens , Göggelmann Christoph , Burhenne Jürgen , Riedel Klaus‐Dieter , Ludwig Jochen , Weiss Johanna , Mikus Gerd , Walter‐Sack Ingeborg , Haefeli Walter E.
Published: July 2003

Aims  A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms.

Methods  In a randomized, placebo‐controlled, double‐blind cross‐over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg kg−1 digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay.

Results  Oral coadministration of clarithromycin resulted in a 1.7‐fold increase of the area under the digoxin plasma concentration–time curve [mean AUC(0,24) ± SD 23 ± 5.2 vs. 14 ± 2.9 µg L−1 h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) ± SD 34 ± 39 vs. 57 ± 41 mL min−1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2‐fold during coadministration of clarithromycin.

Conclusions  Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P‐glycoprotein.
CYP2D6, GST‐M1 and GST‐T1 enzymes: expression in parathyroid gland and association with the parathyroid hormone concentration during early renal replacement therapy
Authors: Yan Feng‐Xiang , Langub M. Chris , Ihnen Mark A. , Hornung Carlton , Juronen Erkki , Rayens Mary K. , Cai Wei‐Min , Wedlund Peter J. , Fanti Paolo
Published: July 2003

Aims  The purpose of this research was to characterize CYP2D6, GST‐M1 and GST‐T1 enzyme expression in human parathyroid tissue, and to determine whether or not there is any association between deficiencies in these enzymes and serum parathyroid hormone concentrations in patients with end‐stage renal disease.

Methods  Surgical human parathyroid tissue was obtained and evaluated by immunohistochemistry for cellular localization of CYP2D6, GST‐M1 and GST‐T1 and colocalization of CYP2D6 with parathyroid hormone. Blood samples were collected from 328 Caucasian patients with end‐stage renal disease for genetic testing of CYP2D6*3, *4, *5, *6, *7 and GST‐M1*0 and GST‐T1*0 alleles. Clinical chemistry data and serum intact parathyroid hormone (iPTH) concentrations were obtained from patient medical records. In 277 of the patients, the same laboratory performed all clinical tests.

Results  CYP2D6, GST‐M1 and GST‐T1 were present in human parathyroid tissue. CYP2D6 was colocalized with parathyroid hormone in parathyroid chief cells. Within the end‐stage renal disease population, a nonfunctional CYP2D6 genotype was present in 18.2%[95% confidence interval (CI) 8.0, 28.4] of patients in the 1st iPTH concentration quintile (iPTH < 64 pg mL−1), in 0% (95% CI 0, 7.5) of those in the 2nd quintile, in 1.8% (95% CI 0, 9.3) of those in the 3rd quintile, in 9.1% (95% CI 1.5, 16.7) of those in the 4th quintile, and in 16.7% (95% CI 6.8, 26.5) of those in the 5th quintile (iPTH > 347 pg mL−1) (P = 0.001). Out of 12 CYP2D6‐deficient females, seven were in the 1st iPTH concentration quintile and the remaining five were in the 5th quintile. Patients deficient in the GST‐M1 and GST‐T1 enzymes displayed a far more uniform frequency distribution relative to serum iPTH concentrations.

Conclusions  The presence of CYP2D6, GST‐M1 and GST‐T1 in parathyroid cells was observed. An association is reported between a lack of CYP2D6 and iPTH concentrations in newly diagnosed end‐stage renal disease patients. Gender and concomitant deficiency in GST‐M1 and/or GST‐T1 appear to define this association further. It remains to be established whether these associations reflect a cause‐effect relationship between deficient expression of metabolizing enzymes and severity of secondary manifestation of renal failure.
The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6
Authors: Prueksaritanont Thomayant , Ma Bennett , Yu Nathan
Published: July 2003

Aims  To identify the cytochrome P450 (CYP) isoforms responsible for the metabolism of simvastatin hydroxy acid (SVA), the most potent metabolite of simvastatin (SV).

Methods  The metabolism of SVA was characterized in vitro using human liver microsomes and recombinant CYPs. The effects of selective chemical inhibitors and CYP antibodies on SVA metabolism were assessed in human liver microsomes.

Results  In human liver microsomes, SVA underwent oxidative metabolism to three major oxidative products, with values for Km and Vmax ranging from about 50 to 80 µM and 0.6 to 1.9 nmol min−1 mg−1 protein, respectively. Recombinant CYP3A4, CYP3A5 and CYP2C8 all catalysed the formation of the three SVA metabolites, but CYP3A4 was the most active. CYP2D6 as well as CYP2C19, CYP2C9, CYP2A6, CYP1A2 did not metabolize SVA. Whereas inhibitors that are selective for CYP2D6, CYP2C9 or CYP1A2 did not significantly inhibit the oxidative metabolism of SVA, the CYP3A4/5 inhibitor troleandomycin markedly (about 90%) inhibited SVA metabolism. Quercetin, a known inhibitor of CYP2C8, inhibited the microsomal formation of SVA metabolites by about 25–30%. Immunoinhibition studies revealed 80–95% inhibition by anti‐CYP3A antibody, less than 20% inhibition by anti‐CYP2C19 antibody, which cross‐reacted with CYP2C8 and CYP2C9, and no inhibition by anti‐CYP2D6 antibody.

Conclusions  The metabolism of SVA in human liver microsomes is catalysed primarily (≥ 80%) by CYP3A4/5, with a minor contribution (≤ 20%) from CYP2C8. CYP2D6 and other major CYP isoforms are not involved in the hepatic metabolism of SVA.
Social Work: Critical Theory and Practice
Authors: Merton Justine
Published: July 2003

Jan Fook  Sage Publications, London, 2002, 179 pp. £17.99. ISBN 0 7619 7250 1
Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population‐based study in northern Sweden
Authors: Andersson C. , Innala E. , Bäckström T.
Published: July 2003

Abstract.  Andersson C, Innala E, Bäckström T (University Hospital, Umeå, Sweden). Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population‐based study in northern Sweden. J Intern Med 2003; 254: 176–183.

Objective.  To describe the clinical expression of acute intermittent porphyria (AIP) in women, their use of exogenous sex hormones, and the effects on AIP.

Design.  A retrospective population‐based study.

Subjects.  All women aged  ≥18 years (n = 190) with DNA‐diagnosed AIP in northern Sweden.

Results.  A total of 166 women (87%) participated; 91 (55%) had manifest AIP. Severe attacks were reported by 82%; 39% reported recurrent premenstrual AIP attacks and 22% reported chronic AIP symptoms. Oral hormonal contraceptives had been used by 58% of all these women and by 50 with manifest AIP (57%). Twelve women (24%) associated oral contraceptives as precipitating AIP attacks; in nine cases their first attack. One woman experienced relief from AIP symptoms. On commencing their treatment, 72% of the women with manifest AIP had not yet suffered their first attack. Twenty‐two women (25%) aged ≥45 years had used hormonal replacement therapy (HRT) at menopause to remedy climacteric symptoms (the percutaneous route was most frequently used); no AIP attack was precipitated. HRT to remedy vaginal dryness was used by 26 women (28%) aged ≥45 years without triggering an AIP attack. Miscarriages were more frequent in women with manifest AIP (50%) than in the latent group (30%, P = 0.014).

Conclusions.  About half of the women with AIP had used oral hormonal contraceptives. As 25% of women with manifest AIP reported attacks associated with such drugs, caution must still be recommended. Menopausal HRT only rarely affected the disorder. Miscarriage was more common amongst women with manifest AIP.
Oestrogen receptor α gene polymorphism is related to aortic valve sclerosis in postmenopausal women
Authors: Nordström P. , Glader C. A. , Dahlén G. , Birgander L. Slunga , Lorentzon R. , Waldenström A. , Lorentzon M.
Published: July 2003

Abstract. Nordström P, Glader CA, Dahlén G, Slunga Birgander L, Lorentzon R, Waldenström A, Lorentzon M (Sports Medicine Unit; Department of Geriatric Medicine; Clinical Chemistry; Section of Cardiology; and National Institute for Working Life, Umeå, Sweden). Oestrogen receptor α gene polymorphism is related to aortic valve sclerosis in postmenopausal women. J Intern Med 2003; 254: 140–146.

Objectives. Aortic valvular sclerosis (AS) is an inflammatory process and not a result of normal ageing. The sclerotic process is accelerated by risk factors such as smoking and high cholesterol levels. The genetic factors for the development of AS are however unknown. Therefore the purpose of the present study was to investigate whether polymorphisms in the oestrogen receptor α (ORα) gene and in the transforming growth factor β (TGF‐β1) gene were related to the presence of AS in postmenopausal women.

Design. Case–control study.

Subjects and methods. Relationships were tested between polymorphisms in the ORα gene defined by the restriction enzymes PvuII and XbaI, and in the TGF‐β1 gene defined by AocI, and AS, lipid levels, and lipoprotein(a) [Lp(a)] in 41 postmenopausal female patients and 41 age‐ and sex‐matched controls. These polymorphisms were also tested in relation to lipid levels and Lp(a), in 99 healthy Caucasian girls, aged 16.9 ± 1.2 years.

Results. In the postmenopausal patients and age‐matched controls, the PvuII polymorphism was independently associated with an increased risk of AS [odds ratio (OR) = 3.38; 95% confidence interval (CI) 1.13–10.09). A genotype defined by at least one restriction site in the PvuII polymorphism and two restriction sites in the TGF‐β1 polymorphism was related to a highly significantly increased risk of AS (OR = 4.58; 95% CI 1.68–12.51). In the adolescent female cohort, presence of two restriction sites in the PvuII polymorphism was associated with higher levels of total cholesterol (TC) (P = 0.02), and low‐density lipoprotein cholesterol (LDL) (P = 0.04).

Conclusions. We have demonstrated that the PvuII polymorphism in the ORα gene is related to both the presence of AS in postmenopausal women and to lipid levels in adolescent females, suggesting that this polymorphism may influence the risk of AS partly by affecting lipid levels.
Constitutive expression of the water deficit‐inducible homeobox gene ATHB7 in transgenic Arabidopsis causes a suppression of stem elongation growth
Authors: HJELLSTRÖM M. , OLSSON A. S. B. , ENGSTRÖM P. , SÖDERMAN E. M.
Published: July 2003

The Arabidopsis gene ATHB7 encodes a transcription factor of the homeodomain‐leucine zipper class. The activity of the gene is dependent on the water conditions of the plant; expression being strongly induced in plants subjected to water deficit or to treatment with abscisic acid (ABA). In this report we demonstrate that ATHB7, when constitutively expressed at levels typical for plants exposed to water‐deficit conditions, caused a reduction in elongation growth in the leaf and in the inflorescence stem. The reduction in stem growth mimics the effect on growth caused by water‐deficit conditions, but is independent of water conditions in plants that express ATHB7 constitutively. These results indicate that ATHB7 in the wild‐type plant may be a mediator of the plant growth response to limiting water conditions in the leaf and in the inflorescence stem. In support of this notion we also show that the ATHB7 promoter in wild‐type plants exposed to water‐deficit conditions is highly active in the elongating parts of the inflorescence stem as well as leaves.
Enhanced tolerance of photosynthesis against high temperature damage in salt‐adapted halophyte Atriplex centralasiatica plants
Authors: QIU N. , LU C.
Published: July 2003

Thermotolerance of photosynthesis in salt‐adapted Atriplex centralasiatica plants (100–400 mm NaCl) was evaluated in this study after detached leaves and whole plants were exposed to high temperature stress (30–48 °C) either in the dark or under high light (1200 mol m−2 s−1). In parallel with the decrease in stomatal conductance, intercellular CO2 concentration and CO2 assimilation rate decreased significantly with increasing salt concentration. There was no change in the maximal efficiency of PSII photochemistry (Fv/Fm) with increasing salt concentration, suggesting that there was no damage to PSII in salt‐adapted plants. On the other hand, there was a striking difference in the response of PSII and CO2 assimilation capacity to heat stress in non‐salt‐adapted and salt‐adapted leaves. Leaves from salt‐adapted plants maintained significantly higher Fv/Fm values than those from non‐salt‐adapted leaves at temperatures higher than 42 °C. The Fv/Fm differences between non‐salt‐adapted and salt‐adapted plants persisted for at least 24 h following heat stress. Leaves from salt‐adapted plants also maintained a higher net CO2 assimilation rate than those in non‐salt‐adapted plants at temperatures higher than 42 °C. This increased thermotolerance was independent of the degree of salinity since no significant changes in Fv/Fm and net CO2 assimilation rate were observed among the plants treated with different concentrations of NaCl. The increased thermotolerance of PSII induced by salinity was still evident when heat treatments were carried out under high light. Given that photosynthesis is considered to be the physiological process most sensitive to high temperature damage, increased thermotolerance of photosynthesis may be of significance since A. centralasiatica, a typical halophyte, grows in the high salinity regions in the north of China, where the temperature in the summer is often as high as 45 °C.
Functional expression of AtHMA4, a P1B‐type ATPase of the Zn/Co/Cd/Pb subclass
Authors: Mills Rebecca F. , Krijger Gerard C. , Baccarini Paul J. , Hall J.L. , Williams Lorraine E.
Published: July 2003

Mechanisms are required by all organisms to maintain the concentration of essential heavy metals (e.g. Zn and Cu) within physiological limits and to minimise the detrimental effects of non‐essential heavy metals (e.g. Cd). Heavy‐metal P‐type ATPases (HMAs) are a subgroup of the P‐type ATPase superfamily that may contribute to metal homeostasis in plants. We cloned and characterised a member of this family, AtHMA4, from Arabidopsis thaliana that clusters with the Zn/Co/Cd/Pb subclass of HMAs on phylogenetic analysis. Sequencing of the AtHMA4 cDNA showed that it contained the conserved motifs found in all P‐type ATPases and also motifs that are characteristic of heavy‐metal ATPases. Escherichia coli mutants defective in the HMAs, CopA and ZntA, were used in functional complementation studies. AtHMA4 was able to restore growth at high [Zn] in the zntA mutant but not at high [Cu] in the copA mutant, suggesting a role in zinc transport. Heterologous expression of AtHMA4 in Saccharomyces cerevisiae made the yeast more resistant to Cd but did not affect sensitivity to other metals compared with vector‐transformed controls. The organ specificity of AtHMA4 was analysed in Arabidopsis and showed that AtHMA4 was expressed in a range of tissues with highest expression in roots. AtHMA4 was upregulated in roots exposed to elevated levels of Zn and Mn but downregulated by Cd. Possible physiological roles of this transporter in Arabidopsis are discussed.
Case of gastric outlet stenosis with features of pyloric stenosis diagnosed by using peppermint oil solution as a new antispasmodic
Authors: Hiki Naoki , Kurosaka Hanzo , Tatsutomi Yusuke , Yamaguchi Hirokazu , Shimizu Nobuyuki , Kubota Keisuke , Aoki Fumio , Shimoyama Shouji , Hirooka Tatsuo , Mafune Ken‐ichi , Kaminishi Michio
Published: July 2003

We report a case of gastric outlet stenosis successfully diagnosed as an antral stenosis of the stomach in an 80‐year‐old male. Severe stenosis can be very difficult to diagnose and treat because it may be difficult to visualize the gastrointestinal tract in the area distal to the stenosis. In the present case, it had not been possible to view the area distal to the stenosis by endoscope using hyoscine‐N‐butylbromide (Buscopan). Peppermint oil solution is clinically inert but can inhibit gastrointestinal motility. In a recent double‐blind, double‐dummy controlled trial we showed that intraluminally administered peppermint oil solution was a more effective and safer antispasmodic agent than Buscopan. In the present case, where there was severe antral stenosis of the stomach, use of peppermint oil solution as an antispasmodic enabled us for the first time to successfully extend the tip of the endoscope to the duodenal bulbs in the area distal to the stenosis.
Comparison of inflammatory and systemic sources of growth factors in acute and chronic human wounds
Authors: Wagner Silvia , Coerper Stephan , Fricke Jens , Hunt Thomas K. , Hussain Zamirul , Elmlinger Martin W. , Mueller Jürgen E. , Becker Horst D.
Published: July 2003

Inflammatory cells are generally assumed to be the primary source of most growth factors/cytokines that participate in wound healing. Correspondingly, most attempts to enhance wound healing have been directed at the wound itself. However, certain key factors such as insulin‐like growth factor‐I (IGF‐I) and related proteins are present in blood in sufficient quantities to suggest significant contributions from outside the wound. Because little is known of the dynamics of IGF family members in wounds, particularly in human wounds, we serially measured the mRNAs and proteins of the IGF family in fluid and tissues taken from acute as well as chronically inflamed human wounds and compared them to their corresponding concentrations in blood. We also measured transforming growth factor‐β1 and ‐β3, vascular endothelial growth factor, interleukin‐1β, matrix metalloproteinases and selected isomers/receptors, all of which are associated with inflammation. All IGF proteins reached their highest concentrations immediately after injury. No difference between IGF‐I mRNA expression between acute and inflamed wounds was found. As a group, IGF‐related proteins, in contrast to transforming growth factor‐β, vascular endothelial growth factor, and interleukin‐1β, are highly correlated to and are generally below their concentrations in blood and are not elevated by inflammation. The IGF family therefore appears to enter wounds, even inflamed wounds, mainly from blood. If blood IGF‐I is low, wound levels are lower. This data suggests that healing impairment due to IGF‐I deficiency can be readily detected and is, at least in part, easily and safely correctable. (WOUND REP REG 2003;11:253–260)
Intra-individual variation in resting metabolic rate during the menstrual cycle
Authors: Henry C. Jeya K. , Lightowler Helen J. , Marchini Jonathan
Published: June 2003

Little information exists on the extent of day-to-day intra-individual variation in resting metabolic rate (RMR) in women. The present study has investigated the intra-individual variation in RMR of women during the menstrual cycle. Nineteen women (naturally cycling non-pill users) were recruited to the study. Anthropometric and RMR measurements were taken at least three times per week for the duration of one complete menstrual cycle; measurements were taken for a second, consecutive cycle in eight of the nineteen subjects. RMR was measured by indirect calorimetry using a ventilated hood system under standardized conditions. The measurements made throughout each complete menstrual cycle were averaged and the levels of inter- and intra-individual variation in RMR were assessed by determining the CV (%). Mean RMR of the group was 5686 (SD 674) kJ/d; inter-individual variation in RMR was 11·8 %. There were wide differences in the intra-individual variation in RMR of women (CV range 1·7–10·4 %). The CV in ten subjects was small (2–4 %), while the CV in nine women was high (5–10 %), indicating a significant variation in RMR during the menstrual cycle in certain subjects. Using statistical models, it has been shown that there was a significant effect on RMR due to a subject-specific level of variability; this was the case even when accounting for a possible training effect. In conclusion, the findings from our present study show that RMR cannot be assumed to be ‘stable’ in all women. The implications of intra-individual variation in RMR and its impact on energy balance needs further research.
Short- and long-term nutritional modulation of acetyl-CoA carboxylase activity in selected tissues of rainbow trout (Oncorhynchus mykiss)
Authors: Rollin Xavier , Médale Françoise , Gutieres Stéphanie , Blanc Denise , Kaushik Sadasivam J.
Published: June 2003

Acetyl-CoA carboxylase (ACoAC) catalyses the carboxylation of acetyl-CoA into malonyl-CoA. This product plays a pivotal role in the regulation of energy metabolism since it is both a substrate for fatty acid synthesis and an inhibitor of the oxidative pathway. The present study was initiated to analyse the modulation of ACoAC activity in liver and selected extrahepatic tissues of rainbow trout (Oncorhynchus mykiss) by dietary changes as a contribution to the understanding of the nutritional control of lipid metabolism in fish. Short-term effects of food intake were studied by measuring ACoAC activity in the liver and dorsal white muscle at different time intervals after a meal. Only slight variations were observed in the muscle during the period 2–72 h after the meal. The long-term effects of an increase in dietary lipids or carbohydrates levels were examined by measuring ACoAC activity in the liver, adipose tissue, intestine, kidney, red muscle, dorsal and ventral white muscles of trout after 3 months of feeding with different diets. ACoAC activity is stimulated by a high-digestible starch diet in the abdominal adipose tissue and the white muscle. A high-lipid diet decreases ACoAC activity in the liver and the intestine, but not in other tissues. Contrary to mammals, a rapid adaptation of ACoAC activity to food supply is not effective in rainbow trout. However, a long-term nutritional control of ACoAC activity does occur in this species, but the target tissue differs with the predominant non-protein energy sources in the diet. The present results suggest the potential existence of two ACoAC isoforms with different tissue distribution as has been observed in mammals and birds.
Ontogeny of brush border carbohydrate digestion and uptake in the chick
Authors: Sklan David , Geyra Asaf , Tako Elad , Gal-Gerber Orit , Uni Zehava
Published: June 2003

Ingestion of carbohydrates from the small intestine is the major route of energy supply in animals. In mammals these functions develop both pre- and postnatally and are coordinated for the sucking period. In birds, the physiological requirements are different and hatchlings ingest diets rich in complex carbohydrates soon after hatching. The present study examined the ontogeny of intestinal carbohydrate uptake in the chicken. The expression of mRNA for a brush border enzyme, sucrase–isomaltase (SI), which is critical in disaccharide digestion, was determined, together with that of the Na–glucose transporter (SGLT)-1, which is the major apical glucose transporter, In addition, the homeobox gene cdx, which is involved in inducing SI expression in mammals was examined. It was found that the expression of cdxA mRNA and cdxA protein increased from day 15 of incubation until hatch, after which further changes were small. CdxA protein was shown to bind to the promoter region of SI in the chick indicating that cdxA is similar to the mammalian cdx2. The mRNA of SI was observed at 15 d incubation, increased from 17 d of incubation to a peak on day 19, decreased at hatch and had a further peak of expression 2 d post-hatch. In contrast, the mRNA of SGLT-1 was not detected until 19 d of incubation when a major peak of expression was observed followed by a decrease to low levels at hatch and small increases post-hatch. It appears that both SI and SGLT-1 mRNA are expressed before hatch in the chick, but the ontogeny of expression is controlled by different mechanisms.
The effect of addition of linoleic acid on food intake regulation in linoleic acid tasters and linoleic acid non-tasters
Authors: Kamphuis Marleen M. J. W. , Saris Wim H. M. , Westerterp-Plantenga Margriet S.
Published: July 2003

In a randomised, single blind, placebo-controlled crossover design study, we investigated whether healthy, non-smoking, dietary unrestrained women (n24), divided into linoleic acid tasters (LAT,n14) and linoleic acid non-tasters (LANT,n10), differed in food intake regulation when linoleic acid was added to ice creams. The determination of subjects as LAT or LANT was done using a 10μM-linoleic acid solution. The ice creams were characterised by the subjects and a taste perception test using the triangle test was conducted three times. Food intake and appetite were measured using the universal eating monitor. LAT and LANT did not differ in characterisation or in taste perception of the ice creams, even though LAT were able to increase their ability to discriminate between the ice cream with linoleic acid from the one containing oleic acid. No effect of LAT status or type of ice cream was found for hedonic value of the ice creams. Linoleic acid taster status did affect food intake regulation. For LAT, but not LANT, the amount eaten was a function of Δsatiety. Subjects ate by weight of food and not by energy content. In conclusion, differences in food intake regulation were seen between LAT and LANT, in that the amount eaten by LAT was a function of Δsatiety, but was not for LANT.
Mathematical modelling of digesta passage rate, mean retention time and in vivo apparent digestibility of two different lengths of hay and big-bale grass silage in ponies
Authors: Moore-Colyer M. J. S. , Morrow H. J. , Longland A. C.
Published: July 2003

Welsh-cross pony geldings (about 300kg live weight) were used in a 4×4 Latin square experiment to determine the rate of passage and apparent digestibility of unchopped big-bale grass silage (BBL), chopped big-bale grass silage (BBS), unchopped grass hay (HL) and chopped grass hay (HS) offered at approximately 15g/kg live weight per d. On day 1 of collection weeks, ponies were fed 85g ytterbium chloride hexahydrate-marked feed 1·5h after the morning meal. Total faecal collections commenced 8h later and continued for 168h. Apparent digestibilities of feed DM, organic matter (OM), crude protein (CP, N×6·25), acid-detergent fibre (ADF) and neutral-detergent fibre (NDF) were also determined. Faecal excretion data were subjected to the models of Pond et al. (1988) and digesta mean retention time (MRT) calculated from these models and using the algebraic method of Thielmans et al. (1978). Silage had significantly (P<0·05) higher digestibilities of DM, OM, CP, ADF and NDF than hay; however, chop length had no effect. All the models of Pond et al. (1988) accurately described (R2>0·8) the pattern of faecal marker excretion. MRT of BBL (29·0h)>BBS(27h)>HS and HL (26h). Compartmental analysis using the G3 model of Pond et al. (1988) showed BBL and HS diets had longer MRT in the time-dependent compartment, whereas BBS and HL had longer MRT in the time-independent compartment. Results from this experiment indicate that BBL and BBS are readily accepted and digested by ponies. While Yb is a successful external marker for determining total tract MRT and for modelling faecal excretion curves in horses, the results did not allow any definite conclusions to be drawn on digesta MRT within the different compartments of the equid gut.
Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring
Authors: Lisle S. J. M. , Lewis R. M. , Petry C. J. , Ozanne S. E. , Hales C. N. , Forhead A. J.
Published: July 2003

In rats, maternal anaemia during pregnancy causes hypertension in the adult offspring, although the mechanism is unknown. The present study investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy. Rats were fed either a control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6) diet from 1 week before mating and throughout gestation. At delivery, the Fe-restricted (IR) mothers were anaemic; the IR pups were also anaemic and growth-retarded at 2 d of age. At 3 and 16 months, systolic blood pressure in the IR offspring (163 (sem 4) and 151 (sem 4) mmHg respectively, n 13) was greater than in control animals (145 (sem 3) and 119 (sem 4) mmHg respectively, n 15, P<0·05). At post mortem at 18 months, there was no difference in kidney weight between treatment groups, although relative kidney weight as a fraction of body weight in the IR offspring was greater than in control animals (P<0·05). Glomerular number was lower in the IR offspring (11·4 (sem 1·1) per 4mm2, n 13) compared with control rats (14·8 (sem 0·7), n 15, P<0·05). Maternal treatment had no effect on glomerular size, but overall, female rats had smaller and more numerous glomeruli per unit area than male rats. When all animals were considered, inverse relationships were observed between glomerular number and glomerular size (r−0·73, n 28, P<0·05), and glomerular number and systolic blood pressure at both 3 months (r−0·42, n 28, P<0·05) and 16 months of age (r−0·64, n 28, P<0·05). Therefore, in rats, maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number.
Plasma enterolactone or intestinal Bifidobacterium levels do not explain adenoma formation in multiple intestinal neoplasia (Min) mice fed with two different types of rye-bran fractions
Authors: Oikarinen S. , Heinonen S. , Karppinen S. , Mättö J. , Adlercreutz H. , Poutanen K. , Mutanen M.
Published: July 2003

The study was designed to evaluate whether two types of rye-bran fractions result in distinct bifidogenic effect or enterolactone production in multiple intestinal neoplasia (Min) mice and whether these parameters are associated with intestinal tumorigenesis in this animal model. The experimental diets were a non-fibre diet (control), a rye-bran diet, and diets containing either the soluble extract or the insoluble fraction prepared from rye bran. The main result on adenoma formation in these experiments was the observation that the soluble extract increased number (P=0·012) and size (P=0·008) of adenomas in the distal small intestine when compared with the non-fibre group. All rye-supplemented diets supported similarly the in vivo growth of Bifidobacterium (108–109 colony forming units/g) in Min mice, whereas the non-fibre diet lowered intestinal Bifidobacterium below the level of detection. The results show that water solubility does not affect the bifidogenicity of rye bran. Mean plasma enterolactone concentration was highest in the rye-bran group (30·0 nmol/l; P=0·002), which along with the soluble-extract group (16·2 nmol/l; P=0·024) differed significantly from the non-fibre diet group (7·5nmol/l). Thus, the mice fed with the rye bran were the best enterolactone producers. In conclusion, rye bran and rye fractions influence adenoma formation in Min mice to a varying degree but plasma enterolactone levels or the production of bifidogenic bacteria do not mediate the effect.
Adaptive responses in men fed low- and high-copper diets
Authors: Harvey Linda J. , Majsak-Newman Gosia , Dainty Jack R. , Lewis D. John , Langford Nicola J. , Crews Helen M. , Fairweather-Tait Susan J.
Published: July 2003

The study of Cu metabolism is hampered by a lack of sensitive and specific biomarkers of status and suitable isotopic labels, but limited information suggests that Cu homeostasis is maintained through changes in absorption and endogenous loss. The aim of the present study was to employ stable-isotope techniques to measure Cu absorption and endogenous losses in adult men adapted to low, moderate and high Cu-supplemented diets. Twelve healthy men, aged 20–59 years, were given diets containing 0·7, 1·6 and 6·0 mg Cu/d for 8 weeks, with at least 4 weeks intervening washout periods. After 6 weeks adaptation, apparent and true absorption of Cu were determined by measuring luminal loss and endogenous excretion of Cu following oral administration of 3 mg highly enriched65Cu stable-isotope label. Apparent and true absorption (41 and 48% respectively) on the low-Cu diet were not significantly different from the high-Cu diet (45 and 48% respectively). Endogenous losses were significantly reduced on the low- (0·45mg/d;P<0·001) and medium- (0·81 mg/d;P=0·001) compared with the high-Cu diet (2·46mg/d). No biochemical changes resulting from the dietary intervention were observed. Cu homeostasis was maintained over a wide range of intake and more rapidly at the lower intake, mainly through changes in endogenous excretion.
Cigarette smoking cessation increases plasma levels of several antioxidant micronutrients and improves resistance towards oxidative challenge
Authors: Polidori M. Cristina , Mecocci Patrizia , Stahl Wilhelm , Sies Helmut
Published: July 2003

Cigarette smoking is associated epidemiologically with increased risk of cardiovascular diseases, but the pathophysiological mechanisms are still not fully understood. There is evidence that smoking is related to increased free radical production and antioxidant depletion, but the effects of smoking cessation on plasma concentrations of antioxidants and susceptibility to oxidative stress are largely unknown. Plasma levels of vitamins A, C, E, uric acid, total thiols, carotenoids (including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) and malondialdehyde (MDA, a biomarker of lipid peroxidation) were measured in fifteen healthy, normolipidaemic subjects (seven males, eight females, 35·2 (sd2·3) years) before and 4 weeks after smoking cessation. To determine plasma resistance towards oxidative challenge, plasma was incubated for up to 5h with the peroxyl radical-generator 2,2′-azobis(2-amidinopropane) (AAPH); MDA and ascorbate levels were measured at various time points. The concentrations of all plasma antioxidants were lower before smoking cessation than afterwards; MDA levels were higher before than after termination of smoking. Upon AAPH exposure, the consumption of plasma ascorbate and the production of MDA occurred at a significantly faster rate before smoking cessation as compared with afterwards. Cigarette smoking cessation is followed by a marked increase in plasma antioxidant concentrations and substantially improves plasma resistance towards oxidative challenge. Given the importance of cigarette smoking as a risk factor for cardiovascular diseases and the pathophysiological role played by oxidative stress in these illnesses, quitting smoking represents an irreplaceable preventive strategy against tobacco-induced oxidative stress and vascular damage.
Forage breeding and management to increase the beneficial fatty acid content of ruminant products
Authors: Dewhurst R. J. , Scollan N. D. , Lee M. R. F. , Ougham H. J. , Humphreys M. O.
Published: July 2003

The declining consumption of ruminant products has been partly associated with their high proportion (but not necessarily content) of saturated fatty acids. Recent studies have focused on the less prominent fact that they are also important sources of beneficial fatty acids, includingn-3 fatty acids and conjugated linoleic acids. α-Linolenic acid (18: 3n-3) is of particular interest because it also contributes to improved flavour of beef and lamb. Many recent studies showed large effects of special concentrates on levels of fatty acids in milk and meat. However, the ‘rumen protection’ treatments, needed to ensure a worthwhile level of fatty acid in products, are expensive. Herbage lipids are the cheapest and safest source of these fatty acids and so breeding to increase delivery of fatty acids from plants into ruminant products is an important long-term strategy. Plant lipids usually contain high levels of polyunsaturated fatty acids, particularly 18: 2n-6 and 18:3n-3 which are the precursors of beneficial fatty acids. Whilst some plants are particularly rich in individual fatty acids (e.g. 18:3n-3 in linseed), there are also useful levels in grass and clover (TrifoliumSpp.). Levels of fatty acids in forages in relation to species and varieties are considered, as well as management and conservation methods. Relationships between levels of fatty acids and existing traits and genetic markers are identified. The effects of forage treatments on the fatty acid content of ruminant products are reviewed. The higher levels of polyunsaturated fatty acids in milk from cows fed clover silages show that the level of fatty acids in herbage is not the only factor affecting levels of fatty acids in ruminant products. Further effort is needed to characterise susceptibility of unsaturated fatty acids to oxidative loss during field wilting and biohydrogenation losses in the rumen, and the relative importance of plant and microbial processes in these losses. The pathways of lipolysis and lipid oxidation are reviewed and other plant factors which offer potential to breed for reduced losses are considered.
Polyunsaturated fatty acids and gene expression in mammalian systems
Authors: Wahle Klaus W. J. , Rotondo Dino , Heys Steven D.
Published: July 2003

Over the last 30 years it has become apparent that specific dietary fatty acids are capable of regulating, either directly or indirectly through various signal pathways, the expression of numerous genes, either positively or negatively. Such nutrient-gene interactions have important effects on cell metabolism, differentiation and growth, and ultimately on disease processes. The present review describes some of the more important fatty acid-gene interactions in relation to health and disease in mammalian species, and focuses on the underlying cell signal mechanisms, including various transcription factors, affected by fatty acids and some of their oxygenated derivatives, e.g. the eicosanoids. The review also attempts to clarify some of the complexities of the effects of fatty acids by suggesting a possible overriding regulation by the redox status of the cell. The latter will at least stimulate controversy in this exciting area of lipid research.
n-3 Polyunsaturated fatty acids, inflammation and obesity-related disease
Authors: Browning Lucy M.
Published: July 2003

Obese individuals are at increased risk from a range of metabolic diseases, including insulin resistance, dyslipidaemia and hypertension. Adipose tissue is an important endocrine organ, secreting a range of inflammatory mediators, including tumour necrosis factor a and interleukin 6. Circulating concentrations of these cytokines are increased in obesity and may contribute to the pathogenesis of metabolic diseases. The present review considers the evidence linking inflammation and obesity-related disease. The data show that an inflammatory phenotype, measured by serum sialic acid concentration, identifies individuals with insulin resistance, dyslipidaemia and hypertension. Serum sialic acid concentration increases progressively in obese individuals with none, one or multiple features of the metabolic syndrome, independent of BMI. Supplementation with long-chain n-3 polyunsaturated fatty acids has shown anti-inflammatory effects in studies of both healthy populations and in models of chronic inflammatory conditions. The effect on insulin sensitivity has been varied, with both positive and negative effects. This variability may relate to the metabolic characteristics of the study population; individuals with high background inflammation may derive greater benefits from n-3 polyunsaturated fatty acid supplements, suggesting a possible interaction between diet and phenotype. Future research is needed to fully evaluate the role of anti-inflammatory strategies in the dietary management of obesity.
Energy balance in obesity
Authors: Webber Jonathan
Published: July 2003

The current epidemic of human obesity implies that whilst energy balance appears to be regulated, the extent of this regulatory process is being overwhelmed in large numbers of the population by environmental changes. Clearly, the shift towards positive energy balance reflects both alterations in energy intake and decreases in physical activity. Increased energy intake and, in particular, the rising proportion of energy from fat is linked with obesity. However, on a population level reduced levels of activity probably play the predominant role. It is apparent that individual susceptibility to weight gain varies enormously. The factors underlying this susceptibility are an area of intense research interest. Variations in BMR from that predicted appear to be linked to the propensity to gain weight. The genes responsible for this variation may include uncoupling proteins-2 and -3, with a number of studies showing a link with obesity. However,in vivostudies of these proteins have not yet demonstrated a physiological role for them that would explain the link with obesity. Non-exercise activity thermogenesis may also protect from weight gain, but the regulation of this type of thermogenesis is unclear, although the sympathetic nervous system may be important. A profusion of hormones, cytokines and neurotransmitters is involved in regulating energy intake, but whilst mutations in leptin and the melanocortin-3 receptor are responsible for rare monogenic forms of obesity, their wider role in common polygenic obesity is not known. Much current work is directed at examining the interplay between genetic background and environmental factors, in particular diet, that both lead to positive energy balance and seem to make it so hard for many obese subjects to lose weight.