Inhibition of HIF1α and PDK Induces Cell Death of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. GBMs, like other tumors, rely relatively less on mitochondrial oxidative phosphorylation (OXPHOS) and utilize more aerobic glycolysis, and this metabolic shift becomes augmented under hypoxia. In the present study, we investigated the physiological significance of altered glucose metabolism and hypoxic adaptation in the GBM cell line U251 and two newly established primary GBMs (GBM28 and GBM37). We found that these three GBMs exhibited differential growth rates under hypoxia compared to those under normoxia. Under normoxia, the basal expressions of HIF1α and the glycolysis-associated genes, PDK1, PDK3, and GLUT1, were relatively low in U251 and GBM28, while their basal expressions were high in GBM37. Under hypoxia, the expressions of these genes were enhanced further in all three GBMs. Treatment with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), induced cell death in GBM28 and GBM37 maintained under normoxia, whereas DCA effects disappeared under hypoxia, suggesting that hypoxic adaptation dominated DCA effects in these GBMs. In contrast, the inhibition of HIF1α with chrysin suppressed the expression of PDK1, PDK3, and GLUT1 and markedly promoted cell death of all GBMs under both normoxia and hypoxia. Interestingly, however, GBMs treated with chrysin under hypoxia still sustained higher viability than those under normoxia, and chrysin and DCA co-treatment was unable to eliminate this hypoxia-dependent resistance. Together, these results suggest that hypoxic adaptation is critical for maintaining viability of GBMs, and targeting hypoxic adaptation can be an important treatment option for GBMs.

Desynchronization of Theta-Phase Gamma-Amplitude Coupling during a Mental Arithmetic Task in Children with Attention Deficit/Hyperactivity Disorder.

INTRODUCTION: Theta-phase gamma-amplitude coupling (TGC) measurement has recently received attention as a feasible method of assessing brain functions such as neuronal interactions. The purpose of this electroencephalographic (EEG) study is to understand the mechanisms underlying the deficits in attentional control in children with attention deficit/hyperactivity disorder (ADHD) by comparing the power spectra and TGC at rest and during a mental arithmetic task. METHODS: Nineteen-channel EEGs were recorded from 97 volunteers (including 53 subjects with ADHD) from a camp for hyperactive children under two conditions (rest and task performance). The EEG power spectra and the TGC data were analyzed. Correlation analyses between the Intermediate Visual and Auditory (IVA) continuous performance test (CPT) scores and EEG parameters were performed. RESULTS: No significant difference in the power spectra was detected between the groups at rest and during task performance. However, TGC was reduced during the arithmetic task in the ADHD group compared with the normal group (F = 16.70, p < 0.001). The TGC values positively correlated with the IVA CPT scores but negatively correlated with theta power. CONCLUSIONS: Our findings suggest that desynchronization of TGC occurred during the arithmetic task in ADHD children. TGC in ADHD children is expected to serve as a promising neurophysiological marker of network deactivation during attention-demanding tasks.

Depression, Stress, Quality of Life, and Dry Eye Disease in Korean Women: A Population-Based Study.

PURPOSE: To determine the relationship between dry eye disease (DED) and depressive symptoms in a nationally representative sample of Korean women. METHODS: This population-based cross-sectional study comprised 6655 women (aged 19 years or older) participating in the fifth annual Korea National Health and Nutrition Examination Survey from 2010 to 2011. Psychological problems associated with clinically diagnosed DED by ophthalmologists and symptoms of DED were assessed using questionnaires and surveys. Data were analyzed using logistic regression to determine the association of depression with allergic disease while controlling for age, lifestyle factors, and medical factors. RESULTS: Among the participants, the prevalence of clinically diagnosed DED and its symptoms was 12.3% and 20.0%, respectively. Subjects with the diagnosis had a higher likelihood of experiencing severe psychological stress [odds ratio (OR), 2.5; 95% confidential interval (CI), 1.6-4.0], depressive mood (OR, 1.5; 95% CI, 1.1-2.0), anxiety/depression problems (OR, 1.5; 95% CI, 1.1-2.0) and tended to have a history of psychological counseling (OR, 1.8; 95% CI, 1.0-3.1). Subjects with symptoms of DED showed similar patterns. CONCLUSIONS: There is a close association between depression, stress, and DED in women who have been clinically diagnosed with it or those presenting with its symptoms.

Attention deficit hyperactivity disorder like behavioral problems and parenting stress in pediatric allergic rhinitis.

OBJECTIVE: Previous studies have reported comorbidity of attention deficit and hyperactivity disorder (ADHD) and allergic diseases. The current study investigated ADHD like behavioral symptoms and parenting stress in pediatric allergic rhinitis. METHODS: Eighty-seven children (6-13 years old) with allergic rhinitis and 73 age- and sex-matched children of control group were recruited. Diagnosis and severity assessments of allergic rhinitis were determined by a pediatric allergist. The Parenting Stress Index-Short Form (PSI-SF), ADHD Rating Scale (ARS), and Child Behavior Checklist (CBCL) were completed by their mothers. RESULTS: In the allergic rhinitis group, the total PSI-SF score (p<0.01), ARS score (p<0.01), the subscale scores of the CBCL including somatization, attentional problems and emotional instability (p=0.01; p<0.01; p<0.01) and prevalence of ADHD (p=0.03) were significantly higher than those of the control group. Among mothers of children with allergic rhinitis, those of children with comorbid ADHD demonstrated significantly higher parenting stress than those without comorbid ADHD (p<0.01). Parenting stress was correlated with severity of child's allergic symptoms and the ARS total score (beta=0.50, p<0.01; beta=0.39, p<0.01). There was a significant correlation between allergic symptom severity and the ARS total score (B=8.4, SD=2.5, t=3.3, p<0.01). CONCLUSION: This study demonstrated that ADHD symptoms were common in children with allergic rhinitis, and this factor increased parenting stress and disrupted the parent-child relationship. Routine evaluation and early management of ADHD symptoms in pediatric allergic rhinitis may benefit families of children with allergic rhinitis.

Calculation of the solvation free energy of neutral and ionic molecules in diverse solvents.

The solvation free energy density (SFED) model was modified to extend its applicability and predictability. The parametrization process was performed with a large, diverse set of solvation free energies that included highly polar and ionic molecules. The mean absolute error for 1200 solvation free energies of the 379 neutral molecules in 9 organic solvents and water was 0.40 kcal/mol, and for 90 hydration free energies of ions was 1.7 kcal/mol. Overall, the calculated solvation free energies of a wide range of solute functional groups in diverse solvents were consistent with experimental data.

Effect of genetic polymorphisms on smoking cessation: a trial of bupropion in Korean male smokers.

BACKGROUND: Even though bupropion is first-line pharmacological agent for smoking cessation, not all the smokers successfully quit smoking by bupropion. It means other factors like genetic predisposition could contribute to the therapeutic outcome. OBJECTIVES: The aim of this study is to elucidate the question of whether the abstinence rates by bupropion trial would be different depending on the genotypes. METHODS: Six candidate genes, thought to be involved in the interaction of nicotine and bupropion (for example, the dopamine receptor type 2, dopamine transporter, norepinephrine transporter, serotonin transporter, catecholamine-O-methyltransferase), and the clinical outcomes of smoking behavior were investigated. The participants were 225 male smokers to whom 150 mg of bupropion SR was administered for 4 weeks. The abstinence rates of specific genotypes were also compared. MAIN RESULTS: The results are as follows: (a) the frequencies of the A1/A2 genotype of the dopamine receptor type 2 TaqI A gene and SLC6A3-9 genotype of the dopamine transporter 1 gene were higher in the nonabstinence group than in the abstinence group (chi2=20.40, P<0.01 for A1/A2, chi2=7.76, P=0.01 for SLC6A3-9). The frequencies of the COMTH/COMTH and A/G genotypes of the norepinephrine transporter gene were higher in the abstinence group than in the nonabstinence group (chi2=8.12,P=0.02 for COMTH/COMTH, chi2=3.04, P<0.01 for A/G). (b) Participants having specific genotypes such as homozygotes (A1/A1 or A2/A2) of DRD2 TaqI A, COMTH/COMTH, AG of NET-8, and LL of 5-HTTLPR showed a higher abstinence rate than the other participants. CONCLUSIONS: It can be concluded that genetic diversity might determine the effects of bupropion on smoking cessation.

Depression like characteristics of 5HTTLPR polymorphism and temperament in excessive internet users.

INTRODUCTION: Excessive internet use (EIU) has been reported to be comorbid with depression and the manifestation of its symptoms. This study examines the characteristics of excessive internet users that are similar to those of patients with depressive disorders in terms of serotonin transporter gene expression and harm avoidance. METHODS: 91 male adolescents with EIU and 75 healthy comparison subjects were recruited. Between group comparisons were made on genetic polymorphisms of the serotonin transport gene and with respect to novelty seeking and harm avoidance (HA) of Cloninger's Temperament Character Inventory. RESULTS: The homozygous short allelic variant of the serotonin transporter gene (SS-5HTTLPR) is more frequent in the EIU group (chi(2)=4.38, df=1, p<0.05). The HA and Beck Depression Inventory (BDI) scores were significantly higher in the EIU group than in the healthy comparison group (t=7.03, df=164, p<0.01; t=2.12, df=164, p=0.04). EIU subjects expressing SS-5HTTLPR also showed higher HA (HA1, HA2, HA4, and total HA) and Young's internet addiction scale scores than EIU subjects expressing the other serotonin transporter gene allele variants (t=2.47, df=89, p=0.01; t=2.33, df=89, p=0.02; t=2.17, df=89, p=0.03; t=2.25, df=89, p=0.03; t=2.93, df=89, p<0.01 respectively). CONCLUSIONS: The EIU group had higher SS-5HTTLPR frequencies, harm avoidance, and BDI scores. SS-5HTTLPR expression was closely related to harm avoidance in EIU. The results of this study suggest that EIU subjects may have genetic and personality traits similar to depressed patients.

Serum homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients.

High homocysteine serum level has been regarded as one of the important factors that influence the development of schizophrenia. Genetic variations of methylenetetrahydrofolate reductase, which is a main enzyme reducing homocysteine level, are reported in schizophrenic patients. We measured the serum level of homocysteine/folate and methylenetetrahydrofolate reductase C677T/A1298C gene polymorphism in 235 patients with schizophrenia. Plasma homocysteine levels were higher and folate levels were lower in patients than in comparison subjects. Variations of C677T were more frequent in patients than in comparison subjects. Patients with the 677TT genotype showed higher homocysteine levels than patients with the CC and CT genotypes. These findings suggest that folate supplement may be beneficial to some schizophrenic patients with homocysteinemia due to the genetic defect of methylenetetrahydrofolate reductase.

Effects of catechol-O-methyltransferase Val158Met polymorphism on the cognitive stability and aggression in the first-onset schizophrenic patients.

We assessed catechol-O-methyltransferase (COMT) polymorphism in 132 first-onset schizophrenic patients and 80 healthy controls. The relationship between COMT polymorphism and cognitive function, aggression and psychiatric symptoms was tested in the schizophrenic group. COMTL carrier had higher digit span score and lower similarity score than COMTH homozygote. COMTL carrier had higher attention and delusion scores and lower inappropriate affect scores than COMTH homozygote. Attention and delusion scores of COMTL allele were higher than COMTH allele. COMTL group had higher aggression than COMTH homozygote. Our results support the theory that COMTL allele was related with increased tonic dopamine activity and cognitive 'stability', which may induce cognitive inflexibility in schizophrenia.

Changes of smoking behavior and serum adrenocorticotropic hormone, cortisol, prolactin, and endogenous opioids levels in nicotine dependence after naltrexone treatment.

This study was done to evaluate the therapeutic effects of naltrexone on smoking behaviors and to measure the changing of brain substances for elucidating the mode of action by naltrexone. Twenty-five voluntarily participated healthy male smokers were randomly assigned to naltrexone group or placebo group for 2 weeks. In this study, naltrexone group showed significant reduction in daily cigarette consumption amount, the expiratory CO levels, brief questionnaire for smoking urge (B-QSU) score, and FTQ score. However, only 2 subjects in naltrexone group quitted smoking completely at 4th week. Plasma levels of pituitary hormones (ACTH, cortisol, and prolactin) and endogenous opioids (beta-endorphin and dynorphin A) were checked weekly before and after the 'provocation and smoking coupled' stimulus once in a week for 3 weeks. In naltrexone group, pituitary hormones showed upward tendencies even though only the prolactin had statistical significance. However, beta-endorphin and dynorphin A were not significantly different between the two groups. It was suggested that naltrexone made effects on hypothalamo-pituitary-adrenocortical axis activity as well as smoking behavior. However, the meaning of these endocrinal changes by naltrexone is not conclusive, whether it is beneficial or aversive.

Association of aggressive behavior in Korean male schizophrenic patients with polymorphisms in the serotonin transporter promoter and catecholamine-O-methyltransferase genes.

The incidence of aggressive behavior in patients with schizophrenia is higher than in the general population. Among particular gene polymorphisms posited to be involved in psychiatric disorders, the catecholamine-O-methyltransferase (COMT) and serotonin transporter (5-HTTPR) genes have been the focus of recent research on aggression. In this study, we hypothesized that both the COMT and the 5-HTTPR genotypes may be dependent on and related to aggression in Korean patients with schizophrenia. The subjects were 168 unrelated male schizophrenic patients diagnosed according to DSM-IV. Among two psychiatric hospital staff and medical university students, 158 unrelated male subjects with no lifetime history of psychiatric disorders were recruited to establish the COMT and 5-HTTPR genotype distribution in the general population. All episodes of aggression from the last discharge to readmission were rated. The Total Overt Aggression Scale (OAS) score (sum of the scores of all episodes of aggression), highest OAS score (highest individual episode score, 0-16), OAS category, and OAS category score (mean score within each category) were recorded. There were statistically significant effects of COMT genotype on the mean OAS 4 (physical aggression against other people) score and the highest OAS score. The most predictive was the OAS 4 score. There was a statistically significant effect of 5-HTTPR genotype on mean total score. Thus, the COMT gene is associated with the severity of aggression and with physical aggression against other people, whereas the 5-HTTPR gene is associated with the summary score of all episodes of aggression.

Alcohol urge and plasma beta-endorphin change after alcohol challenge with naltrexone pretreatment in social drinkers.

The authors have investigated the effect of naltrexone (NTX) on lowering the urge of alcohol drinking and the action mechanism of NTX. Fifteen healthy male social drinkers voluntarily participated. The experimental method was a double-blind, placebo-controlled cross-over design. To eliminate NTX effect, 1 week washout cross-over interval was taken. Subjects ingested NTX, 50 mg/day, or placebo for 1 week. Then, the alcohol (0.5 ml/kg) challenge test was done in the evening. Blood samples were taken immediately before drinking, at 20 min and at 60 min after alcohol drinking. Plasma beta-endorphin, plasma ACTH and serum cortisol levels were checked. Subjects completed self-report questionnaires such as the visual analog scales of drink urge and the alcohol sensation scales at regular intervals. In the case of NTX pretreatment, the subjects reported significantly (P=.013) less urge to drink alcohol on the self-reporting urge scales, especially at postdrinking 20 min and 60 min than placebo pretreatment. After alcohol challenge, the subjects reported significantly more dizziness (P=.015) in the case of NTX pretreatment, and reported less mood elevation trend, though not significant (P=.052). Basal plasma beta-endorphin levels were not different, but in the case of NTX pretreatment, the increasing degree of plasma beta-endorphin during 20 min after alcohol challenge was significantly (P=.039) higher than with placebo pretreatment. This results show that the NTX reduced the urge to drink alcohol with the mechanism of partially blocking the opioid positive reward system and partially mimicking the alcohol effect.