The common exon 3 polymorphism of the growth hormone receptor gene and the effect of growth hormone therapy on growth in Korean patients with Turner syndrome

Objective Recombinant human growth hormone (GH) can achieve final adult height gain in girls with Turner syndrome (TS), but its efficacy varies widely across individuals. The exon 3‐deleted polymorphism of growth hormone receptor (d3‐GHR) has been reported to be associated with responsiveness to GH therapy. The short‐term growth response of Turner patients to GH therapy was analysed according to their GHR‐exon 3 polymorphism genotype. Design and patients This was a retrospective study of 175 TS patients. Auxological and endocrine parameters were measured, and the GHR‐exon 3 genotype was analysed. Allelic frequencies of GHR‐exon 3 genotype were compared between patients with TS and control individuals. GH had been administered to 147 patients, 115 of which remained pre‐pubertal after the first follow‐up year. Changes in height standard deviation score (SDS), height velocity (HV), body mass index (BMI), IGF‐1 and IGF binding protein‐3 (IGFBP‐3) concentrations were compared between these patients, grouped according to genotype, after the first follow‐up year. Results There was no difference in GHR‐exon 3 genotype frequency between the TS and control groups of Koreans. According to the GHR‐exon 3 genotype (fl/fl group vs. d3/fl and d3/d3 group), HV gain and height SDS gain did not differ significantly at the first year of GH therapy. Moreover, changes in IGF‐1, IGFBP‐3 concentration and BMI showed no significant difference between the groups with and without d3‐GHR after 1 year of GH therapy. Conclusion The distribution of the GHR‐exon 3 genotype was similar in the TS and control groups in a Korean population. The growth promotion efficacy of GH therapy did not differ significantly between TS patients with and without the d3‐GHR allele. These findings indicate that the GHR‐exon 3 genotype may not be a major factor to affect the GH response in Korean Turner patients.     

Association of 4-repeat allele of the dopamine D4 receptor gene exon III polymorphism and response to methylphenidate treatment in Korean ADHD children.

In the present study, we investigated the association between the 4-repeat allele at the dopamine receptor D4 (DRD4) gene and the response to treatment with methylphenidate (MPH) in Korean children with attention deficit hyperactivity disorder (ADHD). The study subjects were 83 children with ADHD (8.40+/-1.73 years) who were recruited from two child psychiatric clinics in South Korea. All of the drug-naive ADHD children were treated with MPH for about 8 weeks. An improvement of more than or equal to [corrected] 50% in the ADHD Rating Scale-IV (ARS) scores after 8 weeks of treatment compared with the baseline ARS scores before the treatment was considered as a 'good response', whereas an improvement of less than [corrected] 50% was considered as a 'poor response'. After the genotyping for DRD4 was performed, we investigated the association between the genotype at DRD4 and the response to MPH treatment. We performed a comparison of the response to MPH treatment between the two largest groups, viz. the subjects with and without the 4/4 genotype at DRD4. According to the ARS scores of the subjects as assessed by their parents and by their teachers, we found that while 71.1 and 80.0% (32/45 and 24/30), respectively, of those with a good response to MPH treatment showed the 4/4 genotype at DRD4, only 31.6 and 37.7% (12/38 and 20/53), respectively, of those with a poor response to MPH treatment showed the 4/4 genotype at DRD4 (Pearson chi2-values=12.926 and 13.737, respectively, both df=1, and both p<0.01). Our findings support the existence of an association between the 4-repeat allele at DRD4 and good response to MPH in Korean ADHD children.     

Association study of dopamine D2, D4 receptor gene, GABAA receptor beta subunit gene, serotonin transporter gene polymorphism with children of alcoholics in Korea: a preliminary study.

The studies on the genetic risk factors of the children of alcoholics (COAs) are still in an early stage. The A1 allele of the dopamine receptor 2 gene (DRD2) may be associated with positive alcohol expectancy of the COAs. In addition, several researchers reported that the COAs might be associated with the GABA A receptor beta3 subunit gene (GABRB3) and serotonin transporter gene (5-HTTLPR). In this study, we investigated the association of the polymorphism of the DRD2, Dopamine D4 receptor gene (DRD4), GABRB3, 5-HTTLPR with the COAs. Twenty-two COAs and 23 age and sex-matched control children were included for the genetic study (children of nonAlcoholics; nonCOAs). All COAs aged 6-18 were recruited and selected from family of alcoholic patients in Alcohol Clinic of the University hospital. The genotyping of the DRD2, DRD4, GABRB3, 5-HTTLPR was carried out. We used the Chi-square method for evaluating the association of genetic polymorphic allelic status with the COAs. The frequency of the A1+ allele at DRD2 in the COAs was significantly higher than nonCOAs. Significant association between the genotype at DRD4 and the COAs was found. The G1- alleles of the GABRB3 in COAs were significantly higher than nonCOAs. However, no association of the polymorphic alleles of the 5-HTTLPR with the COAs was found. We found that the children of alcoholics had a significantly increased number of risk alleles of candidate genes of alcohol drinking expectancy. Despite of several limitations, this study provides some preliminary information on the risk and protective factors associated with the COAs, which can be used as a foundation for prevention and intervention of future psychopathology.     

Immunotoxic effects of 2-bromopropane in male Sprague-Dawley rats: a 28-day exposure study

Immunotoxic effects of 2-bromopropane were investigated in male Sprague-Dawley rats. The rats were treated orally daily with 2-bromopropane at 100, 330, or 1000 mg/kg for 28 consecutive days. Four days before necropsy, the rats were immunized intravenously with sheep red blood cells (SRBCs). The body and thymus weights were significantly reduced by treatment with 2-bromopropane at the highest dose. In addition, the numbers of splenic and thymic cells were decreased by 2-bromopropane. In hematology, the numbers of white blood cells, red blood cells, and platelets were significantly reduced. Among the serum clinical parameters, the levels of chloride ion were significantly increased by 2-bromopropane. The antibody response to SRBCs was significantly suppressed at the highest dose. With immunized animals, immunophenotyping of splenic and thymic cells was performed to investigate the changes of the number of macrophages, B cells, and T cells in spleen and the number of CD4+ and CD8+ cells in thymus. The numbers of most cell types were significantly decreased in the spleen when animals were treated with 2-bromopropane at 1,000 mg/kg. Likewise, all cell types of thymus were significantly decreased by 2-bromopropane. The present results suggest that 2-bromopropane may have an immunotoxic potential in male Sprague-Dawley rats when the rats are exposed for 28 d.     

Changes in pyridoxal kinase immunoreactivity in the gerbil hippocampus following spontaneous seizure

To identify the roles of pyridoxal kinase (PLK) in epileptogenesis and the recovery mechanisms in spontaneous seizure, a chronological and comparative analysis of PLK expression in the gerbil hippocampus was conducted. PLK immunoreactivity in a pre-seizure group of seizure sensitive (SS) gerbils was more strongly detected than that in a seizure resistant (SR) group. The density of PLK immunoreactivity in a 30-min postictal group was significantly lower than that of a pre-seizure group. In a 12 h postictal group, PLK immunodensity recovered to pre-seizure level. The over-expression of PLK in the hippocampus of pre-seizure SS gerbils suggests that PLP play an important role in the modulation of GAD activity and GABA reuptake as mediated by membrane transporter via neurons.     

Criteria for definition of regional functional improvement on quantitative post-stress gated myocardial SPET after bypass surgery in patients with ischaemic cardiomyopathy

Myocardial viability can be defined as functional improvement of dysfunctional myocardium after revascularization. The purpose of this study was to define the optimal criteria for definition of regional functional improvement after coronary artery bypass graft (CABG) surgery on quantitative gated single-photon emission tomography (SPET). Thirty-two patients (26 men, 6 women; age 56 +/- 13 years) with coronary artery disease (three-vessel disease, 17; two-vessel disease, 15; previous history of myocardial infarction, 9) and severe left ventricular dysfunction (LVEF < or = 35%) underwent CABG. Rest thallium-201/dipyridamole stress technetium-99m methoxyisobutylisonitrile gated myocardial SPET was performed before and 3 months after CABG. Global LV functional improvement was defined as either an improvement in LVEF of 10% ( n = 15) or an improvement in LVEF of 5% combined with a decrease in end-systolic volume of 10 ml ( n = 2) after CABG on quantitative gated SPET. Postoperative regional wall thickening improvement (DeltaRWT), regional wall motion improvement (DeltaRWM) and regional resting (DeltaRP) and stress perfusion improvement (DeltaRstrP) were used to determine global functional improvement by ROC curve analysis, and the optimal criteria for definition of viable regional dysfunctional myocardium were defined on the ROC curves. Correlations were verified by determining the number of improved myocardial regions and LVEF improvement. LVEF was improved from 25% +/- 6% to 34% +/- 11% after CABG. A total of 229 segments were dysfunctional (wall motion < or = 2 mm, thickening < or = 20%) before CABG. On ROC curve analysis using global functional improvement as an indicator of viability, the areas under the ROC curves (AUCs) of DeltaRWT and DeltaRWM were 0.717 and 0.620, respectively. The AUC of DeltaRWT was significantly larger than that of DeltaRWM ( P = 0.009) and the optimal cut-off value of DeltaRWT was 15%. The AUCs of DeltaRP and DeltaRstrP were not significant. The correlation coefficients between summed DeltaRWT and DeltaRWM and LVEF improvement were 0.591 and 0.472, respectively. The number of segments with a DeltaRWT of more than 15% correlated with LVEF improvement (rho = 0.533 by Spearman rank correlation). Regional wall thickening improvement showed the best correlation with global LV functional improvement after CABG. The most reliable regional criterion of myocardial viability was improvement in regional wall thickening by > or = 15% on quantitative gated SPET.     

A randomized controlled trial of tolterodine and oxybutynin on tolerability and clinical efficacy for treating Chinese women with an overactive bladder

Objective To compare the tolerability and clinical efficacy of tolterodine and oxybutynin in the treatment of Hong Kong Chinese women with an overactive bladder. Patients and methods A randomized controlled trial was conducted at two urogynaecology centres in Hong Kong. In all, 106 women with urodynamically confirmed detrusor instability were recruited. Baseline severity assessments included a visual analogue scale (VAS), urinary diary and urinary pad-test. The women were randomized to receive either oral tolterodine 2 mg or oxybutynin 5 mg twice daily for 10 weeks. Treatment responses were assessed at 4 and 10 weeks using the VAS and urinary diary. Treatment tolerability was assessed at baseline, 4 and 10 weeks using the Xerostomia Questionnaire. A urinary pad-test was repeated at 10 weeks. Results The perceived change from baseline VAS was better in the tolterodine than the oxybutynin group after 10 weeks of treatment (per-protocol analysis, P = 0.043). The two drugs were effective in reducing the symptoms of frequency (P < 0.001). Tolterodine was significantly better than oxybutynin in reducing urinary leakage (urinary pad-test; median change - 5.00 g vs 0 g, P = 0.019). Both drugs caused a significant worsening of dry mouth (overall dryness, P < 0.005; discomfort, P < 0.005; sleep, P = 0.021; speaking, P = 0.045; swallowing, P = 0.004; and liquid consumption, P = 0.017). Conclusions Both oxybutynin and tolterodine were effective in ameliorating the severity of the symptoms of detrusor instability. Tolterodine was better than oxybutynin in both subjective and objective outcome measures, but both drugs caused similar worsening of dry mouth that may limit the tolerability of these medications.