The effects of dietary supplementation with n-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a randomized, double blind trial

STUDY OBJECTIVE: To determine the effect of dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) on disease variables in patients with rheumatoid arthritis. DESIGN: Multicenter, randomized, placebo controlled, double blind. SETTING: Three Danish hospital Departments of Rheumatology. PATIENTS: Fifty-one patients with active rheumatoid arthritis. INTERVENTION: Random allocation to 12 weeks of treatment with either six n-3 PUFA capsules (3.6 g) or six capsules with fat composition as the average Danish diet. MAIN RESULTS: Significant improvement of morning stiffness and joint tenderness. No significant effect on the four other assessed clinical parameters. No serious side effects. CONCLUSIONS: Dietary supplementation with n-3 PUFA in patients with rheumatoid arthritis improved two out of six patient reported disease parameters. Further studies are needed to clarify the more precise role of n-3 PUFA in the treatment of rheumatoid arthritis.     

Molecular characterization of CTX‐M‐15‐producing clinical isolates of Escherichia coli reveals the spread of multidrug‐resistant ST131 (O25:H4) and ST964 (O102:H6) strains in Norway

Nationwide, CTX‐M‐producing clinical Escherichia coli isolates from the Norwegian ESBL study in 2003 (n=45) were characterized on strain and plasmid levels. Bla_CTX‐M allele typing, characterization of the genetic environment, phylogenetic groups, pulsed field gel electrophoresis (PFGE), serotyping and multilocus sequence typing were performed. Plasmid analysis included S1‐nuclease‐PFGE, polymerase chain reaction‐based replicon typing, plasmid transfer and multidrug resistance profiling. Bla_CTX‐M‐15 (n=23; 51%) and bla_CTX‐M‐14 (n=11; 24%) were the major alleles of which 18 (78%) and 6 (55%), respectively, were linked to ISEcp1. Thirty‐two isolates were of phylogenetic groups B2 and D. Isolates were of 29 different XbaI‐PFGE‐types including six regional clusters. Twenty‐three different O:H serotypes were found, dominated by O25:H4 (n=9, 20%) and O102:H6 (n=9, 20%). Nineteen different STs were identified, where ST131 (n=9, 20%) and ST964 (n=7, 16%) were dominant. Bla_CTX‐M was found on ≥100 kb plasmids (39/45) of 10 different replicons dominated by IncFII (n=39, 87%), FIB (n=20, 44%) and FIA (n=19, 42%). Thirty‐nine isolates (87%) displayed co‐resistance to other classes of antibiotics. A transferable CTX‐M phenotype was observed in 9/14 isolates. This study reveals that the majority of CTX‐M‐15‐expressing strains in Norway are part of the global spread of multidrug‐resistant ST131 and ST‐complex 405, associated with ISEcp1 on transferrable IncFII plasmids.     

Effect of Cholesterol Levels on Villous Histology in Colonic Adenomas

To date no studies have examined the relationship between cholesterol levels and the occurrence of specific colonic polyp histologies. Villous histology has a greater predilection for subsequent malignancies than other histologies. Consequently, we examined the effect of cholesterol levels on the occurrence of villous adenomas. Just under one in 10 (9.5%, 15/158) patients had polyps with villous histologies. Cholesterol levels were positively and nonlinearly associated with a greater likelihood of villous histology, suggesting that a threshold exists for the effect of cholesterol level on the likelihood of having polyps with villous histology [odds ratios (OR) for combined two variable quadratic effect: cholesterol OR, 1.18; 95% confidence interval (CI), 1.02–1.37 and cholesterol squared OR, 1.004; 95% CI, 1.00–1.02]. Our data suggest that, in patients with polyps, higher cholesterol levels increase the likelihood of having polyps with villous histology, but that the effect of cholesterol level reaches a threshold.     

Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.     

Acutely sodded expanded polytetrafluoroethylene grafts produce only prostacyclin: a qualitative difference from saphenous veins

Select subsets of patients require prosthetic graft material for revascularization. Although arterial prosthetic grafts of large caliber perform acceptably, grafts of <6 mm exhibit a high attrition rate. Microvessel endothelial sodding, a method resulting in the lining of prosthetic grafts with autologous endothelium, improves graft patency; however, aggressive antiplatelet therapy is still required, because terminating an antiplatelet regimen accelerates graft attrition. The present investigation was designed to address the acute production of vasoactive substances in microvessel endothelial cell sodded expanded polytetrafluoroethylene (ePTFE) grafts in an attempt to delineate a possible mechanism behind the continued requirement for antiplatelet therapy. Equal lengths of acutely sodded ePTFE grafts (canine falciform ligament source) and saphenous veins (SV) (canine source) were evaluated by superfusion bioassay. Basal secretion from ePTFE grafts relaxed the biodetector ring 1 +/- 3%, whereas SV relaxed the ring 10 +/- 3% (p < 0.05, ePTFE vs. SV). Relaxation with acetylcholine stimulation was 49 +/- 7% in grafts and 50 +/- 10% in veins (p = NS). Calcium ionophore stimulation produced relaxation of 37 +/- 9% from ePTFE grafts and 100 +/- 23% from SV (p < 0.05). Indomethacin added to perfusate reduced relaxations from sodded ePTFE grafts to 20.2 +/- 9.2% with acetylcholine stimulation and 12.5 +/- 4.3% with calcium ionophore (p < 0.05 vs. control); addition of N(G)-monomethyl-L-arginine (L-NMMA) had no effect on the release of vasoactive substances from ePTFE grafts. In contrast, relaxations of effluent from SV stimulated by acetylcholine and calcium ionophore were significantly attenuated with indomethacin and L-NMMA (p < 0.05 vs. control). Scanning electron microscopy demonstrated confluent endothelium in SV and a nonconfluent endothelial cell layer in grafts. Acutely sodded ePTFE grafts produce vasoactive substances that quantitatively and qualitatively differ from those produced by canine SV. The ePTFE grafts produce mainly prostanoids, whereas SV produce both nitric oxide and prostanoids. The endothelial cell isolation procedure and absence of immediate graft luminal confluence may contribute to the observed differences.     

Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.      

Evaluation of attempted prevention of unexpected infant death in very high-risk infants by planned health care

Three hundred and ninety-six babies born in Sheffield between 1982 and 1990 identified as being at "very high risk" of unexpected infant death by means of a scoring system, received an intensive programme of health care including a case discussion between a paediatrician, the GP and the health visitor held in the family doctor's surgery, weekly visits from the health visitor and informal hospital admission. Significantly fewer sudden unexpected infant deaths occurred in this group than were expected by logistic regression anlysis or occurred in the best available control group with comparable scores ( p = 0.024). Problems in evaluation include identification of an adequate control population, ethical difficulties in introducing a controlled study when the programme is already perceived as effective, and the calculation of "expected death rates". The results of this study indicate that very energetic programmes of intervention may prevent some deaths in vulnerable infants.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein