Efficacy of a Synbiotic Containing Lactobacillus paracasei DKGF1 and Opuntia humifusa in Elderly Patients with Irritable Bowel Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background/Aims: There is increasing evidence that supplementation with pre- and probiotics appears to have positive effects on irritable bowel syndrome (IBS). The aim of this study was to determine the effects of a new synbiotic formulation on gastrointestinal symptoms in elderly patients with IBS. Methods: Sixty-seven IBS patients aged ≥60 years were randomly assigned to either a placebo group (n=34) or a synbiotic group (n=33). During a 4-week intervention, subjects used a placebo or a synbiotic containing Lactobacillus paracasei DKGF1 and extracts of Opuntia humifusa once a day. Patients were evaluated with the subject global assessment, visual analog scale, and Bristol stool chart. The primary outcome was the overall responder rate and the secondary outcome was the responder rates for abdominal symptom reduction at week 4. Results: Overall, responder rates were significantly higher in the synbiotic group (51.5%) than in the placebo group (23.5%) (p=0.017). Abdominal pain (58.8% vs 81.8%) and psychological well-being (26.4% vs 60.6%) were noticeably improved in the synbiotic group (p=0.038 and p=0.004, respectively). However, there were no significant differences in gas and bloating symptoms (p=0.88 and p=0.88, respectively). In patients with constipation-dominant and diarrhea-dominant IBS (n=16), the synbiotic significantly improved abdominal pain and defecation symptoms (responder rates for the placebo vs the synbiotic: 22.2% vs 85.7%, p=0.04). There were no adverse events in either group. Conclusions: The results indicate that this new synbiotic supplement can potentially relieve abdominal symptoms in elderly IBS patients.

Clozapine Blood Concentration Predicts Corrected QT-Interval Prolongation in Patients With Psychoses.

BACKGROUND: Corrected QT-interval (QTc) prolongation (QTP) is a rare but fatal adverse effect of antipsychotics. Clozapine is the only antipsychotic recommended for treatment of resistant schizophrenia; however, clozapine has been reported to cause QTP. We sought factors predictive of QTP in patients who had antipsychotic polypharmacy involving clozapine. We explored whether the clozapine blood concentration might predict QTP. METHODS: We included 133 patients with schizophrenia spectrum disorder who had antipsychotic polypharmacy involving clozapine. We used the χ2 and nonparametric tests to compare clozapine therapeutic drug monitoring (TDM) values and QTc-prolonged person (QTPP) status. Multivariate regression and mediator models were used to identify risk factors for QTPP status and QTP. RESULTS: In total, 111 patients were prescribed clozapine. The QTPP rates were 31.3% (20) for men and 23.2% (16) for women. Compared with the non-QTPP group, the QTPP group exhibited significantly higher daily dose of all antipsychotics including clozapine, a higher clozapine dose, and elevated clozapine and norclozapine TDM values. Furthermore, such patients were prescribed a greater number of antipsychotics. Multivariate logistic regression revealed that only the clozapine TDM value could be predictive factor for QTPP status (P = 0.018). A clozapine TDM value above the therapeutic range (>600 mg/dL) was associated with a high risk of QTPP status (adjusted odds ratio, 6.5; 95% confidence interval, 1.7-25.2; P = 0.006). The mediator model revealed that the clozapine TDM values completely mediated the association between the clozapine dose and the QTc interval. CONCLUSIONS: The clozapine blood concentration reliably predicts QTP in patients with clozapine use.

Extracutaneous mastocytoma of colon: a case report and literature review.

Extracutaneous mastocytoma is a rare benign tumor composed of mature mast cells and is located in tissues other than the skin. We report the case of a 61-year-old male who was diagnosed with extracutaneous mastocytoma via colonoscopic polypectomy and biopsy. To our knowledge, this was the first case of a solitary extracutaneous mastocytoma of the colon. We reported this case and reviewed the literature.

[How to Study the Sex and Gender Effect in Biomedical Research?]

Men and women are different, but this difference has not been well reflected in clinical trials and preclinical studies of biomedical science. Gender medicine, which systematically analyzes research results according to sex and gender, has been emphasized to overcome this problem. On the other hand, researchers still have difficulty in applying gender medicine to their research. To perform rigorous gender medicine, using correct terms, a thorough literature review during research planning, appropriate statistical analysis and reporting, and cautious interpretation of the results are necessary. Applying gender medicine will increase the reproducibility of studies, promote discoveries, expand the study relevance, and ultimately improve patient care in both men and women. Here, this study reviewed the practical issues on applying gender medicine to both preclinical and clinical studies in the field of biomedical science.

Effect of Heat-killed Lactobacillus casei DKGF7 on a Rat Model of Irritable Bowel Syndrome.

Non-viable bacteria, referred to as "paraprobiotics," have attracted attention as potentially safer alternatives to probiotics. The aim of this study was to investigate the efficacy of heat-killed Lactobacillus casei DKGF7 on the symptomatic improvement of irritable bowel syndrome (IBS) in a rat disease model and to elucidate the underlying mechanisms that contribute to the beneficial effects of heat-killed probiotics. Seven male Wistar rats were induced with IBS by restraint stress and administered heat-killed L. casei DKGF7 for four weeks and then compared with seven rats in the control group. Stool consistency measured four weeks after initial treatment was the primary outcome measure. To investigate the mechanism of action of the heat-killed bacteria on IBS, we measured serum corticosterone levels, inflammatory cytokines in colon tissue, and expression of tight junction proteins (TJPs) in the epithelium. The treatment group showed significantly better stool consistency scores than the control group at week 4, as well as at every measured time point (all p values < 0.05). The treatment group showed lower serum corticosterone levels, lower colonic inflammatory cytokine levels, and higher expression of TJPs compared with the control group. Paraprobiotics such as heat-killed L. casei DKGF7 can improve stool consistency in a rat IBS model, which may indicate a potential therapeutic strategy for IBS treatment.

High Galacto-Oligosaccharide Production and a Structural Model for Transgalactosylation of ß-Galactosidase II from Bacillus circulans.

The transgalactosylase activity of ß-galactosidase produces galacto-oligosaccharides (GOSs) with prebiotic effects similar to those of major oligosaccharides in human milk. ß-Galactosidases from Bacillus circulans ATCC 31382 are important enzymes in industrial-scale GOS production. Here, we show the high GOS yield of ß-galactosidase II from B. circulans (ß-Gal-II, Lactazyme-B), compared to other commercial enzymes. We also determine the crystal structure of the five conserved domains of ß-Gal-II in an apo-form and complexed with galactose and an acceptor sugar, showing the heterogeneous mode of transgalactosylation by the enzyme. Truncation studies of the five conserved domains reveal that all five domains are essential for enzyme catalysis, while some truncated constructs were still expressed as soluble proteins. Structural comparison of ß-Gal-II with other ß-galactosidase homologues suggests that the GOS linkage preference of the enzyme might be quite different from other enzymes. The structural information on ß-Gal-II might provide molecular insights into the transgalactosylation process of the ß-galactosidases in GOS production.

SOD1 suppresses pro-inflammatory immune responses by protecting against oxidative stress in colitis.

Superoxide dismutase 1 (SOD1) binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free superoxide radicals in the body. Reactive oxygen species (ROS), including free superoxide radicals, play important roles in colitis. However, the role of SOD1 in oxidative stress under colitis remains unclear. Here, we examined the role of SOD1 in the DSS-induced mouse model of colitis. SOD1 deficiency resulted in severe oxidative stress with body weight loss, epithelial barrier disruption and decreased antioxidant enzyme activities. The levels of neutrophils, monocytes, pro-inflammatory CD11c+ macrophages and CD11b+CD103- dendritic cells (DCs) were increased, while anti-inflammatory CD206+ macrophages and CD11b-CD103+ DCs were decreased, in DSS-treated SOD1-knockout (KO) mice compared to DSS-treated wild-type mice. Furthermore, rescue of SOD activity in SOD1-KO mice by oral gavage of B. amyloliquefaciens SOD (BA SOD) significantly ameliorated enhanced DSS-induced colitis in these mice by suppressing p38-MAPK/NF-κB signaling, which can induce inflammation and apoptosis. Taken together, our results suggest that SOD1-mediated inhibitory responses play a crucial role in limiting the development of DSS-induced colitis, and that BA SOD is a promising candidate for treating colitis.

Potential Role of PDGFRß-Associated THBS4 in Colorectal Cancer Development.

Colorectal cancer is a significant cause of death since it frequently metastasizes to several organs such as the lung or liver. Tumor development is affected by various factors, including a tumor microenvironment, which may be an essential factor that leads to tumor growth, proliferation, invasion, and metastasis. In the tumor microenvironment, abnormal changes in various growth factors, enzymes, and cytokines can wield a strong influence on cancer. Thrombospondin-4 (THBS4), which is an extracellular matrix protein, also plays essential roles in the tumor microenvironment and mediates angiogenesis by transforming growth factor-ß (TGFß) signaling. Platelet-derived growth factor receptor ß (PDGFRß), which is a receptor tyrosine kinase and is also a downstream signal of TGFß, is associated with invasion and metastasis in colorectal cancer. We identified that PDGFRß and THBS4 are overexpressed in tumor tissues of colorectal cancer patients, and that PDGF-D expression increased after TGFß treatment in the colon cancer cell line DLD-1. TGFß and PDGF-D increased cellular THBS4 protein levels and secretion but did not increase THBS4 mRNA levels. This response was further confirmed by the inositol 1,4,5-triphosphate receptor (IP3R) and stromal interaction molecule 1 (STIM1) blockade as well as the PDGFRß blockade. We propose that the PDGFRß signal leads to a modification of the incomplete form of THBS4 to its complete form through IP3R, STIM1, and Ca2+-signal proteins, which further induces THBS4 secretion. Additionally, we identified that DLD-1 cell-conditioned medium stimulated with PDGF-D promotes adhesion, migration, and proliferation of colon myofibroblast CCD-18co cells, and this effect was intensified in the presence of thrombin. These findings suggest that excessive PDGFRß signaling due to increased TGFß and PDGF-D in colorectal tumors leads to over-secretion of THBS4 and proliferative tumor development.

Enhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma.

Neurotransmitters are reported to be involved in tumor initiation and progression. This study aimed to elucidate the prognostic value of γ-aminobutyric acid type A receptor δ subunit (GABRD) in colon adenocarcinoma (COAD) using the data from The Cancer Genome Atlas (TCGA) database. The GABRD mRNA expression levels in the COAD and normal tissues were compared using the Wilcoxon rank-sum test. The correlation between clinicopathologic characteristics and GABRD expression was analyzed by Wilcoxon rank-sum test or Kruskal-Wallis test and logistic regression. The prognostic value of GABRD mRNA expression in patients with COAD was determined using the Kaplan-Meier curve and Cox regression analysis. Finally, the molecular mechanisms of GABRD in COAD were predicted by gene set enrichment analysis (GSEA). The COAD tissues exhibited higher GABRD mRNA expression levels than the normal tissues. The logistic regression analysis revealed that GABRD mRNA expression was correlated with TNM stage, N stage, M stage, and microsatellite instability (MSI) status. The Kaplan-Meier survival curve and log-rank test revealed that patients with COAD exhibiting high GABRD mRNA expression were associated with poor overall survival (OS). The multivariate analysis indicated that increased GABRD mRNA expression was an independent prognostic factor and was correlated with a poor OS. The GSEA revealed that GABRD was involved in signaling pathways, including cell adhesion molecules, gap junction, melanogenesis, and mTOR signaling pathway, as well as the signaling pathways associated with basal cell carcinoma or bladder cancer development. In summary, enhanced GABRD mRNA expression may be a potential independent prognostic biomarker for COAD.

Peptide transporter2 (PTR2) enhances water uptake during early seed germination in Arabidopsis thaliana.

KEY MESSAGE: PTR2 in Arabidopsis thaliana is negatively regulated by ABI4 and plays a key role in water uptake by seeds, ensuring that imbibed seeds proceed to germination. Peptide transporters (PTRs) transport nitrogen-containing substrates in a proton-dependent manner. Among the six PTRs in Arabidopsis thaliana, the physiological role of the tonoplast-localized, seed embryo abundant PTR2 is unknown. In the present study, a molecular physiological analysis of PTR2 was conducted using ptr2 mutants and PTR2CO complementation lines. Compared with the wild type, the ptr2 mutant showed ca. 6 h delay in testa rupture and consequently endosperm rupture because of 17% lower water content and 10% higher free abscisic acid (ABA) content. Constitutive overexpression of the PTR2 gene under the control of the Cauliflower mosaic virus (CaMV) 35S promoter in ptr2 mutants rescued the mutant phenotypes. After cold stratification, a transient increase in ABA INSENSITIVE4 (ABI4) transcript levels during induction of testa rupture was followed by a similar increase in PTR2 transcript levels, which peaked prior to endosperm rupture. The PTR2 promoter region containing multiple CCAC motifs was recognized by ABI4 in electrophoretic mobility shift assays, and PTR2 expression was repressed by 67% in ABI4 overexpression lines compared with the wild type, suggesting that PTR2 is an immediate downstream target of ABI4. Taken together, the results suggest that ABI4-dependent temporal regulation of PTR2 expression may influence water status during seed germination to promote the post-germinative growth of imbibed seeds.

MSI status is associated with distinct clinicopathological features in BRAF mutation colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Microsatellite stable (MSS) BRAF p.V600E mutation colorectal cancer (BRAF-CRC) has a poor prognosis, whereas microsatellite instability (MSI) in BRAF-CRC is associated with a favorable prognosis. Although usually considered a single clinical entity, the MSI BRAF-CRC subtype shows some distinct characteristics in comparison with the MSS BRAF-CRC subtype. METHODS: We conducted a meta-analysis to investigate the influence of clinicopathological features on MSI status in BRAF-CRC. We searched publications up to March 2019 from PubMed, Embase, and the Cochrane Library. The effect of MSI status on outcome parameters was assessed using odds ratios (ORs) with 95% confidence intervals (CIs) and fixed- or random-effects models according to the heterogeneity. RESULTS: After reviewing 2839 reports, 16 eligible studies including 1381 patients with BRAF-CRC met the criteria. The MSI BRAF-CRC subtype was associated with older age, female sex (OR = 1.70; 95% CI = 1.35-2.14; P < 0.00001), proximal tumor location (OR = 5.10; 95% CI = 3.70-7.03; P < 0.00001), early TNM stage (OR = 5.28; 95% CI = 3.93-7.09; P < 0.00001), and poor differentiation (OR = 2.29; 95% CI = 1.60-3.28; P < 0.00001). CONCLUSIONS: MSI was significantly correlated with distinct favorable clinicopathological characteristics in BRAF-CRC. These results suggest that MSI status should be considered as a stratification factor for better management of the BRAF-CRC.

The risk of herpes zoster virus infection in patients with depression: A longitudinal follow-up study using a national sample cohort.

The features of herpes zoster share some commonalities with depression, including decreased cellular immunity, a close correlation with nutritional status, and a higher prevalence in the elderly population. We aimed to assess the association between herpes zoster infection and depression in the Korean population.We performed a longitudinal follow-up study of a nationwide sample cohort derived from the Korean National Health Insurance Service database. Individuals diagnosed with depression between 2002 and 2013 (n = 58,278) as well as matched controls (n = 233,112), with both groups comprising 34.3% male and 65.7% female subjects, were extracted and analyzed for the presence of herpes zoster infection. Depression was diagnosed based on the International Classification of Diseases tenth revision (ICD-10) codes F31-F39, while herpes zoster was diagnosed as ICD-10 B02.The rate of herpes zoster infection was higher in the depressed group (6.8% [3967/58,278]) than in the control group (6.3% [14,689/233,122], P < .001). The adjusted hazard ratio (HR) for herpes zoster infection was 1.09 (95% CI: 1.05-1.13) in the depressed group (P < .001). Subgroup analyses revealed that the adjusted HRs for herpes zoster infection were higher only in women younger than 60 years among participants with depression. These HRs were 1.13 (95% CI: 1.02-1.25; P = .016) in women younger than 40 years and 1.11 (95% CI: 1.04-1.17; P < .001) in women aged 40-59 years.Depression is a predictor of herpes zoster infection in Korean women younger than 60 years.

Genome Sequence of Bacillus subtilis natto VK161, a Novel Strain That Produces Vitamin K2.

Bacillus subtilis strain natto VK161 was selected for its high production of vitamin K2 Its genome was sequenced and annotated in the Department of Energy-Joint Genome Institute (DOE-JGI) annotation pipeline. It resulted in a chromosome of 4,073,396 bp, which is composed of 4,332 protein-coding genes, 23 rRNA genes, and 77 tRNA genes.

[Rectal Ulcer Developed in Systemic Lupus Erythematosus without Ischemic Colitis].

Rectal involvement by systemic lupus erythematosus (SLE) is quite rare. Approximately 14 cases have been reported worldwide, but only one with ischemic colitis has been reported in Korea. A 17-year-old female patient was hospitalized with abdominal pain and hematochezia. Sigmoidoscopy revealed only a simple rectal ulcer without ischemic colitis. cytomegalovirus and bacterial infections were excluded. A sigmoidoscopic rectal biopsy indicated a rectal invasion by SLE, but the patient showed an acute worsening conditions that did not respond to treatment. This paper reports a case of rectal ulcer that developed in SLE without ischemic colitis with a review of the relevant literature.

Organophosphorus hydrolase-poly-ß-cyclodextrin as a stable self-decontaminating bio-catalytic material for sorption and degradation of organophosphate pesticide.

A region suffering from an attack of a nerve agent requires not only a highly sorptive material but also a fast-acting catalyst to decontaminate the lethal chemical present. The product should be capable of high sorptive capacity, selectivity and quick response time to neutralize the long lasting harmful effects of nerve agents. Herein, we have utilized organophosphorus hydrolase (OPH) as a non-toxic bio-catalytic material held in with the supporting matrix of poly-ß-cyclodextrin (PCD) as a novel sorptive reinforced self-decontaminating material against organophosphate intoxication. OPH coated PCD (OPH-PCD) will not only be providing support for holding enzyme but also would be adsorbing methyl paraoxon (MPO) used as a simulant, in a host-guest inclusion complex formation. Sorption trend for PCD revealed preference towards the more hydrophobic MPO against para-nitrophenol (pNP). The results show sorption capacity of 1.26 mg/g of 100 µM MPO with PCD which was 1.7 times higher compared to pNP. The reaction rate with immobilized OPH-PCD was found to be 23% less compared to free enzyme. With the help of OPH-PCD, continuous hydrolysis (100%) of MPO into pNP was observed for a period of 24 h through packed bed reactor with good reproducibility and stability of enzyme. The long-term stability also confirmed its stable nature for the investigation period of 4 days where it maintained activity. Combined with its fast and reactive nature, the resulting self-decontaminating regenerating material provides a promising strategy for the neutralization of nerve agents and preserving the environment.

A Highly Efficient CRISPR-Cas9-Mediated Large Genomic Deletion in Bacillus subtilis.

In Bacillus subtilis, large genomic deletions have been carried out for genome reduction, antibiotic overproduction, and heterologous protein overexpression. In view of the eco-friendliness of B. subtilis, it is critical that engineering preserves its food-grade status and avoids leaving foreign DNA in the genome. Existing methods of generating large genomic deletions leave antibiotic resistance markers or display low mutation efficiency. In this study, we introduced a clustered regularly interspaced short palindromic repeat-derived genome engineering technique to develop a highly efficient method of generating large genomic deletions in B. subtilis without any trace of foreign DNA. Using our system, we produced 38 kb plipastatin-synthesizing pps operon deletion with 80% efficiency. The significant increase in mutation efficiency was due to plasmids-delivered Streptococcus pyogenes-originated SpCas9, target-specific sgRNA and a donor DNA template, which produces SpCas9/sgRNA endonuclease complex continuously for attacking target chromosome until the mutagenic repair occurs. Our system produced single-gene deletion in spo0A (∼100%), point mutation (∼68%) and GFP gene insertion (∼97%) in sigE and demonstrated its broad applicability for various types of site-directed mutagenesis in B. subtilis.

[Pancreatic Panniculitis in Patients with Chronic Pancreatitis: Case Report and Review of Literature].

Pancreatic panniculitis is a rare complication characterized by subcutaneous fat necrosis associated with pancreatic disease. It has been postulated that pancreatic panniculitis is caused by the systemic activity of pancreatic enzymes that lead to microcirculatory disturbances. We report a 41-year-old heavy alcoholic woman with pancreatic panniculitis that coexisted with acute and chronic pancreatitis. She was diagnosed with chronic pancreatitis and alcoholic liver cirrhosis 5 years ago. She presented with multiple, tender, erythematous, subcutaneous nodules with heat sensation on both lower legs. Laboratory evaluation revealed an increase in the serum blood amylase and lipase. Histopathologic findings showed fat necrosis with inflammation around the necrotic subcutaneous fat tissue. The lesions subsided gradually with an improvement of acute pancreatitis.

Persistent otolith dysfunction even after successful repositioning in benign paroxysmal positional vertigo.

To evaluate utricular and saccular function during the acute and resolved phases of BPPV, ocular and cervical vestibular evoked myogenic potentials (VEMPs) were studied in 112 patients with BPPV and 50 normal controls in a referral-based University Hospital. Ocular (oVEMPs) and cervical VEMPs (cVEMPs) were induced using air-conducted sound (1000Hz tone burst, 100dB normal hearing level) at the time of initial diagnosis and 2 months after successful repositioning in patients with BPPV, and the results were compared with those of the controls. Abnormalities of cVEMPs and oVEMPs in patients with BPPV were prevalent and significantly higher compare to the healthy control group (p<0.01 in each VEMP by chi-square test). In the patient group, difference between the proportions of abnormal responses of cVEMP and oVEMP was not significant in both affected (p=0.37, chi-squared test) and non-affected (p=1.00) ears. The abnormalities were more likely reduced or absent responses rather than delayed ones; reduced or absent responses are 17.6% in cVEMPs (p=0.04, chi-square) and 21.6% in oVEMPs (p<0.01). The non-affected ear in the BPPV group also showed significantly higher abnormalities of cVEMP and oVEMP when compared to the control group. The follow-up VEMPs after repositioning maneuvers were not significantly different compared to the initial values from both stimulated affected and non-affected ears. Although most patients had unilateral BPPV, bilateral otolithic dysfunction was often shown by persistently reduced or absent cervical and ocular VEMPs, suggesting that BPPV may be caused by significant bilateral damage to the otolith organs.

Influence of anxiety symptoms on improvement of neurocognitive functions in patients with major depressive disorder: A 12-week, multicenter, randomized trial of tianeptine versus escitalopram, the CAMPION study.

BACKGROUND: Previous research has reported evidence that patients with major depressive disorder (MDD) show anxiety symptoms and neurocognitive impairments. However, the influence of anxiety on neurocognitive function in MDD patients during antidepressant treatment is unclear. METHOD: MDD patients (n=164) completed a 12-week, multicenter, randomized trial assigned in a 1:1 ratio to either tianeptine or escitalopram. Changes of anxiety symptoms were assessed by the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D), self-rated subjective cognitive impairment on memory and concentration, the Mini-Mental Status Examination (MMSE), Continuous Performance Test (CPT), Verbal Learning Test (VLT), and Raven's Progressive Matrices (RPM) were assessed every 4 weeks. RESULTS: During 12 weeks of treatment, decrease in the HAM-A score was significantly associated with improvement of subjective cognitive impairments on memory (p<0.001) and concentration (p<0.001), and objective measures on delayed memory (p=0.006) and reasoning ability (p=0.002), after adjusting for covariates such as baseline HAM-A scores, time, sex, age, education years and assigned medication using the Mixed effects and Generalized Estimated Equation model analysis. However, the other cognitive outcome variables, immediate memory, commission error, and MMSE, which showed significant improvement through 12-week study period, showed no significant association with improvement of anxiety. CONCLUSION: Improvement of anxiety symptoms was significantly associated with improvement in subjective and objective neurocognitive functions such as delayed memory and reasoning ability in elderly MDD patients during antidepressant treatment, but not significantly associated with improvement of immediate memory and commission error. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01309776.

Association between the dopamine transporter gene (DAT1) and attention deficit hyperactivity disorder-related traits in healthy adults.

BACKGROUND: The dopamine transporter gene (DAT1) is an established genetic risk factor for attention deficit hyperactivity disorder (ADHD). Therefore, we hypothesized that DAT1 may also influence the manifestation of ADHD-related traits in the normal population. METHODS: A quantitative association study was carried out on 1289 healthy adults. ADHD-related traits were measured using the 25-item Wender Utah Rating Scale (WURS-25). This scale is a self-administered instrument intended to retrospectively measure features of childhood ADHD. Previous studies typically identified three component factors: (i) impulsivity, (ii) inattention, and (iii) mood instability. Our group found that these factors were associated with various diagnoses, such as bipolar disorder and major depression. Six polymorphic markers within the DAT1 gene (rs27072, rs11133767, rs429699, rs27048, rs2937639), including the 3'-untranslated region variable number of tandem repeats, were used as genetic markers. RESULTS: The WURS-25 total score was not associated with any of the markers that we examined. However, the mood instability trait was associated significantly with rs2937639 in male participants (P=0.008); this result was supported by several haplotype-wise findings among the surrounding markers (P=0.00001-0.004). CONCLUSION: Our study results suggest that DAT1 polymorphisms may modulate mood instability traits in the normal population. Considering that mood instability tends to persist through the entire course of ADHD and is highly prevalent in many diseases that are comorbid with ADHD, this trait may be a core endophenotype that defines the role of the DAT1 gene in various psychiatric conditions.