Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

A blood-based predictor for neocortical Aß burden in Alzheimer's disease: results from the AIBL study.

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.

Macrophage secretion of miR-106b-5p causes renin-dependent hypertension.

Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. Vitamin D deficiency causes pro-inflammatory macrophage infiltration in metabolic tissues and is linked to renin-mediated hypertension. We tested the hypothesis that impaired vitamin D signaling in macrophages causes hypertension using conditional knockout of the myeloid vitamin D receptor in mice (KODMAC). These mice develop renin-dependent hypertension due to macrophage infiltration of the vasculature and direct activation of renal juxtaglomerular (JG) cell renin production. Induction of endoplasmic reticulum stress in knockout macrophages increases miR-106b-5p secretion, which stimulates JG cell renin production via repression of transcription factors E2f1 and Pde3b. Moreover, in wild-type recipient mice of KODMAC/miR106b-/- bone marrow, knockout of miR-106b-5p prevents the hypertension and JG cell renin production induced by KODMAC macrophages, suggesting myeloid-specific, miR-106b-5p-dependent effects. These findings confirm macrophage miR-106b-5p secretion from impaired vitamin D receptor signaling causes inflammation-induced hypertension.

Development and validation of a prognostic scale for use in patients with advanced cancer.

The aim of this study was to develop a new prognostic indicator to help predict survival in advanced cancer patients more accurately. Data on 329 patients obtained from a multi-centre study in London were analysed. A multifactorial Cox regression model was applied and validated using bootstrapping techniques. Predictive scores were calculated and used to produce a new prognostic index. The value of the index in predicting 14-day survival was then assessed. Four variables were found to be associated with worse survival: primary lung cancer, secondary liver cancer, raised C-Reactive protein and poor performance status (ECOG 4). Survival curves showed that patients designated as 'high' risk by the resulting index had significantly shorter survival than those designated as 'low' risk. A high score on the newly derived prognostic index is associated with poorer survival, but its clinical utility is limited by the relatively low predictive probability of the score.

Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma.

Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O6-methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.

Patient-reported outcome scores underestimate the impact of major complications in patients undergoing spine surgery for degenerative conditions.

OBJECTIVE Patient-reported outcomes (PROs) such as the Oswestry Disability Index (ODI) and EuroQol-5D (EQ-5D) are widely used to evaluate treatment outcomes following spine surgery for degenerative conditions. The goal of this study was to use the Charlson Comorbidity Index (CCMI) as a measure of general health status, for comparison with standard PROs. METHODS The authors examined serial CCMI scores, complications, and PROs in 371 patients treated surgically for degenerative lumbar spine conditions who were enrolled in the Quality and Outcomes Database from a single center. The cohort included 152 males (41%) with a mean age of 58.7 years. Patients with no, minor, or major complications were compared at baseline and at 1 year postoperatively. RESULTS Minor complications were observed in 177 patients (48%), and major complications in 34 (9%). There were no significant differences in preoperative ODI, EQ-5D, or CCMI among the 3 groups. At 1 year, there was a significantly greater deterioration in CCMI in the major complication group (1.03) compared with the minor (0.66) and no complication groups (0.44, p < 0.006), but no significant difference in ODI or EQ-5D. CONCLUSIONS Despite equivalent improvements in PROs, patients with major complications actually had greater deterioration in their general health status, as evidenced by worse CCMI scores. Because CCMI is predictive of medical and surgical risk, patients who sustained a major complication now carry a greater likelihood of adverse outcomes with future interventions, including subsequent spine surgery. Although PRO scores are a key metric, they fail to adequately reflect the potential long-term impact of major perioperative complications.

Decrease of epidermal histidase activity by tumor-promoting phorbol esters.

The potent skin tumor promoter (12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulates epidermal macromolecular synthesis as well as proliferation, but little is known of specific functional aberrations produced by TPA. This report presents results of a study on the effects of TPA on epidermal histidase (L-histidine ammonia lyase), an enzyme found in normal epidermis but not in dermis or in mouse squamous cell carcinomas. Histidase activity was assayed on postmitochondrial supernatants obtained from hairless mouse epidermis after removal by keratotome. Topical TPA treatment at doses active in tumor promotion (1.7 to 17.0 nmoles/application) produced dose-dependent decreases in epidermal histidase specific activity at 19 hr posttreatment. The onset of the decrease occurred at 12 hr with recovery to control level specific activity by 5 days, showing kinetics similar to those obtained for stimulation of DNA synthesis. This decrease in histidase could not be attributed to a general inhibition of soluble protein synthesis or to the appearance of an inhibitor of histidase activity. The strong promoter TPA produced a greater histidase decrease than did the moderate promoter and mitogen 12,13-didecanoyl phorbol at equimolar dose, while phorbol, a nonpromoter and nonmitogen, produced no effects on histidase. The relationship of this histidase depression to tumor promotion and not initiation is further indicated by the finding that (a) Tween 60, a structurally unrelated tumor promotor, also produced a decrease in histidase; and (b) the tumor initiator urethan and an initiating dose of 9,10-dimethybenz(a)anthracene showed no effects on histadase activity.

Longchain n-3 polyunsaturated fatty acids and blood vessel function.

The cardiovascular health benefits of longchain n-3 polyunsaturated fatty acids (PUFAs) have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms. The majority of such cardiovascular benefits of n-3 PUFAs are likely to be mediated in the vascular wall and at the vascular endothelium level, since this monolayer of cells plays a central role in the regulation and maintenance of cardiovascular homeostasis and function. While these processes include endothelium-derived vasorelaxant and vasoconstrictor compounds, the vascular endothelium also plays host to many receptors, binding proteins, transporters and signalling mechanisms. Accordingly, endothelial dysfunction, which underlies many cardiovascular disease conditions, can trigger acute vascular events including vasospasm, thrombosis or restenosis leading to ischaemia. The longchain n-3 PUFAs have been reported to possess several properties that may positively influence vascular function. These include favourable mediator profiles (nitric oxide, eicosanoids) that influence vascular reactivity, change in vascular tone via actions on selective ion channels, and maintenance of vascular integrity. In addition to direct effects on contractility, n-3 PUFAs may affect vascular function, and the process of atherogenesis, via inhibition of vascular smooth muscle cell proliferation at the gene expression level, and by modifying expression of inflammatory cytokinesis and adhesion molecules. Collectively, these properties are consistent with pleiotropic actions of longchain n-3 PUFAs, and may explain the beneficial cardiovascular protection of this family of fatty acids that have been clearly evident through epidemiological data as well from more recent large-scale clinical trials.

A pathogenic glutamate-to-aspartate substitution (D296E) in the pyruvate dehydrogenase E1 subunit gene PDHA1.

In a patient with fatal neonatal lactic acidosis due to pyruvate dehydrogenase deficiency, the only potential mutation detected was c.888C>G in PDHA1, the gene for the E1alpha subunit of the complex. This would result in a substitution of glutamate for aspartate (D296E). Pathogenicity of this minor alteration in amino acid sequence was demonstrated by expression studies. By comparing the mutant sequence with the known structures of the E1 components of pyruvate dehydrogenase and the closely related branched chain alpha-ketoacid dehydrogenase, an explanation for the profound consequences of the mutation can be proposed.

Elevated nerve growth factor levels in young spontaneously hypertensive rats.

It is generally agreed that sympathetic innervation of vascular tissues in spontaneously hypertensive rats (SHR) is greater than that existing in vascular tissues from normotensive Wistar-Kyoto (WKY) rats. One factor responsible for regulation of the growth of peripheral sympathetic nerves is the peptide nerve growth factor, which is released from effector cells. In the present study, an enzyme immunoassay was used to measure nerve growth factor levels in mesenteric arteries (densely innervated) and aortas (sparsely innervated) from both young (20-day-old) and mature (6-month-old) SHR and WKY rats. The nerve growth factor content of mesenteric arteries and aortas from 20-day-old SHR was significantly greater than that present in corresponding tissues from WKY rats. In contrast, the nerve growth factor content found in mesenteric arteries and aortas of adult SHR did not differ significantly from that found in the corresponding adult WKY rat tissues. Moreover, when the tissues were obtained from adult animals, nerve growth factor levels were substantially higher in mesenteric arteries compared with aortas, regardless of the rat strain. These results support the hypothesis that the greater nerve growth factor content of vascular tissues from young SHR is involved in the early increased sympathetic innervation of blood vessels in this animal model of hypertension.

Prevention of nerve conduction deficit in diabetic rats by polyunsaturated fatty acids.

The influence of diets containing gamma-linolenic acid (GLA; 18:3n-6) on sciatic nerve conduction velocity (NCV) was determined in diabetic rats. NCV was lower in diabetic rats fed diets supplemented with olive oil or sunflower seed oil than in nondiabetic rats; rats supplemented with GLA during a 5-wk diabetic period, however, did not exhibit significantly lower NCV. The mean proportion of the phospholipid fatty acid linoleic acid (18:2n-6) was higher in the sciatic nerves of diabetic rats than in the nondiabetic groups irrespective of dietary lipid treatment. Additionally, the proportion of linoleic acid was higher in the diabetic rats fed sunflower oil than in all other groups. Dietary GLA supplementation did not significantly influence the fatty acid composition of nerve membrane phospholipids and there was no obvious correlation between the fatty acid composition of nerve membrane phospholipids and NCV. The content of fructose and glucose in sciatic nerves was higher, whereas that of myo-inositol was lower, in diabetic rats than in nondiabetic rats; however, this was not significantly influenced by dietary GLA. GLA administration did not significantly influence Na(+)-K(+)-exchanging ATPase or ouabain binding activity in sciatic nerve preparations, both of which remained nonsignificantly different in the diabetic and nondiabetic groups. The results suggest that dietary GLA can prevent the deficit in NCV induced by diabetes and that this effect is independent of the nerve phospholipid fatty acid profile, sugar and polyol content, Na(+)-K(+)-exchanging ATPase activity, and ouabain binding. GLA may prevent the deficit in NCV indirectly, possibly by its role as a precursor of vasodilatory prostaglandins. These results confirm that GLA is the active component of evening primrose oil.

Resistance vessel gene expression of nerve growth factor is elevated in young spontaneously hypertensive rats.

OBJECTIVE: In this study we determined whether the enhanced production of nerve growth factor (NGF) and the associated hypernoradrenergic innervation of the vasculature of the spontaneously hypertensive rat (SHR) was associated with an increased gene expression of messenger (m)RNA encoding for nerve growth factor. DESIGN: It has been shown previously that the hypernoradrenergic innervation of the SHR occurs early, as does the enhanced expression for NGF. In this study we analysed the content of NGF mRNA in blood vessels from young SHR and normotensive Wistar-Kyoto (WKY) rats. METHODS: Total RNA was isolated from mesenteric arteries from 2-, 10- and 43-day-old SHR and WKY rats and RNA was also isolated from caudal arteries from 43-day-old rats. The RNA was subjected to Northern transfer or slot blots and the content of NGF mRNA measured after hybridization with a 32P-labelled complementary (c)DNA probe for NGF. RESULTS: Slot blot analysis indicated a larger concentration of NGF mRNA in mesenteric and caudal arteries from SHR than for tissues from WKY rats. CONCLUSIONS: In this genetic model of hypertension the results indicate an association between an enhanced level of NGF mRNA and the appearance of vascular hypernoradrenergic hypertension.

Effects of dietary sodium and fish oil on blood pressure development in stroke-prone spontaneously hypertensive rats.

The postulated antihypertensive effect of dietary fish oil and the influence of dietary sodium on this effect were evaluated in young stroke-prone spontaneously hypertensive rats (SHRSP) by direct intra-arterial measurement of blood pressure. Weaning rats were fed synthetic diets containing olive oil or eicosapentaenoic acid-enriched fish oil (5% of dry weight) with normal (0.23%) or high (2.8%) sodium content. Catheters were implanted after 3 months for blood pressure measurement under resting conditions and to sample blood for catecholamine determinations. Effects of fish oil on vascular reactivity were assessed in the in situ blood-perfused mesentery. The overall observation, from a series of experiments, was that feeding diets containing 5% fish oil to young SHRSP resulted in a small but consistent suppression of the development of hypertension. This effect could be counteracted, however, by increasing dietary sodium intake. Observations after ganglion blockade indicate that the antihypertensive effect of fish oil is unlikely to result from a reduction in sympathetic vascular tone.

An outbreak of toxoplasmosis linked to cats.

Clinical, serologic, and epidermiologic evidence documents an outbreak of toxoplasmosis involving ten of 30 members of an extended family. The index patient had unusual clinical manifestations including brain abscesses, progressive chorioretinitis, seizures, neurologic deficits, hepatosplenomegaly, pneumonitis, and eosinophilia. Toxoplasmosis was confirmed by demonstrating the organism in brain tissue and cerebrospinal fluids; clinical and serologic evidence also indicated infection with Toxocara (viscd children. Of the 11 such children, seven (68%) were seropositive, six of whom had high acute-phase titers (greater than or equal to 1024) to Toxoplasma and a disease consistent with acute toxoplasmosis. All six of the latter group required specific chemotherapy. Geophagia was associated statistically with acute toxoplasmosis among the children; it also increased the risk of infection with Toxocara and enteroparasites. Two school-aged children and two adults had serologic evidence of acute toxoplasmosis, but only one of the group was symptomatic. Epidemiologic evidence indicates that this outbreak was probably caused by ingesting oocysts from cat feces. We suggest that the severe and unusual clinical manifestations of the index patient resulted from simultaneous infection with Toxoplasma and Toxocara.

Adrenal origin of plasma catecholamines after decapitation: a study in normal and diabetic rats.

The concentrations of catecholamines and the activities of dopamine-beta-hydroxylase were measured in blood obtained from decapitated diabetic and aged-matched control rats. The activity of dopamine-beta-hydroxylase in blood from diabetic rats was much greater (5 fold) than that seen for control rats. For both diabetic and control rats, decapitation was accompanied by an increase in levels of adrenaline and noradrenaline with no change in the activity of plasma dopamine-beta-hydroxylase. The results are consistent with a predominantly adrenal origin of catecholamines and extra-adrenal origin of dopamine-beta-hydroxylase. The high activity of dopamine-beta-hydroxylase in diabetes indicates either an increased activity of the sympathetic nervous system or changes in dopamine-beta-hydroxylase turnover.

A contrasting effect of the diabetic state upon the contractile responses of aortic preparations from the rat and rabbit.

Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (65 mg kg-1). Rabbits were rendered diabetic by injecting alloxan (100 mg kg-1) into the lateral ear vein. Diabetes was confirmed by a significant elevation of serum glucose in both species 8 weeks after injection. The maximum contraction to noradrenaline (NA), 5-hydroxytryptamine (5-HT) and KCl was markedly diminished in thoracic aortic rings (AR) from diabetic rats with no change in the EC50 of the agonists. There were no differences in the contractile properties of AR from diabetic rabbits to NA, 5-HT or KCl. Diabetes did not alter the responsiveness of AR from the rat to angiotensin II (AII). However, AR from diabetic rabbits displayed a decreased maximal contraction and an increased EC50 to AII. The magnitude of the acetylcholine-induced relaxation to precontracted AR was not different between diabetic and control rats and rabbits. The contractile responses of AR to NA, 5-HT and KCl were depressed in diabetic rats, regardless of the control tissue to which they were compared. The decrease in maximal contraction to NA, 5-HT and KCl seen in diabetic animals was prevented by insulin replacement. The results demonstrated that while both rats and rabbits exhibited a similar degree of hyperglycemia after treatment with a diabetogenic agent, aortic preparations from the rabbit are not affected in the same way as the aorta from the diabetic rat when exposed to NA, 5-HT and KCl. This feature may be related to the marked differences between the extent of sympathetic innervation of the aorta in the rabbit and rat. Furthermore, the decrease in maximal contraction in rat aorta was non-specific with respect to agonists since it could also be demonstrated with KCl. Therefore, it follows that the diabetic state may affect processes responsible for contraction beyond the level of receptor activation.

Influence of blood sampling conditions upon histamine concentrations in rat plasma: a study of a complex relationship with plasma epinephrine.

The concentrations of histamine reported vary considerably from species to species. The present studies sought to determine if blood sampling techniques were at least in part responsible for this large variability. Since plasma catecholamines are influenced by the stress associated with blood sampling, these biogenic amines also were measured. Finally, we explored the possible existence of a relationship between plasma histamine and plasma catecholamine concentrations. The present study confirms that concentrations of histamine in rat plasma are particularly large and establishes that the manner (e.g. awake, anesthetized) and site (e.g. intravenous, decapitation) of blood removal influence the concentrations obtained. The lowest histamine values were seen in samples taken from blood vessels in anesthetized rats. Blood obtained after decapitation showed increasing concentrations of plasma histamine in sequentially obtained samples. An inverse relationship appeared to exist between plasma histamine and plasma catecholamines (predominantly epinephrine). An inhibitory role of epinephrine upon decapitation-associated histamine release was suggested by the observation that both adrenalectomy and catecholamine depletion (alpha-methyl-para-tyrosine) elevated histamine concentrations. Our studies with propranolol, as well as work by other investigators, establish an inhibitory role of ?-receptor stimulation on the release of histamine. On the other hand, histamine injected into the perfused rat adrenal caused a marked release of adrenomedullary catecholamines. In summary our study suggests the presence of a complex interaction between catecholamines and histamine in the regulation of the release of the individual amines. Our findings point to the existence of a histamine-adrenal axis in which the release of histamine may facilitate the release of epinephrine which in turn may restrict further release of histamine.

Myocardial opiate receptor activity is stereospecific, independent of muscarinic receptor antagonism, and may play a role in depressing cardiac function.

Earlier work has shown that morphine sulfate can produce a dose-related decrease in heart rate (HR) and cardiac output (CO) in isolated working rat hearts. This response is preventable with the use of the opiate receptor antagonist, naloxone hydrochloride. In this study, the stereospecificity of the opiate response was tested with the use of levorphanol tartrate and its d-isomer, dextrorphan, in our Langendorff rat heart model. The interaction of muscarinic receptor activity with the opiate response was tested by first adding bethanechol chloride to the perfusate in the presence and absence of atropine (5 X 10(-9) mmol/L). Our earlier studies with morphine sulfate were then repeated in the presence of the same concentration of atropine. At a concentration of 5 X 10(-6) mmol/L, levorphanol tartrate produced a significant decrease in CO (p less than 0.05), while a similar concentration of dextrorphan produced little change in either HR or CO. Bethanechol chloride, in a concentration of 3 X 10(-6) mmol/L, produced a significant decrease in HR and CO (p less than 0.05), which was prevented by atropine. When morphine sulfate was added to the standard perfusate (3 X 10(-4) mmol/L), HR and CO were significantly decreased (p less than 0.05). This change was not prevented by the addition of atropine. The opiate effect on myocardial function is mediated by a stereospecific opiate receptor, which acts independently of muscarinic receptor antagonism.

Dietary polyunsaturated fatty acid and antioxidant modulation of vascular dysfunction in the spontaneously hypertensive rat.

Two currently available edible oils-olive and canola-and two oil blends of plant origin having different n-3/n-6 polyunsaturated fatty acid (PUFA) ratios were evaluated for their ability to modify vascular dysfunction in the spontaneously hypertensive rat (SHR). Synthetic diets supplemented with test oils (5% w/w) were fed for 12 weeks, and segments of thoracic aorta used to assess vascular function. Vessels from the SHR displayed a spontaneous constrictor response after the inhibition of endothelial cell nitric oxide (NO) with N(omega)-nitro-L-arginine (NOLA). Dietary alpha -linoleate enrichment led to a reduction (P<0.05) in this abnormality with a dietary n-3/n-6 PUFA ratio of 1.0 (blend-1) yielding the best outcome. Relaxation to acetylcholine (ACh) was unaffected by dietary lipid supplementation. NOLA treated rings also displayed contractions to ACh that were abolished by indomethacin, thromboxane antagonists SQ29548, picotamide and flavonoids kaempferol and quercetin. In contrast, alpha-tocopherol, rutin and the lipoxygenase inhibitor esculetin resulted in only partial (30-55%) inhibition, and were ineffective against the NOLA-induced contraction suggesting the operation of different biochemical mechanisms in mediating the spontaneous and Ach-induced contractions. Results implicate plant-based oils and antioxidants as potential modulators of vascular function.

Dietary n-3 and n-6 polyunsaturated oils and airway contractility.

Recent reports suggest modulation of chronic obstructive pulmonary disease by dietary polyunsaturated fatty acids. In the present study, we re-examined this possibility by using an established animal model of pulmonary sensitisation. Adult guinea pigs were fed diets supplemented (10% w/w) with either olive, canola or safflower oil for 4 weeks before sensitising with ovalbumin and continuing on various diets for a further 6 week period. Neither the contraction following ovalbumin challenge, nor the responses to histamine, carbachol and various eicosanoid mediators - prostaglandin F(2 alpha), leukotriene C(4), thromboxane mimetic U44619 - of isolated segments of airway tissue were altered (P>0.05, ANOVA) by the dietary lipid treatment. Lipid analysis showed changes in membrane linoleic acid (18:2n-6) and alpha -linolenic acids (alpha 18:3n-3) in lung phospholipids consistent with dietary intakes. However, no significant further desaturation/elongation of these dietary precursors was evident. Ovalbumin induced contraction was fully reversed by the lipoxygenase inhibitor esculetin whilst indomethacin resulted in a slight increase possibly due to the inhibition of bronchodilator prostanoids. Results confirm that under the conditions employed airway function was not influenced by the variable dietary intakes of n-3 and n-6 PUFA.