Population pharmacokinetics of oral busulfan in children

Purpose To characterize the population pharmacokinetics of oral busulfan in 48 children including pooled data from three transplantation centres with the aim of estimating the variability in the kinetics of busulfan and to identify covariates that could be used for dose calculation.Methods A total of 508 plasma samples from 250 administrations (mean 9 samples per patient over 4 days of treatment) were collected from 48 children receiving busulfan orally every 6 h. The dosing varied between 13 and 20 mg/kg with seven patients receiving a dose of 600 mg/m². The busulfan formulations administered varied considerably. They included 2-mg tablets (Myleran), gelatine capsules, crushed tablets suspended in water and suspension for administration via nasogastric tube. Samples were analysed for busulfan either by HPLC using postcolumn photolysis or by LC-MS. Plasma concentration-time data were analysed by population pharmacokinetic modelling using NONMEM.Results Busulfan kinetics were best described by a one-compartment model (subroutine ADVAN 2 TRANS 2). Residual variability was modelled using a combined additive and proportional error model. The influence of different covariates on the pharmacokinetic parameters was tested. The best results were obtained by inclusion of body surface area (BSA) as a covariate for clearance (Cl/F) and volume of distribution (V/F). The final population estimates were: Cl/F 4.13 l/h per m² ±26%, V/F 21.3 l/m² ±31% and ka 1.31 h^–1 ±110% (population mean ± interindividual variability, IIV). Variability in one patient during the 4 days of treatment (interoccasion variability, IOV) for Cl/F (10%) and V/F (19%) were calculated to be less than interindividual variability, fulfilling the condition for individualization of busulfan dosage regimens.Conclusions In our paediatric population, BSA, not body weight, is the best predictor of Cl/F and V/F. Our final estimations reflect the wide interpatient variability after oral administration of busulfan with an IIV for ka of 110%.     

A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk

A common 936 C/T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels. In our case-control study, we investigated the role of this polymorphism for breast cancer risk. VEGF genotype was determined in 500 women with breast cancer and 500 sex- and age-matched healthy control subjects. Carriers of a 936T-allele were more frequent among controls (29.4%) than among patients (17.6%; p = 0.000014). The odds ratio for carriers of a 936T-allele for breast cancer was 0.51 (95% confidence interval 0.38-0.70). Additionally, VEGF plasma levels were determined in 21 nonsmoking post-menopausal controls; carriers of a 936T allele had significantly lower levels (median 23 pg/ml; range 6-50 pg/ml) than noncarriers (37; 21-387; p = 0.034). We conclude that carriers of a VEGF 936T-allele are at decreased risk for breast cancer, this, however, requiring further confirmation in a larger study.     

山东省0～7岁儿童先天性及遗传性疾病调查报告

目的:通过对山东省9个县(市、区)0～7岁儿童出生缺陷的调查,了解影响山东省出生人口素质的重要遗传病、先天性疾病及其影响因素。方法:用随机整群抽样方法,根据地域分布、经济、社会、人口分布等确定示范点,并对183 249例0～7岁儿童进行基线调查。采用回归性询问填表法初筛可疑阳性患儿,并按全国统一诊断标准逐个查体,明确诊断,填写统一调查表,录入微机,并进行统计学处理。结果:①筛查183 249例儿童,确诊先天性及遗传性疾病2782例,发病率为15.18‰(2 782/183 249)。②不同地区发病率有显著差异(P<0.0001)。③排前10位的疾病分别为腹股沟疝及脐疝(n=442)、智力低下(n=317)、鞘膜积液(n=245)、先天性心脏病(n=243)、眼部畸形及视力障碍(n=122)、肢体畸形(n=206)、脑瘫(n=202)、唇(腭)裂(n=124)、先天性耳前瘘管(n=233)及聋哑(n=115)。④多胞胎76例(2.73％,76/2 783)。⑤出生时妊娠周数<37周的206例,占7.40％(206/2 782),>42周的76例,占2.74％(76/2 782),平均39.59±2.10周。⑥出生时体重<1.6kg的16例,1.6～2.7kg的363例,两者占13.62％;≥4.0kg的巨大儿325例(11.68％,325/2 782),平均3.30±0.58kg;母亲年龄18～22岁37例,35～45岁127例,>45岁7例,平均28.3±3.9岁。⑦患儿男性占68.6％(1 908/2 782),女性占31     

Estimating the incidence of typhoid fever and other febrile illnesses in developing countries

To measure the incidence of typhoid fever and other febrile illnesses in Bilbeis District, Egypt, we conducted a household survey to determine patterns of health seeking among persons with fever. Then we established surveillance for 4 months among a representative sample of health providers who saw febrile patients. Health providers collected epidemiologic information and blood (for culture and serologic testing) from eligible patients. After adjusting for the provider sampling scheme, test sensitivity, and seasonality, we estimated that the incidence of typhoid fever was 13/100,000 persons per year, and the incidence of brucellosis was 18/100,000 persons per year in the district. This surveillance tool could have wide applications for surveillance for febrile illness in developing countries.     

Genetic variation in the psychomotor stimulant properties of cocaine in<Emphasis Type="Italic"> Mus musculus</Emphasis>

Rationale. The psychomotor stimulant properties of drugs are argued to be a key feature of abuse liability. Several studies, primarily using inbred strains of mice, have demonstrated genetic variation in the psychomotor stimulant properties of cocaine. As of yet, however, no gene(s) has been identified which influences this phenotype. Objectives. The purpose of the present study was to examine a number of inbred strains of mice, including several closely related substrains, for cocaine-induced locomotor activation. Such substrain differences would suggest the possibility of a major gene effect. These data will also help to further characterize the range of genetic variation in response to cocaine. Methods. Mice from 11 inbred strains were initially injected with saline and activity monitored for 30 min; mice were then removed from the activity monitor, injected with saline or one of six doses of cocaine, and activity was monitored for an additional 30 min. Results. Compared to several other closely related C57BL substrains, we found the C57BL/10SnJ substrain to be significantly less activated following cocaine administration. In contrast, the C57BR/cdJ and C57L/J substrains showed extremely high levels of cocaine-induced locomotor activation. Conclusions. The genetic similarity between C57BL/10SnJ and the other closely related C57BL substrains suggests the possibility that the aberrant behavioral response to cocaine observed in B10SnJ mice may be due to a major gene effect. Similarly, the differences found in the C57BR/cdJ and C57L/J substrains may also be influenced by a major gene. The strains examined in this study will be useful tools for identification of relevant quantitative trait loci. Electronic Publication     

Exaggerated response to restraint stress in rats congenic for the chromosome 1 blood pressure quantitative trait locus

1. To understand the roles of a putative hypertension gene in the chromosome 1 quantitative trait locus (QTL) region, the response to restraint stress was studied in strains congenic for this QTL. 2. To establish congenic strains, the QTL region was introgressed from stroke-prone spontaneously hypertensive rats (SHRSP)/Izm to Wistar-Kyoto/Izm (WKY/Izm) rats by repeated backcrossing. Two congenic strains (WKYpch1.0 and WKYpch1.1) were established to cover the whole QTL region between D1Wox29 and D1Arb21 (approximately 40 cM) and a smaller region between D1Smu11 and D1Arb21 (approximately 10 cM), respectively. After telemetry probes were implanted, rats were exposed to restraint stress to investigate the blood pressure response. 3. Basal blood pressure measured by radiotelemetry differed significantly between WKY rats and WKYpch1.0 (103 +/- 10 and 116 +/- 4 mmHg, respectively; P = 0.002 by anova). When exposed to restraint stress, WKYpch1.0 showed a greater increase in blood pressre than did WKY rats. The exaggerated response in the WKYpch1.0 strain was abolished by chemical sympathectomy using guanethidine. The WKYpch1.1 rats did not differ significantly from WKY rats either in basal blood pressure or in the response to restraint stress. 4. In conclusion, a QTL for high blood pressure was successfully introgressed in the established congenic strain, WKYpch1.0. A gene (or genes) in the chromosome 1 QTL region modulates the cardiovascular responses to restraint stress in these congenic rats, probably through the sympathetic nervous system.     

HLA class II genetic association of type 1 diabetes mellitus in Czech children

Abstract:  To examine human leukocyte antigen (HLA) class II association of type 1 diabetes mellitus (DM) in Czech children, we performed a case–control study of 261 patients diagnosed before the age of 15 and 289 non-diabetic control children. Complete HLA-DQA1, DQB1 genotyping and DRB1*04 subtyping were carried out by polymerase chain reactions with sequence-specific primers. The effect of the DRB1*04 subtypes was studied in DRB1*04 alleles carried on DQB1*0302-DQA1*03 haplotypes. The risk was statistically evaluated by testing 2 × 2 tables, considering corrected p-values < 0.05 significant. The DQB1*0302 (odds ratio, OR = 9.0), DQB1*0201 (OR = 3.4) and DQA1*03 (OR = 7.5) alleles were significantly associated with diabetes risk, while the DQB1*0602 (OR = 0.02), DQB1*0301 (OR = 0.08), DQB1*0503 (OR = 0.13), DQB1*0603 (OR = 0.20), DQA1*01 (OR = 0.28) and DQA1*02 (OR = 0.26) alleles were significantly protective. Of the DQA1-DQB1 genotypes, we point out the extremely high risk of OR = 116 conferred by HLA-DQA1*05-DQB1*0201/DQA1*03-DQB1*0302. Among DRB1*04 subtypes, DRB1*0403 was significantly protective (OR = 0.05, CI 95% 0.01–0.45). Since none of the remaining DRB1*04 subtypes was associated with type 1 DM, our study may present another piece of evidence that the DRB1*0401 and DRB1*0404 alleles do not modify type 1 diabetes risk generally in European populations.     

我国人群中缺血性和出血性脑卒中发病的相对比例

目的　探讨我国人群中出血性和缺血性脑卒中发病的相对比例。方法　 1 991～ 2 0 0 0年按照世界卫生组织MONICA方案对我国 1 5组人群脑卒中事件进行监测。结果　 1 996～ 2 0 0 0年 1 5组人群的CT检查率从 1 4 .8%～ 97.5 %不等 ,缺血性和出血性脑卒中的比例从 0 .37∶1～ 3 .82∶1不等 ,两者的相关系数为 0 .71 (P =0 .0 0 3)。在CT检查率达到 80 %以上的人群 ,缺血性与出血性脑卒中的比例无一例外 ,均 >1 .0。从 1 991～ 2 0 0 0年 ,1 0年间均有资料的 1 2组人群CT检查率从 41 .1 %增加到88 3 % ,缺血性与出血性脑卒中的比例则从 1 .2 5∶1增加到 1 .85∶1 ,两者的相关系数为 0 .77(P =0 0 1 )。经CT检查的病例中 ,无论任何一年缺血性与出血性脑卒中的比例均大于 1 .0。结论　我国人群中脑卒中发病是以缺血性脑卒中为主。CT检查率偏低是造成部分人群“出血性脑卒中发病为主”假象的主要因素。     

An Ile93Met substitution in the UCH-L1 gene is not a disease-causing mutation for idiopathic Parkinson’s disease

Objective To ascertain whether a coding mutation(Ⅱe93Met) in ubiquitin carboxy-terminal hydrolase(UCH-L1) gene plays a role in idiopathic Parkinson‘s disease(IPD).Methods Polymerase chain reaction-restriction fragment length polymorphism assay(PCR-RFLP) was used to distingusih the wild-type(two DNA fagments of 34 and 126bp)from the variant allele(three fragments of 34,60 and 66bp)because the mutation created a new site for restriction engonuclease Bsm F1.DNA was isolated from various blood samples using a phenolchlorofom extraction.     

A pilot study on a gene-hormone interaction in female suicide attempts

Abstract. This one-year naturalistic study included all suicide attempters in a catchment area. In the first published set of analyses, an association between menses and suicide attempts was replicated. According to the polymorphism of the serotonin transporter promoter area, the subjects can be classified as S individuals (s/s or s/l) or L individuals (l/l). In the second published set of analyses, L females appeared protected from suicide attempts since they were underrepresented among female (and not male) attempters. This new, unpublished third set of analyses tested for an interaction between the same polymorphism and low hormonal activity (during menses and menopause). In fertile female attempters, the proportion of L women in the menses (41%, 7/17) was significantly higher than expected in the population (15.5 %) and almost significantly higher than in S female attempters (22%,19/87). L females were also overrepresented in postmenopausal attempters. Despite sample size limitations, this gene-hormone interaction needs to be further investigated in female suicide attempters.