Sexual differentiation of neural mechanisms of stress sensitivity during puberty.

Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice (Peromyscus californicus), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.

Comparative Transcriptional Analyses in the Nucleus Accumbens Identifies RGS2 as a Key Mediator of Depression-Related Behavior.

BACKGROUND: Major depressive disorder is one of the most commonly diagnosed mental illnesses worldwide, with a higher prevalence in women than in men. Although currently available pharmacological therapeutics help many individuals, they are not effective for most. Animal models have been important for the discovery of molecular alterations in stress and depression, but difficulties in adapting animal models of depression for females has impeded progress in developing novel therapeutic treatments that may be more efficacious for women. METHODS: Using the California mouse social defeat model, we took a multidisciplinary approach to identify stress-sensitive molecular targets that have translational relevance for women. We determined the impact of stress on transcriptional profiles in male and female California mouse nucleus accumbens (NAc) and compared these results with data from postmortem samples of the NAc from men and women diagnosed with major depressive disorder. RESULTS: Our cross-species computational analyses identified Rgs2 (regulator of G protein signaling 2) as a transcript downregulated by social defeat stress in female California mice and in women with major depressive disorder. RGS2 plays a key role in signal regulation of neuropeptide and neurotransmitter receptors. Viral vector-mediated overexpression of Rgs2 in the NAc restored social approach and sucrose preference in stressed female California mice. CONCLUSIONS: These studies show that Rgs2 acting in the NAc has functional properties that translate to changes in anxiety- and depression-related behavior. Future studies should investigate whether targeting Rgs2 represents a novel target for treatment-resistant depression in women.

Associations of lipoproteins with cardiovascular and infection-related outcomes in patients receiving hemodialysis.

BACKGROUND: In hemodialysis (HD) patients, higher lipid levels are associated with lower mortality. Lipid-lowering therapy does not reduce all-cause mortality or cardiovascular (CV) mortality. Lipoproteins play a role in the innate immune system. Our objective was to determine whether protection from infection might counterbalance adverse CV outcomes associated with lipoproteins. METHODS: We examined associations between serum apolipoprotein (Apo) A1, B, C2, C3, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol and triglyceride levels and infectious mortality or hospitalization, CV mortality or hospitalization, and all-cause mortality in 433 prevalent HD patients. Cox models with time-varying apolipoprotein concentrations collected every 6 months for up to 2 years were used for analyses. RESULTS: Median follow-up time for all-cause mortality was 2.7 years (25th-75th percentile range: 2.2-3.4 years). One hundred seventy-nine (41%) patients had an infection-related event. In multivariable models, higher Apo B and LDL were associated with lower risks of infection-related outcomes (hazard ratio Apo B 0.92 [95% confidence interval 0.86-0.99 per 10 mg/dL, P = .03]; hazard ratio LDL 0.93 [95% confidence interval 0.87-1.00 per 10 mg/dL, P = .05]). Sixty-three (15%) participants had a CV-related event. No significant associations were observed between lipoproteins and CV outcomes. Eighty-seven (20%) participants died. Higher Apo A1, Apo B, and Apo C3 were associated with lower risks of all-cause mortality. There was no interaction between the use of lipid-lowering medication and any of the outcomes. CONCLUSION: Associations of lipoproteins with lower risk of serious infection accompanied by no significant association with CV events may help to explain the paradoxical association between lipids and survival and lack of benefit of lipid-lowering therapies in HD.

Validating Appetite Assessment Tools Among Patients Receiving Hemodialysis.

OBJECTIVE: To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). DESIGN: Cross-sectional. SUBJECTS: Two hundred twenty-one patients receiving HD enrolled in seven dialysis facilities in Northern California. INTERVENTION: We assessed 5 appetite assessment tools (self-assessment of appetite, subjective assessment of appetite, visual analog scale [VAS], Functional Assessment of Anorexia/Cachexia Therapy [FAACT] score, and the Anorexia Questionnaire [AQ]). MAIN OUTCOME MEASURES: Reported food intake, normalized protein catabolic rate, and change in body weight were used as criterion measures, and we assessed associations among the appetite tools and biomarkers associated with nutrition and inflammation. Patients were asked to report their appetite and the percentage of food eaten (from 0% to 100%) during the last meal compared to usual intake. RESULTS: Fifty-eight (26%) patients reported food intake ≤ 50% (defined as poor appetite). The prevalence of anorexia was 12% by self-assessment of appetite, 6% by subjective assessment of appetite, 24% by VAS, 17% by FAACT score, and 12% by AQ. All the tools were significantly associated with food intake ≤ 50% (P < .001), except self-assessment of appetite. The FAACT score and the VAS had the strongest association with food intake ≤ 50% (C-statistic 0.80 and 0.76). Patients with food intake ≤ 50% reported weight loss more frequently than patients without low intake (36% vs 22%) and weight gain less frequently (19% vs 35%; P = .03). Normalized protein catabolic rate was lower among anorexic patients based on the VAS (1.1 ± 0.3 vs 1.2 ± 0.3, P = .03). Ln interleukin-6 correlated inversely with food intake (P = .03), but neither interleukin-6 nor C-reactive protein correlated with any of the appetite tools. Furthermore, only the self-assessment of appetite was significantly associated with serum albumin (P = .02), prealbumin (P = .02) and adiponectin concentrations (P = .03). CONCLUSIONS: Alternative appetite assessment tools yielded widely different estimates of the prevalence of anorexia in HD. When considering self-reported food intake as the criterion standard for anorexia, the FAACT score and VAS discriminated patients reasonably well.

Associations of Trimethylamine N-Oxide With Nutritional and Inflammatory Biomarkers and Cardiovascular Outcomes in Patients New to Dialysis.

OBJECTIVES: Trimethylamine N-oxide (TMAO) is a product of metabolism of phosphatidylcholine (lecithin) and carnitine by the intestinal microbiome. Elevated serum concentrations of TMAO have been linked to adverse cardiovascular outcomes in the general population. We examined correlates of serum TMAO and the relations among serum TMAO concentrations, all-cause mortality, and cardiovascular mortality and hospitalizations in a nationally derived cohort of patients new to hemodialysis (HD). METHODS: We quantified serum TMAO by liquid chromatography and online tandem mass spectrometry and assessed nutritional and cardiovascular risk factors in 235 patients receiving HD and measured TMAO in pooled serum from healthy controls. We analyzed time to death and time to cardiovascular death or hospitalization using Cox proportional hazards regression. RESULTS: Serum TMAO concentrations of patients undergoing HD (median, 43 µM/L; 25th-75th percentile, 28-67 µM/L) were elevated compared with those with normal or near-normal kidney function (1.41 ± 0.49 µM/L). TMAO was directly correlated with serum albumin (Spearman rank correlation, 0.24; 95% CI, 0.12-0.35; P <.001), prealbumin (Spearman rank correlation, 0.19; 95% CI, 0.07-0.31; P = .003), and creatinine (Spearman rank correlation, 0.21; 95% CI, 0.08-0.33; P = .002) and inversely correlated with log C-reactive protein (Spearman rank correlation, -0.18; 95% CI, -0.30 to -0.06; P = .005). Higher serum concentrations of TMAO were not significantly associated with time to death (Spearman rank correlation, 0.84; CI, 0.65-1.09; P = .19) or time to cardiovascular hospitalization or cardiovascular death (Spearman rank correlation, 0.88; CI, 0.57-1.35; P = .55). CONCLUSIONS: Serum TMAO concentrations were markedly elevated and correlated directly with biochemical markers of nutritional status and inversely with markers of inflammation in patients receiving HD. There was no significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations. In patients receiving dialysis-in contrast with the general population-adverse vascular effects of TMAO may be counterbalanced by associations with nutritional or inflammatory status.

Prealbumin is associated with visceral fat mass in patients receiving hemodialysis.

OBJECTIVE: Albumin and prealbumin are associated with nutritional status and inflammatory status. Each has a residual effect on mortality outcomes when included in regression models that include the other. Prealbumin is increased in the obese mouse model as a consequence of stabilization of prealbumin by retinol binding protein 4 (RBP4) secreted by adipocytes. We carried out this study to establish the contribution of adiposity to prealbumin levels in prevalent patients receiving dialysis and the relationship of prealbumin to RBP4. DESIGN AND METHODS: We determined whether prealbumin was associated with adiposity in patients receiving hemodialysis (HD), controlling for the effects of inflammation and nutrition. We evaluated body composition in 48 prevalent patients receiving HD by magnetic resonance imaging (MRI), measuring total skeletal muscle mass (SM), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and serum albumin, prealbumin, RBP4, and interleukin-6 (IL-6) levels. We used normalized protein catabolic rate (nPCR) to report nutrition and separately analyzed the determinants of albumin and then of prealbumin by multiple stepwise regression. RESULTS: Thirty-two patients were women, 16 patients were diabetic, and median age and body mass index were 54.5 and 27.3 kg/m(2), respectively. Median total adipose tissue (TAT) was 24.3 kg and VAT was 3.25 kg. Prealbumin was positively associated with VAT, nPCR, and RBP4 and was negatively associated with IL-6; r(2) for the model was 0.64. By contrast, albumin was positively associated with nPCR and negatively associated with IL-6 but not with any measure of adiposity (r(2) for the model = 0.2). CONCLUSIONS: Prealbumin, like albumin, is associated with markers of nutrition (nPCR) and inflammation, but unlike albumin, prealbumin levels are positively associated with visceral adiposity.

Relationship between adiposity and cardiovascular risk factors in prevalent hemodialysis patients.

OBJECTIVE: Increased body mass index (BMI) is associated with reduced all-cause and cardiovascular (CV) mortality in hemodialysis (HD) patients, whereas CV risk increases with BMI in the general population. In the general population, obesity is associated with inflammation, decreased high-density lipoprotein (HDL) cholesterol, increased low-density lipoprotein (LDL) cholesterol, and triglycerides (TGs), all risk factors for CV disease. Low-density lipoprotein cholesterol does not predict CV risk in HD, whereas increased C-reactive protein and interleukin-6 (IL-6), low HDL and apolipoprotein (apo) AI, and increased fasting TGs do predict risk. Renal failure is associated with dyslipidemia and inflammation in normal-weight patients. We hypothesized that the effects of obesity may be obscured by renal failure in HD. METHODS: We explored the relationship between adipose tissue pools and distribution, i.e., subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (measured by magnetic resonance imaging) and measures of inflammation (C-reactive protein, IL-6, ceruloplasmin, and alpha1 acid glycoprotein), HDL and LDL cholesterol, total TGs, apo AI, apo B, apo CII (an activator of lipoprotein lipase), apo CIII (an inhibitor of lipoprotein lipase), and the adipokines, leptin and adiponectin, in 48 patients with prevalent HD. RESULTS AND CONCLUSIONS: Total TG concentrations were positively correlated with VAT controlled for age, sex, and weight. Both apo CII and apo CIII were correlated only with VAT. Adiponectin was inversely correlated with VAT, and leptin was positively associated with SAT. C-reactive protein and alpha1 acid glycoprotein were weakly associated with SAT, whereas ceruloplasmin was strongly associated with VAT according to multiple regression analysis. In contrast, apo B, LDL, apo AI, HDL, and IL-6 were not correlated with any measure of body composition, potentially mitigating the effects of obesity in HD.