Effects of comorbid alcohol use disorder on bipolar disorder: Focusing on neurocognitive function and inflammatory markers.

BACKGROUND: Alcohol use disorder (AUD) is a highly prevalent comorbid disorder in patients with bipolar disorder (BD). Both BD and AUD were found to be associated with inflammation and cognitive deficits, but few study has been done on BD comorbid with AUD (BD+AUD). We aimed to investigate the impacts of comorbid AUD and BD on cognitive function, inflammatory and neurotrophic markers. METHOD: We recruited 641 BD patients, 150 patients with BD+AUD, and 185 healthy controls (HC). Neuropsychological tests [Wisconsin card sorting test (WCST), continuous performance test (CPT), and Wechsler memory scale - third edition (WMS-III)] and cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1), and brain-derived neurotrophic factor (BDNF)] were assessed. RESULTS: BD+AUD patients had worse cognitive performance than those without AUD. There was a significant difference in the plasma levels of TNF-α, IL-8, and BDNF (P < 0.001, <0.001, and 0.01, respectively) between the patients and the HC groups. Post hoc analysis showed that BD+AUD patients had higher levels of TNF-α and IL-8 than BD-only patients (P < 0.001). Additionally, plasma IL-8 levels were negatively associated with number of completed categories in WCST (P = 0.02), and TNF-α levels were negatively associated with visual immediate index in WMS-III (P = 0.05). CONCLUSION: Our results suggest that comorbid AUD and BD might worsen cognitive impairments and inflammatory processes. Further longitudinal studies on BD+AUD may be needed.

Single-nucleotide polymorphisms in genes related to oxidative stress and ion channels in chickens are associated with semen quality and hormonal responses to thermal stress.

Heat stress causes economic loss of livestock industry in tropical areas. Exploring genetic markers for selection of thermotolerance will benefit chicken production. Oxidative stress and fluid-salt balance are tightly associated with thermotolerance and productivity in domestic animals. The study aimed to identify single-nucleotide polymorphisms (SNPs) in genes related to oxidative stress and ion-channel regulation and their associations with semen quality and hormonal responses. In total, 28 SNPs within 11 candidate genes were identified to associate with hormonal changes and semen quality in both broiler- and layer-type Taiwan country chickens (TCCs) after exposure to acute heat stress at 38 °C for 4 h. Acute heat stress significantly affected plasma levels of triiodothyronine and corticosterone and reduced sperm motility, viability, and concentrations in both strains at Day 1 after exposure. In the B-strain TCCs, five SNPs within NDUFA8 and DAB2IP had significant effects on plasma adrenaline and corticosterone levels, and six SNPs within TRPC1, SLC9A9, and TRPC7 markedly affected plasma corticosterone and triiodothyronine levels. In the L2 strain, 15 SNPs within PSMA2, TPK1, MTF1, and CUL1 exerted effects on plasma corticosterone and triiodothyronine levels. Five SNPs within CUL3, TRPC1, and SLC9A9 in the B strain and two SNPs within MTF1 in the L2 strain were associated with sperm concentrations at Day 1 after exposure to heat stress. In conclusion, acute heat stress impaired semen quality and altered plasma corticosterone and triiodothyronine levels in TCCs. Some SNPs involved in oxidative stress and ion-channel regulation were identified to associate with the hormonal and semen alterations. These SNPs in conjunction with differential hormonal responses and semen quality serve as genetic markers for thermotolerance selection in sire lines of chickens.

Effects of acute heat stress on protein expression and histone modification in the adrenal gland of male layer-type country chickens.

The adrenal gland responds to heat stress by epinephrine and glucocorticoid release to alleviate the adverse effects. This study investigated the effect of acute heat stress on the protein profile and histone modification in the adrenal gland of layer-type country chickens. A total of 192 roosters were subject to acute heat stress and thereafter classified into a resistant or susceptible group according to body temperature change. The iTRAQ analysis identified 80 differentially expressed proteins, in which the resistant group had a higher level of somatostatin and hydroxy-δ-5-steroid dehydrogenase but a lower parathymosin expression in accordance with the change of serum glucocorticoid levels. Histone modification analysis identified 115 histone markers. The susceptible group had a higher level of tri-methylation of histone H3 lysine 27 (H3K27me3) and showed a positive crosstalk with K36me and K37me in the H3 tails. The differential changes of body temperature projected in physiological regulation at the hypothalamus-pituitary-adrenal axis suggest the genetic heterogeneity in basic metabolic rate and efficiency for heat dissipation to acclimate to thermal stress and maintain body temperature homeostasis. The alteration of adrenal H3K27me3 level was associated with the endocrine function of adrenal gland and may contribute to the thermotolerance of chickens.

Add-on memantine may improve cognitive functions and attenuate inflammation in middle- to old-aged bipolar II disorder patients.

OBJECTIVES: Chronic inflammation and neuroprogression underlie bipolar disorder (BP) and associated cognitive deficits. Memantine (MM) exerts neuroprotective effects by reducing neuroinflammation. Therefore, we investigated whether add-on low-dose MM (5 mg/day) in BP-II patients may improve cognition and inflammation. METHODS: We combined two 12-week randomized, double-blind, placebo-controlled studies (NCT01188148 and NCT03039842) for analysis. Each participant was allocated to the MM or placebo group. Symptom severity, neuropsychological tests, and the cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1), and brain-derived neurotrophic factor (BDNF)] were evaluated at baseline and endpoint. A subgroup analysis of middle- to old-aged BP-II patients was also performed. RESULTS: We recruited 155 BP-II patients (23 of which were middle- to old-aged) for the MM group and 170 patients (20 of which were middle- to old-aged) for the placebo group. Add-on MM did not result in significant improvements in cognitive functions in all BP-II patients, but a group difference in TNF-α levels was found in the MM group (P=0.04). Specifically, in middle- to old-aged BP-II patients, there was a significant time and group interaction effect on omission T-scores, hit reaction time T-scores, and hit reaction time standard error T-scores on continuous performance tests (CPTs) in the MM group (P=0.007, 0.02, and 0.01, respectively), and a decrease in plasma TNF-α levels (P=0.04). LIMITATIONS: The sample size of middle- to old-aged BP-II patients were limited. CONCLUSION: Add-on MM may attenuate inflammation in BP-II and improve cognition in middle- to old-aged BP-II patients.

Cytotoxicity Produced by Silicate Nanoplatelets: Study of Cell Death Mechanisms.

Nano-silicate platelets (NSP), an exfoliated product from natural clays, have been validated for biosafety and as an effective supplement to alleviate mycotoxicosis. Since NSP induced noticeable cell death, we therefore investigated further the mechanism of cytotoxicity caused by NSP. Exposure to NSP impaired membrane integrity and caused cell death in a dose-dependent manner. Reactive oxygen species (ROS) generation other than of NADH oxidase origin, and subcellular interactions by internalized NSP also contributed to NSP-induced cell death. NSP persistently provoked receptor-interacting protein 1 Ser/Thr (RIP1) kinase and caspase 6 and 3/7 activation without altering caspase 8 activity and induced evident chromatolysis of necrosis in the later stage. These events proceeded along with increased ER stress and mitochondrial permeability, to final Cyt-C (Cytochrome C) release and AIF (apoptosis inducing factor) translocation, a hallmark of cell necroptosis. Fluorescent probing further manifested NSP traffic, mostly adherence on the cell surfaces, or via internalization, being compartmentalized in the nuclei, cytosols, and mitochondria. Pharmacological approaches with specific inhibitors suggested that endocytosis and particularly RIP1 kinase provocation mediate NSP-induced cell death independent of caspase activation. In conclusion, the necroptotic process contributes to most of the cell death induced by NSP due to membrane interactions/impaired integrity, ROS generation, and subcellular interactions by internalized NSP.

Dietary supplementation of 25-hydroxycholecalciferol improves cardiac function and livability in broiler breeder hens-amelioration of blood pressure and vascular remodeling.

A supplement of 69 µg 25-hydroxycholecalciferol (25-OH-D3)/kg feed suppressed the mortality in feed-restricted broiler breeder hens and in hens allowed ad libitum feed intake (Ad-hens) in a feeding trial from age 26 to 60 wk. Outcomes for the mechanisms found that 25-OH-D3 relieved systemic hypoxia, pathological cardiac remodeling and arrhythmias, and hepatopathology to improve hens' livability. In the study, we further evaluated the effect of 25-OH-D3 on blood pressure and vascular remodeling relative to cardiac pathogenesis of sudden death (SD). Ad libitum feed intake increased mechanical loading and contributed to maladaptive cardiac hypertrophy as evidenced by consistently elevated peripheral arterial blood pressure in Ad-hens before SD (P < 0.05). In planned longitudinal measurements, Ad-hens also showed higher right ventricle systolic pressure and right ventricle diastolic pressure (RVDP) (P < 0.05). Supplemental 25-OH-D3 relieved peripheral hypertension and prevented time-dependent increases of RVDP in Ad-hens through the renin-angiotensin system and circulating nitric oxide availability and by regulating vascular remodeling including elastin/collagen ratio and smooth muscle cell proliferation in the pulmonary artery for improved elasticity/stiffness (P < 0.05). The antihypertensive effect via the renin-angiotensin system and nitric oxide regulation in respect to heart rate and arrhythmias by 25-OH-D3 were further confirmed in 51 week-old feed-restricted broiler breeder hens challenged with salt loading for 5 wk. Despite feed restriction, the most feed-efficient hens of feed-restricted groups also exhibited cardiac pathological hypertrophy, in conjunction with higher right ventricle systolic pressure, RVDP, plasma nitric oxide levels, and more dramatic arterial remodeling (P < 0.05). These results suggest that peripheral and pulmonary hypertension are the key drivers of SD and that 25-OH-D3 is an effective antihypertensive supplement to alleviate cardiac pathogenesis and improve livability in broiler breeder hens.

Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder.

Background: Neuroticism personality trait is recognized as an important endophenotypic predictor of generalized anxiety disorder (GAD). Furthermore, endophenotype-based pathway approaches have recently been shown to have greater advantages for gene-finding strategies than traditional case-control studies. In the present study, in addition to conventional case-control methods, we used pathway analyses to test whether the tri-allelic serotonin transporter promoter polymorphism (combining 5-HTTLPR and rs25531) is associated with risk of GAD through its effects on trait neuroticism. Methods: We included 2236 Han Chinese adults in this study, including 736 patients with GAD and 1500 healthy participants. We genotyped the 5-HTTLPR and rs25531 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism method. We used the Neuroticism scale of the Maudsley Personality Inventory (MPI) short version (MPI-Neuroticism) to measure participants' tendency toward neuroticism. Results: Using endophenotype-based path analyses, we found significant indirect effects of the tri-allelic genotype on risk of GAD, mediated by MPI-Neuroticism in both men and women. Compared to women carrying the S'S' genotype, women carrying the L' allele had higher levels of MPI-Neuroticism, which in turn were associated with higher risk of GAD. Men, however, showed the opposite pattern. Using traditional case-control comparisons, we observed that the effect of tri-allelic genotype on GAD was significant, but only in women. Limitations: Participants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism. Conclusion: These findings are the first to show that the triallelic 5-HTTLPR polymorphism is associated with elevated risk of GAD, and that this effect is mediated via increased trait neuroticism, a sex-dependent risk pathway.

Age-dependent association of polymorphisms in the promoter and 5'-untranslated region of the norepinephrine transporter gene with generalized anxiety disorder.

BACKGROUND: Norepinephrine transporter (NET), which regulates synaptic norepinephrine for noradrenergic signaling, is involved in the pathogenesis of anxiety, while expression of the NET gene differs at different ages. Here, we examine whether genetic variants in the NET gene are associated, in an age-specific manner, with increased risk of generalized anxiety disorder (GAD), one of the most disabling anxiety disorders. METHODS: Three common single-nucleotide polymorphisms (SNPs) in the promoter (rs168924: A/G; rs2242446: T/C) and 5'-untranslated region (5'-UTR) (rs2397771: G/C) of the NET gene were genotyped in 2,317 Han-Chinese participants (791 GAD patients and 1,526 controls; age: 20-65). Potential confounding factors, such as gender, stress levels and psychiatric comorbidities, were included as covariates. RESULTS: An interaction between age and NET genotypes and haplotypes was found for the risk of GAD. In the younger participants, rs168924 minor allele G homozygotes had the lowest incidence of GAD; however, older subjects displayed an inverse pattern, with homozygous G/G carriers presenting the highest prevalence of GAD. Additionally, younger individuals carrying 2 copies of the GGT haplotype composed of rs2397771-rs168924-rs2242446 had the lowest rate of GAD. However, those with 2 copies of the same haplotype exhibited the highest risk of GAD in the older groups. LIMITATIONS: Only 3 common SNPs in the promoter and 5'-UTR of the NET gene were analyzed. CONCLUSIONS: Our findings are the first to demonstrate that potentially functional SNPs in the NET promoter and 5'-UTR are associated with an increased risk of GAD, and that such associations are determined in an age-specific way.

Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: a 12-week double-blind randomized clinical trial.

BACKGROUND: The aim of this study is to determine whether adding combination of agents with anti-inflammatory and neurotrophic effects is more efficacious than mood stabilizer alone in improving clinical symptoms, plasma brain-derived neurotrophic factor (BDNF), cytokine levels, and metabolic profiles in patients with bipolar spectrum disorder. METHODS: In a randomized, double-blind, controlled 12-week clinical trial, patients with moderate mood symptoms (HDRS ≥ 18 or YMRS ≥ 14) were recruited. The patients were randomly assigned to a group while still undergoing regular valproate (VPA) treatments: VPA + dextromethorphan (DM) (30 mg/day) + memantine (MM) (5 mg/day) (DM30 + MM5) (n = 66), VPA + DM (30 mg/day) (DM30) (n = 69), VPA + MM (5 mg/day) (MM5) (n = 66), or VPA + Placebo (Placebo) (n = 69). Symptom severity, immunological parameters [plasma tumor necrosis factor (TNF)-α and C-reactive protein (CRP)] and plasma brain-derived neurotrophic factor (BDNF) were regularly examined. Metabolic profiles [cholesterol, triglycerides, glycosylated hemoglobin (HbA1C), fasting serum glucose, body mass index (BMI)] were measured at baseline and at 2, 8, and 12 weeks. RESULTS: Depression scores were significantly (P = 0.03) decreases and BDNF levels significantly (P = 0.04) increased in the DM30 + MM5 group than in the Placebo group. However, neither depressive scores nor BDNF levels were significantly different between the DM30, MM5, and Placebo groups. Changes in certain plasma cytokine and BDNF levels were significantly correlated with metabolic parameters. CONCLUSION: We concluded that add-on DM30 + MM5 was significantly more effective than placebo for clinical symptoms and plasma BDNF levels. Additional studies with larger samples and mechanistic studies are necessary to confirm our findings. Trial registration NCT03039842 (https://register.clinicaltrials.gov/). Trial date was from 1 Jan 2013 to 31 December 2016 in National Cheng Kung University Hospital. Registered 28 February 1 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03039842?term=NCT03039842&rank=1.

Genomic regions and pathways associated with thermotolerance in layer-type strain Taiwan indigenous chickens.

This study aimed to investigate genetic markers and candidate genes associated with thermotolerance in a layer-type strain Taiwan indigenous chickens exposed to acute heat stress. One hundred and ninety-two 30-week-old roosters were subjected to acute heat stress. Changes in body temperature (BT, ΔT) were calculated by measuring the difference between the initial BT and the highest BT during heat stress and the results were categorized into dead, susceptible, tolerant, and intermediate groups depending on their survival and ΔT values at the end of the experiment. A genome-wide association study on survival and ΔT values was conducted using the Cochran-Armitage trend test and Fisher's exact test. Association analyses identified 80 significant SNPs being annotated to 23 candidate genes, 440 SNPs to 71 candidate genes, 64 SNPs to 25 candidate genes, and 378 SNPs to 78 candidate genes in the dead versus survivor, tolerant versus susceptible, intermediate versus tolerant, and intermediate versus susceptible groups, respectively. The annotated genes were associated with apoptosis, cellular stress responses, DNA repair, and metabolic oxidative stress. In conclusion, the identified SNPs of candidate genes provide insights into the potential mechanisms underlying physiological responses to acute heat stress in chickens.

BDNF Val66Met polymorphism to generalized anxiety disorder pathways: Indirect effects via attenuated parasympathetic stress-relaxation reactivity.

The valine66methionine (Val66Met) polymorphism (rs6265) of the brain-derived neurotrophic factor (BDNF) gene has been shown to influence autonomic arousal pathways, which in turn predict elevated syndromal anxiety in healthy humans. We examined whether the BDNF variant is associated with an increased risk of generalized anxiety disorder (GAD), one of the most prevalent anxiety disorders, through altering parasympathetic stress/relaxation reactivity. A total of 2,250 Han Chinese adults (750 GAD patients and 1,500 healthy controls) were included in the genotyping. High-frequency heart rate variability, an index of vagal (parasympathetic) activity, was measured during the supine-standing-supine test (5 min in each position); vagal withdrawal and vagal activation were calculated as baseline supine minus standing and recovery supine minus standing, respectively. Analysis of healthy participants indicated that Val/Val homozygotes displayed significantly blunted vagal withdrawal and vagal activation compared with Met allele carriers. After analyzing the entire sample, these effects remained significant. Furthermore, both attenuated vagal response patterns were found to be significantly associated with a higher incidence of GAD. Lastly, the path analysis identified a significant indirect effect of BDNF on the risk of GAD via diminishing vagal response to either orthostatic stress or supine relaxation. Even when further testing the subsample comprising only comorbidity- and medication-free GAD patients and healthy controls to minimize the confounding bias, the results still remained. Our findings demonstrate that individuals carrying the BDNF Val/Val genotype, compared to Met-carriers, may be at higher risk of GAD due to blunted vagal reactivity in response to both stress and relaxation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

ALDH2 Gene: Its Effects on the Neuropsychological Functions in Patients with Opioid Use Disorder Undergoing Methadone Maintenance Treatment.

OBJECTIVE: Patients with opioid use disorder (OUD) have impaired attention, inhibition control, and memory function. The aldehyde dehydrogenase 2(ALDH2) gene has been associated with OUD and ALDH2 gene polymorphisms may affect aldehyde metabolism and cognitive function in other substance use disorder. Therefore, we aimed to investigate whether ALDH2 genotypes have significant effects on neuropsychological functions in OUD patients undergoing methadone maintenance therapy (MMT). METHODS: OUD patients undergoing MMT were investigated and followed-up for 12 weeks. ALDH2 gene polymorphisms were genotyped. Connors' Continuous Performance Test (CPT) and the Wechsler Memory Scale-Revised (WMS-R) were administered at baseline and after 12 weeks of MMT. Multivariate linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the ALDH2 genotypes and performance on the CPTs and WMS-R. RESULTS: We enrolled 86 patients at baseline; 61 patients completed the end-of-study assessments. The GEE analysis showed that, after the 12 weeks of MMT, OUD patients with the ALDH2 *1/*2＋*2/*2 (ALDH2 inactive) genotypes had significantly higher commission error T-scores (p= 0.03), significantly lower hit reaction time T-scores (p= 0.04), and significantly lower WMS-R visual memory index scores (p= 0.03) than did patients with the ALDH2 1*/*1 (ALDH2 active) genotype. CONCLUSION: OUD patients with the ALDH2 inactive genotypes performed worse in cognitive domains of attention, impulse control, and memory than did those with the ALDH2 active genotype. We conclude that the ALDH2 gene is important in OUD and is associated with neuropsychological performance after MMT.

Attenuated vagally-mediated heart rate variability at rest and in response to postural maneuvers in patients with generalized anxiety disorder.

BACKGROUND: Altered heart rate variability (HRV), an index of autonomic nervous system function, has been reported in generalized anxiety disorder (GAD), but the results have been mixed. Thus, the present study, using a large sample size and better methodology, aims to examine whether GAD is associated with impaired HRV, both at rest and in response to posture challenges. METHODS: In total, 1832 participants were recruited in this study, consisting of 682 patients with GAD (including 326 drug- and comorbidity-free GAD patients) and 1150 healthy controls. Short-term HRV was measured during the supine-standing-supine test (5-min per position). Propensity score matching (PSM), a relatively novel method, was used to control for potential confounders. RESULTS: After PSM algorithm, drug- and comorbidity-free GAD patients had reductions in resting (baseline) high-frequency power (HF), an index for parasympathetic modulation, and increases in the low-frequency/HF ratio (LF/HF), an index for sympathovagal balance as compared to matched controls. Furthermore, the responses of HF and LF/HF to posture changes were all attenuated when compared with matched controls. Effect sizes, given by Cohen's d, for resting HF and HF reactivity were 0.42 and 0.36-0.42, respectively. CONCLUSIONS: GAD is associated with altered sympathovagal balance, characterized by attenuation in both resting vagal modulation and vagal reactivity, with an almost medium effect size (Cohen's d ≈ 0.4), regardless of medication use or comorbidity status.

Dietary Supplementation of 25-Hydroxycholecalciferol Improves Livability in Broiler Breeder Hens-Amelioration of Cardiac Pathogenesis and Hepatopathology.

A supplement of 69 µg 25-hydroxycholecalciferol (25-OH-D3)/kg feed increased livability in feed restricted (R-hens) broiler breeder hens by 9.9% and by 65.6% in hens allowed ad libitum feed intake (Ad-hens) in a feeding trial from age 26-60 weeks. Hens with higher bodyweight and/or adiposity suffered sudden death (SD) earlier in conjunction with compromised heart rhythms and over-ventilation. In the study with the same flock of hens, we demonstrate that 25-OH-D3 improved hen's livability and heart health by ameliorating systemic hypoxia, acidosis, and cardiac pathological hypertrophy through calcineurin-NFAT4c signaling and MHC- expression in association with reduced plasma triacylglycerol and hepatic steatosis and fibrosis (p < 0.05). In contrast to live hens sampled at 29, 35, and 47 weeks, SD hens exhibited severe cardiac hypertrophy that was either progressive (Ad-groups) or stable (R-groups). Actual and relative liver weights in SD hens from any group declined as the study progressed. Heart weight correlated significantly to total and relative liver weights in SD-hens of both R- and Ad-groups. In contrast to normal counterparts sampled at 35 and 47 weeks, R-hens exhibiting cardiac hypertrophy experienced severe hypoxia and acidosis, with increased bodyweight, absolute and relative weights of liver and heart, hepatic and plasma triacylglycerol content, and cardiac arrhythmia (p < 0.05). The present results demonstrate that pathological cardiac hypertrophy and functional failure are causative factors of SD and this pathogenic progression is accelerated by hepatopathology, particularly during the early age. Increased feed efficiency with rapid gains in BW and fat increase hens' risk for hypoxia, irreversible cardiac hypertrophy, and arrhythmias that cause functional compromise and SD. Additional supplementation of 69 mg/kg feed of 25-OH-D3 to the basal diet is effective to ameliorate cardiac pathogenesis and prevent SD in broiler breeder hens.