Association of early growth response-1 gene polymorphisms with total IgE and atopy in asthmatic children

Early growth response-1 ( Egr-1 ) is expressed in human airways and found to modulate tumor necrosis factor, immunoglobulin E (IgE), airway responsiveness, and interleukin-13-induced inflammation in mice. We investigated the effects of Chinese-tagging single nucleotide polymorphisms (SNPs) of Egr-1 on asthma traits in 298 Chinese asthmatic children and 175 controls, and a replication community cohort of 191 controls. Tag SNP (−4071 A→G) and three additional SNPs (−1427 C→T, −151 C→T and IVS1 −42 C→T) were genotyped by restriction fragment length polymorphism (RFLP). Significant associations were found between plasma total IgE concentration and −4071 A→G (p = 0.008) and IVS1 −42 C→T (p = 0.027) in asthmatic patients. After Bonferroni correction, only −4071 A→G showed significant association. Multivariate regression analysis confirmed this significant association with a standardized coefficient β of 0.156 (95% CI: 0.046–0.317; p = 0.009) in asthmatics among the three SNPs with age and gender-adjusted. In −4071 A→G, IgE_log was significantly higher in patients with the GG genotype than the AA genotype (p = 0.009). In addition, −4071 A→G was significantly associated with atopy (p = 0.016) and high total IgE concentration (p = 0.030) among asthmatics. Patients with the G allele had a 3.5-fold risk of having atopy and a 2.0-fold risk of having high total IgE concentration than those homozygous for the A allele. This is the first report to show significant association of Egr-1 polymorphisms with plasma total IgE and atopy in asthmatics. It may help to explore the pharmacogenetics of Egr-1 inhibitors.     

Total homocysteine, folate, and cobalamin, and their relation to genetic polymorphisms, lifestyle and body mass index in healthy children and adolescents

We investigated total homocysteine (tHcy) concentrations and relations between tHcy and folate, cobalamin (Cbl), genetic polymorphisms (MTHFR 677C > T, MTHFR 1298A > C, MTHFR 1793G > A), blood pressure (BP), body mass index (BMI), cholesterol, triglycerides, sports activities, family and individual history of cardiovascular disease (CVD) and lifestyle issues in 264 healthy children and adolescents (2-17 y). THcy concentrations significantly increased while folate and Cbl decreased with age without gender differences. Age, folate and Cbl were significant predictors for tHcy concentrations. THcy was higher but within normal ranges in MTHFR 677TT homozygotes (10.6%) and carriers of the MTHFR 1793A allele (8%). Only two individuals (0.8%), both with low tHcy concentrations, were homozygous for MTHFR 1793AA. THcy concentration correlated positively with creatinine, triglycerides, BMI and systolic BP and was not related to cholesterol, sports activities and family history of CVD. In conclusion, tHcy concentrations in this pediatric population were significantly influenced by age, folate and Cbl concentrations. No gender differences for tHcy, folate or Cbl concentrations were observed. Both the MTHFR 677TT genotype and the MTHFR 1793A allele were not associated with hyperhomocysteinemia. The prevalence of the MTHFR 1793AA genotype was too low for meaningful interpretation.     

Reduced total plasma homocyst(e)ine in children and adolescents with type 1 diabetes

OBJECTIVES: The objective was to investigate total plasma homocyst(e)ine (tHcy), methylenetetrahydrofolate reductase (MTHFR) genotype, and the contribution of diet to homocysteine values in children and adolescents with type 1 diabetes and a control group. STUDY DESIGN: A total of 78 children with type 1 diabetes and 59 members of an age- and sex-matched control group were recruited. Fasting samples were collected for tHcy, MTHFR genotype, serum vitamin B(12), serum folate, red cell folate, and plasma creatinine. Food frequency questionnaires targeted intake of folate, vitamin B(6), and vitamin B(12). RESULTS: Fasting tHcy was reduced in patients compared with the control group (4.7 vs 5.9 micromol/L, P <.001). Serum folate (P =.002), red cell folate(P <.001), and serum vitamin B(12) (P =.005) were higher, and plasma creatinine was lower. A significant difference in tHcy values between patients and the control group persisted after correction was done for these factors (r = 0.1, P =.02). No difference was seen in the frequency of MTHFR polymorphisms. tHcy was not elevated in those patients with the 677TT or 677T/1298C genotypes, although red cell folate was significantly higher in members of the case (P =.01) and control groups (P =.05) with a 677 TT genotype. Dietary intake of folate correlated with serum folate (r = 0.4,P =.005). CONCLUSION: tHcy values are lower in children and adolescents with type 1 diabetes. Higher serum levels of folic acid and vitamin B(12), reflecting differences in dietary intake between children with diabetes and members of a control group, partially account for this difference.     

Analysis of MTHFR 1298A>C in addition to MTHFR 677C>T polymorphism as a risk factor for neural tube defects in the Turkish population

Maternal folic acid intake in the periconceptional period is strongly related to reduction in recurrence and occurrence of birth defects involving the neural tube. Among the single nucleotide polymorphisms (SNPs) influencing the folate metabolism, the methylenetetrahydrofolate reductase (MTHFR) gene has been the one most exclusively studied. Many studies have reported significant association between MTHFR 677C>T and increased risk of neural tube defects (NTDs). Our previous study did not support this observation. The present study aimed to determine the prevalence of 1298A>C polymorphism in addition to 677C>T in the same Turkish population as a risk factor for NTDs. We genotyped case (95 offspring with NTDs, 80 mothers, 72 fathers) and control (93 healthy children) populations for MTHFR 677C>T and MTHFR 1298 A>C polymorphisms. The comparison demonstrated a significant increase in the 1298AA/677TT genotype frequency among mothers of offspring with NTDs (OR 5.23 [1.06-25.9]; p=0.067). The 677CT genotype was only 1.35 times higher than controls among mothers when 677C>T polymorphism was evaluated alone, while 677CT/1298AC in the current study demonstrated a 3.8 times increase in this risk. These observations led us to conclude that although not statistically significant, MTHFR 1298AC polymorphism might be a risk factor for the occurrence of NTDs in the Turkish population.     

Mutations of MTHFR,MTR, MTRR genes as high risk factors for neural tube defects

Neural tube defects (NTDs) have a polygenic background. There are numerous genes known to be high-risk genetic factors for NTDs. Ones of them are mutations of foliate metabolisms pathways genes. This paper shows the results of analysis of common mutations of MTHFR, MTR and MTRR genes. Results of screening mutations 2756A-->G and 66A-->G in MTR and MTRR genes respectively show that are might have an effect on NTDs incidence among the examined population. Analysis of data for the studied population does not prove the influence of mutations 677C-->T and 1298A-->C of MTHFR gene on NTDs.     

急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系

目的：探讨亚甲基四氢叶酸还原酶（MTHFR）基因单核苷酸多态性对急性淋巴细胞白血病（ALL）患儿使用大剂量甲氨蝶呤（HD-MTX）化疗后毒副反应的影响。方法：应用RT-PCR-变性梯度凝胶电泳结合DNA测序技术,对52例ALL患儿MTHFR C677T、A1298C和G1793A基因型进行检测。按照国立癌症研究所常规毒性判定标准（NCI-CTC）对患儿HD-MTX化疗后的不良反应统一评价。结果：MTHFR 1298AC基因型患儿发生血小板减少的风险较AA型提高了13.7倍（OR=13.7,95%CI=1.18～159.36,P=0.036）。MTHFR C677T和G1793A各基因型发生各类HD-MTX化疗不良反应的差异无统计学意义（P>0.05）。结论：MTHFR A1298C多态性可能与ALL患儿HD-MTX化疗后的毒副反应相关。     

Genetic determinants of hyperhomocysteinaemia: the roles of cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase

Over the last decade mild hyperhomocysteinaemia has widely been recognised as a new risk factor for arteriosclerosis and thrombosis. Main regulating enzymes of homocysteine (Hcy) metabolism are cystathionine beta-synthase (CBS), methionine synthase and methylenetetrahydrofolate reductase (MTHFR). Early studies on patients with vascular disease described elevated Hcy concentrations after methionine loading and decreased CBS activity, resembling heterozygotes for CBS deficiency. Therefore, heterozygosity for CBS deficiency was proposed as the main cause of mild hyperhomocysteinaemia. However, more recent enzymatic and molecular genetic studies have demonstrated that heterozygosity for CBS deficiency is not or only a very minor cause of mild hyperhomocysteinaemia in vascular disease. We discovered two common genetic causes of mild hyperhomocysteinaemia, the 677C > T and the 1298A > C mutations in the coding region of MTHFR. The 677C > T mutation causes reduced enzyme activity with thermolabile protein properties, elevated Hcy and low-normal or decreased plasma folate levels. The 1298A > C mutation relates also to decreased enzyme activity, but not to thermolabile protein, and Hcy and folate levels are not influenced. However, compound heterozygosity for these two mutations, i.e. individuals with the 677CT/1298AC genotype, have elevated Hcy and decreased plasma folate levels. Gene-enviroment interactions between 677C > T and folate is demonstrated in individuals with the 677TT genotype. Those with low-normal folate have elevated Hcy, whereas those with high-normal folate have normal Hcy concentrations. The elevated Hcy levels due to these mutations can be normalised by administration of folate, but whether folate reduces the risk of cardiovascular disease remains to be established. CONCLUSION: Heterozygosity for cystathionine beta-synthase deficiency is a minor cause of hyperhomocysteinaemia. The current data on mutations in the methylenetetrahydrofolate reductase gene do not tell us whether elevated plasma homocysteine plays a causal role in vascular disease. Low cellular vitamin status may be a possible cause and homocysteine may just be a marker for this situation.     

Glycemic control in adolescents with type 1 diabetes mellitus improves lipid serum levels and oxidative stress

Introduction:  Atherosclerosis begins in childhood, and diabetes is a risk factor for coronary heart disease. Dyslipidemia is prevalent in children with type 1 diabetes mellitus (T1DM), with an association between elevated hemoglobin A1c (HbA1c), serum lipid levels, and oxidative stress. Our aim was to examine the effect of metabolic control on serum lipid levels and oxidative stress in adolescents with T1DM.
Methods:  Twenty-six adolescents (13 boys and 13 girls), aged 15.65 ± 1.5 yr, with disease duration of 5.9 ± 2.8 yr and average HbA1c 10.8 ± 1.9% were assigned to intensive insulin therapy for 3 months. Comparisons for HbA1c, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, total triglycerides (TG), total cholesterol (TC), apolipoprotein AI, apolipoprotein AII, apolipoprotein B (ApoB), and thiobarbituric acid reactive substances (TBARS) were done between patients whose HbA1c improved by 0.5% or more (GR1) and the rest of the cohort (patients whose HbA1c improved by <0.5%, did not change, or increased) (GR2).
Results:  ApoB (p = 0.047) and TBARS (p = 0.01) were significantly lower at the end of the study in GR1. In GR2, TC (p = 0.01) and LDL (p = 0.03) were significantly higher at study end. Overall, significant beneficial changes in TC (p = 0.006), TG (p = 0.04), LDL (p = 0.02), ApoB (p = 0.015), and oxidative stress (p = 0.001) were found in GR1 compared with GR2.
Conclusions:  We provide direct evidence for the beneficial effect of tight metabolic control on serum lipids and oxidative stress in adolescents with T1DM, indicating that tight metabolic control may reduce cardiovascular risk in these patients.     

MTHFR、TS联合作用与ALL患儿HD-MTX化疗毒副作用的关系

目的：探讨 MTHFR、TS基因多态性联合作用对ALL患儿HD-MTX化疗后不良反应的影响,以及与MTX血药浓度变化之间的关系;分析MTHFR、TS基因多态性联合作用在个体化治疗及疾病防治中的作用。方法 ALL患儿73例,提取其基因组DNA,PCR扩增后测序鉴定MTHFR C677T、MTHFR A1298C、TS 5’-UTR的基因型。观察所有ALL患儿HD-MTX化疗后的毒副作用,并监测MTX血药浓度。以Logistic 回归分析基因多态性与化疗毒副作用的危险度;采用Fisher精确概率法比较 HD-MTX 化疗后 MTHFR C677T、MTHFR A1298C、TS 的不同基因型之间42～48 h MTX血药浓度的差异,以P＜0.05为差异有显著性。结果（1）MTHFR677 CT／TT合并1298 AC／CC基因型者,其血红蛋白降低发生的风险下降了2.9倍,而黏膜损害发生的风险则增加了4.3倍,但差异均无显著性。（2）MTHFR1298 AC／CC合并TS 3R／3R基因型者,其发生黏膜损害的风险增加了5.4倍,差异有显著性（χ2＝4.911,P＝0.027）。（3）MTHFR677 CT／TT合并TS 3 R／3R基因型与HD-MTX化疗毒副作用的发生无关。（4）MTHFR677 CT／TT＋MTHFR1298 AC／CC＋TS 3 R／3 R基因型者,其黏膜损害发生的风险增加了7.5倍,且差异有显著性（χ2＝5.295,P ＝0.021）。结论 TS和MTHFRC677T基因多态性可与ALL患儿HD-MTX化疗后黏膜损害的发生有关。     

Methylene tetrahydrofolate reductase mutations as genetic risk factors for neural tube defects (NTF)

Folic acid supplementation before conception and during the first trimester of pregnancy prevents about 70% of all neural tube defects (NTD). Folic acid is a cofactor in the homocysteine metabolism. Its product--S-adenosylmethionine is a major methyl donor for reactions taking place in a cell. The 677 C-->T mutation in the methylene tetrahydrofolate reductase gene leads to thermolability and decreased activity of the enzyme. In the individuals homozygous for that mutation hyperhomocystynemia and lowered plasma folate level are observed. Presence of the MTHFR 677 C-->T mutation increases the requirements for folic acid, especially at the time of rapid foetal growth. Studies showed higher rate of TT homozygotes in people with NTD and their parents compared with the control group. Hyperhomocystynemia has been associated with higher risk of recurrent miscarriages in women. It was also proved that stillbirths are a risk factor associated with NTDs. TT homozygosity varies among different country populations, from 6% to 16%. An additional risk factor for NTD is MTHFR 1298 A-->C mutation. Combined heterozygosity for the 1298 A-->C and 677 C-->T mutations is associated with increased homocysteine and lowered plasma folate levels. This genotype is more frequent in NTD patients compared with controls. Further investigations in the field of genetic aspects of NTD in Poland will be very important for the primary prevention of NTD.     

Methylenetetrahydrofolate Reductase TT Genotype as a Predictor of Cardiovascular Risk in Hypertensive Adolescents

Methylenetetrahydrofolate reductase (MTHFR) is associated with homocysteine level. In deficit of MTHFR, cardiovascular risk is increased with hyperhomocysteinemia and hypomethionemia. Mutation of the MTHFR gene is associated with the risk for premature cardiovascular diseases. However, the association between MTHFR mutation and cardiovascular risk is still controversial. The purposes of this study were to determine whether MTHFR genotype is associated with cardiovascular risks in hypertensive adolescents and to investigate the association between MTHFR genotype and carotid intima-media thickness (IMT). Forty-three hypertensive adolescents were included in this study. Serum lipid levels, insulin, vitamin B₁₂, folate, renin, aldosterone, angiotensin converting enzyme, and homocysteine levels were evaluated. The carotid IMT and diameter were estimated by ultrasound. Brachial–ankle pulse wave velocity was also measured. Polymerase chain reaction was conducted to amplify genomic DNA fragment containing C677T position of the MTHFR gene. The height, weight, body mass index, obesity index, arm circumference, fat mass, and fat distribution were significantly greater in patients with C677T mutation. The C677T mutation group showed significantly greater carotid IMT, higher homocysteine, and lower folic acid levels than the normal genotype group. Interpretation of MTHFR genotype might be useful in predicting the development of premature coronary artery disease in hypertensive adolescents.     

Improved glycemic control and lower frequency of severe hypoglycemia with insulin detemir; long-term experience in 105 children and adolescents with type 1 diabetes

Objective:  To assess the effect of the insulin analog detemir on glycemic control and severe hypoglycemia in children and adolescents with type 1 diabetes.
Research design and methods:  A retrospective chart analysis was performed in 105 patients with type 1 diabetes after switching to insulin detemir between 2004 and 2007. In children below 12 yr of age (n = 53), evening neutral protomin hagedorn (NPH) insulin was replaced by insulin detemir if therapeutic goals were not reached and blood glucose levels were unpredictable or hardly controllable. In adolescents above 12 yr of age (n = 52), insulin detemir was started when changing to intensified insulin therapy.
Results:  In children below 12 yr of age, hemoglobin A1c (HbA1c) at start was 8.3 ± 0.8% and after 12 months of treatment with insulin detemir significantly lowered (7.6 ± 0.6%, p < 0.001). In the age-group above 12 yr of age at the start of the study, the improvement of HbA1c after 12 months of treatment was less pronounced (8.0 ± 1.2 vs. 7.6 ± 1.0%) but still significant (p < 0.01). The risk for severe hypoglycemia was significantly decreased compared with patients attending the outpatient clinic between 1995 and 2003 (4.8/100 patient years vs. 7.6/100 patient years, p = 0.003). From the beginning to the end of the follow-up period, body mass index dropped significantly in children below 12 yr of age but no effect was observed in adolescents.
Conclusions:  Use of insulin detemir allows a safe nocturnal glycemic control in children and adolescents with type 1 diabetes and is associated with significantly improved HbA1c levels and fewer severe hypoglycemic events. This makes insulin detemir a most valuable new tool for the treatment of children and adolescents with type 1 diabetes.     

Health-related quality of life in intensively treated young patients with type 1 diabetes

Abstract:  This study aimed to analyse the impact of the disease and treatment on health-related quality of life (HRQOL) in intensively treated young patients with diabetes. Our main hypothesis was that metabolic control, gender, age and socio-economic status predict HRQOL. All children and adolescents (n = 400, 191 girls) and parents in a geographic population of two paediatric clinics in Sweden [mean age 13.2 yr, ±SD 3.9, range 2.6–19.6; mean duration of diabetes 5.1 yr, ±SD 3.8, range 0.3–17.6; yr mean haemoglobin A1c (HbA1c) 7.1%, ±SD 1.2, range 4.0–10.7] received the DISABKIDS questionnaire, a validated combined chronic generic and condition-specific HRQOL measure for children, and the EuroQol-5D questionnaire. Parents as proxy perceived HRQOL lower than their children. Adolescents with separated parents reported lower generic HRQOL (GeHRQOL) and diabetes-specific HRQOL (DiHRQOL) than those with parents living together (p = 0.027 and p = 0.043, respectively). Adolescent girls reported lower GeHRQOL (p = 0.041) and DiHRQOL (p = 0.001) than boys did. Parents of girls <8 yr of age reported lower DiHRQOL (p = 0.047) than did parents of boys <8 yr. In addition, a difference was found in HRQOL between centres. Intensive insulin therapy did not seem to lower HRQOL. If anything, along with better metabolic control, it increased HRQOL. A correlation between DiHRQOL and HbA1c was found in adolescents (r = −0.16, p = 0.046) and boys aged 8–12 yr (r = −0.28, p = 0.045). We conclude that the diabetes team can influence the HRQOL of the patients as there was a centre difference and because HRQOL is influenced by glycaemic control and insulin regimen. Girls seem to need extra support.     

MTHFR 677C→T And 1298A→C POLYMORPHISMS IN CHILDREN WITH DOWN SYNDROME AND ACUTE MYELOID LEUKEMIA IN BRAZIL

Down syndrome (DS) is an important risk factor associated with acute leukemia (AL). The presence of polymorphisms that reduce 5,10-methylenetetrahydrofolate reductase (MTHFR) activity has been linked to the multifactorial leukemogenic process. The authors have conducted a study to test whether 677C→T and/or 1298A→C polymorphisms of MTHFR would play an additional role in susceptibility of acute myeloid leukemia (AML) in DS children. They also verified whether any polymorphism in the MTHFR gene was associated with the risk of DS. Genetic polymorphisms determination was carried out in 248 samples from healthy individuals as controls and a total of 115 DS children (65 without leukemia and 50 with AML). The present study failed to reveal any association between these polymorphisms and risk of AML in DS children. The data also indicate that MTHFR polymorphisms are not associated with risk of being a DS child.     

Physical activity and overweight in children and adolescents using intensified insulin treatment

Aim:  To describe physical activity and inactivity and parameters associated with overweight in a population-based study of children and adolescents on intensive insulin treatment.
Methods:  Physical activity and inactivity were evaluated in 723 type 1 diabetic subjects, 240 children aged 6–10 yr and 483 adolescents aged 11–19 yr, using a questionnaire that can estimate total amount of time spent on inactivity and light, moderate and vigorous activity.
Results:  Overall, 54% of the participants do not fulfil the international recommendations of 60 min of moderate-to-vigorous activity per day. Girls are less active than boys in childhood (70 vs. 88 min/d, p = 0.01) and in adolescence (47 vs. 57 min/d, p = 0.02). Furthermore, this study shows that those who are more active are also those who seldom skip meals (p < 0.001). Forty-three percent of the participants watch TV for more than 2 h a day, and TV viewing was found to be related to overweight in children and adolescents with type 1 diabetes [OR: 2.5 (1.40–4.54), p = 0.002]. No statistical differences in physical activity were noted between the different intensified insulin regimens. Patients wearing insulin pumps were not less active.
Conclusion:  To increase physical activity to recommended level and limit TV viewing should be an important issue in education of all children and adolescents with type 1 diabetes, independent of insulin regimen.     

Gene polymorphism and folate metabolism: a maternal risk factor for Down syndrome

The high birth frequency of Down syndrome (DS), trisomy 21 (T21), has been a subject of interest to the clinicians and researchers due to its complexity in phenotypic expression. In addition to the maternal age, identification of the mechanistic basis for T21 requires an understanding of the cellular-molecular events and other biochemical pathways that could promote maternal meiotic nondisjunction. Recent studies have linked the increased frequency of polymorphism of methylenetetrahydrofolate reductase (MTHFR, C677T) and methionine synthase gene (MTRR, A66G) in mothers with DS child. Based on evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, researchers have observed that mothers with mutation in MTHFR (C677T) and MTRR (A66G) gene have elevated levels of plasma homocysteine. This was found to be associated with a 2.6 to 2.9 fold increased risk of having child with DS compared to mothers without the mutation. Subsequent studies evaluating Italian, Irish, French, and Indian-Gujarati women could not demonstrate an association of MTHFR gene polymorphism in mothers with DS child. However, the Irish study did find an increased risk of DS associated with the MTRR polymorphism and an interactive effect of MTRR and MTHFR polymorphisms with increased risk. Interestingly, an increase in plasma homocysteine was found to be a risk factor for DS in several of the studies. Despite the differences, the published studies suggest a common theme of abnormal folate metabolism associated with increased risk of having a child with DS. These observations suggest that there seems to be a geographic variation in gene polymorphism and it could not be attributable to meiotic nondysjunction in all mothers with DS child but increased homocysteine in all different study group does suggest that there may be a gene-nutritional or gene-gene or gene-nutritional-environmental factors involved in increased frequency of meiotic nondisjunction which needs transnational and multinational study design.     

The addition of rosiglitazone to insulin in adolescents with type 1 diabetes and poor glycaemic control: a randomized-controlled trial

Objective:  To evaluate the effect of rosiglitazone, an insulin sensitizer, on glycaemic control and insulin resistance in adolescents with type 1 diabetes mellitus (T1DM)
Research design and methods:  Randomized, double-blind, placebo-controlled crossover trial of rosiglitazone (4 mg twice daily) vs. placebo (24 wk each, with a 4 wk washout period). Entry criteria were diabetes duration >1 yr, age 10–18 yr, puberty (≥Tanner breast stage 2 or testicular volume >4 mL), insulin dose ≥1.1 units/kg/day, and haemoglobin A1c (HbA1c) >8%. Responses to rosiglitazone were compared with placebo using paired t -tests.
Results:  Of 36 adolescents recruited (17 males), 28 completed the trial. At baseline, age was 13.6 ± 1.8 yr, HbA1c 8.9 ± 0.96%, body mass index standard deviation scores (BMI-SDS) 0.94 ± 0.74 and insulin dose 1.5 ± 0.3 units/kg/day. Compared with placebo, rosiglitazone resulted in decreased insulin dose (5.8% decrease vs. 9.4% increase, p = 0.02), increased serum adiponectin (84.8% increase vs. 26.0% decrease, p < 0.01), increased cholesterol (+0.5 mmol/L vs. no change, p = 0.02), but no significant change in HbA1c (−0.3 vs. −0.1, p = 0.57) or BMI-SDS (0.08 vs. 0.04, p = 0.31). Insulin sensitivity was highly variable in the seven subjects who consented to euglycaemic hyperinsulinaemic clamps. There were no major adverse effects attributable to rosiglitazone.
Conclusion:  The addition of rosiglitazone to insulin did not improve HbA1c in this group of normal weight adolescents with T1DM.     

Plasma total homocysteine levels in children with type 1 diabetes: relationship with vitamin status, methylene tetrahydrofolate reductase genotype, disease parameters and coronary risk factors

The objectives of this study were: to determine plasma total homocysteine tHcy levels and the prevalence of hyperhomocysteinemia in children with type 1 diabetes, to determine correlates of plasma tHcy levels with nutritional factor such as serum folic acid and vitamin B12 levels, genetic factors as methylenetetrahydrofolate reductase MTHFR gene polymorphism (C677T and A1298C), to attempt to identify possible dependencies between tHcy and the degree of metabolic control, the duration of the disease and presence of complications, and also to determine the relationship between other coronary risk factors. Plasma tHcy levels and other related parameters performed in 32 children with type 1 diabetes and 23 age-sex matched healthy children. Median tHcy level was higher in the patient group (11.38, 3.28 to 66.01 micromol/l) than the control group (8.78, 1.06 to 13.66 mol/l) (p < 0.05). A 28.1 per cent (n = 9) of the diabetic patients had hyperhomocysteinemia, four case with mild and five case with moderate. Plasma tHcy levels were positively correlated with disease duration and C-reactive protein CRP levels and negatively correlated with disease onset age. The hyperhomocysteinemic group had higher CRP levels, longer disease duration and early onset of disease than non-hyperhomocysteinemic group (p < 0.05 in both), respectively. The hyperhomocysteinemic group had significantly higher CRP, total cholesterol, triglyceride, apolipoprotein B, systolic blood pressure, blood urea nitrogen and creatinine levels and lower folate, apolipoprotein A1 levels and glomerular filtration rate values than the control group. Plasma tHcy levels were higher in diabetic children with poor metabolic control. Because of hyperhomocysteinemia is common in diabetic children and plasma tHcy levels correlated with early onset of the disease and disease duration, we recommend the usage of plasma tHcy levels as a risk indicator parameter with other coronary risk factor for detecting and preventing cardiovascular disease in diabetic children.     

Cardiovascular fitness is negatively associated with homocysteine levels in female adolescents

OBJECTIVE: To examine the association between cardiovascular fitness and homocysteine levels in adolescents. DESIGN: Cross-sectional study. SETTING: Madrid, Murcia, Granada, Santander, and Zaragoza, Spain. PARTICIPANTS: One hundred fifty-six Spanish adolescents (76 boys and 80 girls) aged (mean +/- SD) 14.8 +/- 1.4 years. MAIN EXPOSURES: Cardiovascular fitness was measured by the 20-m shuttle run test. Pubertal stage, birth weight, smoking status, and socioeconomic status were determined, and the sum of 6 skinfold thickness measurements, and serum folic acid and vitamin B(12) levels were measured. Methylenetetrahydrofolate reductase (MTHFR; 677C>T genotype) polymorphism was done by DNA sequencing. MAIN OUTCOME MEASURE: Fasting homocysteine levels. RESULTS: Mean values of homocysteine were significantly higher in the MTHFR 677CT and TT genotype subgroups compared with the CC genotype subgroup in adolescent boys, whereas in adolescent girls, mean values of homocysteine were significantly higher in the MTHFR 677CT and TT genotype subgroup compared with the CC and CT genotype subgroups. Multiple regression analyses showed that cardiovascular fitness was significantly associated with homocysteine levels in female adolescents after controlling for potential confounders including the MTHFR 677C>T genotype (beta = -0.40; semipartial correlation = -0.35; P = .007). No associations were found between cardiovascular fitness and homocysteine levels in male adolescents (beta = 0.12; semipartial correlation = 0.08; P = .51). CONCLUSION: The results suggest that cardiovascular fitness is negatively associated with homocysteine levels in female adolescents after controlling for potential cofounders including MTHFR 677C>T genotype.     

Standard dosing of tacrolimus leads to overexposure in pediatric renal transplantation recipients

Abstract:  Tacrolimus dosage in pediatric RTRs is empirically based on weight. There is evidence that adolescents are at greater risk of toxicity than young children on this dosing regimen. We investigated the rate of tacrolimus overexposure within the first three wk post-transplantation in pediatric RTRs receiving tacrolimus 0.15 mg/kg twice daily. Of 63 RTRs studied, 41 (65.1%) experienced a tacrolimus level above the therapeutic range (supratherapeutic), the majority (48.8%) on days two to four post-transplant. Patients with supratherapeutic levels were older (14.2 vs. 9.9 yr, p = 0.016), taller (146.7 vs. 126.5 cm, p = 0.029), larger (1.36 vs. 1.01 m², p = 0.039) and heavier (44.1 vs. 29.3 kg, p = 0.043) and by day 12 were receiving much lower tacrolimus doses than those without supratherapeutic levels (0.425 vs. 0.198 mg/kg/day, p = 0.0002). Supratherapeutic levels were more common among white (British) children than other ethnic groups (74 vs. 45%, p = 0.02). There were no observed differences in rates of patient or graft survival, or acute rejection during the three-yr study period. Adolescent patients appear to be at greater risk of excessive tacrolimus dosing on a standard regimen. We therefore outline a regimen restricting tacrolimus dosage given to larger/older patients, but emphasize the need for a prospective randomized trial to define optimal dosing.