bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noninvasive breath tests can detect alterations in gastric emptying in the mouse
Authors: Symonds E. , Butler R. , Omari T. 
Published: March 2003

AbstractBackground Noninvasive breath tests may have significant utility for the measurement of gastric emptying in mice, but the tests’ sensitivity for detection of changes in gastric emptying has not been evaluated.Materials and methods Hydroxypropyl methyl cellulose was incorporated into a liquid meal to delay gastric emptying, and mice were injected with erythromycin to accelerate emptying of a liquid or solid meal. All test meals were labelled with 13C‐acetic acid or 13C‐octanoic acid. Breath samples collected at intervals were analysed for 13CO2 content, and gastric emptying rates were calculated from the resultant 13CO2 excretion curves.Results As predicted, hydroxypropyl methyl cellulose slowed emptying compared with water (14·21 ± 0·94 min vs. 9·17 ± 0·47 min, P < 0·001), while erythromycin treatment accelerated emptying of liquids (10·96 ± 0·78 min vs. 16·41 ± 1·94 min, P < 0·05) and solids (108·81 ± 18·06 vs. 157·95 ± 12·01 min, P < 0·05) compared with the saline injected controls.Conclusions These data indicate that in mice the breath test is sensitive enough to detect differences in gastric emptying induced by meal composition and pharmacological agents. Noninvasive measurement of gastric emptying in mice will be useful as a method to evaluate the effect of nutrients or drugs on the motility of the gastrointestinal tract.
Immunophenotypic analyses of CD34+ cell subsets in bone marrow from HIV‐infected patients during highly‐ active antiretroviral therapy
Authors: Müller F. , Tjønnfjord G. E. , Nordøy I. , Kvale D. , Mellbye O. J. , Aukrust P. , Frøland S. S. 
Published: March 2003

AbstractBackground Because increased bone marrow lymphopoiesis might contribute to immunologic reconstitution during highly‐active antiretroviral therapy (HAART), we examined the effect of HAART on CD34+ cell subsets in bone marrow from HIV‐infected patients.Materials and Methods In 12 HIV‐infected patients, bone marrow and peripheral blood were collected before then 4 and 26 weeks after initiating HAART. Bone marrow in 28 HIV‐seronegative controls was also examined. Immunophenotypic analyses of CD34+ cell subsets in bone marrow were performed by flow cytometry.Results Our main findings in bone marrow were: (i) HIV‐infected patients had increased proportions of CD34+ cells expressing T‐ and B‐cell markers before initiating HAART; (ii) in contrast, these patients had decreased proportions of CD34+ cells expressing myeloid‐associated markers; (iii) although HAART induced an increase in peripheral T‐cell counts, the percentage of CD34+ cells expressing T‐cell markers tended to decrease during such therapy; (iv) HAART induced a decrease in serum IgG accompanied by a slight decrease in the proportion of CD34+ cells expressing B‐cell markers; (v) in contrast, HAART induced a significant increase in peripheral granulocyte counts, accompanied by a slightly increased proportion of CD34+ cells expressing myeloid‐associated molecules.Conclusion Our findings are compatible with an HIV‐related block in T‐cell differentiation, leading to accumulation of T‐cell progenitors in bone marrow, and such a block may be removed by HAART.
Effect of Simvastatin on markers of triglyceride‐rich lipoproteins in familial hypercholesterolaemia
Authors: Dane‐Stewart C. A. , Watts G. F. , Mamo J. C. L. , Barrett P. H. R. , Martins I. J. , Dimmitt S. B. , Redgrave T. G. 
Published: March 2003

AbstractBackground We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B‐48 and remnant‐like particle‐cholesterol (RLP‐C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG‐CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB‐48 and RLP‐C in FH patients after long‐ and short‐term simvastatin therapy and after a wash‐out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant‐like emulsion labeled with cholesteryl 13C‐oleate.Methods Fifteen FH patients were studied after > 6 months 40 mg day−1 simvastatin treatment (long‐term), a wash‐out period (4 weeks), and 4 weeks of simvastatin treatment (short‐term). Apolipoprotein B‐48 was determined by SDS‐PAGE and Western blotting/enhanced chemiluminescence and RLP‐C by an immunoseparation assay. The FCR of the chylomicron remnant‐like emulsion was determined from the appearance of 13CO2 in the breath and by multicompartmental mathematical modelling.Results Both long‐ and short‐term treatment with simvastatin were associated with decreases in the plasma concentration of apoB‐48 (P < 0·05) and RLP‐C (P < 0·001), but there was no significant change in the FCR of the emulsion.Conclusions We suggest that long‐ and short‐term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride‐rich remnants in heterozygous FH, as measured by fasting apoB‐48 and RLP‐C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up‐regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured kinetically by the 13CO2 breath test.
Statins decrease bone turnover in postmenopausal women: a cross‐sectional study
Authors: Rejnmark L. , Buus N. H. , Vestergaard P. , Andreasen F. , Larsen M. L. , Mosekilde L. 
Published: March 2003

AbstractBackground Statins have been suggested as potential agents in the management of osteoporosis. Reviews of medical records have shown an increased bone mass and some studies have shown a reduced occurrence of fractures in subjects on long‐term treatment with statins. We studied the effects of treatment with statins on calcium homeostasis, bone turnover and bone mineral density.Design In a cross‐sectional design, plasma levels of parathyroid hormone (PTH) and biochemical markers of bone turnover, bone mineral density (BMD) and body composition (fat‐ and lean tissue‐mass) were measured in 140 postmenopausal women who had been treated with a statin for more than 2 years (median 4 years) and compared to 140 age‐ and gender‐matched, population‐based controls.Results Plasma levels of bone turnover markers were lower in the statin‐treated subjects than in the controls: osteocalcin (−9%, P = 0·03), bone‐specific alkaline phosphatase (−14%, P < 0·01), and C‐terminal telopeptide of type I collagen (−11%, P < 0·01). On the other hand, plasma PTH levels were 16% higher in the statin‐treated subjects than in the controls (P < 0·01). However, body composition and BMD at the lumbar spine, hip, forearm and whole body did not differ between the two groups. No correlation could be demonstrated between changes in biochemical quantities and dose or duration of statin use.Conclusion Our data show that statins affect the function of bone cells. Most likely, the effect is antiresorptive.
Impaired system A amino acid transport mimics the catabolic effects of acid in L6 cells
Authors: Bevington A. , Brown J. , Butler H. , Govindji S. , M‐Khalid K. , Sheridan K. , Walls J. 
Published: March 2003

AbstractBackground Metabolic acidaemia stimulates protein catabolism in skeletal muscle cells, leading to muscle wasting. As this occurs without decreasing cytosolic pH, the initial signal is unclear. A possible explanation is that extracellular pH acts on solute transporters at the cell surface, inhibiting nutrient influx.Design Influx through glucose and Pi transporters and System A amino acid transporters into L6 skeletal muscle cells was assessed using 3H‐2‐deoxyglucose (2‐DG), 33Pi and 14C‐methylaminoisobutyrate (MeAIB), respectively. Protein degradation (PD) was assessed from 14C efflux from cells prelabelled with 14C‐Phe. Branched‐chain amino acids and Phe were assayed by selective fluorimetric assays.Results While acid (pH 7·1) had little immediate effect on 2‐DG or 33Pi influx, exposure to pH 7·1 rapidly inhibited MeAIB influx. To determine whether System A inhibition was sufficient to trigger PD, it was blocked at pH 7·5 by a saturating dose (10 mmol L−1) of nonmetabolisable substrate (MeAIB). Like acid, this increased PD and decreased total protein. It also mimicked the decreases in protein synthesis, DNA synthesis, glucose transport and glycolysis, and depletion of branched‐chain amino acids and Phe, which are induced in L6 by acid. The onset of inhibition of PD by an extracellular Gln load was retarded at pH 7·1, and stimulation of PD by acid was negligible if PD had already been stimulated by Gln depletion. The stimulatory effect of MeAIB on PD was selectively blunted by an excess of Gln, whereas the inhibitory effect of Gln on PD was blocked by excess MeAIB.Conclusions The similarity of changes in response to MeAIB and acid implies that these share a common intracellular signalling pathway triggered by inhibition of System A. Even though System A is only a minor contributor to total Gln influx in L6 cells, it is suggested that blockade of System A with acid or MeAIB induces a catabolic state by denying Gln access to a key intracellular regulatory site.
Effect of low doses of 5‐methyltetrahydrofolate and folic acid on plasma homocysteine in healthy subjects with or without the 677C→T polymorphism of methylenetetrahydrofolate reductase
Authors: Litynski P. , Loehrer F. , Linder L. , Todesco L. , Fowler B. 
Published: March 2003

AbstractBackground  The 677C→T polymorphism of methylenetetrahydrofolate reductase can lead to increased homocysteine. Moderate increases of homocysteine can be lowered by folic acid (0·4–10 mg day−1). This study compared the effect of folic acid with 5‐methyltetrahydrofolate, the active form of folate generated by this reductase, on homocysteine levels in healthy subjects and whether this is influenced by the 677C→T polymorphism.Materials and methods  Either 400 µg day−1 of [6RS] 5‐methyltetrahydrofolate or 400 µg day−1 of folic acid were administered orally to 10 wild‐type and 10 homozygous subjects. Total homocysteine and folate were determined before and after 3 and 7 weeks of treatment, and 24 weeks after stopping treatment.Results  After 3 and 7 weeks of treatment with 5‐methyltetrahydrofolate, homocysteine levels fell from 11·6 ± 1·5 to 9·0 ± 2·3 and 8·7 ± 1·8 (P < 0·005) in wild‐type subjects and from 16·9 ± 6·8 to 12·3 ± 4·3 and 11·6 ± 4·4 µmol/L, mean ± SD (P < 0·005) in homozygous subjects, proving biological availability of 5‐methyltetrahydrofolate irrespective of the 677C→T genotype.After folic acid for 3 and 7 weeks, values fell from 12·6 ± 3·3 to 9·2 ± 2·9 and 9·2 ± 2·7 (P < 0·005) and from 15·6 ± 4·9 to 11·7 ± 3·9 and 9·1 ± 2·4 µmol L−1, mean ± SD (P < 0·005) in wild‐type and homozygous subjects, respectively.Six months after stopping treatment, homocysteine levels remained lower than pretreatment levels, with statistical significance, only in homozygous subjects treated with 5‐methyltetrahydrofolate (12·1 ± 2·5 vs. 16·9 ± 6·8, P < 0·01).Conclusions  5‐methyltetrahydrofolate showed comparable efficacy in reducing homocysteine as folic acid. A prolonged effect 6 months after ceasing treatment with 5‐methyltetrahydrofolate in homozygous subjects represents a further phenotypic effect of the 677TT methylenetetrahydrofolate reductase genotype.
Post‐transcriptional regulation of VEGF expression by oxidised LDL in human macrophages
Authors: Salomonsson L. , Pettersson S. , Englund M. C. O. , Wiklund O. , Ohlsson B. G. 
Published: March 2003

AbstractBackground Accumulation of oxidised low density lipoproteins (oxLDL) in macrophages and their subsequent transformation into lipid‐filled foam cells is generally considered an early event in atherosclerosis. Vascular Endothelial Growth Factor (VEGF) may contribute to atherogenesis through increased vascular permeability, chemoattraction towards monocytes and intraplaque vessel formation. In this study we investigate the effect and regulation of VEGF expression in human macrophages stimulated with oxLDL.Materials and methods Vascular Endothelial Growth Factor mRNA and protein expression was assayed using RT‐PCR and ELISA, respectively. The activity of mitogen‐activated protein kinases (MAPKs) was investigated using Western blots.Results In human monocyte‐derived macrophages, oxLDL significantly increased VEGF mRNA expression and subsequent protein secretion in a concentration‐dependent manner after 6 h and 18 h, respectively. Using an in vitro mRNA decay assay, we show that this oxLDL‐induced VEGF expression partly is regulated through increased stability of the VEGF mRNA. Involvement of MAPKs has previously been implicated in the stabilisation of VEGF mRNA. Activity of the p38 MAPK, but not the c‐jun‐N‐terminal kinase (JNK), increased in macrophages stimulated with oxLDL (50 µg mL−1) for 5–15 min. Preincubation with SB202190 (20 µM), a specific inhibitor of p38 MAPK, significantly decreased the oxLDL‐induced VEGF mRNA expression by 40%. The prolonged half‐life of VEGF mRNA, induced by oxLDL, was not inhibited by SB202190.Conclusions OxLDL increases VEGF expression and p38 MAPK activity in human macrophages. The increased VEGF mRNA expression by oxLDL is mediated through at least two intracellular pathways, one involving p38 MAPK and another that independently of p38 MAPK activity increases VEGF mRNA stability.
Nontransferrin‐bound iron in the plasma of haemodialysis patients after intravenous iron saccharate infusion
Authors: Kooistra M. P. , Kersting S. , Gosriwatana I. , Lu S. , Nijhoff‐Schutte J. , Hider R. C. , Marx J. J. M. 
Published: March 2003

AbstractBackground Many haemodialysis patients treated with recombinant human erythropoietin (r‐HuEPO) receive intravenous iron supplementation on a regular basis. It has been shown previously that this may result in a transient ‘oversaturation’ of transferrin.Methods Ten stable haemodialysis patients on r‐HuEPO treatment received 100 mg iron saccharate in 60 min, and 1 week later 100 mg in 6 min. Conventional iron metabolism parameters and nontransferrin‐bond iron, detected with HPLC after addition of nitrilotriacetate and pretreatment with cobalt, were measured. Also, iron was measured in dialysate.Results Serum iron increased from 9·6 ± 6·2 to 213·7 ± 49·4 µmol L−1 (P < 0·001) when iron was given in 60 min, and from 11·1 ± 4·7 to 219·3 ± 43·7 µmol L−1 (P < 0·001) when iron was given in 6 min. Transferrin saturation increased from 0·22 ± 0·18 to 4·75 ± 1·35 in protocol 1 and 0·26 ± 0·16 to 4·91 ± 1·38 in protocol 2. Nontransferrin‐bound iron increased from 0·74 ± 0·69 to 3·79 ± 1·41 µmol L−1 in protocol 1, and from 0·90 ± 0·92 to 2·90 ± 0·96 µmol L−1 in protocol 2. No significant iron concentrations were found in dialysate before or during the iron saccharate infusion.ConclusionNontransferrin‐bound iron exists in plasma of dialysis patients after infusion of iron saccharate. There was no difference when 100 mg iron was given in 60 min or in 6 min. Before iron infusion, appreciable concentrations of nontransferrin‐bound iron could already be detected. The clinical significance is not clear, but the findings may be important since nontransferrin‐bound iron can act as a catalytic agent in the formation of hydroxyl radicals, thus potentially inducing cell damage and atherosclerosis.
Angiostatin prolongs the survival of mice with leptomeningeal metastases
Authors: Reijneveld J. C. , Taphoorn M. J. B. , Kerckhaert O. A. J. , Drixler T. A. , Boogerd W. , Voest E. E. 
Published: March 2003

AbstractBackground As a result of the more effective treatment of primary tumours, the incidence of leptomeningeal metastases (LM) is increasing. Current treatment modalities have little effect on the survival of patients with LM. We investigated whether antiangiogenic treatment inhibits the progression of leptomeningeal tumours.Materials and methods To assess the role of angiogenesis in leptomeningeal tumours, we inoculated melanoma cells in the subarachnoid space in balb/c mice. At different stages, the mice were sacrificed and the microvessel density was determined. Human specimens of LM were compared with the mouse model. For the intervention studies, the mice were treated with the angiogenesis inhibitor angiostatin. Survival was the endpoint in these studies.Results Tumour seeding in the early disease stages was concentrated around the pre‐existent arachnoid vasculature. In the more advanced stages, the tumour masses covered larger areas of the leptomeninges. Arachnoidal microvessel density in this advanced stage was increased compared with control mice. Systemic treatment of the mice with LM with angiostatin (100 mg kg−1 day−1) resulted in prolonged survival compared with mice treated with vehicle and with approximately one‐fifth of the long‐term survivors of the angiostatin‐treated group.Conclusions This study shows that neovascularization is important in the growth of LM in mice. Systemic targeting of the vascular compartment may be a useful approach in novel therapeutic strategies for patients with LM.
Intracellular glutathione and lipid peroxide availability and the secretion of vasoactive substances by human umbilical vein endothelial cells after incubation with TNF‐α
Authors: Scalera F 
Published: March 2003

AbstractBackground The major pathophysiologic changes observed in preeclampsia suggest that endothelial cell dysfunction plays an important role in this disorder. The pathway mediating to endothelial cell dysfunction is unknown, however, the pathogenesis of preeclampsia is thought to be related to increased oxidative stress and increased vasoconstriction. The concentration of tumor necrosis factor alpha (TNF‐α), a cytokine produced by macrophages and many other cell types, has been observed to be significantly increased in preeclampsia. It has been hypothesized that TNF‐α overproduction by the placenta may then may produce an increase in plasma levels and subsequent endothelial dysfunction in preeclampsia. This study investigated the effect of TNF‐α on glutathione and lipid peroxide levels and on the secretion of vasoactive substances by human umbilical vein endothelial cells (HUVECs).Methods Human umbilical vein endothelial cells were incubated for 24 h in the presence of different concentrations of TNF‐α (0–1000 pg mL−1) that were shown in an earlier experiment to have no effects on the vitality and proliferation rate of HUVECs. The levels of reduced glutathione (GSH) and lipid peroxides (LPOs), assessed by malondialdehyde and 4‐hydroxyalkenal, were measured in endothelial cell lysates. For the measurement of vasoactive substances, levels of prostacyclin (PGI2), determined by 6‐keto‐prostaglandin F1a, thromboxane A2 (TXA2), measured by thromboxane B2, endothelin‐1 (ET‐1), and nitric oxide (NO), measured by total nitrite, were assessed in endothelial cell supernatants.Results At lower concentrations (10–100 pg mL−1), TNF‐α increases the intracellular content of LPO and GSH, stimulates the secretion of ET‐1 and TXA2, but inhibits the secretion of PGI2 in endothelial cells compared with control cells. At concentration of 1000 pg mL−1, TNF‐α increases the secretion of PGI2 and TXA2, but it decreases the ET‐1 concentration. TNF‐α has no effect on NO secretion.Conclusion These findings demonstrate that at concentrations corresponding to values in plasma from preeclamptic women, TNF‐α induces oxidative stress and results in altered secretion of vasoactive substances in favour of vasoconstrictors in human endothelial cells. We conclude that TNF‐α may participate in the pathway leading to endothelial cell dysfunction seen in preeclampsia.
Human RAGE GLY82SER dimorphism and HLA class II DRB1‐DQA1‐DQB1 haplotypes in type 1 diabetes
Authors: Prevost G. , Fajardy I. , Fontaine P. , Danze P. M. , Besmond C. 
Published: March 2003

AbstractAdvanced glycation end products (AGEs) are believed to play an important role in the development of diabetic complications. AGEs increase in diabetes and modulate cellular functions through binding to a specific cell surface receptor (RAGE). The RAGE gene maps to chromosome 6p in the HLA class III area and is telomeric to the class II region at 250 kb from DRA. A recent report described the characterization of a major RAGE gene variant as a biallelic single base polymorphism (G/A 557) in the exon 3 sequence leading to a change of a glycine to a serine at position 82. Using DGGE and PCR‐RFLP, we have investigated the distribution of this dimorphism in conjunction with HLA class II genes in large populations of type 1 diabetic patients and healthy subjects. Although no association of this RAGE gene polymorphism with disease susceptibility was found, we report a strong linkage disequilibrium between the variant carrying the serine amino acid at position 82 and two HLA‐DR2 and HLA‐DR4 specificities. In particular, we describe two major extensive HLA class II haplotypes associated with this serine variant and identified as DRB1*0401‐DQA1*0301‐DQB1*0301 in the diabetic group and DRB1*1501‐DQA1*0102‐DQB1*0602 in control individuals. These data were partially confirmed by family transmission analysis.
HLA‐DRB1*12 is associated with protection against complicated typhoid fever, independent of tumour necrosis factor α
Authors: Dharmana E. , Joosten I. , Tijssen H. J. , Gasem M. H. , Indarwidayati R. , Keuter M. , Dolmans W. M. V. , Van der Meer J. W. M. 
Published: March 2003

SummaryWe investigated whether HLA‐DR2 or ‐DR12 alleles in 63 Javanese patients with complicated or non‐complicated typhoid fever were associated with severity of disease. No association was observed between HLA type and susceptibility to disease. However, in patients we did find a negative association of DR12 (DRB1*12021) with complicated typhoid fever (P = 0.05; OR = 0.3; 95% CI: 0.1–1.0). No effect of DR2 (DRB1*1502) on outcome (P = 0.46; OR = 1.5; 95% CI: 0.5–4.5) was demonstrated. The odds ratio for DR12 remained unchanged after adjusting for DR2. Tumour necrosis factor α (TNF‐α) production capacity in lipopolysaccharide (LPS)‐stimulated whole blood culture, as measured by non‐equilibrium radioimmunoassay, was significantly lower in complicated than in non‐complicated cases (P = 0.02), confirming previous data. No significant correlation of either DR12 (P = 0.47) or DR2 (P = 0.89) was found with TNF‐α production capacity. Apparently, protection against complications by DR12 is attributable to other mechanisms.