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Biomedical subjects

L J Roberts

Publications and source records attributed to L J Roberts.

At least 127 records · Page 7Linked to original sources
PubMed1996

Knowledge and use of periconceptual folic acid supplements by British Forces Germany personnel and dependents.

Periconceptual dietary folic acid supplementation reduces the incidence of neural tube defects (NTDs). Their use has been advocated by the Chief Medical Officer (CMO), the Consultant Advisor in Obstetrics & Gynaecology (O&G), the Senior Consultant in O&G British Forces in Germany (BFG) and by Medical Administration & Technical Instruction (MA&TI) in all NAAFI outlets. An audit of awareness of the recommendations and use of such supplements amongst pregnant women in BFG was performed over a 12 week period in BMH Rinteln. 16.6% (5/6) and 17.6% (34/193) of those with and without a history of a pregnancy affected by a NTD respectively had taken the correct dose before conception. Knowledge of and compliance with the recommendations is poor. An opportunity to positively influence health in a "captive" population is being lost.

Female↗
PubMed1996

Evidence against an increase in capillary permeability in subjects exposed to high altitude.

A potential pathogenetic cofactor for the development of acute mountain sickness and high-altitude pulmonary edema is an increase in capillary permeability, which could occur as a result of an inflammatory reaction and/or free radical-mediated injury to the lung. We measured the systemic albumin escape by intravenously injecting 5 muCi of 125I-labeled albumin and the plasma concentrations of cytokines, F2-isoprostanes (products of lipid peroxidation), and acute-phase proteins in 24 subjects exposed to 4,559 m. Ten subjects developed acute mountain sickness, and four subjects developed high-altitude pulmonary edema. The transcapillary escape rate of albumin was 6.9 +/- 2.0%/h (SD) at low (550 m) and 6.3 +/- 1.9%/h at high (4,559 m) altitude (P = 0.23; n = 24). The subjects with high-altitude pulmonary edema had a modest but insignificant increase in the transcapillary escape rate of albumin (4.6 +/- 1.9%/h at low vs. 5.7 +/- 1.9%/h at high altitude; P = 0.42; n = 4). Plasma concentrations of fibrinogen, alpha 1-acid glycoprotein, C-reactive protein, and interleukin-6 were unchanged in the early phases and significantly increased by the end of the observation period in the subjects with high-altitude pulmonary edema, whereas tumor necrosis factor-alpha and F2-isoprostanes did not change at all. This suggests that the inflammatory reaction was rather a consequence than a causative factor of high-altitude pulmonary edema. In summary, these data argue against a dominant role for increased systemic capillary permeability in the development of acute mountain sickness and high-altitude pulmonary edema.

Acclimatization↗
PubMed1996

Structural determinants of substrates for the prostaglandin transporter PGT.

We recently identified a broadly expressed transporter, PGT, that transports primarily prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha). In the current study, we examined the structural determinants of potential PGT substrates in detail. Rat PGT was transiently expressed in HeLa cells, the timed uptake of tracer PGE2 was determined in the presence of various concentrations of unlabeled prostanoids; and the resulting inhibitory constants (Ki) were determined by curve-fitting. PGE2 and PGF2 alpha, both known to be transported, had similar affinities for PGT (Ki = 49-50 nM). The strongest interaction (Ki = 13-19 nM) was obtained with prostanoids lacking the 9- or 11-position oxygen groups. A relatively high affinity was also obtained for the bicycloendoperoxides U44069, PGH2, and U46619 (Ki = 29-39 nM). However, a radioactive representative from this group, U46619, was not transported. Structural modifications that produced a moderately reduced affinity relative to that of PGE2 (Ki = 56-286 nM) included reduction in C5 = C6, the addition of a benzene group at position C18, and isomerization at the C8 position. In complementary studies, tracer isoprostane B-iso-PGF2 alpha was found to be transported at approximately 13% the rate of tracer PGE2. Substantially weaker interaction (Ki = > 700 nM) was seen when the 1-position COO- anionic group was neutralized or when the 15(S)-OH group was changed to 15(R)-OH or to 15-keto. These results with the cloned rat PGT are very similar to those previously reported in the in vitro perfused rat lung and indicate that PGT probably represents the predominant route by which certain prostanoids, including F2 isoprostanes, are transported across plasma membranes.

Animals↗
PubMed1995

Disability income, cocaine use, and repeated hospitalization among schizophrenic cocaine abusers--a government-sponsored revolving door?

BACKGROUND: Many patients with serious mental illness are addicted to drugs and alcohol. This comorbidity creates additional problems for the patients and for the clinicians, health care systems, and social-service agencies that provide services to this population. One problem is that disability income, which many people with serious mental illness receive to pay for basic needs, may facilitate drug abuse. In this study, we assessed the temporal patterns of cocaine use, psychiatric symptoms, and psychiatric hospitalization in a sample of schizophrenic patients receiving disability income. METHODS: We evaluated 105 male patients with schizophrenia and cocaine dependence at the time of their admission to the hospital. They had severe mental illness and a long-term dependence on cocaine, with repeated admissions to psychiatric hospitals; many were homeless. The severity of psychiatric symptoms and urinary concentrations of the cocaine metabolite benzoylecgonine were evaluated weekly for 15 weeks. RESULTS: Cocaine use, psychiatric symptoms, and hospital admissions all peaked during the first week of the month, shortly after the arrival of the disability payment, on the first day. The average patient spent nearly half his total income on illegal drugs. CONCLUSIONS: Among cocaine-abusing schizophrenic persons, the cyclic pattern of drug use strongly suggests that it is influenced by the monthly receipt of disability payments. The consequences of this cycle include the depletion of funds needed for housing and food, exacerbation of psychiatric symptoms, more frequent psychiatric hospitalization, and a high rate of homelessness. The troubling irony is that income intended to compensate for the disabling effects of severe mental illness may have the opposite effect.

Adult↗
PubMed1995

A 20-nucleotide element in the intestinal fatty acid binding protein gene modulates its cell lineage-specific, differentiation-dependent, and cephalocaudal patterns of expression in transgenic mice.

A sequence of epithelial cell proliferation, allocation to four principal lineages, migration-associated differentiation, and cell loss occurs along the crypt-villus axis of the mouse intestine. The sequence is completed in a few days and is recapitulated throughout the life-span of the animal. We have used an intestine-specific fatty acid binding protein gene, Fabpi, as a model for studying regulation of gene expression in this unique developmental system. Promoter mapping studies in transgenic mice identified a 20-bp cis-acting element (5'-AGGTGGAAGCCATCACACTT-3') that binds small intestinal nuclear proteins and participates in the control of Fabpi's cephalocaudal, differentiation-dependent, and cell lineage-specific patterns of expression. Immunocytochemical studies using confocal and electron microscopy indicate that it does so by acting as a suppressor of gene expression in the distal small intestine/colon, as a suppressor of gene activation in proliferating and nonproliferating cells located in the crypts of Lieberkühn, and as a suppressor of expression in the growth factor and defensin-producing Paneth cell lineage. The 20-bp domain has no obvious sequence similarities to known transcription factor binding sites. The three functions modulated by this compact element represent the types of functions required to establish and maintain the intestine's remarkably complex spatial patterns of gene expression. The transgenes described in this report also appear to be useful in characterizing the crypt's stem cell hierarchy.

Animals↗
PubMed1995

Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage.

BACKGROUND: It has been hypothesized that the pathogenesis of diseases induced by cigarette smoking involves oxidative damage by free radicals. However, definitive evidence that smoking causes the oxidative modification of target molecules in vivo is lacking. We conducted a study to determine whether the production of F2-isoprostanes, which are novel products of lipid peroxidation, is enhanced in persons who smoke. METHODS: We measured the levels of free F2-isoprostanes in plasma, the levels of F2-isoprostanes esterified to plasma lipids, and the urinary excretion of metabolites of F2-isoprostanes in 10 smokers and 10 nonsmokers matched for age and sex. The short-term effects of smoking (three cigarettes smoked over 30 minutes) and the effects of two weeks of abstinence from smoking on levels of F2-isoprostanes in the circulation were also determined in the smokers. RESULTS: Plasma levels of free and esterified F2-isoprostanes were significantly higher in the smokers (242 +/- 147 and 574 +/- 217 pmol per liter, respectively) than in the nonsmokers (103 +/- 19 and 345 +/- 65 pmol per liter; P = 0.02 for free F2-isoprostanes and P = 0.03 for esterified F2-isoprostanes). Smoking had no short-term effects on the circulating levels of F2-isoprostanes. However, the levels of free and esterified F2-isoprostanes fell significantly after two weeks of abstinence from smoking (250 +/- 156 and 624 +/- 214 pmol per liter, respectively, before the cessation of smoking, as compared with 156 +/- 67 and 469 +/- 108 pmol per liter after two weeks' cessation; P = 0.03 for free F2-isoprostanes and P = 0.02 for esterified F2-isoprostanes). CONCLUSIONS: The increased levels of F2-isoprostanes in the circulation of persons who smoke support the hypothesis that smoking can cause the oxidative modification of important biologic molecules in vivo.

Adult↗
PubMed1995

Topical benzoic acid induces the increased biosynthesis of prostaglandin D2 in human skin in vivo.

BACKGROUND: Benzoic acid is one of the most commonly used preservatives in cosmetics, foodstuffs, and drug preparations. Nonetheless, products containing this compound frequently induce cutaneous erythema. Previous studies have suggested that prostaglandins may mediate the cutaneous vasodilation because ingestion of cyclooxygenase inhibitors before the application of benzoic acid markedly diminishes this symptom. However, the prostaglandin responsible has not been conclusively determined. Recently we showed that cutaneous erythema similar to that associated with application of venzoic acid is induced by the topical administration of another preservative, sorbic acid, and is mediated by the increased biosynthesis of prostaglandin (PG)D2 in the skin. This study was designed to determine whether the cutaneous vasodilation induced by benzoic acid is mediated by this prostaglandin in humans. DESIGN: Benzoic acid (10% in petrolatum) was applied to the forearms of healthy volunteers. Blood was obtained from the antecubital vein draining the treated site and assayed for vasodilating prostaglandins and histamine. RESULTS: Topical application of benzoic acid to four volunteers resulted in a 29- to 8000-fold increase in plasma levels of PGD2 and a 72- to 370-fold increase in levels of 9 alpha,11 beta-PGF2, the stable plasma metabolite of PGD2, in blood drawn from the antecubital vein draining the treated sites. In contrast, there were no changes in plasma levels of other vasodilating prostaglandins, PGE2 or prostacyclin (PGI2). Increases in levels of PGD2 and 9 alpha,11 beta-PGF2 were not found in blood drawn simultaneously from veins in the contralateral arm, indicating the increased biosynthesis of PGD2 from the site of benzoic acid application. Increased formation of PGD2 in response to topical application of benzoic acid was dose dependent over a concentration range of 0.01% to 15%. The increased synthesis of PGD2 was not accompanied by a release of histamine, suggesting that PGD2 was not derived from the mast cell. CONCLUSIONS: PGD2 mediates the vasodilation associated with topical application of benzoic acid.

Administration, Cutaneous↗
PubMed1995

Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prostaglandin D2.

Symptoms of mastocytosis have been attributed to the overproduction of both histamine and prostaglandin (PG) D2. Recently, we developed an assay for the major urinary metabolite of PGD2 (PGD-M), 9 alpha,11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid, and demonstrated that urinary excretion of this compound is markedly increased in patients with mastocytosis. It had been shown previously that measurement of the urinary excretion of histamine metabolites provides a more sensitive biochemical diagnostic indicator of systemic mastocytosis than does measurement of unmetabolized histamine. Therefore, we examined the correlation between the urinary excretion of the histamine metabolite, NT-methylhistamine, and PGD-M in urine samples from patients with mastocytosis. Urinary excretion of NT-methylhistamine and PGD-M was measured in 46 urine samples from 17 patients with histologically documented mastocytosis. Both compounds were quantified by mass spectrometry. In all urine collections showing an increase above normal (2 SD above the mean) in the excretion of NT-methylhistamine, the fold increase above normal in the urinary excretion of PGD-M was substantially greater. Further, in some urine samples from four patients whose excretion of NT-methylhistamine was consistently normal, the excretion of PGD-M was increased above normal by as much as 300%. These data indicate that quantification of the urinary excretion of PGD-M is a more sensitive biochemical diagnostic indicator of mastocytosis than is the quantification of NT-methylhistamine.

Adult↗
PubMed1995

First trimester fetal nuchal translucency: problems with screening the general population. 1.

OBJECTIVE: To evaluate the feasibility of measuring first trimester nuchal translucency in an unselected population, to assess the relationship with gestation and maternal age and to measure reproducibility. DESIGN: A prospective observational study. SETTING: University College Hospital, London. SUBJECTS: One thousand and four women attending for a routine first trimester dating scan between eight and thirteen weeks of gestation. Measurements of nuchal translucency were attempted in 1368 (80.3%) and successful in 1127 (82% of attempts). RESULTS: Nuchal translucency is most easily measured at 11 weeks of gestation. If a cut-off of > or = 3 mm is used, 6% of unselected fetuses between eight and thirteen weeks of gestation are classified as abnormal. Nuchal translucency increases with gestational but not maternal age. Reproducibility is poor: by repeating measurements with a different operator, the same operator using a different still image, or the same operator using the same still image, 18.8%, 17.5% or 12.4% of nuchal translucency measurements, respectively, change their classification as normal or abnormal. CONCLUSIONS: If nuchal translucency > or = 3mm were used as an indication for karyotyping, 6% of the normal pregnant population would be screen positive. However, the percentage will vary greatly depending on the gestational age profile of the screened population. The poor reproducibility of nuchal translucency measurement could diminish its usefulness as a screening test for Down's syndrome.

Adult↗
PubMed1995

First trimester fetal nuchal translucency: problems with screening the general population. 2.

OBJECTIVE: To investigate first trimester nuchal translucency > or = 3 mm as a screening test for aneuploidy in the normal pregnant population. DESIGN: A pilot observational study. SETTING: University College Hospital, London. SUBJECTS: One thousand one hundred and twenty-seven women had measurements of nuchal translucency at the time of their dating scan (8-13 weeks of gestation). RESULTS: Seventy fetuses (6%) had a nuchal translucency > or = 3 mm. Five karyotypically abnormal fetuses were identified by standard routine techniques (three trisomy 21, two trisomy 18), all in high risk mothers (> or = 39 years). Only two had nuchal translucency > or = 3 mm (one trisomy 21, one trisomy 18). CONCLUSIONS: Although nuchal translucency measurement is feasible and promising, there is at present insufficient data to warrant its introduction for screening of the general population, or to replace traditional second trimester screening.

Adult↗
PubMed1995

Formation of F2-isoprostanes during oxidation of human low-density lipoprotein and plasma by peroxynitrite.

F2-Isoprostanes are novel bioactive prostaglandin F2-like compounds produced by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. F2-Isoprostanes are initially formed in situ on phospholipids and subsequently released. Quantification of the F2-isoprostanes has been found to represent a valuable and reliable marker of lipid peroxidation. Oxidative modification of low-density lipoprotein (LDL) is a key process for the recognition of LDL by the scavenger receptors on macrophages. The oxidative mechanism responsible for the modification of LDL in vivo remains unclear, but an attractive candidate is the powerful oxidant peroxynitrite, which can be formed by reaction of nitric oxide and superoxide in the vessel wall. To further explore the potential role of peroxynitrite in the oxidative modification of plasma lipids, we investigated whether incubation of LDL and plasma with peroxynitrite or SIN-1, which decomposes to form nitric oxide and superoxide, catalyzes the formation of F2-isoprostanes. Incubation of LDL with peroxynitrite (0.125 to 1 mmol/L) or SIN-1 (0.5 and 1 mmol/L) induced a concentration-dependent increase in the formation of F2-isoprostanes, reaching a maximum of 5.5 +/- 2.05-fold (SEM) and 18.2 +/- 4.0-fold above control values, respectively. The increase of F2-isoprostanes induced by SIN-1 was essentially completely inhibited by superoxide dismutase. Incubation of plasma with peroxynitrite or SIN-1 yielded similar results. These results indicate that peroxynitrite can induce the formation of F2-isoprostanes in lipoproteins. Since F2-isoprostanes can exert potent biological activity such as vasoconstriction, they may contribute to the vascular pathobiology associated with atherosclerosis.

Antihypertensive Agents↗
PubMed1995

Effects of a selective DP receptor agonist (BW 245C) and antagonist (BW A868C) on the canine colonic epithelium: an argument for a different DP receptor?

Earlier studies showed that PGD2 produced both increases and decreases in short-circuit current across the canine proximal colon. PGD2 metabolites had opposing effects: 11 beta-PGF2 alpha elicited only increases in Isc, and 13,14-dihydro-15-keto-PGD2 elicited only decreases. The stimulant effects involved FP receptors, but the receptors involved in mediating the inhibitory effects remained undefined. Here we show that the tissue, although it is capable of producing both PGD2 and PGE2, did not produce 11 beta-PGF2 alpha in measurable amounts. The selective DP receptor agonist BW 245C did not mimic the inhibitory effects of PGD2, producing only dose-dependent increases in short-circuit current. Further, these responses were not significantly inhibited by BW A868C. Cross-desensitization experiments suggested that the stimulant effects of BW 245C involved the EP receptor. However, on a standard preparation (rabbit platelets), both PGD2 and BW 245C inhibited ADP-induced aggregation and were antagonized by BW A868C. 11 beta-PGF2 alpha had no effects. The decreases in short-circuit current across the canine colonic epithelium elicited by PGD2 and 13,14-dihydro-15-keto PGD2 are not mimicked by other prostanoids, nor by the selective agonist BW 245C, and thus appear to involve receptors other than the classical DP receptor.

Animals↗
PubMed1994

Isoprostanes. Novel markers of endogenous lipid peroxidation and potential mediators of oxidant injury.

It was recently discovered that a series of structurally unique prostaglandin F2-like compounds (F2-isoprostanes) capable of exerting potent biological activity are produced in vivo in humans by a noncyclooxygenase mechanism involving free radical catalyzed peroxidation of arachidonic acid. Considerable evidence has been obtained suggesting that quantification of F2-isoprostanes represents an important advance in our ability to assess oxidant status in vivo in humans. This has allowed us to implicate oxidant stress in the pathogenesis of human disease-for example, the hepatorenal syndrome. In addition to the F2-isoprostanes, we recently discovered that E-ring and D-ring isoprostanes are also produced in abundance in vivo by rearrangement of the isoprostane endoperoxide intermediates. We have also been able to demonstrate that one of the E2-isoprostanes, 8-epi-PGE2, is a potent renal vasoconstrictor in the rat. Insights into factors that may influence the formation of E2/D2-isoprostanes relative to F2-isoprostanes should be important in advancing our understanding of the biological consequences of the formation of isoprostanes in vivo.

Animals↗
PubMed1994

Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes.

15-Lipoxygenase (15-LO) catalyzes hydroperoxidation of fatty acids, a reaction of potential relevance to inflammation, membrane remodeling, and atherosclerosis. In human leukocytes, 15-lipoxygenation of arachidonic acid produces 15-(S)-hydroxyeicosatetraenoic acid and lipoxin A4, which suppress white cell chemotaxis, adherence, and activation, and antagonize proinflammatory leukotrienes. Interleukin (IL)-13, produced by T-helper subset 2 (TH-2) lymphocytes, specifically and potently induced 15-LO gene expression and enzyme activity in human monocytes. Among other TH-2 lymphokines, this induction of 15-LO is shared by IL-4 but not by IL-10. Interferon-gamma, a product of TH-1 lymphocytes, blocked IL-13-mediated induction of 15-LO. The induction of the anti-inflammatory 15-LO pathway by IL-13 reveals a new facet of IL-13 biology that supports its role as a cytokine with potential to down-regulate inflammatory pathways. The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis.

Arachidonate 15-Lipoxygenase↗