Abstract Background Obesity is a risk factor for postmenopausal breast cancer incidence and pre- and postmenopausal breast cancer mortality, which may be explained by several metabolic and hormonal ...factors (sex hormones, insulin resistance, and inflammation) that are biologically related. Differential effects of dietary composition on weight loss and these metabolic factors may occur in insulin-sensitive vs. insulin-resistant obese women. Objective To examine the effect of diet composition on weight loss and metabolic, hormonal and inflammatory factors in overweight/obese women stratified by insulin resistance status in a 1-year weight loss intervention. Methods and Results. Nondiabetic women who were overweight/obese (n = 245) were randomly assigned to a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich (18% energy), higher fat (35% energy), lower carbohydrate (45% energy) diet. All groups lost weight at follow-up (P < 0.0001), with mean (SEM) percent loss of 9.2 (1.1)% in lower fat, 6.5 (0.9)% in lower carbohydrate, and 8.2 (1.0)% in walnut-rich groups at 12 months. The diet x time x insulin resistance status interaction was not statistically significant in the model for overall weight loss, although insulin sensitive women at 12 months lost more weight in the lower fat vs. lower carbohydrate group (7.5 kg vs 4.3 kg, P = 0.06), and in the walnut-rich vs. lower carbohydrate group (8.1 kg vs 4.3 kg, P = 0.04). Sex hormone binding globulin increased within each group except in the lower carbohydrate group at 12 months (P < 0.01). C-reactive protein and interleukin-6 decreased at follow-up in all groups (P < 0.01). Conclusions Findings provide some support for differential effects of diet composition on weight loss depending on insulin resistance status. Prescribing walnuts is associated with weight loss comparable to a standard lower fat diet in a behavioral weight loss intervention. Weight loss itself may be the most critical factor for reducing the chronic inflammation associated with increased breast cancer risk and progression.
Background
Low level of responses (low LRs) to alcohol established using the Self‐Report of the Effects of Alcohol (SRE) questionnaire are genetically influenced phenotypes related to heavy drinking ...and alcohol problems. To date, most studies using SREs focused on scores for the number of drinks needed for effects across the first 5 times of drinking (SRE‐5), and few evaluated scores that also included the prior 3 months and heaviest drinking periods (SRE‐T). This paper evaluates characteristics of SRE‐5 and SRE‐T within and across generations.
Methods
Data were extracted from 407 participants across 2 generations of 107 families in the San Diego Prospective Study (SDPS). Pearson's product–moment correlations for SRE‐5 and SRE‐T were determined across first‐degree relatives both within and across generations and sexes, as well as correlations of each measure to maximum drinking quantities and alcohol problems.
Results
Responding to 4 hypotheses, first the analyses demonstrated significant within‐generation positive correlations for both SRE measures across brother–brother and sister–sister pairs as well as cross‐generation correlations for fathers and sons, although correlations for mothers and daughters were not robust. Second, both SRE‐5 and SRE‐T correlated with maximum drinks and alcohol problems for both sexes and both generations. Third, within parental and offspring generations SRE‐T correlated more robustly than SRE‐5 to maximum drinks and alcohol problems. Fourth, across generations SRE values for sons were more closely related to drinking quantities and problems than for their fathers, but the mother–daughter SRE relationships to adverse alcohol characteristics were not different.
Conclusions
Both the SRE‐5 and SRE‐T offered useful information about propensities toward heavier drinking and alcohol problems in SDPS families. Correlations with adverse alcohol outcomes were greater for the more broad‐based SRE‐T, but both scores appeared to be genetically influenced and continue to operate in a robust manner in both generations of these families.
The Self Report of the Effects of alcohol questionnaire records the number of standard drinks needed for up to 4 effects during 3 timeframes (higher scores means lower responses /drink). Here, SRE values for 407 participants across 2 generations in the San Diego Prospective Study revealed that scores correlated significantly within males and females in each generation (Table 2), within each sex across generations, and correlated with maximum drinks and alcohol problems more robustly in the second generation.
Sleep quality affects memory and executive function in older adults, but little is known about its effects in midlife. If it affects cognition in midlife, it may be a modifiable factor for later-life ...functioning.
We examined the association between sleep quality and cognition in 1220 middle-aged male twins (age 51-60 years) from the Vietnam Era Twin Study of Aging. We interviewed participants with the Pittsburgh Sleep Quality Index and tested them for episodic memory as well as executive functions of inhibitory and interference control, updating in working memory, and set shifting. Interference control was assessed during episodic memory, inhibitory control during working memory, and non-memory conditions and set shifting during working memory and non-memory conditions.
After adjusting for covariates and correcting for multiple comparisons, sleep quality was positively associated with updating in working memory, set shifting in the context of working memory, and better visual-spatial (but not verbal) episodic memory, and at trend level, with interference control in the context of episodic memory.
Sleep quality was associated with visual-spatial recall and possible resistance to proactive/retroactive interference. It was also associated with updating in working memory and with set shifting, but only when working memory demands were relatively high. Thus, effects of sleep quality on midlife cognition appear to be at the intersection of executive function and memory processes. Subtle deficits in these age-susceptible cognitive functions may indicate increased risk for decline in cognitive abilities later in life that might be reduced by improved midlife sleep quality. (JINS, 2018, 24, 67-76).
We recently reported that interleukin-6 (IL-6), an inflammatory marker associated with breast pathology and the development of breast cancer, decreases with diet intervention and weight loss in both ...insulin-sensitive and insulin-resistant obese women. Here, we tested whether an individual’s genotype at an IL6 SNP, rs1800795, which has previously been associated with circulating IL-6 levels, contributes to changes in IL-6 levels or modifies the effect of diet composition on IL-6 in these women. We genotyped rs1800795 in overweight/obese women (N = 242) who were randomly assigned to a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich (18% energy), higher fat (35% energy), lower carbohydrate (45% energy) diet in a 1-year weight loss intervention study of obesity-related biomarkers for breast cancer incidence and mortality. Plasma IL-6 levels were measured at baseline, 6 and 12 months. At baseline, individuals with a CC genotype had significantly lower IL-6 levels than individuals with either a GC or GG genotype (p < 0.03; 2.72 pg/mL vs. 2.04 pg/mL), but this result was not significant when body mass index (BMI) was accounted for; the CC genotype group had lower BMI (p = 0.03; 32.5 kg/m2 vs. 33.6 kg/m2). We did not observe a 2-way interaction of time*rs1800795 genotype or diet*rs1800795 genotype. Our findings provide evidence that rs1800795 is associated with IL-6 levels, but do not support a differential interaction effect of rs1800795 and diet composition or time on changes in circulating IL-6 levels. Diet intervention and weight loss are an important strategy for reducing plasma IL-6, a risk factor of breast cancer in women, regardless of their rs1800795 genotype.
Optimism and resilience promote health and well-being in older adults, and previous reports suggest that these traits are heritable. We examined the association of selected single-nucleotide ...polymorphisms (SNPs) with optimism and resilience in older adults.
Candidate gene association study that was a follow-on at the University of California, San Diego, sites of two NIH-funded multi-site longitudinal investigations: Women's Health Initiative (WHI) and SELenium and vitamin E Cancer prevention Trial (SELECT).
426 women from WHI older than age 50 years, and 509 men older than age 55 years (age 50 years for African American men) from SELECT.
65 candidate gene SNPs that were judged by consensus, based on a literature review, as being related to predisposition to optimism and resilience, and 31 ancestry informative marker SNPs, genotyped from blood-based DNA samples and self-report scales for trait optimism, resilience, and depressive symptoms.
Using a Bonferroni threshold for significant association (p = 0.00089), there were no significant associations for individual SNPs with optimism or resilience in single-locus analyses. Exploratory multi-locus polygenic analyses with p <0.05 showed an association of optimism with SNPs in MAOA, IL10, and FGG genes, and an association of resilience with a SNP in MAOA gene.
Correcting for Type I errors, there were no significant associations of optimism and resilience with specific gene SNPs in single-locus analyses. Positive psychological traits are likely to be genetically complex, with many loci having small effects contributing to phenotypic variation. Our exploratory multi-locus polygenic analyses suggest that larger sample sizes and complementary approaches involving methods such as sequence-based association studies, copy number variation analyses, and pathway-based analyses could be useful for better understanding the genetic basis of these positive psychological traits.
Alzheimer's dementia (AD) begins many years before its clinical symptoms. Metabolic dysfunction represents a core feature of AD and cognitive impairment, but few metabolomic studies have focused on ...cognitive aging in midlife. Using an untargeted metabolomics approach, we identified metabolic predictors of cognitive aging in midlife using fasting plasma sample from 30 middle-aged (mean age 57.2), male-male twin pairs enrolled in the Vietnam Era Twin Study of Aging (VETSA). For all twin pairs, one twin developed incident MCI, whereas his co-twin brother remained to be cognitively normal during an average 5.5-year follow-up. Linear mixed model was used to identify metabolites predictive of MCI conversion or cognitive change over time, adjusting for traditional risk factors. Results from twins were replicated in an independent cohort of middle-aged adults (mean age 59.1) in the Wisconsin Registry for Alzheimer's Prevention (WRAP). Results in twins showed that higher baseline levels of four plasma metabolites, including sphingomyelin (d18:1/20:1 and d18:2/20:0), sphingomyelin (d18:1/22:1, d18:2/22:0, and d16:1/24:1), DAG (18:2/20:4), and hydroxy-CMPF, were significantly associated with a slower decrease in one or more domains of cognitive function. The association of sphingomyelin (d18:1/20:1 and d18:2/20:0) was replicated in WRAP. Our results support that metabolic perturbation occurs many years before cognitive impairment and plasma metabolites may serve as early biomarkers for prediction or monitoring of cognitive aging and AD in midlife.
Background
Optimal macronutrient distribution of weight loss diets has not been established. The distribution of energy from carbohydrate and fat has been observed to promote differential plasma ...lipid responses in previous weight loss studies, and insulin resistance status may interact with diet composition and affect weight loss and lipid responses.
Methods and Results
Overweight and obese women (n=245) were enrolled in a 1‐year behavioral weight loss intervention and randomly assigned to 1 of 3 study groups: a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut‐rich, higher fat (35% energy), lower carbohydrate (45% energy) diet. Blood samples and data available from 213 women at baseline and at 6 months were the focus of this analysis. Triglycerides, total cholesterol, and high‐ and low‐density lipoprotein cholesterol were quantified and compared between and within groups. Triglycerides decreased in all study arms at 6 months (P<0.05). The walnut‐rich diet increased high‐density lipoprotein cholesterol more than either the lower fat or lower carbohydrate diet (P<0.05). The walnut‐rich diet also reduced low‐density lipoprotein cholesterol in insulin‐sensitive women, whereas the lower fat diet reduced both total cholesterol and high‐density lipoprotein cholesterol in insulin‐sensitive women (P<0.05). Insulin sensitivity and C‐reactive protein levels also improved.
Conclusions
Weight loss was similar across the diet groups, although insulin‐sensitive women lost more weight with a lower fat, higher carbohydrate diet versus a higher fat, lower carbohydrate diet. The walnut‐rich, higher fat diet resulted in the most favorable changes in lipid levels.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01424007.
Objective: Positive psychological factors (PPFs) have been reported to have a significant impact on health in the general population. However, little is known about the relationship of these factors ...with mental and physical health in schizophrenia.
Method: One hundred and thirty-five outpatients with schizophrenia and 127 healthy comparison subjects (HCs), aged 26-65 years, were evaluated with scales of resilience, optimism, happiness, and perceived stress. Measures of mental and physical health were also obtained. Regression analyses examined associations of a PPF composite with health variables.
Results: Relative to the HCs, the schizophrenia group had lower levels of PPFs. However, there was considerable heterogeneity, with over one-third of schizophrenia participants having values within the 'normative' range. The PPF composite was positively related to mental and physical health variables and with biomarkers of inflammation and insulin resistance. The relationship between PPFs and mental health was particularly strong for individuals with schizophrenia.
Conclusion: A sizable minority of adults with chronic schizophrenia have levels of resilience, optimism, happiness, and perceived stress similar to HCs. Psychosocial interventions to enhance PPFs should be tested in patients with serious mental illnesses, with the goal of improving their mental health (beyond controlling symptoms of psychosis) and their physical health.
Highlights • We modeled acute psychological stress induced by first-time tandem skydive. • Blood transcriptome, physiological and flow-cytometry measurements were collected. • Early immunomodulation ...was manifested by selective up-regulation of NK-cell genes. • Cell-type correction revealed a molecular signature specific to the adrenal cortex. • Hundreds of co-regulated genes demonstrate gender specific immune response profiles.
Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the ...effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects. Moderators predicting AMPH sensitivity were assessed, including the rs4680 single-nucleotide polymorphism for catechol-O-methyltransferase (COMT). After placebo, patients exhibited PPI deficits with 60 ms prepulse intervals; these deficits were 'rescued' by amphetamine. The magnitude of amphetamine-enhanced PPI was greater in patients than in HS (p<0.032), and was associated with positive symptoms (p<0.007), antipsychotic load (p<0.015), hedonic effects of AMPH (p<0.003), and with the presence of at least one methionine allele in rs4680 (p<0.008). No significant effects of amphetamine on MCCB performance were detected in either group, though pro-attentional effects of amphetamine in patients were associated with greater amphetamine-enhanced TCT learning. Amphetamine acutely 'normalized' PPI in antipsychotic-medicated schizophrenia patients; no concurrent acute neurocognitive changes were detected by the MCCB. Findings suggest that in the context of appropriate antipsychotic medication, a low dose of amphetamine enhances brain processes associated with higher function in schizophrenia patients, without accompanying changes in MCCB performance.
PDF
