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Biomedical subjects

M J James

Publications and source records attributed to M J James.

At least 19 recordsLinked to original sources
PubMed2000

Dietary polyunsaturated fatty acids and inflammatory mediator production.

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = 90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.

Arachidonic Acid↗
PubMed1999

Cytokines (IL-1beta, IL-6, TNF-alpha, TGF-beta1, and TGF-beta2) and prostaglandin E2 in human milk during the first three months postpartum.

Postpartum changes in the concentrations of IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1 (TGF-beta1), TGF-beta2, and prostaglandin E2 in 257 human milk samples collected longitudinally from 49 healthy mothers during the first 12 wk of lactation were determined by ELISA or RIA. The proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha were present in only a proportion of samples, and there was a wide range of concentrations detected at each time in the present study (IL-1beta, <15-400 pg/mL; IL-6, <15-1032 pg/mL; TNF-alpha, <15-2933 pg/mL). Concentrations of prostaglandin E2 increased after the first week and remained elevated for the remainder of the study (range, < 10-9966 pg/mL). The antiinflammatory cytokines TGF-beta1 (range, 43-7108 pg/mL) and TGF-beta2 (range, 208-57935 pg/mL) were present in substantial quantities in all samples, and there was little change in the mean concentration during 12 wk of lactation. The present study shows that immunomodulating agents are normally present in human milk in physiologically relevant quantities for at least the first 3 mo of the breast-fed infant's life.

Adjuvants, Immunologic↗
PubMed1998

Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes.

The formation and deposition of monosodium urate (MSU) microcrystals in articular and periarticular tissues is the causative agent of acute or chronic inflammatory responses known as gouty arthritis. Mononuclear phagocyte activation is involved in early triggering events of gout attacks. Because stimulated mononuclear phagocytes can constitute an important source of the inducible isoform of cyclooxygenase (COX-2), we evaluated the effects that proinflammatory microcrystals might have on COX-2 protein expression in crystal-stimulated monocytes. We found that MSU crystals, but not calcium pyrophosphate dihydrate (CPPD) crystals, induced COX-2, which correlated with the synthesis of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). Crystal-induced de novo synthesis of COX-2 was dependent on transcriptional and translational events. Inhibition of tyrosine phosphorylation, by herbimycin A, blocked crystal-induced COX-2. Similarly, an inhibitor of the p38 mitogen-activated protein kinase, SB 203580, inhibited the stimulation of COX-2. Colchicine inhibited crystal-induced COX-2. In all cases, prostanoid synthesis was concomitantly inhibited. Taken together, these results implicate COX-2 in the development of MSU-induced inflammation.

Benzoquinones↗
PubMed1998

Low density lipoprotein of synovial fluid in inflammatory joint disease is mildly oxidized.

Oxidatively modified low density lipoprotein (LDL) has many biological activities which could contribute to the pathology of the atherosclerotic lesion. Because atherosclerosis has an inflammatory component, there has been much interest in the extent to which LDL could be oxidatively modified in vivo by inflammation. The present study examined LDL present in an accessible inflammatory site, the inflamed synovial joint, for evidence of compositional change and oxidative modification. LDL was isolated from knee joint synovial fluid (SF) from subjects with inflammatory arthropathies and also from matched plasma samples. SF and plasma LDL had similar free cholesterol and alpha-tocopherol content, but SF LDL had a lower content of esterified cholesterol. On electrophoresis, SF LDL was slightly more electronegative than LDL from matched plasma samples, but the changes were much less than those resulting from Cu2+-treatment of LDL. Oxidized cholesterol was not detected in any samples, but cholesterol ester hydroperoxide levels were greater in SF than in plasma LDL. When samples from three subjects were incubated with macrophages, the SF LDL did not cause significant loading of the cells with cholesterol or cholesterol esters, in contrast to the situation with acetylated LDL. Overall, the SF LDL displayed evidence of slightly increased oxidation by comparison with matched plasma samples. Despite their isolation from an environment with active inflammation, changes were modest compared with those resulting from Cu2+ treatment. Thus, extensive LDL oxidation is not a necessary correlate of location in a chronic inflammatory site, even though it is characteristic of atherosclerotic lesions.

Animals↗
PubMed1997

Inhibition of prostaglandin endoperoxide synthase-2 expression in stimulated human monocytes by inhibitors of p38 mitogen-activated protein kinase.

Prostaglandin endoperoxide synthase (PGHS; cyclooxygenase), the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids, has two isoforms. PGHS-1 is constitutively expressed and involved in homeostasis, whereas PGHS-2 is inducible in monocytes in response to proinflammatory agents. Using freshly elutriated human monocytes, we examined the effect on PGHS-2 expression of certain cytokine-suppressive anti-inflammatory drugs such as SK&F 86002. Incubation with serum-treated zymosan (STZ) stimulated the expression of PGHS-2 in a time- and dose-dependent manner. SK&F 86002 dose-dependently inhibited this STZ-induced expression of PGHS-2 protein, which correlated with a decrease in prostaglandin E2 and thromboxane A2 production. However, suppression of PGHS-2 expression is not the result of suppressed cytokine production, because SK&F 86002 suppressed PGHS-2 expression initiated by IL-1beta and TNF-alpha, in addition to other stimuli. Moreover, this effect was selective in that the protein expression of two other important enzymes involved in the metabolism of arachidonic acid, cytosolic phospholipase A2 and 5-lipoxygenase, was not affected. Stimulation with STZ caused a time-dependent increase in levels of PGHS-2 mRNA; incubation with cytokine-suppressive agents caused a decrease of these levels, suggesting the involvement of transcription and/or mRNA stability events in the inhibition of PGHS-2. These results indicate a new and potentially important anti-inflammatory property of SK&F 86002, namely the specific suppression of PGHS-2 induction.

Arachidonate 5-Lipoxygenase↗
PubMed1997

Regulation of tumor necrosis factor-alpha and IL-1 beta synthesis by thromboxane A2 in nonadherent human monocytes.

Synthesis of TNF-alpha and IL-1beta, by monocytes/macrophages can be partially regulated by the eicosanoid, PGE2. We report here that inhibition of both PGE2 and thromboxane A2 (TXA2) synthesis by a prostaglandin H synthase inhibitor, NS-398, had no effect on the synthesis of either TNF-alpha or IL-1beta, even though the addition of PGE2 to these treated cells dose-dependently inhibited TNF-alpha and IL-1beta synthesis. Because TXA2 is a major eicosanoid product of stimulated human monocytes, we examined its influence on cytokine production. Inhibition of thromboxane synthase by carboxyheptyl imidazole (CI) resulted in inhibition of TNF-alpha (61 +/- 4.3%; n = 8; p < 0.001) and IL-1beta (54 +/- 4.2%; n = 8; p < 0.001) synthesis by serum-treated zymosan-stimulated nonadherent human monocytes. This effect was observed when cytokine production was measured by ELISA or bioactivity assays. Furthermore, the addition of a TXA2 agonist, carbocyclic TXA2, to CI-treated monocytes dose-dependently restored the levels of TNF-alpha and IL-1beta synthesis to those found with serum-treated zymosan stimulation alone. Inhibition of TXA2 activity by the thromboxane receptor antagonists, pinane TXA2 or SQ 29,548, also inhibited the production of TNF-alpha (67 +/- 2.4% and 65 +/- 2.7%, respectively; n = 8; p < 0.001) and IL-1beta (59 +/- 3.3% and 70 +/- 1.2%, respectively; n = 8; p < 0.001). Treatment with CI resulted in a partial decrease in TNF-alpha mRNA levels (60 +/- 12.0%; n = 4), but had little or no effect on IL-1beta mRNA levels. These novel observations implicate TXA2 as an important paracrine or autocrine facilitator of TNF-alpha and IL-1beta production in stimulated human monocytes and suggest that levels of TNF-alpha and IL-1beta synthesis are determined in part by the balance between TXA2 and PGE2 production in human monocytes.

Cells, Cultured↗
PubMed1997

Dietary n-3 fatty acids and therapy for rheumatoid arthritis.

OBJECTIVE: To examine the potential for dietary n-3 fats to be component of therapy for rheumatoid arthritis (RA). METHODS: Studies of encapsulated fish oil use in RA were reviewed and critiqued, and possible biochemical mechanisms for fish oil effects were examined. The potential for use of n-3 fats was evaluated within a dietary framework rather than a quasi-pharmaceutical framework. RESULTS: There is consistent evidence from double-blind, placebo-controlled clinical trials that dietary n-3 fats, supplied as fish oil, can have beneficial effects in RA. The beneficial effects appear modest, but their size and extent may have been moderated by common trial design factors such as high n-6 polyunsaturated fat diets and concurrent antiinflammatory drug use. Mechanisms for the clinical effects of n-3 fats in RA may involve their ability to suppress production of inflammatory mediators, including n-6 eicosanoids and proinflammatory cytokines. Suppression of n-6 eicosanoid and cytokine production will be possible using foodstuffs that are rich in n-3 fats and poor in n-6 fats. CONCLUSIONS: There are many overlapping biochemical effects of n-3 fatty acids and antiinflammatory pharmaceuticals that could explain the clinical actions of n-3 fats in RA. They suggest that there is the potential for complementarity between drug therapy and dietary choices that increase intake of n-3 fats and decrease intake of n-6 fats. In particular, there is the potential for drug-sparing effects. Future studies with n-3 fats in RA need to address the fat composition of the background diet and the issue of concurrent drug use.

Arthritis, Rheumatoid↗
PubMed1996

Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and tissue phospholipids.

n-9 Eicosatrienoic acid (ETrA), also known as Mead acid, is a minor fatty acid in essential fatty acid (EFA)-sufficient healthy subjects but is found at increased levels in EFA deficiency. This study examined the influence of dietary ETrA from a biological source on plasma and tissue ETrA. A synthetic fat-free diet was prepared to which was added Mut 48 oil which contains 19% ETrA (wt%) as well as other n-9 fatty acids. Blends of vegetable oils were used to achieve overall diets with 5% fat (wt%) and varying amounts of ETrA at two different dietary levels of linoleic acid (LA), approximately 4.4 and 19% of total fatty acids. These diets were fed to 5-week-old Dark Agouti rats for four weeks. Plasma lipid fractions and liver, spleen, and peritoneal exudate (PE) cells were analyzed for fatty acid composition. ETrA was present at up to 20% total fatty acids in plasma triglyceride, cholesterol ester, and phospholipid fractions. ETrA also accumulated to substantial levels in phospholipids of liver and spleen (up to 15% of total fatty acids) and PE cells (up to 11%). ETrA was found in plasma and tissue phospholipids in proportion to the amount of ETrA present in the diet. The incorporation was reduced in diets with higher LA content compared to diets containing similar amounts of ETrA but lower LA. All rats remained apparently healthy, and histological survey of major organs revealed no abnormality. While the long-term implications for health of ingestion of diets rich in ETrA remain to be established, rats appear to tolerate high levels of dietary ETrA without adverse effects. Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis adversely.

8,11,14-Eicosatrienoic Acid↗
PubMed1996

The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil.

The effect of a flaxseed oil-based diet on tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) synthesis was examined in healthy volunteers. Use of flaxseed oil in domestic food preparation for 4 wk inhibited TNF alpha and IL-1 beta production by approximately 30%. Fish-oil supplementation (9 g/d) continued for a further 4 wk; TNF alpha and IL-1 beta synthesis were inhibited by 74% and 80%, respectively. There was a significant inverse exponential relation between TNF alpha or IL-1 beta synthesis and mononuclear cell content of eicosapentaenoic acid (EPA), an n--3 fatty acid derived from ingested EPA (fish oil) or metabolism of ingested alpha-linolenic acid (flaxseed oil). Cytokine production decreased as cellular EPA increased to approximately 1% of total fatty acids. Further increases in EPA content did not result in further decreases in cytokine production. The results indicate that vegetable oils rich in n--3 fatty acids inhibit TNF alpha and IL-1 beta synthesis.

Adult↗
PubMed1996

Dietary (n-9) eicosatrienoic acid from a cultured fungus inhibits leukotriene B4 synthesis in rats and the effect is modified by dietary linoleic acid.

Eicosatrienoic acid (ETrA) is the (n-9) homologue of (n-6) arachidonic acid (AA) and (n-3) eicosapentaenoic acid (EPA). ETrA can be synthesized endogeneously, but tissue levels are normally undetectable except in essential fatty acid (EFA) deficiency. An ETrA-rich oil extracted from a cultured fungus was used to prepare diets which had varying levels of ETrA (0-8 g/kg diet) in combination with one of two levels of linoleic acid (LA, 2.2 or 9.5 g/kg diet). All diets were sufficient in essential fatty acids. Groups of rats were fed these diets for 4 wk after which leucocyte fatty acid content and leukotriene B4 (LTB4) synthesis were measured. The influence of dietary LA on ETrA accumulation in cells was studied and correlations with LTB4 synthesis determined. ETrA was efficiently incorporated into peritoneal exudate cell (PEC) phospholipids with no evident saturation being observed with levels up to 10 mol/100 mol total fatty acids in peritoneal exudate cells. Cellular ETrA levels were lower (P < 0.001) in rats fed the higher level of LA. ETrA accumulation in peritoneal exudate cells correlated (r(2) = 0.63, P < 0.05) with reduced LTB4 synthesis which was attributable to LTA hydrolase inhibition. Thus, dietary ETrA from a biological source can accumulate in leucocytes and suppress inflammatory eicosanoid synthesis. The findings justify further studies into the biochemical and anti-inflammatory effects of dietary ETrA, which could be incorporated into palatable food additives.

8,11,14-Eicosatrienoic Acid↗
PubMed1996

Confinement of PGL, an imprinted gene causing hereditary paragangliomas, to a 2-cM interval on 11q22-q23 and exclusion of DRD2 and NCAM as candidate genes.

Paragangliomas of the head and neck region, also known as glomus tumours, are mostly benign tumours of neuro-ectodermal origin. We mapped the familial form by linkage analysis in 6 families to chromosome region 11q22-q23, between the markers STMY and CD3D which currently span a 16-cM interval. Here, we performed detailed haplotype analysis of this region in a single Dutch multibranch 7-generation family. A region of 2 cM between the markers D11S938/D11S4122 and D11S1885 was shared between all patients of whom disease haplotypes could be reconstructed. In support of this localization, a recombination observed in a small French family with 2 affected nieces places the PGL gene proximal to marker D11S908, genetically coincident with D11S1885.

Chromosome Mapping↗
PubMed1995

Differences in fatty acid composition of immature and mature articular cartilage in humans and sheep.

Chondrocytes are imbedded in an avascular, highly charged extracellular matrix which could form a barrier to the transfer of dietary essential fatty acids (EFA) to chondrocytes. A study was designed to assess the composition of immature and mature joint cartilage with respect to essential and nonessential fatty acids relevant to EFA deficiency. Cartilage and muscle samples were obtained from human fetus, infant and adult cadavers, and from fetal and mature sheep. Lipid extracts were prepared and the fatty acid composition determined. In human and sheep joint cartilage, linoleic acid (LA; 18:2n-6) content was lower, and n-9 eicosatrienoic acid (ETrA; 20:3n-9) and arachidonic acid (AA; 20:4n-6) were higher in fetuses compared to mature subjects. An intermediate pattern was seen in infant cartilage. n-3 Fatty acids tended to be higher in fetal than in mature cartilage in humans and in sheep. In human muscle (and in other noncartilaginous comparison tissues), similar differences between fetuses and adults were seen in LA and AA, but not in ETrA. In fetal sheep muscle, very low LA, reduced AA and raised ETrA levels compared to mature sheep muscle were seen. However, although the pattern is characteristic of EFA deficiency, the abundance of n-6 EFA in liver and spleen of human fetuses and of n-3 EFA in liver and spleen of fetal sheep suggests that placental transfer of EFA is not likely to be limiting. During fetal development, the metabolism of fatty acids is distinctive and differs between the species. ETrA appears to be a readily measurable component of some tissues at certain stages of development when its presence in tissues does not indicate EFA deficiency.

8,11,14-Eicosatrienoic Acid↗
PubMed1995

Diet and arthritis.

Choice of diet is one way in which an individual can influence his/her own health, and it is to be expected that patients will seek their physician's expert opinion regarding dietary matters. Respect for the legitimacy of these enquiries and balanced informed discussion, which includes general advice for a prudent diet, as well as disease-specific recommendations when indicated, can be the key to a productive relationship between patients and physician. The issue of dietary advice has an impact on the management of most forms of arthritis including osteoarthritis (obesity/energy balance), gout (dietary purines, energy balance, alcohol, fluid intake) and rheumatoid arthritis (n-3 fatty acids). Food hypersensitivity appears to be a rare cause of polyarthritis, and elimination diets and fasting have little or no place in routine practice. Strategies under investigation include oral tolerization, the utility of which remains to be established.

Arthritis↗
PubMed1995

Differences exist in the relationships between dietary linoleic and alpha-linolenic acids and their respective long-chain metabolites.

Increased concentrations of cellular eicosapentaenoic acid (EPA) have been shown to be beneficial in coronary heart disease, hypertension, and inflammatory disorders. Successful long-term strategies for increasing cellular EPA concentrations require information on the relationships between cellular concentrations of EPA and dietary amounts of alpha-linolenic acid (alpha-LA), a precursor of EPA, and dietary amounts of linoleic acid (LA), an antagonist of alpha-LA conversion to EPA. A dietary intervention study with healthy human volunteers that incorporated alpha-LA-rich vegetable oil (flaxseed oil), against a background diet low in LA, allowed us to examine these relationships. Linear relationships were found between dietary alpha-LA and EPA in plasma fractions and in cellular phospholipids. By contrast there was no relationship observed between dietary LA and tissue concentrations of its metabolite, arachidonic acid (AA). There was an inverse relationship between dietary alpha-LA and docosahexaenoic acid concentrations in the phospholipids of plasma, neutrophils, mononuclear cells, and platelets. The results indicate that increasing dietary alpha-LA will elevate tissue EPA concentrations in a predictable manner. This insight will facilitate the rational planning of practical dietary strategies for the long-term elevation of EPA concentrations in tissues.

Adult↗
PubMed1995

A urodynamic study of laser ablation of the prostate and a comparison of techniques.

OBJECTIVE: To evaluate the effect of laser ablation of the prostate on symptomatic and urodynamic parameters and to compare laser delivery systems. PATIENTS AND METHODS: The study comprised 81 patients of whom 79 were waiting for transurethral resection of the prostate (TURP) and two who presented in acute urinary retention. The 79 patients (median age 65 years, range 45-82) underwent pre-operative urodynamics and all patients completed American Urological Association (AUA) symptom score questionnaires before surgery. Visually-guided laser ablation of the prostate (VLAP) was performed and the urodynamics and symptom scores were repeated 3 months later. RESULTS: The improvements in symptom scores and flow rates were statistically significant and comparable with other published data. There were also significant improvements in voiding pressure. There were no significant differences between the various laser fibres used. There were few complications. CONCLUSION: The effectiveness of VLAP in improving symptoms and flow rates in patients with benign prostatic hyperplasia (BPH) is confirmed. The procedure also reduced voiding pressure, confirming the relief of bladder outflow tract obstruction. VLAP is confirmed as a safe and effective treatment for BPH. Continued follow-up is needed to determine the long-term effects.

Aged↗