Docosahexaenoic acid-enriched canola oil increases adiponectin concentrations: a randomized crossover controlled intervention trial.

BACKGROUND AND AIMS: Little is known about the effect of various dietary fatty acids on pro- and anti-inflammatory processes. We investigated the effect of 5 oils containing various amounts of alpha-linolenic acid (ALA), linoleic acid (LA), oleic acid (OA) and docosahexaenoic acid (DHA) on plasma inflammatory biomarkers and expression levels of key inflammatory genes and transcription factors in whole blood cells. METHODS AND RESULTS: In a randomized, crossover controlled nutrition intervention, 114 adult men and women with abdominal obesity and at least one other criterion for the metabolic syndrome consumed 5 experimental isoenergetic diets for 4 weeks each, separated by 4-week washout periods. Each diet provided 60 g/3000 kcal of different oils: 1) control corn/safflower oil blend (CornSaff; LA-rich), 2) flax/safflower oil blend (FlaxSaff; ALA-rich), 3) conventional canola oil (Canola; OA-rich), 4) high oleic canola oil (CanolaOleic; highest OA content), 5) DHA-enriched high oleic canola oil (CanolaDHA; OA- and DHA-rich). Gene expression in whole blood cells was assessed in a subset of 62 subjects. CanolaDHA increased plasma adiponectin concentrations compared with the control CornSaff oil treatment (+4.5%, P = 0.04) and FlaxSaff (+6.9%, P = 0.0008). CanolaDHA also reduced relative expression levels of interleukin (IL)1B compared with CornSaff and Canola (-11% and -13%, respectively, both P = 0.03). High-sensitivity C-reactive protein concentrations were lower after Canola than after FlaxSaff (-17.8%, P = 0.047). CONCLUSION: DHA-enriched canola oil exerts anti-inflammatory effects compared with polyunsaturated fatty acids from plant sources.

Ki-ras mutations in adenomas: a characteristic of cancer-bearing colorectal mucosa.

Activating mutations in the Ki-ras2 oncogene are frequently observed in sporadic colorectal adenomas and their incidence is reported to rise in large and tubulovillous adenomas to values close to those in carcinomas. This study shows that this property is a feature of adenomas growing in large bowel that has already demonstrated its propensity to engender malignant tumours: i.e., bowel in which there is a synchronous carcinoma. Adenomas from cancer-free bowel do not share this high incidence of Ki-ras mutations. This difference in mutation incidence between adenomas from cancer-free and cancer-bearing patients does not appear to derive from sampling bias relative to adenoma size, site, or patient age, nor is it found in another gene (APC) known to be of importance in adenoma formation. Large, dysplastic adenomas from cancer-bearing bowel, however, are particularly liable to carry Ki-ras mutations when they arise in patients over 70 years old. The observations suggest that the role of Ki-ras mutations may be more subtle than merely enhancing adenoma growth. Adenoma cells of cancer-prone individuals may suffer more mutational events than those in persons selected as cancer-free.

Renal expression of interleukin-2 receptor mRNA in patients with crescentic glomerulonephritis.

We studied paraffin sections of renal biopsies from 7 patients with crescentic glomerulonephritis (CGN) by in situ hybridisation, to detect sites of interleukin-2 receptor (IL-2R) mRNA expression. Frozen sections from a further patient with CGN were studied by immunohistochemistry with a monoclonal antibody to CD25, to detect IL-2R protein. Positive control sections were taken from biopsies of acute cellular renal transplant rejection and negative controls from biopsies of membranous glomerulonephritis. No autoradiographic signal was detected in negative controls. IL-2R mRNA expression was seen in rejected transplants and in sections from 4 to 7 patients with CGN. Expression was seen in cortical interstitial cells, renal tubular epithelial cells, cells within glomerular crescents and in one glomerulus at the margin of Bowman's capsule. Tubular cell expression of IL-2R protein was confirmed by immunohistochemistry. We have confirmed that IL-2R mRNA expression occurs locally within the kidneys in CGN and have identified expression in tubular epithelial cells. The results suggest that local activation of immunocompetent cells occurs in the kidney and may be of significance in the pathogenesis of CGN.

Expression of tissue kallikrein in human kidney.

1. We studied the distribution of human tissue kallikrein mRNA in normal and diseased kidney, using in situ hybridization, together with immunohistochemical localization of renal kallikrein protein. Materials studied were (a) normal tissue from kidneys removed because of localized renal carcinoma, (b) kidneys removed because of post-traumatic haemorrhage and (c) renal biopsy specimens from patients with membranous glomerulonephritis and nephrotic syndrome. 2. A 1.35 kb EcoRI fragment of human tissue kallikrein cDNA was labelled with [32P]dCTP using the random-primer technique, and used for in situ hybridization. A specific rabbit antibody to active human urinary kallikrein was employed for immunocytochemistry, using a peroxidase-antiperoxidase method. 3. By in situ hybridization, no tissue kallikrein gene expression was seen in the carcinoma nephrectomy specimens. Positive expression was seen in the trauma nephrectomy tissue, and in four of five nephrotic syndrome biopsies. In all kidneys, expression was confined to the renal cortex. The dominant site of gene expression was the distal tubule. Apart from one area of positive signal related to an epithelial cell of Bowman's capsule, expression was not observed in glomeruli. Expression was also seen in the walls of large- and medium-sized blood vessels. 4. By immunohistochemistry, the dominant site of immunoreactivity was the distal tubule. Dense staining was also seen in granular peripolar cells and in isolated parietal epithelial cells close to the vascular pole. Isolated immunoreactive cells were seen in the media of large- and medium-sized arteries. 5. The tissue kallikrein gene in the kidney may not be constitutively expressed, but is expressed in response to physiological or pathological stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrarenal localization of interleukin-1 beta mRNA in crescentic glomerulonephritis.

Il-1 beta is a potent proinflammatory peptide, and induces expression of other cytokines which are involved in the immune response. Kidney biopsies from nine patients with crescentic GN were studied by in-situ hybridization to determine the site of expression of Il-1 beta mRNA. Biopsies from nine patients with nonproliferative renal disease were studied as negative controls, and tonsillar tissue was studied as a positive control. An Il-1 beta cDNA probe was 32P-labelled by random primers and hybridized to paraffin-embedded tissue sections after de-waxing. Il-1 beta mRNA was expressed in tonsil, but not in negative controls. Positive mRNA expression was seen in four of the nine crescentic biopsies. This was observed in interstitial cells with morphological characteristics of macrophages adjacent to tubular cells, in cells within the glomerular tuft, and in tubular epithelial cells. Il-1 beta mRNA is expressed in renal tissue in crescentic GN. Tubular and interstitial expression of Il-1 beta mRNA appears of equal prominence to glomerular expression. Intrarenal cytokine synthesis may be involved in the pathogenesis of crescentic glomerulonephritis.

Effect of treatment mode on the natural history of acquired cystic disease of the kidney in patients on renal replacement therapy.

The natural history of acquired cystic disease of the kidney has been investigated in a long-term follow-up study of patients on renal replacement therapy. A cohort of 145 end-stage renal failure patients was initially investigated with ultrasonography to determine the degree of cystic change. Seventy-three patients were available for follow up a minimum of 3 years later. The grade of cystic disease progressed in dialysis patients and progression was more marked in haemodialysis patients than patients maintained on CAPD. Patients with functioning renal transplants did not show progression of cystic change and in two patients regression was seen. Nine patients maintained on chronic dialysis at the time of initial ultrasound subsequently received renal grafts, and three of these patients had evidence of regression of cystic change on follow-up scanning. After 3 years follow-up a single haemodialysis patient had evidence of a solid lesion in a cystic kidney and this has not progressed during a further 12 months of follow-up. Acquired cystic disease of the kidney is a progressive disease in chronic dialysis patients. However, over a follow-up period of 3 years, patients with functioning renal grafts do not show similar progression. The incidence of solid renal tumours has been shown to be low.

Can low-dosage aluminium hydroxide control the plasma phosphate without bone toxicity?

Sixteen patients treated exclusively by haemodialysis using reverse osmosis water treatment for up to 7 years (mean 49.3 +/- 17 months) were assessed for evidence of bone aluminium accumulation and toxicity. All patients were treated with aluminium hydroxide phosphate binders for the duration of dialysis but the dosage was restricted to a maximum of 2.85 g daily (mean daily dose 2.6 +/- 0.8 g). The mean plasma phosphate over the 12 months prior to the study was 1.68 +/- 0.42 mmol/l and in only three patients was adequate control of the plasma phosphate not achieved. No patient had evidence of fracturing bone disease. Bone aluminium staining was present in only two patients but was seen at the calcification front in only one of these. Three patients had histological evidence of osteomalacia, but in none was aluminium staining present. Mean bone aluminium was moderately high at 36.67 +/- 31 micrograms/g and in only three patients exceeded 40 micrograms/g. This study indicates that adequate control of the plasma phosphate can be achieved with low dosage of aluminium hydroxide, and in the medium term is not associated with evidence of bone aluminium toxicity.

Mefenamic acid nephropathy: an interstitial and mesangial lesion.

Six cases of acute renal failure associated with mefenamic acid therapy are described. Five patients were non-oliguric and five patients had clinical features of salt and water depletion. In these patients the presenting symptoms were abdominal pain, diarrhoea and vomiting. Renal biopsy in five patients showed interstitial nephritis and mesangial proliferation. All patients recovered without specific therapy after withdrawal of the drug, but in four patients mild renal impairment persisted. These findings indicate that both interstitial and mesangial changes are common features of acute renal failure due to mefenamic acid therapy.

Acquired cystic disease of the kidney in patients with end-stage chronic renal failure: a study of prevalence and aetiology.

Renal ultrasound scanning was performed in 100 patients with end-stage renal failure treated by both haemodialysis and continuous ambulatory peritoneal dialysis (CAPD). Each kidney was assessed for the presence of acquired cystic disease and solid lesions. The appearances were divided into five grades from grade 0 (no cysts detected) to grade 4 (greater than 15 cysts per kidney). Other intra-abdominal organs were also scanned for the presence of cysts. The findings were then correlated with possible aetiological factors, including the type of dialysis used. Sixty-three percent of all the patients had acquired cystic disease of the kidney (ACDK). No solid lesions were found and no cysts were detectable in other organs. The presence and grade of ACDK did not correlate with the age or sex of the patient, the nature of the underlying renal disease, or the duration of chronic renal failure. There was a significant correlation between the grade of ACDK and the duration of both haemodialysis (P less than 0.001) and CAPD (P less than 0.01). The presence of residual renal function did not influence the development of cysts. ACDK had no effect on haemoglobin or other laboratory parameters measured.

An inhibitory role for noradrenaline in the mouse vas deferens.

1 Noradrenaline (0.1-3.0 muM) inhibited the twitch responses to single pulse field stimulation of the isolated vas deferens of the mouse. The higher concentrations of noradrenaline (ca. 0.3-3.0 muM) were required to make the tissue contract.2 Phentolamine (10 muM) abolished the contractor response to higher concentrations of noradrenaline and antagonized the inhibitory effect of lower concentrations on the twitch response.3 Propranolol (10 muM) potentiated both the contractor and the inhibitory effect of noradrenaline on the twitch response.4 Isoprenaline (0.1-3.0 muM) and salbutamol (1.0-3.0 muM) both inhibited the twitch response. Their effects were antagonized by propranolol (10 muM), but not by practolol (10 muM).5 The effects of uptake(1) and uptake(2) blocking agents were determined. Cocaine (10 muM) reduced the size of the twitch response in 2 out of 4 experiments. Imipramine (0.18 muM) also reduced the size of the twitch, as did oestradiol (3.7 muM) and a combination of cocaine and oestradiol.6 Contractor responses to exogenous noradrenaline showed tachyphylaxis, but when this was not very marked, the response could be shown to be potentiated by uptake blocking agents.7 The inhibitory effect of noradrenaline on the twitch response was greatly potentiated by cocaine (10 muM) and much less so by oestradiol (3.7 muM).8 It is concluded that the transmitter responsible for the twitch response is either an unknown substance released from the sympathetic neurone, or noradrenaline acting upon a receptor with none of the characteristics of known alpha- or beta-adrenoceptors. In either case, noradrenaline can inhibit the output, probably by stimulation of presynaptic alpha-adrenoceptors.