[Premature outflow tract ventricular contraction combined with complete bundle branch block: the characteristic electrocardiographic and ablation target potential features].

Objective: To explore the characteristics of electrocardiogram(ECG) and target potential features of premature ventricular contraction (PVC) in patients with complete left/right bundle branch block (CL/RBBB) and compare with those without CL/RBBB. Methods: A retrospective analysis was done in 8 outflow tract PVC patients with CL/RBBB, who successfully underwent radiofrequency ablation from August 2009 to June 2017. According to the bundle branch block chamber, patients were divided into the complete right bundle branch block (CRBBB) group (n=4) and the complete left bundle branch block (CLBBB) group (n=4). The control group were those who successfully underwent ablation at the same position as the above two groups but without CL/RBBB. The characteristics of ECG and target potential features were compared among groups. Results: One case in the CRBBB group was successfully ablated in the great cardiac vein with precordial R/S>1 transition at V(1) and one case in the CLBBB group was successfully ablated in the right coronary cusp with precordial R/S>1 transition at V(2), while other 6 cases were all with precordial R/S>1 transition at lead V(4). Precordial R/S>1 transition was not later than sinus rhythm (SR) in the CLBBB group. No statistical difference was found in the QRS complex duration between SR and PVC in the CL/RBBB patients [(134.38±23.80)ms vs (156.75±25.93)ms, P>0.05], while statistical difference was shown in the control group [(92.63±5.76)ms vs (140.25±15.97)ms, P<0.05]. Conclusion: Bundle branch block can lead to misjudgment of PVC origin with CL/RBBB during sinus rhythm, thus the origin chamber of the PVC should be determined according to the mapping and ablation result.

Hunger and disinhibition but not cognitive restraint are associated with central norepinephrine transporter availability.

The relationship between food-intake related behaviours measured by the Three-Factor Eating Questionnaire (TFEQ) and in vivo norepinephrine transporter (NET) availability has not been explored yet. We investigated ten obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2) and ten normal-weight healthy controls (HC, BMI 23.9 ± 2.5 kg/m2) with (S,S)-[11C]-O-methylreboxetine ([11C]MRB) positron emission tomography (PET). All participants completed the TFEQ, which measures cognitive restraint, disinhibition and hunger. Image analysis required magnetic resonance imaging data sets onto which volumes-of-interests were drawn. Tissue time activity curves (TACs) were obtained from the dynamic PET data followed by kinetic modeling of these regional brain TACs applying the multilinear reference tissue model (2 parameters) with the occipital cortex as reference region. Obese individuals scored significantly higher on the hunger subscale of the TFEQ. Correlative data analysis showed that a higher degree of hunger correlated negatively with the NET availability of the insular cortex in both obese individuals and HC; however, this finding was more pronounced in obesity. Further, for obese individuals, a negative correlation between disinhibition and NET BPND of the locus coeruleus was detected. In conclusion, these initial data provide in vivo imaging support for the involvement of the central NE system in maladaptive eating behaviors such as susceptibility to hunger.

Emotional eating and in vivo norepinephrine transporter availability in obesity: A [11 C]MRB PET pilot study.

OBJECTIVE: Emotional eating (EE) has been linked to norepinephrine dysfunction. Therefore, we aimed to investigate the relationship between EE and norepinephrine transporter (NET) availability. METHOD: Ten severely obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2 ) and ten non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m2 ) matched for age and sex were studied using (S,S)-[11 C]-O-methylreboxetine ([11 C]MRB) positron emission tomography (PET). Kinetic modeling of regional tissue time activity curves was performed using multilinear reference tissue model 2 (MRTM2, with the occipital cortex as a reference region) to estimate binding potential based on individual PET-MR coregistration. To test for associations of EE and NET availability, participants completed the EE subscale of the Dutch Eating Behavior Questionnaire before scanning. RESULTS: Obese individuals and non-obese, healthy controls did not significantly differ regarding EE scores and regional NET availability. For obese individuals only, correlative data analyses pointed to a sinoidal distribution pattern as a higher degree of EE related to lower NET availability in the locus coeruleus and to higher NET availability in the left thalamus. DISCUSSION: These results indicate that central in vivo NET availability is altered in EE of individuals with obesity. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:152-156).

[Epidemiological characteristics of dyslipidemia in remote rural areas of Xinjiang, 2009-2010].

Objective: This study aimed to estimate the prevalence of dyslipidemia, hypertriglyceridemia, hypercholesterolemia, high blood low density lipoprotein cholesterol (LDL-C), and low blood high density lipoprotein cholesterol (HDL-C) in remote rural areas of Xinjiang and analyze these indicators' epidemiological characteristics. Methods: A survey of 13 000 individuals (aged ≥18 years) was conducted using a four-stage cluster random sampling method in Jiashi, Xinyuan, Aheqi, and Shawan Counties, Xinjiang, in 2009-2010. After nonpermanent residents were excluded, 12 154 individuals were included in this study. Questionnaire and physical examinations were conducted, including collection of fasting blood to detect TG, TC, LDL-C, and HDL-C. The results were calculated after complex weighting and compared according to the prevalence of different gender and age groups. Results: The overall levels of TG, TC, LDL-C, and HDL-C were 1.34±1.09, 4.45±1.16, 2.36±0.86, and 1.37±0.58 mmol/L, respectively. After complex weighting, the overall prevalence of dyslipidemia was 35.4%; that among men (42.9%) was greater than that among women (29.5%; χ2=234.19, P<0.001), and the prevalence was 35.9%, 34.5%, and 35.1% (χ2=1.52, P=0.467) in participants aged 18-44, 45-59, and ≥60 years, respectively. The overall prevalence of hypertriglyceridemia was 11.4%; that among men (13.5%) was greater than that among women (9.8%; χ2= 40.72, P<0.001), and the prevalence was 9.6%, 13.0%, and 13.2% (χ2=38.71, P<0.001) in participants aged 18-44, 45-59, and ≥60 years, respectively. The prevalence of hypercholesterolemia was 5.7%; that among men(5.0%) was greater than that among women (6.2%; χ2=6.95, P=0.008), and the prevalence was 3.5%, 7.4%, and 8.4% (χ2=105.24, P<0.001) in participants aged 18-4, 45-59, and ≥60 years, respectively. The prevalence of high blood LDL-C was 2.8%, and there was no significant difference between men (3.0%) and women (2.4%; χ2=1.43, P=0.231); the prevalence was 3.5%, 7.4%, and 8.4% (χ2=42.81, P<0.001) in participants aged 18-44, 45-59, and ≥60 years, respectively. The prevalence of low blood HDL-C was 24.0%; that among men (31.6%) was greater than that among women (18.0%; χ2=304.02, P<0.001), and the prevalence was 27.8%, 20.6% and 19.5% (χ2=96.61, P<0.001) in participants aged 18-44, 45-59, and ≥ 60 years, respectively. Conclusions: Low blood HDL-C was the main type of dyslipidemia among the population in remote rural areas of Xinjiang. The prevalence of dyslipidemia among men was greater than that among women, and there was a trend of younger men than women showing dyslipidemia.

[Association between CETP polymorphisms and haplotypes with dyslipidemia in Xinjiang Uygur and Kazak residents].

OBJECTIVE: To explore the relationship between the polymorphisms and haplotypes in the CETP gene and dyslipidemia among Xinjiang Kazak and Uygur residents. METHODS: A population status survey was performed from 2010 to 2011 in Kashgar Xinjiang Uygur and Kazak residents, stratified cluster sampling method was used to select Uygur, Kazak residents with abnormal blood lipid values (n=367 and 345, respectively) as the dyslipidemia groups, and to select residents with normal lipid values as control group from the same area (n=374 and 390, respectively). SNaPshot technology was applied to detect the DNA of CETP gene rs3764261, rs1800775, rs708272 and rs5882 loci in all selected residents, and linkage disequilibrium analysis and haplotype construction were performed. RESULTS: (1) In Uygur residents, the dyslipidemia risk of rs708272 CT (OR=0.64, 95%CI 0.46-0.91, P=0.01) and TT genotype (OR=0.60, 95%CI 0.40-0.91, P=0.02) was significantly lower than CC genotype. Dyslipidemia risk of rs3764261 GT (OR=0.55, 95%CI 0.40-0.74, P=0.00) and TT genotype (OR=0.47, 95%CI 0.28-0.78, P<0.01) was significantly lower than GG genetype. Dyslipidemia risk of the rs1800775 CC genotype was higher than AA genotype (OR=1.79, 95%CI 1.17-2.74, P=0.01). There was no statistical significance in CETP gene of the 4 genotype and allele frequency between the dyslipidemia and normal lipid groups in Kazak residents (all P>0.05). (2) In Uighur residents with dyslipidemia, HDL-C level was significantly higher in rs708272 TT genotype carriers than in CC and CT genotypes (all P<0.05) and in rs3764261 TT genotype carriers than in GG genotype carriers (P=0.008), while was significantly lower in rs1800775 CC genotype carriers with AA genotype carriers (P=0.008). (3) Linkage disequilibrium analysis showed that there was strong linkage disequilibrium between rs3764261 and rs708272 (D'=0.869, r(2)=0.869), rs1800775 and rs708272 (D'=0.845, r(2)=0.446) in Uighur residents, and there was strong linkage disequilibrium between rs3764261 and rs708272 (D'=0.963, r(2)=0.963), rs1800775 and rs708272 (D'=0.988, r(2)=0.630) in Kazak residents. (4) Significant differences were observed in frequency distribution of haplotype GACA(OR=0.579, 95%CI 0.388-0.864, P=0.006), GATA (OR=2.183, 95%CI 1.231-3.873, P=0.006), GCCA (OR=0.723, 95%CI 0.549-0.954, P=0.001), TATA (OR=0.723, 95%CI 0.549-0.954, P=0.021) and TATG (OR=0.601, 95%CI 0.429-0.841, P=0.002) in Uighur residents with normal or abnormal lipid profiles, while significant difference was observed in frequency distribution of haplotype GCCG (OR=1.961, 95%CI 1.207-3.188, P=0.005) in Kazak residents with normal or abnormal lipid profiles. CONCLUSION: CETP genotype rs708272, rs3764261 and rs1800775 polymorphism is closely related to dyslipidemia and haplotype GACA, TATA and TATG will reduce the risk of dyslipidemia, while haplotype GATA, GCCA will increase the risk of dyslipidemia in Uygur residents. The four CETP polymorphisms are not related to the risk of dyslipidemia, but haplotype GCCG is related to increased risk of dyslipidemia in Kazakhs residents.

Association of APOA1 gene polymorphisms (rs670, rs5069, and rs2070665) with dyslipidemia in the Kazakhs of Xinjiang.

The aim of this study was to investigate the potential association between apolipoprotein A1 (APOA1) gene rs670, rs5069, and rs2070665 polymorphisms and dyslipidemia in the Kazakh population of Xinjiang, China. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) was used to identify APOA1 (rs670, rs5069, and rs2070665) genotypes in 736 subjects (341 dyslipidemia patients and 395 control subjects). The frequencies of the CC genotype for rs1421085 were found to be 7.2% (obese group), 4.4% (overweight group), and 5.6% (control group). Polymorphisms of the three loci of the APOA1 gene in Kazakh subjects met Hardy-Weinberg equilibrium. The frequencies of the A allele for rs670 were found to be 14.3% (dyslipidemia group) and 12.7% (control group). The frequencies of the T allele for rs5069 and rs2070665 were: dyslipidmia group (7.2 and 30.1%, respectively) and control group (7.7 and 32.5%, respectively). Frequency distributions of the 3 types of genotypes and alleles of the three loci showed no statistically significant difference (P > 0.05). Significant differences were observed in lipoprotein (α) [Lp(α)] between patients with the rs2070665 CT + TT and CC genotypes (P < 0.05); however, none of the other relevant indicators differed significantly between the two genotypes. No significant association was identified between rs670 or rs5069 and the lipid-related metabolic indices assessed in the study. These findings indicate that the polymorphisms in the APOA1 gene (rs670, rs5069, and rs2070665) are not associated with dyslipidemia in the Kazakh population assessed in this study.

The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight.

OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. METHODS: In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [(11)C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL-Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a small group of lean-to-morbidly obese individuals (n=20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain's homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n=19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL-Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual's emotional well-being was. CONCLUSIONS: This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network.

Lutein alleviates arsenic-induced reproductive toxicity in male mice via Nrf2 signaling.

This study aims to investigate the mechanisms involved in the action of lutein (LU) alleviating arsenic-induced reproductive toxicity using mice model. Forty male Kunming mice were received following treatments by gavage: normal saline solution (control), arsenic trioxide (ATO; 5 mg/kg/day), LU (40 mg/kg/day), and ATO + LU (5 mg/kg/day + 40 mg/kg/day). At the end, the mice were killed by cervical dislocation and weighed. Pathological examination was done on the testis. The biomedical parameters including superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed. The messenger RNA (mRNA) and protein expression of Nrf2, heme oxygenase 1 (HO-1), glutathione S-transferase (GST), nicotinamide adenine dinucleotide phosphate dehydrogenase, quinone 1 (NQO1) in testis were detected by real-time polymerase chain reaction and Western blot. We found that there was a decrease in sperm count; testis somatic index; the activities of SOD, GSH, total antioxidative capacity (p < 0.01, respectively) in ATO-treated mice, while there was an increase in the levels of sperm abnormalities, MDA, and 8-OHdG than control (p < 0.01, respectively). The groups treated with ATO + LU showed recovery of the measured parameters between those of ATO or saline-treated group. The antagonized interaction between ATO and LU was statistically significant (p < 0.01). Mice treated with ATO + LU also showed greater mRNA expression of Nrf2, HO-1, NQO1, and GST than ATO or saline-treated groups. These findings suggest that LU alleviates reproductive toxicity induced by arsenic in male mice via Nrf2 signaling, which implicates a possible mechanism of LU in preventing the reproductive injury, and elucidates that consuming the rich plant sources of LU will alleviate the reproductive toxicity induced by chemicals.

Association between polymorphisms of fat mass and obesity-associated gene and metabolic syndrome in Kazakh adults of Xinjiang, China.

The aim of this study was to assess the association between three FTO polymorphisms (rs9939609, rs8057044, and rs1421085) and metabolic syndrome (MS)-related outcomes in the low-income, rural, nomadic minority Khazakh population in far western China. A total of 489 subjects (245 MS patients, 244 controls) were included in the study and DNA samples were genotyped for the three polymorphisms by matrix-assisted laser desorption/ionization time of flight mass spectrometry. The frequencies of the rs1421085 and rs9939609 genotypes and alleles did not differ significantly between MS patients and control, while the frequencies of rs8057044 G alleles and GG genotypes were higher in MS patients (P < 0.05) than in control subjects (G: 61.16 vs 53.53%, GG: 39.07 vs 29.05%) and the frequencies of rs8057044 A genotypes and alleles were lower (P < 0.05) in MS patients compared with controls (AA: 17.36 vs 21.99%, A: 38.84 vs 46.47%). Risk analysis of the rs8057044 polymorphism revealed individuals with GA and GG genotypes to have 1.112 and 1.731 times higher risks of developing MS than those with the AA genotype, respectively, while the G allele was found to be associated with a 1.367 times higher risk of developing MS compared with the A allele. These apparent correlations, however, did not hold true when adjusted for BMI. Weight, WC, HC, and BMI differed significantly between rs8057044 GG and AA+GA genotypes (P < 0.05).

Polymorphisms in the PPARγ gene and their association with metabolic syndrome in Uyghurs and Kazakhs from Xinjiang, China.

We investigated the association between polymorphisms rs1801282 and rs3856806 of the PPARγ gene and metabolic syndrome (MS) among Uyghurs and Kazakhs. Mass spectrometry techniques were used to detect the PPARγ genotypes rs1801282 and rs3856806 in 987 subjects, CC genotype and C allele frequencies were 83.6 and 91.7%, respectively, at rs1801282 in Kazakhs, which were higher than those in Uyghurs (72.3 and 85.0%, respectively; P < 0.05). CC genotype and C allele frequencies were 73.6 and 85.3%, respectively, at the rs3856806 loci in Kazakhs, which were higher than those in Uyghurs (60.7 and 77.9%, respectively; P < 0.05). For the rs3856806 polymorphism in Kazakhs, CT/TT genotype and T allele frequencies were 21.2 and 12.4% for MS subjects, which were lower than those for the control group (31.6 and 17.0%, respectively; P < 0.05). Risk analysis of Kazakhs revealed that individuals with the CT and TT genotypes at rs3856806 had an increased risk, 0.524- and 0.770-fold, respectively, of developing MS than those possessing the CC genotype. Individuals with the T allele also had an increase in risk, by 0.699-fold, of developing MS than those with the C allele. For Uyghurs, those with the CC genotype at rs1801282 had higher systolic blood pressure than those with the CG/GG genotype. Among Kazakhs, those with the CC genotype at rs3856806 had higher triglyceride and waist-hip ratio levels but lower high-density lipoprotein cholesterol levels than those with the CT/TT genotype. The rs1801282 and rs3856806 PPARγ polymorphisms differ between Uyghurs and Kazakhs from Xinjiang Province, China.

Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

BACKGROUND: Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters. METHODS: We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. RESULTS: TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7 ng/mL and 50.8 ng/mL, respectively, consistent with modest selectivity for NET in vivo. Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5 ng/mL and 23.9 ng/mL, respectively. A single-dose, open-label PET study (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21 ng/mL, and at doses of greater than 4 mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35 ng/mL. CONCLUSIONS: These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.

Analysis of the haplotype and linkage disequilibrium of PPARγ gene polymorphisms rs3856806, rs12490265, rs1797912, and rs1175543 among patients with metabolic syndrome in Kazakh of Xinjiang Province.

We investigated the relationship between haplotype and linkage disequilibrium of the PPARγ gene polymorphisms rs3856806, rs12490265, rs1797912, and rs1175543 and metabolic syndrome (MS) in the Kazakh people of Xinjiang Province. For PPARγ, rs3856806, rs12490265, rs1797912, and rs1175543 genotypes were detected in 489 subjects (including 245 MS patients and 244 controls) using matrix-assisted laser desorption-ionization time-of-flight mass spectrometry. Frequencies of rs3856806T, rs12490265A, rs1797912C, and rs1175543G alleles in MS patients were significantly lower than those of controls [rs3856806T allele: 12.53 vs 17.01% (P = 0.044), rs12490265A allele: 31.84 vs 38.52% (P = 0.029), rs1797912C allele: 35.31 vs 43.24% (P = 0.011), rs1175543G allele: 40.61 vs 47.54% (P = 0.029)]. Significant linkage disequilibrium was observed between the PPARγ rs1797912 and rs1175543 polymorphisms as well as between the rs12490265 and rs1175543 polymorphisms. A total of 14 haplotypes were found. Patients with rs3856806T, rs12490265A, rs1797912C, and rs1175543G were observed 0.267 times more frequently [95% confidence interval = 0.126-0.566] than those with rs3856806C, rs12490265G, rs1797912A, and rs1175543A, respectively. The PPARγ gene polymorphisms rs3856806, rs12490265, rs1797912, and rs1175543 were associated with MS in Kazakh subjects. Very strong linkage disequilibrium was found between the PPARγ rs1797912 and rs1175543 polymorphisms as well as between the rs12490265 and rs1175543 polymorphisms. AGCC and GAAT haplotypes may serve as protective factors against MS. The rs3856806T, rs12490265A, rs1797912C, and rs1175543G alleles may enhance the protective effect of MS.

Epidemiological analysis of dyslipidemia in adults of three ethnicities in Xinjiang, China.

This study investigated the prevalence and distribution of dyslipidemia in adults of Uygur, Kazak, and Han ethnicity in Xinjiang, China. A questionnaire including general data, physical examination (blood pressure, body height, and body weight) and blood lipid [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)] was administered to 11,506 adults in Xinjiang, China from 2009 to 2010 using a stratified sampling method. The overall prevalence rates of dyslipidemia in Uygur, Kazak, and Han adults were 42.4, 31.6, and 30.2%, respectively; they were 42.4, 31.8, and 28.2% after age standardization (P < 0.01). After standardization, the overall prevalence rates in Uygur, Kazak, and Han men were 52.6, 35.4, and 33.2%, respectively, which were significantly higher than that in women of the corresponding ethnicities (P < 0.01). In Uygur, Kazak, and Han adults, there were significant differences with respect to the standardized prevalence rates of high TG (9.3, 9.3, and 17.3%), high TC (5.2, 6.9, and 6%), low HDL-C (33.6, 20.8, and 11.1%), and high LDL-C (2.4, 2.9, and 2%) (P < 0.05). The prevalence rates of dyslipidemia in Uygur, Kazak, and Han adults in Xinjiang are higher than the average levels in China, with significant differences in ethnicity, age, and gender. Han adults exhibited the highest prevalence rate of high TG. Meanwhile, Uygur adults had the highest prevalence rate of low HDL-C. Kazak adults had high prevalence rates of high TC, low HDL-C, and high LDL-C.

Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD.

BACKGROUND: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [(11)C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [(11)C]MRB (a NET ligand) and [(11)C]AFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys. METHODS: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12mg/kg/h and 0.045-1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated. RESULTS: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31±10 and 99±21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8mg/kg, approx. 300-600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. CONCLUSION: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET.

Prediction of G-protein-coupled receptor classes in low homology using Chou's pseudo amino acid composition with approximate entropy and hydrophobicity patterns.

We use approximate entropy and hydrophobicity patterns to predict G-protein-coupled receptors. Adaboost classifier is adopted as the prediction engine. A low homology dataset is used to validate the proposed method. Compared with the results reported, the successful rate is encouraging. The source code is written by Matlab.

Effect of charcoal-containing cigarette filters on gas phase volatile organic compounds in mainstream cigarette smoke.

Of the chemicals identified to date in mainstream cigarette smoke with known toxicological properties, the volatile organic compounds (VOCs) are considered the most hazardous group owing to their high abundance and toxicity. In this research we evaluate a recently introduced line of cigarettes that contain charcoal in their filters. The amount of charcoal in these filters ranged from 45 mg to 180 mg and were either dispersed among the filter material or contained in a small cavity in the filter segment. Charcoal has long been used for removing VOCs from both water and air. Our findings indicate that these cigarettes reduce machine generated mainstream smoke deliveries of a wide range of VOCs compared to a similar, non-charcoal filtered, cigarette. However, this reduction is dependent not only on the amount of charcoal present but also on the volume of smoke being drawn through the filter. While a brand with 45 mg charcoal reduces VOC delivery under ISO smoking conditions, charcoal saturation and breakthrough occur under more intense smoking conditions. Breakthrough is minimised for brands with the most charcoal. Overall, the brands with the most charcoal are effective at reducing VOC deliveries under even intense smoking conditions.

Laser assisted ultrasound guided aspiration improves procedure time and reduces number of withdrawals.

This study evaluated the performance of in-vitro freehand aspiration of a simulated cyst with ultrasound aspiration guided by a newly designed laser assisted (LA) device. The LA device was equipped with an adjustable light source generating a sector light plane. This laser light plane was parallel to and overlapped the ultrasound acoustical plane, to help with needle positioning. Five operators randomly performed 30 freehand or LA ultrasound guided aspirations of a simulated cyst. The frequency was set at 8 MHz and depth at 4 cm. Procedure time and number of syringe withdrawals were statistically compared before and after using the LA device. Both experienced and inexperienced operators required significantly less time to perform the aspiration and had fewer syringe withdrawals when using the LA device. The LA device provides a reference plane in space, allowing the operator to more accurately position and adjust needle direction. Additional in-vivo testing is required to test the clinical practicability.

Using pseudo amino acid composition and binary-tree support vector machines to predict protein structural classes.

Compared with the conventional amino acid composition (AA), the pseudo amino acid composition (PseAA) as originally introduced by Chou can incorporate much more information of a protein sequence; this remarkably enhances the power to use a discrete model for predicting various attributes of a protein. In this study, based on the concept of Chou's PseAA, a 46-D (dimensional) PseAA was formulated to represent the sample of a protein and a new approach based on binary-tree support vector machines (BTSVMs) was proposed to predict the protein structural class. BTSVMs algorithm has the capability in solving the problem of unclassifiable data points in multi-class SVMs. The results by both the 10-fold cross-validation and jackknife tests demonstrate that the predictive performance using the new PseAA (46-D) is better than that of AA (20-D), which is widely used in many algorithms for protein structural class prediction. The results obtained by the new approach are quite encouraging, indicating that it can at least play a complimentary role to many of the existing methods and is a useful tool for predicting many other protein attributes as well.

Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.

OBJECTIVE: The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. METHOD: Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. RESULTS: Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. CONCLUSIONS: Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.

Non-MAO A binding of clorgyline in white matter in human brain.

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon-11 (C-11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium-substituted [11C]clorgyline ([11C]clorgyline-D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline-D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C-11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline-D2. Thus deuterium-substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non-MAO A binding which is most apparent in the white matter. The characterization of the non-MAO A binding component of this widely used MAO A inhibitor merits further investigation.