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1.
Acta Pharmacol Sin ; 38(3): 415-423, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28112181

RESUMO

The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P =0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P =0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.


Assuntos
Antígeno CTLA-4/genética , Imunossupressores/administração & dosagem , Interleucina-3/genética , Tacrolimo/administração & dosagem , Adulto , Povo Asiático , Feminino , Rejeição de Enxerto/genética , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único
2.
J Nutr ; 146(3): 509-15, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26817714

RESUMO

BACKGROUND: Evidence exists that maternal zinc status during pregnancy is linked to adverse pregnancy outcomes including abortion, fetal growth restriction, and neural tube defects. However, it remains unclear whether maternal serum zinc concentration (SZC) during pregnancy is associated with risk of preterm birth. OBJECTIVE: This study was designed to investigate the association between maternal SZC during pregnancy and risk of preterm birth. METHODS: For this substudy of the China-Anhui Birth Cohort Study, 3081 maternal-singleton pairs with detailed birth records and available serum samples were identified. The maternal SZC was determined with flame atomic absorption spectroscopy. A total of 169 preterm births were identified. In this study, the women were divided into tertiles on the basis of their SZC: low (<76.7 µg/dL), medium (76.7-99.6 µg/dL), and high (≥99.7 µg/dL). The ORs for preterm birth were estimated by using multiple logistic regression models. RESULTS: The median SZC was 87.3 µg/dL (range: 11.1-211 µg/dL). Incidences of preterm birth were 7.3% and 6.0% among subjects with low and medium SZCs, respectively, which were significantly higher than 3.1% among subjects with a high SZC [ORs (95% CIs) for low and medium SZCs: 2.45 (1.60, 3.74), P < 0.001, and 2.00 (1.29, 3.09), P < 0.01, respectively]. After adjustment for prepregnancy body mass index, maternal age, time of serum collection, gravidity, parity, and monthly income, adjusted ORs were 2.41 (95% CI: 1.57, 3.70; P < 0.001) and 1.97 (95% CI: 1.27, 3.05; P < 0.01) among subjects with low and medium maternal SZCs. CONCLUSIONS: Maternal serum zinc concentration during pregnancy is inversely associated with risk of preterm birth in the Chinese population, and the results are driven by maternal SZC in the first trimester.


Assuntos
Povo Asiático , Nascimento Prematuro/sangue , Nascimento Prematuro/epidemiologia , Zinco/sangue , Adulto , Índice de Massa Corporal , China/epidemiologia , Feminino , Humanos , Incidência , Recém-Nascido , Modelos Logísticos , Estado Nutricional , Gravidez , Estudos Prospectivos , Fatores de Risco , Fatores Socioeconômicos , Adulto Jovem
3.
Zhongguo Wei Zhong Bing Ji Jiu Yi Xue ; 24(3): 145-8, 2012 Mar.
Artigo em Zh | MEDLINE | ID: mdl-22401158

RESUMO

OBJECTIVE: To demonstrate the pharmacokinetic profile of meropenem when administered by 3-hour infusion in patients undergoing continuous veno-venous hemofiltration (CVVH). METHODS: The study was conducted in 10 patients, who were treated with CVVH. Each subject received meropenem in 3-hour infusion of 500 mg every 6 hours. Blood samples were collected before infusion (0 hour) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6 hours (just before the infusion of the next dose) after the beginning of the fourth infusion. The concentrations of meropenem in plasma were measured by high-performance liquid chromatography method, and mean serum meropenem concentration-time curve was plotted. RESULTS: Peak plasma drug concentrations measured 3 hours post-infusion were (25.05 ± 5.64) mg/L, and trough levels after 6 hours of infusion were (13.03 ± 3.01) mg/L. The area under the plasma concentration-time curve (AUC) was (118.42 ± 26.78) mg x h⁻¹ x L⁻². The elimination half-life (T1/2) was (3.74 ± 0.55) hours. The mean residence time (MRT) was (4.99 ± 0.84) hours. The volume of distribution (Vb) was (22.85 ± 9.85) L and clearance of meropenem (CL) was (4.49 ± 1.32) L/h. The percentage of time that the serum drug concentration was above the minimum inhibitory concentration (MIC) accounting for the interval time of infusion (%T>MIC) was 100% (MIC 8 mg/L) in all the 10 patients. CONCLUSION: Based on these data, we concluded that satisfactory pharmacodynamic parameters could be attained in CVVH patients treated with meropenem by a prolonged infusion time of 3 hours with a dosage of 500 mg for every 6 hours.


Assuntos
Hemofiltração , Tienamicinas/administração & dosagem , Tienamicinas/farmacocinética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/terapia , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Feminino , Humanos , Infusões Intravenosas , Masculino , Meropeném , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/metabolismo , Sepse/terapia
4.
Pharmacogenet Genomics ; 21(11): 713-20, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21886016

RESUMO

BACKGROUND: CYP3A5 genetic polymorphisms contribute to marked interindividual differences in the metabolism of and response to tacrolimus in humans. OBJECTIVE: This study was aimed to clarify the impact of the CYP3A5*3 variant on tacrolimus dose requirements and acute rejection rates in patients with organ transplantation. METHODS: A literature search was performed up to August 2009 by using the Cochrane library, PubMed, Medline, and EMBase. RESULTS: Twenty-three studies (a total of 1779 patients) were included in this meta-analysis. Eighteen studies (1443 patients) were involved in renal transplantation and five studies (336 patients) in liver transplantation. Results of meta-analysis demonstrated that, in renal transplant patients, despite the presence of significant heterogeneity, CYP3A5 expressers required higher mean tacrolimus daily doses by 0.045 mg/kg (95% confidence interval (CI), 0.033-0.056) than nonexpressers. Furthermore, sub-analysis of the time of posttransplantation showed that CYP3A5 expressers required higher daily doses than nonexpressers by 0.010, 0.084, 0.041, 0.037, and 0.044 mg/kg at week 2, and at month 1, 3, 6, and 12, respectively. Subset analysis of the ethnicity of organ recipients indicated that mean tacrolimus daily doses were 0.056, 0.037, and 0.077 mg/kg higher in CYP3A5 expressers than non- expressers for white, Chinese, and Japanese patients, respectively. In contrast, for liver transplant patients, higher tacrolimus daily doses were required not only in CYP3A5 expressers of the organ donors than nonexpressers by 0.024 mg/kg (95% CI, 0.019-0.028), but also in CYP3A5 expresser of the organ recipients than nonexpresser by 0.012 mg/kg (95% CI, 0.005-0.018). However, a significant difference in the acute organ rejection rate was observed only at one month (odds ratio, 3.27; 95% CI, 1.57-6.81; P=0.002). CONCLUSION: Tacrolimus daily dose requirements may vary with the presence of the CYP3A5*3 variant, ethnicity of the organ recipients, and the time of posttransplantation. In addition, the acute organ rejection rate may be higher in CYP3A5 expressers than nonexpressers over the first month after transplantation.


Assuntos
Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Humanos , Transplante de Fígado , Modelos Genéticos , Polimorfismo Genético/efeitos dos fármacos , Análise de Sobrevida
5.
Mol Genet Metab ; 103(4): 388-93, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21546300

RESUMO

BACKGROUND: A common follicle-stimulating hormone (FSH) receptor (or FSHR) polymorphism Ser680Asn (rs6166) was found to be associated with altered ovarian response in women undergoing in-vitro fertilization. To further investigate such an association, a meta-analysis was conducted. METHODS: A PubMed literature search was conducted to identify all cohort studies investigating such a relationship. The following parameters-basal FSH levels, total FSH doses, oocytes retrieved, and pregnancy rates-were used to evaluate the ovarian function, its response to exogenous FSH and in-vitro fertilization and intracytoplasmic sperm injection outcome. RESULTS: A total of 1421 cases were collected from eight studies. Of them, a significantly lower basal FSH level was observed in patients harboring Asn/Asn (NN) genotype than those carrying the Ser/Ser (SS) genotype both in Asian (WMD: -2.57 mIU/ml, 95% CI: -2.96 to -2.19, P<0.0001) and Caucasian retrospective groups (WMD: -1.86 mIU/ml, 95%CI: -2.07 to -1.66, P<0.0001) with no heterogeneity. Moreover, carriers of the SS tended to require greater FSH doses than NN (WMD: -268.82IU, 95% CI: -561.28 to 23.63, P=0.07). Other parameters, such as oocytes retrieved and pregnancy rate, were not significantly different between the groups. CONCLUSION: Carriers of the SS variant have slightly higher basal FSH levels, tending to require higher doses of exogenous FSH for stimulation.


Assuntos
Ovário/fisiopatologia , Polimorfismo Genético , Receptores do FSH/genética , Povo Asiático , Feminino , Fertilização in vitro , Genótipo , Humanos , Gravidez , Serina/genética , Resultado do Tratamento , População Branca
6.
Pharmacogenet Genomics ; 20(9): 525-31, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20588203

RESUMO

BACKGROUND: Whether the loss-of-function allele CYP3A5*3 variant is associated with significantly impaired metabolism of cyclosporine A (CsA) in transplant patients is still controversial because of the lack of prospective, large-scale clinical studies performed among diversely ethnic populations. OBJECTIVES: This meta-analysis was designed to determine whether the CYP3A5*3 variant could affect CsA blood concentrations and the rate of acute rejection in renal transplant recipients. METHODS AND RESULTS: All relevant publications were retrieved online from 1966 to March 2010, in which 14 studies were chosen, and 1821 renal transplant patients were enrolled. The results showed that there were significant differences in the CsA dose-adjusted trough concentration (C0) between the CYP3A5*3/*3 and CYP3A5*1/*1 carriers [weighted mean difference (WMD): 10.06 mug/l per mg/kg, 95% confidence interval (CI): 3.12-17.00, P=0.004] and between the non-CYP3A5*1 allele carriers and the CYP3A5*1 allele carriers (WMD: 8.32 mug/l per mg/kg, 95% CI: 3.16-13.49, P=0.002). In addition, a subgroup analysis stratified by ethnicity indicated that a significant difference in CsA dose-adjusted C0 was observed between the non-CYP3A5*1 allele carriers and the CYP3A5*1 allele carriers in Asian patients, but not in Caucasian patients. Moreover, a significant difference in the mean daily dose was observed between the non-CYP3A5*1 allele carriers and the CYP3A5*1 allele carriers (WMD: -0.19 mg/kg, 95% CI: -0.31 to -0.07, P=0.002). However, the meta-analysis suggested that there was little or no association of the CYP3A5*3 variant with the acute rejection rate in renal transplant patients treated with CsA [odds ratio=0.94, 95% CI: 0.57-1.54, P=0.80]. CONCLUSION: We concluded that the CYP3A5*3 variant could be associated, to a certain extent, with increased CsA dose-adjusted C0 in blood and reduced mean daily doses, but that this genetic variant allele seemed to have little effect on the acute rejection rate in renal transplant patients taking CsA.


Assuntos
Ciclosporina/farmacologia , Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/genética , Transplante de Rim/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Relação Dose-Resposta a Droga , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade
7.
J Clin Pharmacol ; 59(6): 890-899, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30861159

RESUMO

The narrow therapeutic window of tacrolimus necessitates daily monitoring and predictive algorithms based on genetic and nongenetic factors. In this study, we constructed predictive algorithms for tacrolimus stable dose in a retrospective cohort of 1045 Chinese renal transplant recipients. All patients were genotyped for CYP3A4 20230T>C (rs2242480), CYP3A4 T>C (rs4646437), CYP3A5*3 6898A>G (rs776746), ABCB1 129T>C (rs3213619); ABCB1 c.1236C>T (rs01128503), ABCB1 c.2677G>T/A (rs2032582) and ABCB1 c.3435C>T (rs1045642) polymorphisms, and the effects of gene-gene and gene-environment interactions on the predictive accuracy of algorithm were evaluated. In wild-type CYP3A4 rs2242480 (TT) carriers, patients who took calcium channel blockers had lower tacrolimus stable doses than those without the concomitant medications (P < 1 × 10-4 ). In contrast, there was no significant difference in mutant type patients. Similarly, the tacrolimus stable doses in wild-type CYP3A5 rs776746 carriers who had hypertension were higher than those without hypertension (P = 4.10 × 10-3 ). More importantly, dose-predictive algorithms with interaction terms showed higher accuracy and better performance than those without interaction terms. Our finding suggested that wild-type CYP3A4 rs2242480 (TT) carriers should be more cautious to take tacrolimus when they are coadministrated with calcium channel blockers, and CYP3A5 rs776746 (AA) carriers may need higher tacrolimus dosage when they are in combination with hypertension.


Assuntos
Transplante de Rim , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Algoritmos , Povo Asiático , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos de Coortes , Citocromo P-450 CYP3A/genética , Combinação de Medicamentos , Feminino , Interação Gene-Ambiente , Variação Genética , Humanos , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Transplantados
8.
Placenta ; 65: 7-14, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29908644

RESUMO

INTRODUCTION: Several reports demonstrated that cadmium (Cd) had proinflammatory activities. The present study aimed to investigate whether Cd induces inflammatory cytokines in mouse placenta and human trophoblast cells. METHODS: Human JEG-3 cells were treated with different concentration of CdCl2 (0-50 µM) or CdCl2 (25 µM) for different times. The pregnant mice were administered with CdCl2 (3.0 mg/kg, i.p.) on GD15. RESULTS: TNF-α, IL-8 and IL-6 mRNAs were elevated in CdCl2-treated JEG-3 cells. Several inflammatory cytokines were up-regulated in Cd-treated placenta of mice. Moreover, keratinocyte chemokine (KC), a functional analogue of human IL-8, was increased in maternal serum and amniotic fluid from CdCl2-exposed mice. Additional experiment showed that gestational Cd exposure activated Akt signaling in mouse placenta. Co-culture with CdCl2 elevated pAkt level in JEG-3 cells in concentration- and time-dependent manners. LY294002, a specific inhibitor of PI3K, blocked CdCl2-evoked Akt phosphorylation in JEG-3 cells. Concomitantly, LY294002 inhibited CdCl2-induced IL-8 in JEG-3 cells. N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, blocked CdCl2-evoked Akt phosphorylation in mouse placenta and human trophoblast cells. Additionally, NAC attenuated Cd-induced up-regulation of KC in amniotic fluid. DISCUSSION: Cd induces inflammatory cytokines partially through activating Akt signaling in mouse placenta and human trophoblast cells. NAC may be exploited for prevention of Cd-induced placental inflammation.


Assuntos
Cádmio/farmacologia , Citocinas/genética , Mediadores da Inflamação/metabolismo , Placenta/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Trofoblastos/efeitos dos fármacos , Animais , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Placenta/metabolismo , Gravidez , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
Zhonghua Yi Xue Za Zhi ; 87(20): 1384-8, 2007 May 29.
Artigo em Zh | MEDLINE | ID: mdl-17785057

RESUMO

OBJECTIVE: To assess the correlation of the multidrug resistance-1 (MDR1) gene single nucleotide polymorphisms (SNP) C1236T, G2677T/A and C3435T with the outcome of induction chemotherapy in patients with de novo acute myeloid leukemia (AML). METHODS: A total of 44 AML patients were enrolled in this study. Genotype of MDR1 C1236T, G2677T/A and C3435T were analyzed with PCR/PFLP assay. Bone marrow smear was made at the end of the first induction chemotherapy to estimate whether complete remission (CR) has been achieved with the clinical characteristics. The Hardy-Weinberg equilibrium for the MDR1 C1236T, G2677T/A and C3435T were tested using a chi(2) analysis. Frequencies of genotype and allele in MDR1 C1236T, G2677T/A and C3435T were compared using a chi(2) test or Fisher's test in terms of the clinical characteristics or achievement of CR. RESULTS: There were significant differences among ethnicities in exon 12, 21, 26, but which were not between healthy chinese volunteers and AML patients. The CR rate of the group with the number of white blood cells (WBC) < 10 x 10(9)/L were significantly higher than that of the group with WBC > 10 x 10(9)/L (chi(2) = 7.207, P = 0.007). There was no correlation between the MDR1 C1236T and C3435T and CR rate (P = 0.349, P = 0.074), but MDR1 G2677T/A genetic polymorphisms were strong associated with the probability of CR (chi(2) = 6.214, P = 0.045). In addition, the CR was lower in G/G genotype at -2677 than non G/G genotype (chi(2) = 6.142, P = 0.013), and was lower in C/T genotype at -3435 than non C/T genotype (chi(2) = 3.991, P = 0.046), even lower than T/T genotype (chi(2) = 5.134, P = 0.023). CONCLUSION: With important prognostic significance, MDR1 genetic polymorphisms, such as G2677T/A can predict whether complete remission can be achieved after the first course of induction chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Leucemia Mieloide/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Leucemia Megacarioblástica Aguda/tratamento farmacológico , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patologia , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/patologia , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão
11.
Zhonghua Yi Xue Za Zhi ; 87(36): 2541-3, 2007 Sep 25.
Artigo em Zh | MEDLINE | ID: mdl-18067828

RESUMO

OBJECTIVE: To investigate the expression of desmoglein 3 (DSG3), a candidate target gene in the antisense RNA (aRNA) from the purified nasopharyngeal tissues in nasopharyngeal carcinoma (NPC). METHODS: Specimens of nasopharyngeal tissues were harvested from 22 NPC patients, aged 44 +/- 11 (NPC group), and 12 normal persons or patients with nasopharyngeal infectious diseases, aged 46 +/- 14. Microdissection technique was used to get homogenous tissue cells from which total RNA was isolated (control group). aRNA was amplified from the total RNA by "in vitro transcription" (IVT). The expression of DSG3 gene was identified using these aRNA by semi-quantitative reverse transcriptase polymerase chain reaction (sqRT-PCR). RESULTS: The average expression level of DSG3 in the NPC group was 3.536 +/- 2.689, significantly higher than that of the control group (0.95 +/- 0.23, df = 32, t = 3.307, P = 0.002). The expression level of DSG3 in the whole expression profiling of the NPC group was 1.06 +/- 1.60, significantly higher than that of the control group (0.48 +/- 0.23, df = 16, t = 2.145, P = 0.048). CONCLUSION: The whole genome expression profiling detected by sqRT-PCR can be used to shift the marker genes from biopsy tissue samples. DSG3 may be a tumor candidate gene in NPC.


Assuntos
Desmogleína 3/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Nasofaríngeas/genética , Adolescente , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/patologia , RNA Antissenso/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
12.
Sci Rep ; 7: 42192, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28176850

RESUMO

Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the "derivation cohort" to develop dose-prediction algorithm, while the remaining 20% constituted the "validation cohort" to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.


Assuntos
Cálculos da Dosagem de Medicamento , Imunossupressores/uso terapêutico , Transplante de Rim , Aprendizado de Máquina , Insuficiência Renal Crônica/imunologia , Tacrolimo/uso terapêutico , Adulto , Teorema de Bayes , Estudos de Coortes , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Medicina de Precisão , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/cirurgia , Transplantados
13.
Reprod Toxicol ; 63: 174-82, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27319394

RESUMO

Cadmium (Cd) is linked with increased risk of fetal growth restriction (FGR). Nevertheless, the mechanism remains unknown. This study established a mouse model of Cd-induced FGR through two exposure methods. Pregnant mice were either administered with CdCl2 (5, 50 and 250ppm) throughout pregnancy through drinking water or intraperitoneally injected with CdCl2 (4.5mg/kg) on GD9. As expected, fetal weight and crown-rump length were reduced in a gender-independent manner. Interestingly, Mt1 and Mt2, two metallothionein genes, were up-regulated in maternal liver. Correspondingly, Cd accumulated mainly in maternal liver and kidney, and only trace amounts of Cd could pass from dam to placentas and fetuses. Further analysis showed that placental Zn concentration was elevated. Conversely, embryonic Zn concentration was reduced. Moreover, placental Znt1 and Znt2, two zinc transporters, were down-regulated in Cd-exposed mice. These results suggest that maternal Cd exposure during pregnancy reduces placental Zn transport and induces fetal growth restriction.


Assuntos
Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Retardo do Crescimento Fetal/induzido quimicamente , Troca Materno-Fetal , Placenta/efeitos dos fármacos , Zinco/metabolismo , Animais , Cádmio/sangue , Cádmio/farmacocinética , Proteínas de Transporte de Cátions/genética , Regulação para Baixo , Poluentes Ambientais/sangue , Poluentes Ambientais/farmacocinética , Feminino , Sangue Fetal/química , Fígado/metabolismo , Metalotioneína/genética , Camundongos , Placenta/metabolismo , Gravidez , Zinco/sangue
14.
Environ Pollut ; 216: 851-857, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27381872

RESUMO

Cadmium (Cd) was a developmental toxicant that induces fetal malformation and growth restriction in mice. However, epidemiological studies about the association of maternal serum Cd level with risk of preterm birth were limited. This study was to investigate whether maternal serum Cd level during pregnancy is associated with risk of preterm birth in a Chinese population. Total 3254 eligible mother-and-singleton-offspring pairs were recruited. Maternal serum Cd level was measured by GFAAS. Based on tertiles, maternal serum Cd concentration was classified as low (LCd, <0.65 µg/L), medium (MCd, 0.65-0.94 µg/L) and high (HCd, ≥0.95 µg/L). Odds ratio (OR) for preterm birth was estimated using multiple logistic regression models. Results showed the rate of preterm birth among LCd, M-Cd and HCd was 3.5%, 3.8%, and 9.4%, respectively. Subjects with HCd had a significantly higher risk for preterm birth (OR: 2.86; 95%CI: 1.95, 4.19; P < 0.001) than did those with LCd. Adjusted OR for preterm birth was 3.02 (95%CI: 2.02, 4.50; P < 0.001) among subjects with HCd compared to subjects with LCd. Taken together, the above results suggest that maternal serum Cd level during pregnancy is positively associated with risk of preterm birth.


Assuntos
Cádmio/sangue , Poluentes Ambientais/sangue , Exposição Materna/efeitos adversos , Nascimento Prematuro/sangue , Animais , Povo Asiático , China , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Modelos Logísticos , Exposição Materna/estatística & dados numéricos , Camundongos , Razão de Chances , Gravidez , Nascimento Prematuro/epidemiologia , Medição de Risco
15.
Sci Rep ; 6: 22631, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26934860

RESUMO

The association between maternal cadmium (Cd) exposure during pregnancy and the increased risk of fetal growth restriction (FGR) remains controversial. The present study evaluated the association between maternal serum Cd level and risk of small for gestational age (SGA) infants in a Chinese population. The present study analyzed a subsample of the C-ABCS cohort that recruited 3254 eligible mother-and-singleton-offspring pairs. Maternal serum Cd level during pregnancy was measured by graphite furnace atomic absorption spectrometry. The rate and odds ratio (OR) for SGA infant were calculated. The rate for SGA infant was 10.6% among subjects with H-Cd (≥1.06 µg/L), significantly higher than 7.5% among subjects with L-Cd (<1.06 µg/L). OR was 1.45 (95% CI: 1.11, 1.90; P = 0.007) among subjects with H-Cd. Adjusted OR for SGA infants was 1.43 (95% CI: 1.09, 1.88; P = 0.007) among subjects with H-Cd. Taken together, we observe the fact that maternal Cd exposure at middle gestational stage, elevates the risk of SGA in contrast to early gestational stage. The present results might be interesting and worth more discussing, and guarantee to further studies.


Assuntos
Cádmio/sangue , Retardo do Crescimento Fetal/sangue , Recém-Nascido Pequeno para a Idade Gestacional , Adulto , Feminino , Humanos , Gravidez
16.
Clin Chim Acta ; 353(1-2): 187-92, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15698606

RESUMO

BACKGROUND: Human cytochrome P450 3A evolved to catalyze the metabolism of numerous common therapy drugs and endogenous molecules. Members of the CYP3A are the majority expressed in human liver and intestine, and there are marked interindividual differences in their protein expression and activity. The activity of CYP3A enzyme in Chinese is highly variable, exceeding 14-fold, and contributes greatly to variation in oral bioavailability and systemic clearance of CYP3A substrates. The genetic factors play an important role in the interindividual variability in CYP3A activity. Detection of CYP3A5 and CYP3A4 variant alleles and knowledge about their allelic frequency in specific ethnic groups are important to lead to individualized drug dosing and improved therapeutics. METHODS: We determined the allelic frequency of the CYP3A5*3 and CYP3A4*18 in a group of 302 Chinese subjects by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. RESULTS: In the group of 302 unrelated individuals, the frequency of the CYP3A5*3 and CYP3A4*18 variant allele in Chinese population were 0.778 (95% CI: 0.754, 0.802) and 0.01 (95% CI: 0, 0.02), respectively. CONCLUSIONS: We developed a simple assay for the detection of the CYP3A4*18 allele and showed that in a Chinese population, CYP3A4*18 and CYP3A5*3 allelic frequencies are similar to that reported previously in Chinese resident in Taiwan. The frequency of the CYP3A5*3 allele in Chinese population is similar to the Japanese but lower than Caucasians. Meanwhile, our findings suggest that an approximate 62% of the Chinese population carrying CYP3A5*3/*3 genotype may appear not to express CYP3A5 protein.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , China , Citocromo P-450 CYP3A , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição
17.
Chin Med J (Engl) ; 118(13): 1076-80, 2005 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-16098259

RESUMO

BACKGROUND: The NASG gene has been confirmed as a tumor-suppressor gene candidate related to nasopharyngeal carcinoma (NPC) by previous studies. We further investigated the expression and the role of NASG in the homogeneous tissue cells by microdissecting the samples of tissue from human NPC, and introduced a new way to study the expression of specific genes in tumor tissue. METHODS: The RNAlater reagent was used to preserve the samples of tissue from the nasopharynx of NPC patients. The samples were microdissected to harvest the homogeneous tissue cells and then total RNA was isolated from them. The antisense RNA (aRNA) was amplified from the total RNA by "in vitro transcription (IVT)". We investigated NASG expression in the homogeneous tumor cells of NPC (22 samples) and compared it with that in the pure epithelial pillar cells of normal nasopharyngeal (10 samples) by semi-quantitative reverse transcription-polymerase chain reaction (sqRT-PCR). RESULTS: The high quality total RNA could be harvested from the microdissected homogeneous tissue cells of the nasopharynx, then sufficient aRNA was derived from it. NASG gene expression was identified using aRNA by sqRT-PCR and showed that there was significant difference between the average value of case groups and that of control group (t = -5.275, df = 30, P < 0.001). The NASG gene in the subgroups WHOII tended to express lower levels than those in the subgroup WHOIII although this difference was not statistically significant (t = -1.584, df = 20, P = 0.129 > 0.05). CONCLUSIONS: Microdissection was an effective method to obtain the homogeneous tissue cells of nasopharyngeal tissue (including the samples of NPC and non-NPC) in our study. Sufficient aRNA from amplifying total RNA could be used in sqRT-PCR to analyse the expression of NASG in the pure tissue cells. NASG should be a tumor-suppression gene candidate regarding to NPC.


Assuntos
Genes Supressores de Tumor , Neoplasias Nasofaríngeas/genética , Nasofaringe/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Microdissecção , Pessoa de Meia-Idade , RNA/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Toxicol Sci ; 145(1): 90-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25673501

RESUMO

Several reports demonstrated that maternal lipopolysaccharide (LPS) exposure at middle gestational stage caused neural tube defects (NTDs). This study investigated the effects of supplementation with vitamin D3 (VitD3) during pregnancy on LPS-induced NTDs. Pregnant mice except controls were ip injected with LPS (25 µg/kg) daily from gestational day (GD)8 to GD12. In LPS+VitD3 group, pregnant mice were orally administered with VitD3 (25 µg/kg) before LPS injection. As expected, a 5-day LPS injection resulted in 62.5% (10/16) of dams and 20.3% of fetuses with NTDs. Additional experiment showed that a 5-day LPS injection downregulated placental proton-coupled folate transporter (pcft) and reduced folate carrier 1 (rfc1), 2 major folate transporters in placentas. Consistent with downregulation of placental folate transporters, folate transport from maternal circulation into embryos was disturbed in LPS-treated mice. Interestingly, VitD3 not only inhibited placental inflammation but also attenuated LPS-induced downregulation of placental folate transporters. Correspondingly, VitD3 markedly improved folate transport from maternal circulation into the embryos. Importantly, supplementation with VitD3 during pregnancy protected mice from LPS-induced NTDs. Taken together, these results suggest that supplementation with VitD3 during pregnancy prevents LPS-induced NTDs through inhibiting placental inflammation and improving folate transport from maternal circulation into the embryos.


Assuntos
Colecalciferol/administração & dosagem , Suplementos Nutricionais , Ácido Fólico/metabolismo , Lipopolissacarídeos/toxicidade , Defeitos do Tubo Neural/prevenção & controle , Placenta/metabolismo , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Regulação para Cima
19.
Sci Rep ; 5: 11262, 2015 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-26053136

RESUMO

We investigated the association between maternal zinc level during pregnancy and the risks of low birth weight (LBW) and small for gestational age (SGA) infants in a large population-based birth cohort study. In this study, 3187 pregnant women were recruited. For serum zinc level, 2940 pregnant women were sufficient (≥56 µg/dL) and 247 deficient (<56 µg/dL). Of interest, 7.3% newborns were with LBW among subjects with low zinc level (RR: 3.48; 95% CI: 2.03, 5.96; P < 0.001). Adjusted RR for LBW was 3.41 (95% CI: 1.97, 5.91; P < 0.001) among subjects with low zinc level. Moreover, 15.0% newborns were with SGA among subjects with low zinc level (RR: 1.98; 95% CI: 1.36, 2.88; P < 0.001). Adjusted RR for SGA was 1.93 (95% CI: 1.32, 2.82; P < 0.001) among subjects with low zinc level. A nested case-control study within above cohort showed that maternal serum zinc level was lower in SGA cases as compared with controls. By contrast, maternal serum C-reactive protein, TNF-α and IL-8 levels were significantly higher in SGA cases than that of controls. Moreover, nuclear NF-κB p65 was significantly up-regulated in placentas of SGA cases as compared with controls. Taken together, maternal zinc deficiency during pregnancy elevates the risks of LBW and SGA infants.


Assuntos
Retardo do Crescimento Fetal/fisiopatologia , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Placenta/metabolismo , Zinco/sangue , Zinco/deficiência , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Desenvolvimento Fetal , Idade Gestacional , Humanos , Recém-Nascido , Interleucina-8/sangue , Troca Materno-Fetal , Gravidez , Fator de Transcrição RelA/biossíntese , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima
20.
PLoS One ; 9(9): e106786, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25255222

RESUMO

Lipopolysaccharide (LPS) is associated with adverse developmental outcomes including embryonic resorption, fetal death, congenital teratogenesis and fetal growth retardation. Here, we explored the effects of maternal LPS exposure during pregnancy on testicular development, steroidogenesis and spermatogenesis in male offspring. The pregnant mice were intraperitoneally injected with LPS (50 µg/kg) daily from gestational day (GD) 13 to GD 17. At fetal period, a significant decrease in body weight and abnormal Leydig cell aggregations were observed in males whose mothers were exposed to LPS during pregnancy. At postnatal day (PND) 26, anogenital distance (AGD), a sensitive index of altered androgen action, was markedly reduced in male pups whose mothers were exposed to LPS daily from GD13 to GD 17. At PND35, the weight of testes, prostates and seminal vesicles, and serum testosterone (T) level were significantly decreased in LPS-treated male pups. At adulthood, the number of sperm was significantly decreased in male offspring whose mothers were exposed to LPS on GD 13-17. Maternal LPS exposure during gestation obviously diminished the percent of seminiferous tubules in stages I-VI, increased the percent of seminiferous tubules in stages IX-XII, and caused massive sloughing of germ cells in seminiferous tubules in mouse testes. Moreover, maternal LPS exposure significantly reduced serum T level in male mice whose mothers were exposed to LPS challenge during pregnancy. Taken together, these results suggest that maternal LPS exposure during pregnancy disrupts T production. The decreased T synthesis might be associated with LPS-induced impairments for spermatogenesis in male offspring.


Assuntos
Lipopolissacarídeos/efeitos adversos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Espermatogênese/efeitos dos fármacos , Esteroides/biossíntese , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Feto/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Hormônio Luteinizante/sangue , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/crescimento & desenvolvimento , Contagem de Espermatozoides , Espermatozoides/citologia , Espermatozoides/efeitos dos fármacos , Esteroides/sangue , Testosterona/biossíntese , Testosterona/sangue
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