Southampton General Hospital

BACKGROUND: A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. METHODS: We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. RESULTS: ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). CONCLUSIONS: In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).

Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

The thrifty phenotype hypothesis proposes that the epidemiological associations between poor fetal and infant growth and the subsequent development of type 2 diabetes and the metabolic syndrome result from the effects of poor nutrition in early life, which produces permanent changes in glucose-insulin metabolism. These changes include reduced capacity for insulin secretion and insulin resistance which, combined with effects of obesity, ageing and physical inactivity, are the most important factors in determining type 2 diabetes. Since the hypothesis was proposed, many studies world-wide have confirmed the initial epidemiological evidence, although the strength of the relationships has varied from one study to another. The relationship with insulin resistance is clear at all ages studied. Less clear is the relationship with insulin secretion. The relative contribution of genes and environment to these relationships remains a matter of debate. The contributions of maternal hyperglycaemia and the trajectory of postnatal growth need to be clarified.

In national samples of 9921 10 year olds and 3259 adults in Britain systolic blood pressure was inversely related to birth weight. The association was independent of gestational age and may therefore be attributed to reduced fetal growth. This suggests that the intrauterine environment influences blood pressure during adult life. It is further evidence that the geographical differences in average blood pressure and mortality from cardiovascular disease in Britain partly reflect past differences in the intrauterine environment. Within England and Wales 10 year olds living in areas with high cardiovascular mortality were shorter and had higher resting pulse rates than those living in other areas. Their mothers were also shorter and had higher diastolic blood pressures. This suggests that there are persisting geographical differences in the childhood environment that predispose to differences in cardiovascular mortality.

Overemphasis on hypothesis testing--and the use of P values to dichotomise significant or non-significant results--has detracted from more useful approaches to interpreting study results, such as estimation and confidence intervals. In medical studies investigators are usually interested in determining the size of difference of a measured outcome between groups, rather than a simple indication of whether or not it is statistically significant. Confidence intervals present a range of values, on the basis of the sample data, in which the population value for such a difference may lie. Some methods of calculating confidence intervals for means and differences between means are given, with similar information for proportions. The paper also gives suggestions for graphical display. Confidence intervals, if appropriate to the type of study, should be used for major findings in both the main text of a paper and its abstract.

Abstract Objective : To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. Design : Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. Subjects : 108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. Setting : Southampton and surrounding community. Main outcome measures : Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. Results : Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 1/min. The most commonly identified virus type was rhinovirus. Conclusions : This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children. Key messages Key messages In this study common cold viruses were found in 80-85% of reported exacerbations of asthma in children Rhinoviruses, which cause most common colds, accounted for two thirds of viruses detected Analysis of diary cards also showed large numbers of similar but less severe episodes that may also be viral in origin

Abstract Objective: To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them. Design: Meta-analyses of the above three diseases using ( a ) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and ( b ) 20 prospective studies (3820 participants) of serum homocysteine and disease risk. Main outcome measures: Odds ratios of the three diseases for a 5 μmol/l increase in serum homocysteine concentration. Results: There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 μmol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies. Conclusions: The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant results—strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 μmol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%). What is already known on this topic There is an association between serum homocysteine concentration and cardiovascular disease, but it is not known whether the association is causal A common single gene mutation that reduces the activity of an enzyme involved in folate metabolism (MTHFR) is associated with a moderate (20%) increase in serum homocysteine What this study adds A meta-analysis of MTHFR studies shows a significantly higher risk of both ischaemic heart disease and deep vein thrombosis (with or without pulmonary embolism) in people with the MTHFR mutation A meta-analysis of prospective studies shows a significant association between homocysteine concentration and ischaemic heart disease similar in size to that expected from the results of the MTHFR studies and a significant association with stroke The MTHFR studies and the prospective studies do not share the same potential sources of error but both yield similar results—strong evidence that the association between homocysteine and cardiovascular disease is causal On this basis a decrease in serum homocysteine of 3 μmol/l (achievable by daily intake of about 0.8 mg folic acid) should reduce the risk of ischaemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24%

Low birthweight is now known to be associated with increased rates of coronary heart disease and the related disorders stroke, hypertension and non-insulin dependent diabetes. These associations have been extensively replicated in studies in different countries and are not the result of confounding variables. They extend across the normal range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. The associations are thought to be consequences of developmental plasticity, the phenomenon by which one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development. Recent observations have shown that impaired growth in infancy and rapid childhood weight gain exacerbate the effects of impaired prenatal growth. A new vision of optimal early human development is emerging which takes account of both short and long-term outcomes.

OBJECTIVE: To study the effect of intrauterine growth and maternal physique on blood pressure in adult life. DESIGN: A follow up study of infants born 50 years previously whose measurements at birth were recorded in detail. SETTING: Preston, Lancashire. SUBJECTS: 449 Men and women born in hospital in Preston during 1935-43 and still living in Lancashire. MAIN OUTCOME MEASURES: Placental weight, birth weight, and blood pressure at age 46 to 54 years. RESULTS: In both sexes systolic and diastolic pressures were strongly related to placental weight and birth weight. Mean systolic pressure rose by 15 mm Hg as placental weight increased from less than or equal to 1 lb (0.45 kg) to greater than 1.5 lb and fell by 11 mm Hg as birth weight increased from less than or equal to 5.5 lb to greater than 7.5 lb. These relations were independent so that the highest blood pressures occurred in people who had been small babies with large placentas. Higher body mass index and alcohol consumption were also associated with higher blood pressure, but the relations of placental weight and birth weight to blood pressure and hypertension were independent of these influences. CONCLUSIONS: These findings show for the first time that the intrauterine environment has an important effect on blood pressure and hypertension in adults. The highest blood pressures occurred in men and women who had been small babies with large placentas. Such discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. Prevention of hypertension may depend on improving the nutrition and health of mothers.

Almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins. In the cellular immune system, specific glycoforms are involved in the folding, quality control, and assembly of peptide-loaded major histocompatibility complex (MHC) antigens and the T cell receptor complex. Although some glycopeptide antigens are presented by the MHC, the generation of peptide antigens from glycoproteins may require enzymatic removal of sugars before the protein can be cleaved. Oligosaccharides attached to glycoproteins in the junction between T cells and antigen-presenting cells help to orient binding faces, provide protease protection, and restrict nonspecific lateral protein-protein interactions. In the humoral immune system, all of the immunoglobulins and most of the complement components are glycosylated. Although a major function for sugars is to contribute to the stability of the proteins to which they are attached, specific glycoforms are involved in recognition events. For example, in rheumatoid arthritis, an autoimmune disease, agalactosylated glycoforms of aggregated immunoglobulin G may induce association with the mannose-binding lectin and contribute to the pathology.

BACKGROUND: Low birth weight is a risk factor for coronary heart disease. It is uncertain how postnatal growth affects disease risk. METHODS: We studied 8760 people born in Helsinki from 1934 through 1944. Childhood growth had been recorded. A total of 357 men and 87 women had been admitted to the hospital with coronary heart disease or had died from the disease. Coronary risk factors were measured in a subset of 2003 people. RESULTS: The mean body size of children who had coronary events as adults was below average at birth. At two years of age the children were thin; subsequently, their body-mass index (BMI) increased relative to that of other children and had reached average values by 11 years of age. In simultaneous regressions, the hazard ratios associated with a 1 SD increase in BMI were 0.76 (95 percent confidence interval, 0.66 to 0.87; P<0.001) at 2 years and 1.14 (95 percent confidence interval, 1.00 to 1.31; P=0.05) at 11 years among the boys. The corresponding figures for the girls were 0.62 (95 percent confidence interval, 0.46 to 0.82; P=0.001) and 1.35 (95 percent confidence interval, 1.02 to 1.78; P=0.04). Low BMI at 2 years of age and increased BMI from 2 to 11 years of age were also associated with raised fasting insulin concentrations (P<0.001 for both). CONCLUSIONS: On average, adults who had a coronary event had been small at birth and thin at two years of age and thereafter put on weight rapidly. This pattern of growth during childhood was associated with insulin resistance in later life. The risk of coronary events was more strongly related to the tempo of childhood gain in BMI than to the BMI attained at any particular age.

Abstract Objective: To examine the prevalence, nature, causes, and consequences of suboptimal care before admission to intensive care units, and to suggest possible solutions. Design: Prospective confidential inquiry on the basis of structured interviews and questionnaires. Setting: A large district general hospital and a teaching hospital. Subjects: A cohort of 100 consecutive adult emergency admissions, 50 in each centre. Main outcome measures: Opinions of two external assessors on quality of care especially recognition, investigation, monitoring, and management of abnormalities of airway, breathing, and circulation, and oxygen therapy and monitoring. Results: Assessors agreed that 20 patients were well managed (group 1) and 54 patients received suboptimal care (group 2). Assessors disagreed on quality of management of 26 patients (group 3). The casemix and severity of illness, defined by the acute physiology and chronic health evaluation (APACHE II) score, were similar between centres and the three groups. In groups 1, 2, and 3 intensive care mortalities were 5 (25%), 26 (48%), and 6 (23%) respectively (P=0.04) (group 1 versus group 2, P=0.07). Hospital mortalities were 7 (35%), 30 (56%), and 8 (31%) (P=0.07) and standardised hospital mortality ratios (95% confidence intervals) were 1.23 (0.49 to 2.54), 1.4 (0.94 to 2.0), and 1.26 (0.54 to 2.48) respectively. Admission to intensive care was considered late in 37 (69%) patients in group 2. Overall, a minimum of 4.5% and a maximum of 41% of admissions were considered potentially avoidable. Suboptimal care contributed to morbidity or mortality in most instances. The main causes of suboptimal care were failure of organisation, lack of knowledge, failure to appreciate clinical urgency, lack of supervision, and failure to seek advice. Conclusions: The management of airway, breathing, and circulation, and oxygen therapy and monitoring in severely ill patients before admission to intensive care units may frequently be suboptimal. Major consequences may include increased morbidity and mortality and requirement for intensive care. Possible solutions include improved teaching, establishment of medical emergency teams, and widespread debate on the structure and process of acute care. Key messages Suboptimal management of oxygen therapy, airway, breathing, circulation, and monitoring before admission to intensive care occurred in over half of a consecutive cohort of acute adult emergency patients. This may be associated with increased morbidity, mortality, and avoidable admissions to intensive care At least 39% of acute adult emergency patients were admitted to intensive care late in the clinical course of the illness Major causes of suboptimal care included failure of organisation, lack of knowledge, failure to appreciate clinical urgency, lack of supervision, and failure to seek advice A medical emergency team may be useful in responding pre-emptively to the clinical signs of life threatening dysfunction of airway, breathing, and circulation, rather than relying on a cardiac arrest team The structure and process of acute care and their importance require major re-evaluation and debate

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.

OBJECTIVE: The purpose of this review is to provide guidance on the development, validation and use of food-frequency questionnaires (FFQs) for different study designs. It does not include any recommendations about the most appropriate method for dietary assessment (e.g. food-frequency questionnaire versus weighed record). METHODS: A comprehensive search of electronic databases was carried out for publications from 1980 to 1999. Findings from the review were then commented upon and added to by a group of international experts. RESULTS: Recommendations have been developed to aid in the design, validation and use of FFQs. Specific details of each of these areas are discussed in the text. CONCLUSIONS: FFQs are being used in a variety of ways and different study designs. There is no gold standard for directly assessing the validity of FFQs. Nevertheless, the outcome of this review should help those wishing to develop or adapt an FFQ to validate it for its intended use.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease involving the cartilage and many of its surrounding tissues. Disease progression is usually slow but can ultimately lead to joint failure with pain and disability. OA of the hips and knees tends to cause the greatest burden to the population as pain and stiffness in these large weight-bearing joints often leads to significant disability requiring surgical intervention. SOURCES OF DATA: The article reviews the existing data on epidemiology of osteoarthritis and the burden of the disease. AREAS OF AGREEMENT: Symptoms and radiographic changes are poorly correlated in OA. Established risk factors include obesity, local trauma and occupation. The burden of OA is physical, psychological and socioeconomic. AREAS OF CONTROVERSY: Available data does not allow definite conclusion regarding the roles of nutrition, smoking and sarcopenia as risk factors for developing OA. GROWING POINTS: Variable methods of diagnosing osteoarthritis have significantly influenced the comparability of the available literature. AREAS TIMELY FOR DEVELOPING RESEARCH: Further research is required to fully understand how OA affects an individual physically and psychologically, and to determine their healthcare need.

BACKGROUND: Large-scale and contemporary population-based studies of heart failure incidence are needed to inform resource planning and research prioritisation but current evidence is scarce. We aimed to assess temporal trends in incidence and prevalence of heart failure in a large general population cohort from the UK, between 2002 and 2014. METHODS: For this population-based study, we used linked primary and secondary electronic health records of 4 million individuals from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex. Eligible patients were aged 16 years and older, had contributed data between Jan 1, 2002, and Dec 31, 2014, had an acceptable record according to CPRD quality control, were approved for CPRD and Hospital Episodes Statistics linkage, and were registered with their general practice for at least 12 months. For patients with incident heart failure, we extracted the most recent measurement of baseline characteristics (within 2 years of diagnosis) from electronic health records, as well as information about comorbidities, socioeconomic status, ethnicity, and region. We calculated standardised rates by applying direct age and sex standardisation to the 2013 European Standard Population, and we inferred crude rates by applying year-specific, age-specific, and sex-specific incidence to UK census mid-year population estimates. We assumed no heart failure for patients aged 15 years or younger and report total incidence and prevalence for all ages (>0 years). FINDINGS: From 2002 to 2014, heart failure incidence (standardised by age and sex) decreased, similarly for men and women, by 7% (from 358 to 332 per 100 000 person-years; adjusted incidence ratio 0·93, 95% CI 0·91-0·94). However, the estimated absolute number of individuals with newly diagnosed heart failure in the UK increased by 12% (from 170 727 in 2002 to 190 798 in 2014), largely due to an increase in population size and age. The estimated absolute number of prevalent heart failure cases in the UK increased even more, by 23% (from 750 127 to 920 616). Over the study period, patient age and multi-morbidity at first presentation of heart failure increased (mean age 76·5 years [SD 12·0] to 77·0 years [12·9], adjusted difference 0·79 years, 95% CI 0·37-1·20; mean number of comorbidities 3·4 [SD 1·9] vs 5·4 [2·5]; adjusted difference 2·0, 95% CI 1·9-2·1). Socioeconomically deprived individuals were more likely to develop heart failure than were affluent individuals (incidence rate ratio 1·61, 95% CI 1·58-1·64), and did so earlier in life than those from the most affluent group (adjusted difference -3·51 years, 95% CI -3·77 to -3·25). From 2002 to 2014, the socioeconomic gradient in age at first presentation with heart failure widened. Socioeconomically deprived individuals also had more comorbidities, despite their younger age. INTERPRETATION: Despite a moderate decline in standardised incidence of heart failure, the burden of heart failure in the UK is increasing, and is now similar to the four most common causes of cancer combined. The observed socioeconomic disparities in disease incidence and age at onset within the same nation point to a potentially preventable nature of heart failure that still needs to be tackled. FUNDING: British Heart Foundation and National Institute for Health Research.

Treatment with systemic corticosteroids is known to increase the risk of fractures but little is known of the fracture risks associated with inhaled corticosteroids. A retrospective cohort study was conducted using a large UK primary care database (the General Practice Research Database [GPRD]). Inhaled corticosteroid users aged 18 years or older were compared with matched control patients and to a group of noncorticosteroid bronchodilator users. Patients with concomitant use of systemic corticosteroids were excluded. The study comprised 170,818 inhaled corticosteroid users, 108,786 bronchodilator users, and 170,818 control patients. The average age was 45.1 years in the inhaled corticosteroid, 49.3 years in the bronchodilator, and 45.2 years in the control groups. In the inhaled corticosteroid cohort, 54.5% were female. The relative rates (RRs) of nonvertebral, hip, and vertebral fractures during inhaled corticosteroid treatment compared with control were 1.15 (95% CI, 1.10-1.20), 1.22 (95% CI, 1.04-1.43), and 1.51 (95% CI, 1.22-1.85), respectively. No differences were found between the inhaled corticosteroid and bronchodilator groups (nonvertebral fracture RR = 1.00; 95% CI, 0.94-1.06). The rates of nonvertebral fractures among users of budesonide (RR = 0.95; 95% CI, 0.85-1.07) and fluticasone propionate (RR = 1.03; 95% CI, 0.71-1.49) were similar to the rate determined for users of beclomethasone dipropionate. We conclude that users of inhaled corticosteroids have an increased risk of fracture, particularly at the hip and spine. However, this excess risk may be related more to the underlying respiratory disease than to inhaled corticosteroid.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving resolvins and protectins. Mechanisms underlying the anti-inflammatory actions of n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor NR1C3 (i.e. peroxisome proliferator activated receptor γ) and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked. In adult humans, an EPA plus DHA intake greater than 2 g day⁻¹ seems to be required to elicit anti-inflammatory actions, but few dose finding studies have been performed. Animal models demonstrate benefit from n-3 fatty acids in rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta-analyses of the data. Clinical trails of fish oil in patients with IBD and asthma are inconsistent with no overall clear evidence of efficacy.

Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.