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Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single-locus analysis showed that the single-nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P < .0038). The gene-gene interaction analysis identified the overall best models, including a 2-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P = .0022) and a 3-locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = .0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we propose a promising data-mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene-gene interactions.

People with cognitive deficits or executive dysfunction are often overweight or obese. Several human neuroimaging studies have found that executive function (EF) predicts food intake and weight gain; however, fewer studies have investigated the relationship between EF and weight loss. The Stroop task is a classic measure of EF that is used in many neuroimaging studies. In the present work, functional near infrared spectroscopy (fNIRS) data were collected during performance of the Stroop task from a sample of overweight or obese adolescents and young adults (n = 31) who participated in a summer fitness and weight loss camp. We assessed the Stroop effect by interference in the reaction time (RT) to visual challenges, and by alterations in levels of oxygenated hemoglobin, as detected by fNIRS. In line with previous studies, we found that the Stroop effect was successfully induced by different visual task conditions among obese/overweight individuals. Moreover, our results reveal that better Stroop task performance is correlated with greater weight loss over a4-weekfitness intervention. Indeed, behavioral data demonstrated that reduced RT interference predicted a greater percentage of weight loss. Moreover, overweight/obese individuals with a greater hemodynamic response in the left ventrolateral and bilateral dorsolateral prefrontal cortex due to the Stroop effect lost more weight during the short-term fitness intervention than participants with lower levels of activation of these neural regions. Overall, our results support a role for prefrontal cortex-mediated EF in influencing food intake and weight loss outcomes in a population of a previously unstudied age.

Background Astigmatism is one of the most significant obstacles for achieving satisfactory visual function. This study was to evaluate the influence of astigmatism on contrast sensitivity (CS) and higher-order aberrations. Methods CS, accommodation response and wavefront aberration were measured in 113 patients with astigmatism, aged 18 - 36 years. Both single and binocular visual performance were examined under four lighting conditions: photopia, photopia with glare, scotopia and scotopia with glare respectively. Accommodation response was classified as normal, abnormal and low. The contribution of the power and axis of astigmatism to CS, accommodation response and wavefront aberration was analyzed. Results As the dioptric power of astigmatism increased, the loss of CS spatial frequency changed from high to intermediate, and then to low frequency. CS scores varied at different illuminance levels, descending in the following sequence: photopia, photopia with glare, scotopia, and scotopia with glare. However, the normal accommodation group showed better CS values under photopia with glare than without glare. The range of influenced direction of sine-wave gratings remained mostly at the meridian line of high dioptric power, which would be expanded when optical accommadation attenuated. The patients with symmetrical astigmatism got higher CS scores with binoculus vision than with dominant eye vision, while the patients with asymmetrical astigmatism did this only at scotopia with glare. Among higher-order aberrations, coma aberration, secondary coma aberration and the total higher order aberration were influenced by astigmatism, all of which rising with the power of astigmatism increased. Conclusions Reducing astigmatism might improve the performance of visual function. Not only the power of astigmatism should be cut down, but also the binocular axes should be made symmetrically.

Aims Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP-C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide. Methods Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC. Results The Cmax and AUC(0,∞) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t1/2 of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in tmax values among the three genotypic groups was not statistically significant. Conclusions Our results suggest that OATP1B1-mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.

Objective We investigated the linkage between SNPs in exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) of MDR1, and explored the effect of linked polymorphism on the absorption of talinolol after a single oral dose of 100 mg. Methods The genotype of 192 healthy Chinese volunteers was determined using PCR-RFLP with respect to the MDR1 alleles of interest, C1236T, G2677T/A and C3435T. Linkage disequilibrium was analyzed using PHASE software. Consecutive eligible subjects received a single oral dose of 100 mg talinolol. Venous blood samples were taken at intervals up to 60 h post dose for HPLC analysis of plasma concentration of talinolol to obtain a pharmacokinetic profile. Results Linkage disequilibrium existed between exon 21 (G2677T/A) and exon 26 (C3435T), exon 12 (C1236T) and exon 21 (G2677T/A), but not between exon 12 (C1236T) and exon 21 (G2677T/A). AUC (0,3h), AUC (0,∞), C max and C max /AUC (0,∞), used as indices of talinolol absorption, were not significantly different between the genotype groups of 2677GG/3435TT, 2677TT/3435TT, 2677GT/3435CT and 2677AT/3435CT. For these 4 groups, AUC(0,3h) were 436.8 ± 50.1, 510.1 ± 86.3, 466.1 ± 77.8 and 437.2 ± 73.4 (μg × h/l) and the C max /AUC (0,∞) were 0.097 ± 0.018, 0.093 ± 0.022, 0.105 ± 0.014 and 0.102 ± 0.027 (h −1 ), respectively. ( P > 0.05). Conclusions The linked MDR1 polymorphisms in exon 21 G2677T/A and exon 26 C3435T apparently did not contribute to the absorptive pharmacokinetics of a single oral dose of 100 mg talinolol.

Background: Human cytochrome P450 2A13 (CYP2A13) is involved in the activation of numerous toxicants and carcinogens, especially in the metabolic activation of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major tobacco-specific carcinogen. A functionally significant coding single nucleotide polymorphism (C3375T) in exon 5 of CYP2A13, which results in an amino acid substitution of Arg 257 to Cys, has been recently reported to exist in White, Black, Hispanic, and Asian individuals, with the variant 3375T allele frequencies being 1.9%, 14.4%, 5.8% and 7.7%, respectively. Since genetic background differs between ethnic groups, our present study aims to characterize the CYP2A13 Arg257Cys polymorphism in Chinese. Methods: 258 healthy Chinese Han volunteers were involved in this study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was employed to genotype for the Arg257Cys polymorphism. Results: Of all the 258 subjects, 27 (10.5%) heterozygotes and 1 (0.4%) homozygote for the 257Cys allele were detected. The frequency of the variant 257Cys allele in this Chinese population was 5.6% (95%CI: 4.2–7.0%). Conclusion: The CYP2A13 Arg257Cys variant represents a common polymorphism in Chinese, with the 257Cys allele frequency being similar to the Hispanic and Asian groups, but significantly lower than the Black. D 2004 Published by Elsevier B.V.

Background: The motive of this study was to investigate the collaboration between MDR1 gene polymorphisms and anesthetic effects following pediatric tonsillectomy. Methods: All together 178 children undergoing tonsillectomy with preoperative sevoflurane–remifentanil anesthesia were selected. In order to determine MDR1 gene polymorphisms of 3435C > T, 1236C > T, and 2677G > T/A, polymerase chain reaction–restriction fragment length polymorphism was used. Mean arterial pressure (MAP), diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR) at T0 (5 mins after the repose), T1 (0 min after tracheal intubation), T2 (5 mins after the tracheal intubation), T3 (0 min after the tonsillectomy), T4 (0 min after removal of the mouth-gag) and T5 (5 min after the extubation) were observed. The visual analog scale (VAS), the face, legs, activity, cry, and consolability (FLACC) pain assessment, and Ramsay sedation score were recorded after the patients gained consciousness. The adverse reactions were also observed. Results: As compared to the CT + TT genotype of MDR1 1236C > T, the time of induction, respiration recovery, eye-opening, and extubation of children with the CC genotype was found to be shorter (all P T CC genotype was found to be superior to those carrying the CT + TT genotype.

Aim: To detect 388G>A and 521T>C variant alleles in the organic anion transporting polypeptide-1B1 (OATP1B1, encoding gene SLCO1B1) gene. Methods: One hundred and eleven healthy volunteers were screened for OATP1B1 alleles in our study. PCR-restriction fragment length polymorphism was used to identify the 388G>A polymorphism and a 1-step tetra-primer method was developed for the determination of 521T>C mutation. Results: The frequencies of the 388G>A and 521T>C variant alleles in the Chinese population were 73.4% and 14.0%, respectively. The frequencies of the SLCO1B1*1 b and *15 haplotypes were 59.9% and 14.0%, respectively. Conclusion: The SLCO1B1*1 b and SLCO1B1*15 variants are relatively common in the Chinese population. Their frequencies are similar to that in the Japanese, but significantly different from that in Caucasians and blacks.

To investigate the pharmacokinetics of mycophenolic acid (MPA), an active metabolite of mycophenolate mofetil (MMF) in Chinese adult liver transplant patients.Thirty-eight liver transplant patients (male 30, female 8) receiving MMF 1.0 g, twice daily in accordance with the recommended regimen were included in this study. Plasma MPA concentrations were measured by high performance liquid chromatography at 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the administration of a single dose. Pharmacokinetic parameters were calculated with 3P97 software.The plasma MPA concentration-time curve was characterized with an early sharp peak reached at 0.5 - 6.0 h after oral administration. And in some patients there was a small second peak due to enterohepatic circulation of mycophenolic acid glucuronide (MPAG), which underwent deglucuronidation and re-absorption as MPA at 4 to 12 h postdose. The mean peak plasma concentration (C(max)) and area under concentration-time curve (AUC(0-12 h)) were (12 +/- 7) microg x mL(-1) and (44 +/- 16) microg x h x mL(-1), respectively. However, a large variability of pharmacokinetic parameters existed in these patients.In view of the inter-individual variability of MMF pharmacokinetics, plasma MPA concentration should be monitored routinely after MMF administration for individual patient.

To investigate the association of CYP2C9*3 and *6 with hyperlipidaemia in Chinese.Four hundred and seventy-six Chinese participated in the study, including 211 uncomplicated hyperlipidaemic patients and 265 healthy controls. PCR-RFLP was used to identify CYP2C9*3 and *6.CYP2C9*6 was not detected in this study. The allelic frequency of CYP2C9*3 was 0.039 (95% CI 0.022, 0.056). A nonsignificant difference existed in CYP2C9*3 frequencies between males and females (P = 0.605, OR = 1.194, 95% CI 0.610, 2.336), patients and controls (P = 0.063, OR = 0.506, 95% CI 0.244, 1.049) in the total population. However, in the female group, CYP2C9*3 frequency in patients with hyperlipidaemia was significantly lower than that in controls (P0.0001, OR = 0.062, 95% CI 0.008, 0.476).The association of CYP2C9*3 with hyperlipidaemia was specific for females in this Chinese population.