Neural correlates of peer evaluation in irritable adolescents: Linking anticipation to receipt of social feedback.

Elevated irritability during adolescence predicts mental health issues in adulthood. Social interactions commonly elicit symptoms of irritability. Prior research has traditionally examined neural activity during the anticipation of, and immediate reaction to, social feedback separately in irritable adolescents. However, studies suggest that irritable adolescents demonstrate altered brain activation when anticipating feedback, and these alterations may have downstream effects on the neural activity when actually presented with feedback. Thus, the goal of this study was to characterize the influence of irritability on the relationship between brain function during anticipation and receipt of social feedback. We leveraged the Virtual School task to mimic social interactions using dynamic stimuli. Parallel region of interest (ROI) analyses tested effects of anticipatory bilateral amygdala (or dorsal anterior cingulate cortex; dACC) activation on the dACC (or bilateral amygdala) activation during receipt of peer feedback. Parallel exploratory whole-brain analyses were conducted to identify the effects of anticipatory bilateral amygdala or dACC activation on other regions during receipt of peer feedback. In ROI analyses, more vs. less irritable adolescents showed distinct relationships between anticipatory bilateral amygdala activation and dACC activation when receiving predictably mean feedback. Across both whole-brain analyses, anticipatory bilateral amygdala and dACC activation were separately associated with activation in socioemotional regions of the brain during subsequent feedback. These relationships were modulated by irritability, and the valence and predictability of the feedback. This suggests that irritable adolescents may engage in altered emotion processing and regulation strategies, depending on the valence and predictability of social feedback.

Is self always prioritised? Attenuating the ownership self-reference effect in memory.

The current study demonstrates the abolishment of the Ownership Self Reference Effect (OSRE) when elaborate details of a distant other-referent are provided. In a 2 (High versus Low information) × 2 (Self versus Other) experimental design, we tested the capacity for the SRE to be modulated with social saliency. Using a well-established ownership paradigm (Collard et al., 2020; Cunningham et al., 2008; Sparks et al., 2016), when the other was made socially salient (i.e. details and characteristics about the other were provided to the participant prior to encoding), no SRE emerged, such that self-owned and other-owned items were recalled with comparable accuracy. In contrast, when the other was not salient (i.e., no details about them were provided), participants accurately recalled a higher proportion of self-owned items, demonstrating a typical SRE in source memory. The degree of self- or other- referencing was not related to measured variables of closeness, similarity or shared traits with the other. Although the SRE is an established and robust effect, the findings of the current study illustrate critical circumstances in which the self is no longer prioritised above the other. In line with our predictions, we suggest that the self has automatic attributed social salience (e.g. through ownership) and that enhancing social salience by elaborating details of the other, prioritisation can expand to encapsulate an other beyond the self and influence incidental memory.

Association between coronary artery vitamin D receptor expression and select systemic risks factors for coronary artery atherosclerosis.

OBJECTIVE: The aim of this study is to analyze the association between coronary artery vitamin D receptor (VDR) expression and systemic coronary artery atherosclerosis (CAA) risk factors. METHODS: Female cynomolgus monkeys (n = 39) consumed atherogenic diets containing the women's equivalent of 1000 IU/day of vitamin D3. After 32 months consuming the diets, each monkey underwent surgical menopause. After 32 postmenopausal months, CAA and VDR expression were quantified in the left anterior descending coronary artery. Plasma 25OHD3, lipid profiles and serum monocyte chemotactic protein-1 (MCP-1) were measured. RESULTS: In postmenopausal monkeys receiving atherogenic diets, serum MCP-1 was significantly elevated compared with baseline (482.2 ± 174.2 pg/ml vs. 349.1 ± 163.2 pg/ml, respectively; p < 0.001; d = 0.79) and at the start of menopause (363.4 ± 117.2 pg/ml; p < 0.001; d = 0.80). Coronary VDR expression was inversely correlated with serum MCP-1 (p = 0.042). Additionally, the change of postmenopausal MCP-1 (from baseline to necropsy) was significantly reduced in the group with higher, compared to below the median, VDR expression (p = 0.038). The combination of plasma 25OHD3 and total plasma cholesterol/high-density lipoprotein cholesterol was subsequently broken into low-risk, moderate-risk and high-risk groups; as the risk increased, the VDR quantity decreased (p = 0.04). CAA was not associated with various atherogenic diets. CONCLUSION: Coronary artery VDR expression was inversely correlated with markers of CAA risk and inflammation, including MCP-1, suggesting that systemic and perhaps local inflammation in the artery may be associated with reduced arterial VDR expression.

Methyl mercury: loaves versus fishes.

Large numbers of individuals suffered severe neurological effects from poisoning with methyl mercury from the consumption of fish contaminated by industrial discharge in Minamata in the 1950s and 1960s and from bread made from fungicide-treated wheat in the early 1970s in Iraq. In both episodes, infants exposed in utero showed developmental delays. Data from Iraq permitted the estimation of dose-response relationships and provided evidence of greater sensitivity of the foetal brain compared to adult. Studies in a number of communities regularly consuming fish have sought to determine whether and at what level of prenatal exposure neurodevelopment defects may be detected, but the findings do not present a consistent picture. Benchmark analysis using data from Iraq and the three largest studies (New Zealand, Faroes, and Seychelles) suggest an overlap in estimated dose corresponding to a 10% increase in prevalence of adverse effects above background level. However, the Seychelles study, examining children up to 9 years of age, has not found a consistent pattern of adverse developmental effects; a possible explanation may be the presence of micronutrients in the ocean fish diet that enhance brain development and/or counter the toxic effects of methyl mercury.

Effects of equol on gene expression in female cynomolgus monkey iliac arteries.

BACKGROUND AND AIMS: To examine effects of equol, the soy phytoestrogen metabolite, on gene expression in the monkey iliac artery. METHODS AND RESULTS: A high fat/high cholesterol diet was fed to eight ovariectomized cynomolgus monkeys for 6.5 years. After biopsy of the left iliac artery, the animals were randomized to two treatment groups for 8 months; the treatment groups were equol (23.7 mg/100 g diet, n = 4) and vehicle (n = 4). The right iliac artery was removed at necropsy. Gene expression in the iliac arteries in response to equol was determined by DNA microarray. Comparison of atherosclerotic lesions and plasma lipids at pre-versus post-equol treatment time points and in vehicle versus equol treatment groups did not identify any significant differences. Despite the lack of effect of equol on these parameters, 59 genes were down-regulated and 279 were up-regulated in response to equol. Comparison of these data to previous work identified 10 genes regulated in opposite directions by equol compared to presence of atherosclerosis plaque (Menopause 2011; 18:1087-1095) and 55 genes differentially expressed in the same direction in response to both equol and estradiol (Eyster et al., Menopause 2014;21:143-152.). CONCLUSIONS: Similar responses of genes to both equol and estradiol may reflect the extent to which equol serves as a natural selective estrogen receptor modulator in the arteries. Opposite responses of 10 genes to equol versus the presence of atherosclerosis implicates those genes in the potential protective effects of equol in arteries.

Impairment of ovarian function and associated health-related abnormalities are attributable to low social status in premenopausal monkeys and not mitigated by a high-isoflavone soy diet.

BACKGROUND: Psychological stress may impair premenopausal ovarian function and contribute to risk for chronic disease. Soy isoflavones may also influence ovarian function and affect health. Here, we report the effects of a psychological stressor (subordinate social status) and dietary soy on reproductive function and related health indices in female monkeys. We hypothesized that reproductive compromise and adverse health outcomes would be induced in subordinate when compared with dominant monkeys and be mitigated by exposure to soy. METHODS: Subjects were 95 adult cynomolgus monkeys (Macaca fascicularis) housed in social groups of five or six. Animals consumed a soy-free, animal protein-based diet during an 8-month Baseline phase and then, during a 32-month Treatment phase, consumed either the baseline diet or an identical diet that substituted high-isoflavone soy protein for animal protein. RESULTS: Across more than 1200 menstrual cycles, subordinate monkeys consistently exhibited ovarian impairment [increased cycle length (P < 0.02) and variability (P < 0.02) and reduced levels of progesterone (P < 0.04) and estradiol (P < 0.04)]. Subordinate status was confirmed behaviorally and was associated with elevated cortisol (P < 0.04) and relative osteopenia (P < 0.05). Consumption of the soy diet had no significant effects. CONCLUSIONS: (i) Psychological stress adversely affects ovarian function and related health indices in a well-accepted animal model of women's health; (ii) Similar effects may extend to women experiencing reproductive impairment of psychogenic origin; (iii) soy protein and isoflavones neither exacerbate nor mitigate the effects of an adverse psychosocial environment; and (iv) this study was limited by an inability to investigate the genetic and developmental determinants of social status.

Impact of soy supplementation on sex steroids and vascular inflammation markers in postmenopausal women using tibolone: role of equol production capability.

OBJECTIVES: Tibolone is often taken concurrently with soy. Tibolone, soy and equol-producing capacity each affect vascular health, whereas their concomitant effects are unknown. We studied the effects of soy on sex steroids and vascular inflammation markers in long-term tibolone users. METHODS: Postmenopausal women (n = 110) on tibolone were screened with a soy challenge to find 20 equol producers and 20 non-producers. All women were treated for 8 weeks in a cross-over trial with soy (52 g of soy protein containing 112 mg of isoflavones) or placebo. Serum estrone, 17beta-estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet-selectin (P-selectin) were assessed. RESULTS: Soy decreased (7.1%) the estrone level, significantly (12.5%) only in equol producers (from 80.2 +/- 10.8 to 70.3 +/- 7.0 pmol/l; p = 0.04). Testosterone was reduced (15.5%; from 586 +/- 62.6 to 495 +/- 50.1 pmol/l, p = 0.02) during soy treatment, and more markedly in equol producers than non-producers (22.1% vs. 10.0%). No changes appeared in SHBG, CRP or ICAM-1, but VCAM-1 increased (9.2%) and P-selectin decreased (10.3%) during soy treatment. CONCLUSIONS: Soy modified the concentrations of estrone, testosterone and some endothelial markers. Equol production enforced these effects. Soy supplementation may be clinically significant in tibolone users.

Habitual fish consumption does not prevent a decrease in LCPUFA status in pregnant women (the Seychelles Child Development Nutrition Study).

Information on the status of long-chain polyunsaturated fatty acids (LCPUFAs) in pregnancy and breast milk in very high fish-eating populations is limited. The aim of this study was to examine dietary intake and changes in fatty acid status in a population of pregnant women in the Republic of Seychelles. Serum docosahexaenoic acid (DHA) decreased significantly between 28-week gestation and delivery (n=196). DHA status did not correlate significantly with length of gestation and was not associated with self-reported fish intake, which was high at 527 g/week. In breast milk, the ratio of DHA to arachidonic acid (AA) was consistent with those observed in other high fish-eating populations. Overall the data suggest that high exposure to LCPUFAs from habitual fish consumption does not prevent the documented decrease in LCPUFA status in pregnancy that occurs as a result of foetal accretion in the third trimester of pregnancy.

Individual differences in equol production capability modulate blood pressure in tibolone-treated postmenopausal women: lack of effect of soy supplementation.

OBJECTIVES: Equol, a gut bacterial metabolite of the isoflavone daidzein, has been associated with beneficial health effects. Recent studies indicate that women with intestinal capacity to convert daidzein to equol also have the capacity to alter steroid metabolism and bioavailability of estrogens. METHODS: We evaluated whether individual equol production capability, while not consuming soy supplement, was associated with lower blood pressure in postmenopausal women using tibolone. In addition, in a randomized, placebo-controlled, cross-over trial we assessed the effect of soy supplementation on blood pressure in both equol-producing (n = 20) and non-equol-producing (n = 20) women using tibolone. Blood pressure was recorded with a validated oscillometric technique. RESULTS: The circulating equol levels rose 20-fold in the equol producers and 1.9-fold in the non-equol producers. At baseline, systolic blood pressure (129.9 +/- 2.6 vs. 138.5 +/- 3.1 mmHg, p = 0.02), diastolic blood pressure (72.2 +/- 1.5 vs. 76.6 +/- 1.3 mmHg, p = 0.01) and mean arterial blood pressure (93.5 +/- 1.7 vs. 99.9 +/- 1.8 mmHg, p = 0.007) were lower in equol producers compared to non-equol producers. Soy supplementation had no effect on blood pressure in either group, whereas the baseline differences persisted. CONCLUSIONS: Postmenopausal women using tibolone characterized as equol producers had lower blood pressure compared to non-equol producers. Soy supplementation for 2 months had no blood pressure-lowering effect.

The biological monitoring of prenatal exposure to methylmercury.

Several biological media have been used as indicators of the fetal body burden of methylmercury and the levels in the primary target tissue, the developing brain. These media include maternal hair and blood. The relative merits of these media will be considered both with regard to current knowledge of the physiology of mercury disposition in the body and also the practicality of field application with respect to sample, collection, transport, storage and processing.

Multisystem evaluations of the long-term effects of tibolone on postmenopausal monkeys.

This long-term study (2 years) was designed to compare the effects of tibolone (LoTib at 0.05 mg/kg and HiTib at 0.2 mg/kg) with those of conjugated equine oestrogens (CEE) alone (0.042 mg/kg) and CEE continuously combined with medroxyprogesterone acetate (MPA) (0.167 mg/kg) on coronary artery atherosclerosis, bone, mammary gland and uterus in ovariectomised cynomolgus monkeys fed a moderately atherogenic diet. Despite reductions in plasma concentrations of high density lipoprotein cholesterol in tibolone-treated monkeys, there was no exacerbation of coronary artery atherosclerosis. Tibolone was equivalent to, or slightly better than, CEE and CEE + MPA in protecting against postmenopausal bone loss and loss of bone strength. Tibolone also resulted in less stimulation of breast and endometrial tissue compared with CEE and CEE + MPA. In conclusion, the results suggest that tibolone is a cardiovascular-safe treatment that is effective for the prevention of osteoporosis and that may have advantages over CEE or CEE + MPA with regard to endometrial and breast safety.

Effects of long-term hormone replacement and of tibolone on choline acetyltransferase and acetylcholinesterase activities in the brains of ovariectomized, cynomologus monkeys.

We examined long-term effects of low and high doses of tibolone, conjugated equine estrogens, and conjugated equine estrogens plus medroxyprogesterone acetate on choline acetyltransferase and acetylcholinesterase activities within different regions of the brain in cynomologus monkeys. All treatments were administered for 2 years. None of the treatments produced significant increases in either choline acetyltransferase or acetylcholinesterase in any of eight brain regions analyzed. In contrast, treatment with conjugated equine estrogens plus medroxyprogesterone acetate, but not conjugated equine estrogens alone, produced significant reductions in both choline acetyltransferase and acetylcholinesterase in the medial septum/diagonal band of Broca compared with untreated controls. Treatment with tibolone also resulted in significant reductions in both choline acetyltransferase and acetylcholinesterase in the medial septum/diagonal band of Broca, and this effect was dose-related. These findings are the first to report the effects of long-term therapies used by postmenopausal women on cholinergic measures in the primate brain. The findings are consistent with recent reports in rats, and suggest that any positive effects of long-term estrogen or hormone replacement therapy on cognitive processes are probably not due to significant effects on choline acetyltransferase or acetylcholinesterase activities.

Premenopausal social status and hormone exposure predict postmenopausal atherosclerosis in female monkeys.

OBJECTIVE: To determine whether premenopausal social subordination in female monkeys predicts postmenopausal atherosclerosis, and whether any such effect is altered by chronic exposure to contraceptive steroids or postmenopausal hormone replacement. METHODS: One hundred seventy-seven (177) premenopausal cynomolgus monkeys (Macaca fascicularis) housed in social groups of five or six were fed an atherogenic diet that, for half of the animals, also contained an oral contraceptive (OC). Individuals were judged socially dominant or subordinate based on behavioral observations. After 26 months animals were oophorectomized, biopsied for iliac atherosclerosis, and for the next 36 months were fed one of three atherogenic diets containing soy protein: 1) phytoestrogen-free; 2) phytoestrogens intact; and 3) phytoestrogen-free plus conjugated equine estrogens. Plasma lipids and menstrual cyclicity were also assessed. Finally, all animals were necropsied and the extent of atherosclerosis measured in the coronary and iliac arteries. RESULTS: The interaction of premenopausal social status and OC exposure predicted postmenopausal coronary artery atherosclerosis (P =.02). Subordinate animals not receiving OCs developed twice the coronary atherosclerosis of similarly untreated dominants (P <.01), an outcome mitigated by premenopausal OC exposure (P <.01). These effects occurred across postmenopausal treatment groups and independent of variation in plasma lipids. The same associations were observed in the iliac arteries, and, to a similar extent, both pre- and post-menopausally. Hormone data suggest that untreated premenopausal subordinates may have been estrogen deficient. CONCLUSION: Premenopausal social subordination exacerbates postmenopausal atherosclerosis, an effect possibly mediated by estrogen deficiency and shown here to be prevented by premenopausal OC exposure. These results occur irrespective of postmenopausal treatment.

A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys.

This study compared the effects of tibolone, a tissue-specific compound for the treatment of climacteric symptoms and the prevention of osteoporosis, with those of conjugated equine estrogens (CEE) with and without medroxyprogesterone (MPA) on bone mineral density and coronary atherosclerosis (CAA) of postmenopausal cynomolgus monkeys. The groups were tibolone [two doses were used, 0.05 mg/kg (LoTib) and 0.2 mg/kg (HiTib)], CEE (0.042 mg/kg), CEE (0.042 mg/kg) plus MPA (0.167 mg/kg given continuously), and a control group given no treatment for 2 yr. Compared with no treatment, bone mineral density was higher by 6.3% (P = 0.0004) in the LoTib group and by 9.5% (P = 0.02) in the HiTib group compared with 4.3% (P = 0.12) for CEE and 4.5% (P = 0.10) for CEE+MPA. Plasma high density lipoprotein cholesterol was reduced by 49% with HiTib and by 34% with LoTib. There were no differences in CAA between control and HiTib (P = 0.60) or LoTib (P = 0.58). CEE and CEE+MPA both reduced CAA by about 62% (CEE vs. control, P = 0.02; CEE+MPA vs. control, P = 0.01). Despite adverse effects of tibolone on plasma lipoprotein concentrations, there was no increase in CAA, suggesting that tibolone is a cardiovascular-safe treatment for climacteric symptoms and the prevention of osteoporosis.

Genetic aspects of nutrition and toxicology: report of a workshop.

The health and resilience of humans and animals is, in large part, determined by the quality and quantity of the diet. This, in turn, may influence an individual's capability to deal with stress including toxic insult. In addition, there may be specific components of the diet that modulate the toxicity of specific toxicants whether the latter are ingested as food or absorbed via other routes. Many examples attest to the importance of interactions between dietary components and toxicants after absorption in the body. Such interactions occur at every level of biological organization from the molecular to the whole organism. Some may be synergistic, others antagonistic. Some may involve direct chemical reaction between the nutrient molecule and the toxicant, others may occur by indirect action at the cellular or organ levels. All examples point to the importance of considering diet when measuring the response to toxic agents whether in animals or humans. In order to foster interaction between the sciences of nutrition and toxicology, The Heinz Institute of Nutritional Sciences as sponsoring a series of workshops. The first of these was held in June, 1999 at the University of Ulster to address evolutionary aspects of nutrition--toxicology (for report see Eur. J. Nutr, 39, 49-52, 2000). In June, 2000, a second workshop was held at the University of Toronto to address genetic aspects, and this is a brief summary of the proceedings. We are beginning to understand the molecular basis of the regulation of gene expression by dietary factors and how genetic changes can affect response to toxicants. Recent advances in technology and a detailed understanding of disease etiology has led to the ability to study molecular determinants of disease risk. The workshop provided a forum for nutritionists, toxicologists, molecular biologists, epidemiologists and others to discuss common interests and to merge their efforts towards an integrated approach to nutrition--toxicology via genetics and genomics. The first session dealt with the mechanism by which nutrients such as fatty acids (Clarke), amino acids (Jefferson) and metal ions (Cousins) can regulate gene expression. In the second session, there were presentations on the effects of nutritional factors on genes of toxicological significance such as phase I and phase II enzymes of drug metabolism (Guengerich, Goodfellow and Grant) as well as on oxidative DNA damage and its repair (Collins, Weindruch). Session three dealt with gene-nutrient interactions in the development of chronic diseases such as diabetes (Hegele, Berdanier) and cancer (Kim, Ambrosone et al.). New developments such as DNA microarrays (McGlynn) and the use of transgenic and knockout models (Sehayek) were presented in the final session.

A comparison of oral micronized estradiol with soy phytoestrogen effects on tail skin temperatures of ovariectomized rats.

OBJECTIVE: Whether phytoestrogen-containing soy supplements have beneficial effects on hot flashes of postmenopausal women and how those effects, if any, compare to estrogen replacement therapy has been uncertain. It is possible that the uncertainty is due to the low doses of soy isoflavones (30-60 mg per day) used in the studies. We used ovariectomized retired breeder rats and a higher dose of soy phytoestrogens to approach these uncertainties experimentally. DESIGN: The treatment groups were as follows: (1) Control group fed a casein/lactalbumin-based diet; (2) Soy(-) group fed alcohol-washed soy protein isolate with the phytoestrogens extracted; (3) Soy(+) group fed phytoestrogen-containing soy protein (equivalent to a woman's dose of 144 mg isoflavones per day)--a dose two to three times higher than that in most studies with women; and (4) E2 group fed oral micronized estradiol (E2) at a dose equivalent to a woman's dose of 1 mg per day. A temperature-transponder was taped to the surface of the tail to measure temperature. Tail skin temperature was significantly increased within a week after ovariectomy. The animals were pair-fed during the last 21 days of treatment for daily temperature measurement. RESULTS: Soy(-) had no effect on skin temperature. E2 had a large effect on skin temperature (about 1.4 degrees C reduction from Control). Soy(+) was intermediate between the E2 treatment and no treatment (about 0.8 degrees C reduction from Control). CONCLUSIONS: Soy phytoestrogens have a modest effect on average skin temperatures, being about half that of E2, even at high doses in the rat model.

SERMs and cardiovascular disease in women. How do these agents affect risk?

The beneficial effects of SERMs, specifically tamoxifen in the treatment and prevention of breast cancer and raloxifene in the prevention of osteoporosis, are well established. In addition, numerous groups of investigators have reported that these agents have a positive impact on cardiovascular health, possibly as a result of their cholesterol-lowering and anticoagulation actions. Although studies clearly showed that tamoxifen therapy improved the levels of some types of lipids, the changes did not appear to translate into a decreased risk of cardiovascular disease. However, the risk of thromboembolic events (as well as endometrial cancer) was increased with the use of tamoxifen, which is often prescribed for breast cancer prevention in healthy women. Similarly, raloxifene treatment had modest positive effects on cardiovascular risk factors but was associated with an increased risk of thromboembolism. When viewed as a whole, study results dictate that the benefits of SERM use for the prevention of cardiovascular disease be carefully weighed against the potential risks.

Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens.

Experimental evidence was sought concerning whether soy phytoestrogens (SPEs) inhibit postmenopausal atherosclerosis progression/extent and, if so, their effectiveness relative to traditional estrogen replacement therapy. Premenopausal cynomolgus monkeys were fed a moderately atherogenic diet (26 months) to induce atherosclerosis. After ovariectomy, the moderately atherogenic diet was continued, and they were treated (36 months) with a control diet (soy protein depleted of SPEs), a diet containing SPEs in soy protein isolate, or a diet containing SPE-depleted soy protein with conjugated equine estrogens (CEE; Premarin) added. SPE effects on plasma lipids were better than those of CEE (higher high density lipoprotein cholesterol and no increase in triglyceride). Relative to the control group, CEE treatment inhibited (P = 0.0001), and SPE treatment partially inhibited (P = 0.10) the progression of atherosclerosis (common iliac artery atherosclerosis before and after treatment). CEE-treated monkeys had much less coronary artery atherosclerosis than the controls (P = 0.0002), whereas SPE-treated monkeys were intermediate in lesion extent between the controls and the CEE-treated animals (P = 0.02). Both CEE and SPE significantly reduced the extent of common carotid and internal carotid artery atherosclerosis, and the two treatment groups were not significantly different.