A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Psychological distress among primary school teachers: a comparison with clinical and population samples.

OBJECTIVES: This analysis explored the level of psychological distress among primary school teachers in the South West of England as compared with clinical and general population samples. STUDY DESIGN: Secondary analysis of data from the Supporting Teachers and Children in Schools (STARS) trial completed by up to 90 teachers at baseline, 9, 18 and 30 months of follow-up. METHODS: We used the Everyday Feelings Questionnaire (EFQ) as a measure of psychological distress. Baseline data on teachers were compared with a population sample of professionals and a clinical sample of patients attending a depression clinic. RESULTS: Our teacher cohort experienced higher levels of psychological distress than comparable professionals from the general population, which were sustained over 30 months of follow-up. Levels of psychological distress were lower than those found in the clinical sample. Using a cut-point indicative of moderate depression, our data suggest that between 19% and 29% of teachers experienced clinically significant distress at each time-point. CONCLUSIONS: We detected high and sustained levels of psychological distress among primary school teachers, which suggests an urgent need for intervention. Effective support for teachers' mental health is particularly important given the potential impact of poor teacher mental health on pupil well-being, pupil attainment and teacher-pupil relationships.

Solid as a rock, flexible as water? Effectiveness of a school-based intervention addressing students' intrapersonal and interpersonal domains.

Students following a preparatory vocational education track seem most in need of an intervention stimulating their competencies and preventing the development of problems in the intrapersonal and interpersonal domain. The aim of the present study was to examine, first, whether Rock & Water, a social emotional learning intervention that uses active forms of learning, is effective in improving students' competencies and preventing problems in the intra- and interpersonal domain, and second, whether intervention effects were influenced by the extent to which multiple systems are involved in the intervention. We conducted a randomized controlled trial with a sample of 7th grade students (N = 1299, Mage = 12.38, 54% boys). Students reported on outcomes of the intra- and interpersonal domains using digital questionnaires. The data were analyzed with Latent Growth Curve models. Results showed that the intervention was most effective when only a core team of teachers was involved in the intervention. The intervention improved several proximal outcomes (i.e., self-control and emotional self-regulation) and distal outcomes in students' intrapersonal and interpersonal domains. The intervention effects were strongest, albeit moderate, in the first year of the intervention. These results show that interventions with an active form of learning and implemented by a core team might be promising interventions for prevocational students, although effort should be put in increasing its effectiveness.

γδ T cells compose a developmentally regulated intrauterine population and protect against vaginal candidiasis.

This most comprehensive analysis to date of γδ T cells in the murine uterus reveals them to compose a unique local T-cell compartment. Consistent with earlier reports, most cells expressed a canonical Vγ6Vδ1 TCR, and produced interleukin (IL)-17A upon stimulation. Nonetheless, contrasting with earlier reports, uterine γδ T cells were not obviously intraepithelial, being more akin to sub-epithelial Vγ6Vδ1+ T cells at several other anatomical sites. By contrast to other tissues however, the uterine compartment also included non-Vγ6+, IFN-γ-producing cells; was strikingly enriched in young mice; expressed genes hitherto associated with the uterus, including the progesterone receptor; and did not require microbes for development and/or maintenance. This notwithstanding, γδ T-cell deficiency severely impaired resistance to reproductive tract infection by Candida albicans, associated with decreased responses of IL-17-dependent neutrophils. These findings emphasise tissue-specific complexities of different mucosal γδ cell compartments, and their evident importance in lymphoid stress-surveillance against barrier infection.

Aspirin inhibits vasopressin-induced hypothalamic-pituitary-adrenal activity in normal humans.

PGs influence ACTH secretion. However, their specific role in modulating the activity of the human hypothalamic-pituitary-adrenal (HPA) axis remains unclear. Acetylsalicylic acid (aspirin) inhibits the synthesis of PGs from arachidonic acid by blocking the cyclooxygenase pathway. In this study we administered a single, clinically relevant dose of aspirin before HPA axis stimulation by a bolus dose of iv arginine vasopressin (AVP) to seven normal males using a randomized, placebo-controlled, single blinded design. Aspirin significantly reduced the cortisol response to AVP [mean peak increase from basal, 221.1 +/- 20.1 vs. 165.4 +/- 22.5 nmol/L (P = 0.0456); mean integrated response, 11,199.3 +/- 1,560.0 vs. 6,162.3 +/- 1,398.6 nmol.min/L (P = 0.0116) for placebo aspirin/AVP and aspirin/ AVP, respectively]. The ACTH response was reduced, but did not reach statistical significance [mean peak increase from basal, 7.5 +/- 2.2 vs. 4.3 +/- 0.3 pmol/L (P = 0.0563); mean integrated response, 142.6 +/- 36.0 vs. 96.2 +/- 8.7 pmol.min/L (P = 0.12) for placebo aspirin/ AVP and aspirin/AVP, respectively]. PGs may influence ACTH secretion by being stimulatory or inhibitory to the HPA axis at different levels, such as hypothalamic or pituitary. Which effect predominates in vivo during dynamic activation of the axis may depend on the level at which the secretory stimulus acts. We showed that when normal male volunteers were treated with the PG synthesis inhibitor, aspirin, they had a blunted HPA axis response to the pituitary corticotroph stimulator, AVP.

Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1-24) infusion tests.

The efficacy of the standard high dose ACTH stimulation test (HDT), using a pharmacological 250-microg dose of synthetic ACTH-(1-24), in the diagnosis of central hypoadrenalism is controversial. The insulin hypoglycemia test is widely regarded as the gold standard dynamic stimulation test of the hypothalamo-pituitary-adrenal (HPA) axis that provides the most reliable assessment of HPA axis integrity and reserve. Alternatively, a prolonged infusion of ACTH causes a continuing rise in plasma cortisol levels that may predict the adrenals' capacity to respond to severe ongoing stress. In nine normal subjects, we compared plasma ACTH and cortisol levels produced by three i.v. bolus low doses of ACTH-(1-24) (0.1, 0.5, and 1.0 microg/1.73 m2; LDTs) with those stimulated by hypoglycemia (0.15 U/kg insulin) and with the cortisol response to a standard 250-microg dose of ACTH-(1-24). The normal cortisol response to an 8-h ACTH-(1-24) infusion (250 microg at a constant rate over 8 h) was determined using three modern cortisol assays: a high pressure liquid chromatography method (HPLC), a fluorescence polarization immunoassay (FPIA), and a standard RIA. In the LDTs, stepwise increases in mean peak plasma ACTH were observed (12.4 +/- 2.0, 48.2 +/- 7.2, 120.2 +/- 15.5 pmol/L for the 0.1-, 0.5-, and 1.0-microg LDTs, respectively; P values all <0.0022 when comparing peak values between tests). The peak plasma ACTH level after insulin-induced hypoglycemia was significantly lower than that produced in the 1.0-microg LDT (69.6 +/- 9.3 vs. 120.2 +/- 15.5 pmol/L; P < 0.0002), but was higher than that obtained during the 0.5-microg LDT (69.6 +/- 9.3 vs. 48.2 +/- 7.2 pmol/L; P < 0.02). In the LDTs, statistically different, dose-dependent increases in peak cortisol concentration occurred (355 +/- 16, 432 +/- 13, and 482 +/- 23 nmol/L; greatest P value is 0.0283 for comparisons between all tests). The peak cortisol levels achieved during the LDTs were very different from those during the HDT (mean peak cortisol, 580 +/- 27 nmol/L; all P values <0.00009. However, the mean 30 min response in the 1.0-microg LDT did not differ from that in the HDT (471 +/- 22 vs. 492 +/- 22 nmol/L; P = 0.2). In the 8-h ACTH infusion test, plasma cortisol concentrations progressively increased, reaching peak levels much higher than those in the HDT [995 +/- 50 vs. 580 +/- 27 nmol/L (HPLC) and 1326 +/- 100 vs 759 +/- 31 nmol/L (FPIA)]. Significant differences in the basal, 1 h, and peak cortisol levels as determined by the three different assay methods (HPLC, FPIA, and RIA) were observed in the 8-h infusion tests. Similarly, in the HDTs there were significant differences in the mean 30 and 60 min cortisol levels as measured by HPLC compared with those determined by FPIA. We conclude that up to 30 min postinjection, 1.0 microg/1.73 m2 ACTH-(1-24) stimulates maximal adrenocortical secretion. Similar lower normal limits at 30 min may be applied in the 1.0-microg LDT and the HDT, but not when lower doses of ACTH-(1-24) are administered. The peak plasma ACTH level produced in the 1.0-microg LDT is higher than in the insulin hypoglycemia test, but is of the same order of magnitude. The peak cortisol concentration obtained during an 8-h synthetic ACTH-(1-24) infusion is considerably higher than that stimulated by a standard bolus 250-microg dose, potentially providing a means of evaluating the adrenocortical capacity to maintain maximal cortisol secretion. Appropriate interpretation of any of these tests of HPA axis function relies on the accurate determination of normal response ranges, which may vary significantly depending on the cortisol assay used.

Adiposity, lipids, alcohol consumption, smoking, and gender.

Indices of obesity, plasma lipids, and lipoprotein levels, plasma cholesteryl ester fatty acid composition, reported alcohol consumption and smoking habits were measured in 88 men and 87 women, ages over 15 years, randomly selected from the total respondents (1192) to a health survey. Most indices of obesity were related to plasma triglycerides and high-density lipoprotein levels in both sexes; to very low-density lipoprotein levels in men only; and to plasma cholesteryl ester fatty acid linoleic acid proportions in women only. The correlations with high-density lipoprotein cholesterol levels were dependent on very low-density lipoprotein triglyceride levels in men but not in women. Indices of obesity were significantly higher in nonsmoking women and reported alcohol consumption correlated with Quetelet's index (body mass index) in men. Smoking habits, but not alcohol consumption, influenced correlations between indices of obesity and plasma triglycerides and very low-density lipoprotein triglyceride levels in men. The present results showed several sex-related differences in relationships with indices of obesity. Lower very low-density lipoprotein levels, higher skinfold measurements, higher cholesteryl ester fatty acid linoleic acid proportions and lower alcohol intake in women than in men may be responsible. The data suggested that in women, altered diet composition may be linked with obesity.

Linoleic acid and susceptibility to fatal ventricular fibrillation in rats.

The effect of linoleic acid on the induction of fatal ventricular fibrillation by intravenous CaCl2 (10%), was studied in rats fed for a month from weaning on a diet with either a high or low content of linoleic acid. Studies were performed in the basal state and after pretreatment with noradrenaline, which increased the sensitivity to CaCl2 equally in animals from both diet groups. Despite considerable differences in the linoleic acid levels in the plasma and myocardium, the two groups did not differ in the incidence of fatal ventricular fibrillation. Our conclusions concerning the effect of linoleic acid on cardiac arrhythmias, and sudden death in particular, are compared with those from other studies.

Modification of nicotinic acid and prostaglandin E1 antilipolytic action in vitro.

In epididymal adipose tissue from rats, human serum antagonizes inhibition of basal lipolysis by nicotinic acid in vitro. Under similar conditions caffeine-stimulated lipolysis was unaffected by the presence of human serum. Very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins were all found to antagonize the action of nicotinic acid on basal lipolysis. VLDL also antagonized prostaglandin E1 (PGE1)-inhibition of basal lipolysis in vitro. The fat cell membrane was suggested as the site at which human serum lipoproteins antagonize nicotinic acid or PGE1 antilipolytic action on basal lipolysis in vitro.

Lecithin:cholesterol acyltransferase activity, plasma and lipoprotein lipids and obesity in men and women.

Lecithin:cholesterol acyltransferase (LCAT) activity, lipid concentration, lipoprotein lipid concentrations and cholesteryl ester linoleic acid proportion were determined in the plasma of 85 subjects randomly selected from a population during a health screen survey. Mean fractional LCAT rate was significantly higher in men than in women. Molar LCAT rate correlated with low density lipoprotein (LDL) cholesterol concentration in men and with nearly all lipoprotein lipid concentrations in women. Most of these relationships were dependent on plasma unesterified cholesterol (UC) concentration. Fractional LCAT rate was correlated only with HDL cholesterol concentration in women and this relation was dependent on the influence of obesity. An inverse relationship between plasma cholesteryl ester (PCE) linoleic acid proportion and molar LCAT rate in women was also explained by influences of obesity on the data. Both fractional and molar LCAT rates were positively correlated with obesity (Quetelet's Index and subscapular skinfold thickness) in women but not in men. This study showed the influence of sex on nearly all correlations involving LCAT activity in combined groups of men and women.

Interactions between the stimulated hypothalamic-pituitary-adrenal axis and leptin in humans.

Leptin, produced by adipocytes, has homeostatic effects on body fat mass through inhibition of appetite and stimulation of the sympathetic nervous system. Several studies have reported that high-dose exogenous glucocorticoids increase circulating leptin concentrations in humans. Conversely, leptin has inhibitory effects on the hypothalamic-pituitary-adrenal (HPA) axis, both at the hypothalamic and adrenal levels. We hypothesized that acute hypercortisolism, in the physiological range, may not alter leptin secretion. Four stimuli of the HPA axis were administered to eight healthy male volunteers in a placebo-controlled study. On separate afternoons, in a randomised order, fasting subjects received i.v. injections of saline, naloxone (125 microg/kg); vasopressin (0.0143 IU/kg); naloxone and vasopressin in combination; or insulin (0.15 U/kg; a dose sufficient to induce hypoglycaemia). Plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol and leptin were measured before and for 120 min after the injection. The cortisol secretory response was greatest after insulin-hypoglycaemia, this response was significantly greater than that following naloxone, naloxone/vasopressin, or vasopressin alone. Despite the cortisol release, leptin concentrations were not increased after any stimulus. Insulin-hypoglycaemia was associated with a decrease in leptin concentration at 60 and 90 min, while naloxone did not alter leptin concentrations. However, basal leptin concentrations were positively correlated with integrated ACTH and cortisol responses to naloxone, but did not correlate with ACTH or cortisol responses to the other stimuli. Thus acute elevations of plasma cortisol, in the physiological range, do not appear to influence plasma leptin concentrations. The fall in plasma leptin concentration after insulin-induced hypoglycaemia may reflect catecholamine secretion after this stimulus.

The insulin hypoglycemia test: hypoglycemic criteria and reproducibility.

The insulin hypoglycemia test (IHT) is widely regarded as the "gold standard" for dynamic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to investigate the temporal relationship between a rapid decrease in plasma glucose and the corresponding rise in plasma adenocorticotropic hormone (ACTH), and to assess the reproducibility of hormone responses to hypoglycemia in normal humans. Ten normal subjects underwent IHTs, using an insulin dose of 0.15 U/kg. Of these, eight had a second IHT (IHT2) and three went on to a third test (IHT3). Plasma ACTH and cortisol were measured at 15-min intervals and, additionally, in four IHT2s and the three IHT3s, ACTH was measured at 2.5- or 5-min intervals. Mean glucose nadirs and mean ACTH and cortisol responses were not significantly different between IHT1, IHT2 and IHT3. Combined data from all 21 tests showed the magnitude of the cortisol responses, but not the ACTH responses, correlated significantly with the depth and duration of hypoglycemia. All subjects achieved glucose concentrations of of < or = 1.6 mmol/l before any detectable rise in ACTH occurred. In the seven tests performed with frequent sampling, an ACTH rise never preceded the glucose nadir, but occurred at the nadir, or up to 15 min after. On repeat testing, peak ACTH levels varied markedly within individuals, whereas peak cortisol levels were more reproducible (mean coefficient of variation 7%). In conclusion, hypoglycemia of < or = 1.6 mmol/l was sufficient to cause stimulation of the HPA axis in all 21 IHTs conducted in normal subjects. Nonetheless, our data cannot reveal whether higher glucose nadirs would stimulate increased HPA axis activity in all subjects. Overall, the cortisol response to hypoglycemia is more reproducible than the ACTH response but, in an individual subject, the difference in peak cortisol between two IHTs may exceed 100 nmol/l.

Increased levels of esterified arachidonic acid in plasma by feeding gamma-linolenic acid.

The effects of diets containing 5% of methyl-gamma-linolenate (delta 6,9,12) or 5% of methyl-alpha-linolenate (delta 9,12,15) on the fatty acid composition of lipids in rat plasma were studied. After 10 days the cholesterol esters and total phospholipids in the plasma of rats fed gamma-linolenate contained higher percentages of arachidonic acid than the corresponding lipid classes in the plasma of rats fed the alpha-isomer. A fairly high percentage of gamma-linolenic acid was incorporated into the cholesterol esters of rats fed methyl-gamma-linolenate.

Changes in high density lipoprotein subfractions and other lipoproteins by exercise.

Seventeen previously sedentary men (aged 30-45) were exercised approximately twice weekly over a 10-week period during which time there was a significant fall in low density lipoprotein cholesterol, but total high density lipoprotein (HDL) did not change. The subfraction HDL2 showed an initial fall at two weeks of training with a subsequent rise above the baseline by 10 weeks. HDL3 cholesterol tended to change in an opposite direction to HDL2 thus accounting for no significant change in total HDL cholesterol. Smoking or drinking habits did not change throughout the study. As body weights did not change significantly through the study, energy intake must have increased with probable increased very low density lipoprotein (VLDL) production. Loss of apoprotein C-peptides from HDL2 associated with activation of lipoprotein lipase, and clearance of VLDL, could have caused redistribution of C-apoproteins between HDL3 leading to the changes seen, with the establishment of a new equilibrium with continued training by 10 weeks.

Lipiodol avid liver metastases from adrenocortical carcinoma; prospects for therapy?

A young lady with liver metastases from adrenocortical carcinoma was given a tracer dose of lipiodol into the hepatic artery and her liver metastases were shown to be extremely lipiodol avid. A therapeutic dose of lipiodol I131 was then given. There was not, however, any evidence of response to this treatment.

Urban/rural differences in red blood cell fatty acid composition, plasma lipids and diet in Melanesian Fijians.

OBJECTIVE: The aim of the study was to compare red blood cell (RBC) fatty acid composition, plasma lipids and lipoproteins and dietary intake between urban and rural Melanesian Fijians. DESIGN: A cross-sectional study was performed in a random subsample (n = 154) from a total survey population of 589 subjects. SETTING: Melanesian Fijians living in the relatively urban settlement of Nabua, Suva and On the remote island of Qamea (rural) were studied. RESULTS: The proportions of myristic acid (1.4% versus 0.3%, P < 0.001) and arachidonic acid (10.1% versus 11.4%, P < 0.01) were significantly higher and proportions of oleic acid (14.4% versus 13.2%, P < 0.05) and linoleic acid (11.9% versus 8.1%, P < 0.001) were significantly lower in RBC from rural compared with urban men, and a similar pattern was seen in women. Plasma cholesterol levels were significantly (P < 0.05) higher in the rural subjects. Urban/rural differences in plasma cholesterol levels were not significant when the proportion of RBC myristate was taken into account. CONCLUSIONS: The results suggest that consumption of myristic acid from coconut fat is greater and the intake of linoleic acid is less in Fijians living on a remote island and may contribute to their higher plasma cholesterol levels compared with their urban counterparts.

Enhancing alcohol problem recognition: a self-regulation model for the effects of self-focusing and normative information.

OBJECTIVE: A self-regulation model for predicting alcohol problem recognition among heavy drinking college students (N = 72) was tested. METHOD: The effects of both self-focusing and normative information concerning alcohol use were assessed in a 2 (self-focusing information: present, absent) x 2 (normative information: present, absent) factorial design. RESULTS: A significant two-way interaction on both a Decisional Balance Measure (DBM) and the Contemplation subscale of the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) revealed that relative to a control condition, either type of information presented alone increased negative evaluations of drinking and problem recognition, whereas presenting both types of information together had less effect on negative evaluations and even decreased problem recognition. The interaction obtained with DBM scores was further qualified by a three-way interaction that limited this pattern to participants scoring higher on self-deception. The same interactive pattern of self-focusing by normative information on problem recognition approached statistical significance on the Precontemplation subscale. Finally, a thinking-aloud procedure employed to obtain immediate reactions to the presentation of experimental information offered corroborative results, with the joint presentation of self-focusing and normative information triggering the most defensive reactions. CONCLUSIONS: Results and their clinical implications are discussed in terms of a self-regulation model for problem recognition.

The influence of maternal factors on placental weight.

The influence of maternal factors on placental weight has been studied. Their effect may be partially masked as it was not possible to eliminate the effect of fetal factors. For a narrow range of birthweights placental weight correlates increasingly closely with maternal pregnant weight, non-pregnant weight, and weight-for-height; it correlates more closely with all of these than with the baby's birthweight. Maternal obesity has a significant effect on placental weight independent of the possible fetal effect. Maternal height and weight gain in pregnancy share no such effect. Pregnancy weight gain is a poor indicator of feto-placental development.

Recording placental size.

It is routine practice in obstetric hospitals to record the weight of the placenta after each delivery, but the practical usefulness of this measurement has been much debated. Theoretically attractive and more accurate estimations of placental size, such as volume, show no better correlation with birth weight; the usefulness of such relationships is in doubt. Although the variations in size appear interesting, our findings add weight to the suggestions of earlier and recent workers that traditional routine measurements which have virtually no significance should be abandoned until some more meaningful procedure can be found.

Blood pressure in a random sample of the New Zealand population.

Blood pressures were measured as part of a health check in a randomly selected sample of the New Zealand population. One thousand, four hundred and ten men and 1605 women over 15 years were studied. Measurements were made by trained observers using the Hawksley Random Zero instrument. Systolic and diastolic pressures increased with age in men and women. There were 29% of men and 24% of women over the age of 45 with pressures over 160/95 mmHg of whom 24% of men and 33% of women were on treatment for hypertension. Of all subjects 9% of men and 12% of women were on treatment for hypertension. Systolic and diastolic pressures correlated significantly with body mass index, waist/hip ratio and skinfold measurements in men and women. The most significant correlation was with the body mass index. No regional or urban/rural differences were seen in systolic or diastolic pressures. A history of hypertension in the fathers of respondents related to blood pressures in the highest tertile of diastolic blood pressures in males, and systolic pressure of females. The association was not seen between mothers of respondents in respect of diastolic pressure.