Aim: Homozygous α -thalassaemia, also called haemoglo-bin (Hb) Bart’ s hydrops fetalis, has been thought to be a lethal condition. Due to prenatal diagnosis and intrauterine blood transfusions, a few patients with H...Aim: Homozygous α -thalassaemia, also called haemoglo-bin (Hb) Bart’ s hydrops fetalis, has been thought to be a lethal condition. Due to prenatal diagnosis and intrauterine blood transfusions, a few patients with Hb Bart’ s hydrops fetalis have survived. This fact raises the urgent questions of clinical management and appropriate follow-up of these patients, both of which are addressed in this article. Methods: We report on a 6.5-y-old patient with homozygous α -thalassaemia and review the literature of 13 other survivors published to date. Transfusion requirements were evaluated and the rate of liver iron accumulation was assessed by biomagnetic liver susceptometry before and after institution of iron-chelating therapy. Psychometric evaluation was carried out using Munich’ s Functional Development Test, the Columbia Mental Maturity Scale, the Kaufman Assessment Battery for Children, and the Peabody Picture Vocabulary Test. Results: Our patient had significant delay of psychomotor development. Psychometric evaluation at the age of 5 y revealed an IQ of 85 and an intellectual level of a 4-y-old child. Early tissue iron overload was seen, but a negative iron balance was achieved after institution of desferrioxamine treatment at dosages used for β -thalassaemia. Conclusion: Homozygous α -thalassaemia should no longer be regarded as a lethal condition. Early intervention during pregnancy and careful haematological as well as neuropsychological follow-up was able to provide long-term survival and good life quality in our patient.展开更多
目的从遗传学角度探讨血铅水平(blood lead level,BLL)和哮喘的关联及VDR基因(维生素D受体基因)与血铅的交互作用。方法采用以医院为基础的1:1配对病例对照研究,选取0～14岁哮喘儿童85例,对照组为同性别、年龄±1岁的非哮喘儿童85...目的从遗传学角度探讨血铅水平(blood lead level,BLL)和哮喘的关联及VDR基因(维生素D受体基因)与血铅的交互作用。方法采用以医院为基础的1:1配对病例对照研究,选取0～14岁哮喘儿童85例,对照组为同性别、年龄±1岁的非哮喘儿童85例。流行病学调查表由国际统一标准儿童哮喘及变态反应性疾病国际研究(International Study of Asthmaand Allergies in Childhood,ISAAC)问卷等汇集而成。用ABI3700XL基因测序仪测定VDR基因的rs7975232多态位点。采用EpiData 3.1建立数据库,SAS9.1进行分析。结果 85例哮喘儿童血铅水平≥50μg/L的发生率为50.6%(43/85),而85例非哮喘儿童的发生率为20.0%(17/85),由条件Logistic回归计算的危险比(hazard ratio,HR)为3.0(95% CI,1.8～8.1),P=0.0003。高血铅儿童(BLL≥50μg/L)rs7975232位点的突变纯合型AA发生频率是低血铅儿童(BLL<50μg/L)的1.6倍;而哮喘儿童该位点突变纯合型AA发生的频率是非哮喘儿童的1.8倍。将rs7975232基因型按病例对照、血铅高低分层,发现患哮喘的高血铅儿童的突变纯合型AA发生频率是非哮喘低血铅儿童的2.1倍(95% CI,0.6～7.4),并有随分层升高突变纯合型频率增大的趋势(P=0.0003)。rs7975232与血铅水平,rs7975232与总IgE之间均存在交互作用。结论血铅水平和哮喘存在关联,VDR基因对此关联产生影响,血铅高的哮喘儿童rs7975232位点突变纯合型发生的频率增大。展开更多
Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine...Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (T PMT) is involved in the metabolism of mercaptopurine and subject to genetic poly morphism, with heterozygous individuals having intermediate and homozygous mutan t individuals having very low TPMT activity. Objective: To assess the associatio n of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design, Set ting, and Patients: TPMT genotyping of childhood ALL patients (n = 814) in Germa ny consecutively enrolled in the ALLBFM (Berlin- Frankfurt- Mü nster) 2000 study from October 1999 to September 2002. Minima l residual disease was analyzed on treatment days 33 and 78 for riskadapted trea tment stratification. A 4- week cycle of mercaptopurine was administered betwee n these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analys es. Main Outcome Measures: Minimal residual disease load before (day 33) and aft er (day 78) mercaptopurine treatment. Loads smaller than 10- 4 were defined as negative. Results: Patients (n = 55) heterozygous for allelic variants of TPMT c onferring lower enzyme activity had a signifi- cantly lower rate of minimal res idual disease positivity (9.1 % ) compared with patients (n = 755) with homozyg ous wild- type alleles (22.8% ) on day 78 (P = .02). This translated into a 2. 9- fold reduction in risk for patients with wild- type heterozygous alleles (r elative risk, 0.34; 95% confidence interval, 0.13- 0.86). Conclusions: TPMT g enotype has a substantial impact on minimal residual disease after administratio n of mercaptopurine in the early course of childhood ALL, most likely through 展开更多
Glutamine synthetase plays a major role in ammonia detoxification, interorgan nitrogen flux, acid-base homeostasis, and cell signaling. We report on two unrelated newborns who had congenital human glutamine synthetase...Glutamine synthetase plays a major role in ammonia detoxification, interorgan nitrogen flux, acid-base homeostasis, and cell signaling. We report on two unrelated newborns who had congenital human glutamine synthetase deficiency with severe brain malformations resulting in multiorgan failure and neonatal death. Glutamine was largely absent from their serum, urine, and cerebrospinal fluid. Each infant had a homozygousmutation in the glutamine synthetase gene (R324C and R341C). Studies that used immortalized lymphocytes expressing R324C glutamine synthetase (R324C-GS) and COS7 cells expressing R341C-GS suggest that these mutations are associated with reduced glutamine synthetase activity.展开更多
文摘Aim: Homozygous α -thalassaemia, also called haemoglo-bin (Hb) Bart’ s hydrops fetalis, has been thought to be a lethal condition. Due to prenatal diagnosis and intrauterine blood transfusions, a few patients with Hb Bart’ s hydrops fetalis have survived. This fact raises the urgent questions of clinical management and appropriate follow-up of these patients, both of which are addressed in this article. Methods: We report on a 6.5-y-old patient with homozygous α -thalassaemia and review the literature of 13 other survivors published to date. Transfusion requirements were evaluated and the rate of liver iron accumulation was assessed by biomagnetic liver susceptometry before and after institution of iron-chelating therapy. Psychometric evaluation was carried out using Munich’ s Functional Development Test, the Columbia Mental Maturity Scale, the Kaufman Assessment Battery for Children, and the Peabody Picture Vocabulary Test. Results: Our patient had significant delay of psychomotor development. Psychometric evaluation at the age of 5 y revealed an IQ of 85 and an intellectual level of a 4-y-old child. Early tissue iron overload was seen, but a negative iron balance was achieved after institution of desferrioxamine treatment at dosages used for β -thalassaemia. Conclusion: Homozygous α -thalassaemia should no longer be regarded as a lethal condition. Early intervention during pregnancy and careful haematological as well as neuropsychological follow-up was able to provide long-term survival and good life quality in our patient.
文摘目的从遗传学角度探讨血铅水平(blood lead level,BLL)和哮喘的关联及VDR基因(维生素D受体基因)与血铅的交互作用。方法采用以医院为基础的1:1配对病例对照研究,选取0～14岁哮喘儿童85例,对照组为同性别、年龄±1岁的非哮喘儿童85例。流行病学调查表由国际统一标准儿童哮喘及变态反应性疾病国际研究(International Study of Asthmaand Allergies in Childhood,ISAAC)问卷等汇集而成。用ABI3700XL基因测序仪测定VDR基因的rs7975232多态位点。采用EpiData 3.1建立数据库,SAS9.1进行分析。结果 85例哮喘儿童血铅水平≥50μg/L的发生率为50.6%(43/85),而85例非哮喘儿童的发生率为20.0%(17/85),由条件Logistic回归计算的危险比(hazard ratio,HR)为3.0(95% CI,1.8～8.1),P=0.0003。高血铅儿童(BLL≥50μg/L)rs7975232位点的突变纯合型AA发生频率是低血铅儿童(BLL<50μg/L)的1.6倍;而哮喘儿童该位点突变纯合型AA发生的频率是非哮喘儿童的1.8倍。将rs7975232基因型按病例对照、血铅高低分层,发现患哮喘的高血铅儿童的突变纯合型AA发生频率是非哮喘低血铅儿童的2.1倍(95% CI,0.6～7.4),并有随分层升高突变纯合型频率增大的趋势(P=0.0003)。rs7975232与血铅水平,rs7975232与总IgE之间均存在交互作用。结论血铅水平和哮喘存在关联,VDR基因对此关联产生影响,血铅高的哮喘儿童rs7975232位点突变纯合型发生的频率增大。
文摘Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (T PMT) is involved in the metabolism of mercaptopurine and subject to genetic poly morphism, with heterozygous individuals having intermediate and homozygous mutan t individuals having very low TPMT activity. Objective: To assess the associatio n of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design, Set ting, and Patients: TPMT genotyping of childhood ALL patients (n = 814) in Germa ny consecutively enrolled in the ALLBFM (Berlin- Frankfurt- Mü nster) 2000 study from October 1999 to September 2002. Minima l residual disease was analyzed on treatment days 33 and 78 for riskadapted trea tment stratification. A 4- week cycle of mercaptopurine was administered betwee n these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analys es. Main Outcome Measures: Minimal residual disease load before (day 33) and aft er (day 78) mercaptopurine treatment. Loads smaller than 10- 4 were defined as negative. Results: Patients (n = 55) heterozygous for allelic variants of TPMT c onferring lower enzyme activity had a signifi- cantly lower rate of minimal res idual disease positivity (9.1 % ) compared with patients (n = 755) with homozyg ous wild- type alleles (22.8% ) on day 78 (P = .02). This translated into a 2. 9- fold reduction in risk for patients with wild- type heterozygous alleles (r elative risk, 0.34; 95% confidence interval, 0.13- 0.86). Conclusions: TPMT g enotype has a substantial impact on minimal residual disease after administratio n of mercaptopurine in the early course of childhood ALL, most likely through
文摘Glutamine synthetase plays a major role in ammonia detoxification, interorgan nitrogen flux, acid-base homeostasis, and cell signaling. We report on two unrelated newborns who had congenital human glutamine synthetase deficiency with severe brain malformations resulting in multiorgan failure and neonatal death. Glutamine was largely absent from their serum, urine, and cerebrospinal fluid. Each infant had a homozygousmutation in the glutamine synthetase gene (R324C and R341C). Studies that used immortalized lymphocytes expressing R324C glutamine synthetase (R324C-GS) and COS7 cells expressing R341C-GS suggest that these mutations are associated with reduced glutamine synthetase activity.
