Study of candidate genes for dyslexia in Brazilian individuals.

Dyslexia or reading disability (RD) is the most common childhood learning disorder and a significantly heritable trait. Many recent studies have investigated the genetic basis of dyslexia, and several candidate genes have been proposed. Among these, DCDC2 and KIAA0319 have emerged as the strongest candidate genes for dyslexia; however studies have not provided uniformly supportive results. The aim of this study was to assess the contribution of proposed candidate genes to the molecular etiology of dyslexia in a Brazilian sample. Large deletions and duplications in the candidate genes DCDC2, KIAA0319, and ROBO1 were investigated in 51 dyslexic subjects. Furthermore, a family-based association study was performed to investigate whether associations observed in other populations with variants in the DCDC2 and KIAA0319 genes were reproducible in Brazilian dyslexic individuals. Our analysis did not detect any deletions or duplications in the genes studied, and we found no evidence that the allelic variants in the two candidate genes were significantly associated with RD in our sample. Our data do not support a role of the DCDC2/KIAA0319 locus in influencing dyslexia as a categorical trait. Given the genetic complexity of dyslexia, it is plausible that both genes contribute to an increased risk, but the relative influence of these 2 genes on RD varies in different study samples, and/or depends on analytical approaches.

Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus.

INTRODUCTION: The aim of this study was to evaluate the effects of high-dose vitamin E supplementation (1200 mg/day) on reducing both microalbuminuria (MA) and oxidative stress in patients with type 1 diabetes mellitus (T1DM) and persistent MA. METHODS: We performed a 12-month, randomized, placebo-controlled, double-blind cross-over trial in ten Caucasian young adults (7m/3f; mean age 18.87 +/- 2.91 years) with T1DM and persistent MA. At baseline and at end of the treatment period, determination of albumin excretion rate (AER) and HbA(1c) and evaluation of the oxidant/antioxidant status were performed. RESULTS: At the beginning of the study, AER and HbA(1c) were not significantly different between the vitamin E and placebo group. No differences in terms of oxidant and antioxidant status were found between the two groups. This was associated with no significantly different urinary VEGF and TGF-beta levels. After 6 months, no significant differences in AER were observed between the two groups (p = 0.59). However, plasma and LDL-vitamin E content were significantly higher in the vitamin E group compared to the placebo group (p = 0.0001 and p = 0.004, respectively). This was associated with a significantly longer lag phase (p = 0.002) and lower MDA (p = 0.049). However, no statistically significant differences were detected in terms of VEGF and TGF-beta urinary levels. CONCLUSION: These data demonstrate that high-dose vitamin E supplementation reduces markers of oxidative stress and improves antioxidant defence in young patients with T1DM. However, although it positively affects the oxidant/antioxidant status, vitamin E supplementation does not reduce AER in patients with T1DM and persistent MA.

Serum angiogenin concentrations in young patients with diabetes mellitus.

BACKGROUND: Angiogenin serum levels were measured in a large group of type 1 diabetic young patients, looking at whether increased Angiogenin concentrations are associated with long-term glycemic control and microvascular complications. MATERIALS AND METHODS: Four groups of patients were compared to 223 age- and sex- matched healthy controls: 196 type 1 diabetic patients (age range 3-24 years, onset of diabetes before the age of 12 years; duration of disease longer than 2 years), without microvascular complications were divided into three groups on the basis of age (group 1, n = 37, age < 6 years; group 2, n = 71, age 6-12 years; group 3, n = 88, age > 12 years); 53 adolescents and young adults (age 16.1-29.7 years) with diabetic microvascular complications (background, preproliferative or proliferative retinopathy, albumin excretion rate 20-200 microg min-1) (group 4). RESULTS: Angiogenin serum levels were significantly increased in diabetic pre-school and pre-pubertal children, and particularly elevated in pubertal subjects compared with age- and sex-matched controls. Adolescents and young adults with microvascular complications had very high angiogenin concentrations. One-year mean HbA1c values were correlated with angiogenin levels (r = 0.389; p < 0.01). In poorly controlled diabetics (HbA1c > 10%), long-term (2 years) improvement of glycemic control determined a significant reduction of angiogenin concentrations in both pre-school and pre-pubertal children as well as in pubertal youngsters. CONCLUSIONS: Angiogenin serum concentrations are increased in diabetic children even before puberty. Severity of microvascular complications is associated with markedly increased angiogenin serum levels. Long-term tight glycemic control determines a consistent reduction of angiogenin concentrations.

Serum copper, zinc, selenium, glutathione peroxidase and superoxide dismutase levels in epileptic children before and after 1 year of sodium valproate and carbamazepine therapy.

To assess whether epileptic children have abnormal values of serum copper (Cu), zinc (Zn), selenium (Se), glutathione peroxidase (GSH-PX) and superoxide dismutase (CuZn-SOD), and to evaluate the effect of long-term therapy with sodium valproate (VPA) and carbamazepine (CBZ) on these parameters, we studied 36 epileptic patients before the beginning of therapy and after 1 year of therapy with VPA or CBZ. Before the beginning of therapy, there were no differences in levels of all parameters studied between controls and epileptics. After 1 year of therapy, patients treated with VPA and CBZ continued to show normal values. In conclusion our study demonstrates that epilepsy per se and treatment with VPA and CBZ do not affect levels of Cu, Zn, Se, GSH-PX and CuZn-SOD concentrations.

Endothelial perturbation in children and adolescents with type 1 diabetes: association with markers of the inflammatory reaction.

OBJECTIVE: The progression of diabetic angiopathy is, in most cases, unpredictable. The aim of this study was to investigate early events that could influence the development of diabetic angiopathy. RESEARCH DESIGN AND METHODS: Circulating levels of von Willebrand factor (vWF) and tissue-plasminogen activator (tPA), defining endothelial perturbation, were measured in 40 young patients with type 1 diabetes. Patients were divided into two groups according to the duration of diabetes (group A, <1 year; group B, >1 year) and compared with a control group of age- and sex-matched healthy individuals. Prothrombin fragment 1 and 2 (F(1+2)), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) levels were also determined as markers of a prothrombotic state and inflammatory response. A total of 16 of the 20 children in group A were re-examined after 12 months. RESULTS: Compared with either normal subjects or patients in group B, children in group A showed increased levels of vWF, tPA, F(1+2), TNF-alpha, and CRP. Significant direct correlations between TNF-alpha or CRP and either vWF, tPA, or F(1+2) were observed. Endothelial perturbation was shown in 70% of group A and 20% of group B. After 1 year, 16 of the 20 patients in group A showed a significant reduction in vWF, tPA, F(1+2), TNF-alpha, and CRP levels, whereas endothelial perturbation was reversed in 5 of these patients. CONCLUSIONS: Endothelial perturbation represents an early and, in some cases, reversible event in the chronology of type 1 diabetes in children. A correlation might exist between the initial inflammatory reaction and the appearance of endothelial perturbation.

Plasma prorenin levels may predict persistent microalbuminuria in children with diabetes.

Diabetic microangiopathy is characterized by increased prorenin concentrations. In the present study, we evaluated plasma prorenin concentrations in a large group of adolescents with onset of diabetes during childhood to determine whether increasing prorenin levels may predict the development of persistent microalbuminuria. Ninety-seven young diabetic patients were studied; they were divided according to the presence of persistent microalbuminuria, at the end of follow-up, into group A and group B (patients who did not develop and who developed persistent microalbuminuria, respectively). One hundred and two healthy subjects, matched for age and sex, were also selected. Patients were followed up for at least 10 years. At the beginning of the study there were no significant differences in prorenin levels between either the two diabetic groups or the healthy controls. During follow-up, an increase in plasma prorenin started at 4 years and became statistically significant (P<0.01) 3 years before the onset of persistent microalbuminuria. No correlation was found between plasma prorenin levels and HbAlc percentages. In conclusion, an increased concentration of prorenin in plasma precedes the elevation of albumin excretion rate (AER) and, therefore, can be useful for identifying patients with onset of diabetes during childhood at risk of developing incipient nephropathy later in life.

Homocysteine levels during fasting and after methionine loading in adolescents with diabetic retinopathy and nephropathy.

OBJECTIVE: To assess plasma homocysteine levels in adolescents and young adults with type 1 (insulin-dependent) diabetes with and without microvascular complications. STUDY DESIGN: Homocysteine levels were measured during fasting and after methionine loading in plasma of 61 patients with onset of diabetes before the age of 12 years and duration of disease longer than 7 years. They had an albumin excretion rate (AER) between 20 and 200 microg/min in 2 of 3 overnight urine collections in a period of 6 months and/or retinopathy. Patients with persistent microalbuminuria were divided into 2 groups: subjects with AER of 20 to 70 microg/min and patients with AER of 70 to 200 microg/min. Adolescents (n = 54) without signs of diabetic retinopathy or nephropathy and matched control subjects (n = 63) were also studied. RESULTS: Homocysteine concentrations before and after methionine load were higher in adolescents with diabetic complications than in healthy subjects (fasting values: 12. 4 +/- 7.9 micromol/L vs 7.8 +/- 4.2 micromol/L; P <.01; after methionine load: 28.1 +/- 13.2 micromol/L vs 16.6 +/- 7.3 micromol/L; P <.005). Values of 11.9 micromol/L or higher were considered to constitute fasting hyperhomocysteinemia. The increase of homocysteine concentrations was particularly evident in young diabetic patients with AER >70 microg/min (fasting values: 14.7 +/- 5.6 micromol/L; after methionine load: 34.2 +/- 12.6 micromol/L) and in patients with proliferative retinopathy (fasting values: 15.1 +/- 5.0 micromol/L; after methionine load: 36.8 +/- 12.5 micromol/L). CONCLUSIONS: Increased plasma homocysteine concentrations may contribute to increased morbidity and death from cardiovascular disease in adolescents and young adults with diabetic retinopathy and nephropathy.

Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuminuria: relation to glomerular hyperfiltration.

Hyperglycemia has been causally linked to vascular and glomerular dysfunction by a variety of biochemical mechanisms, including a glucose-dependent abnormality in nitric oxide (NO) production and action. NO is a candidate for mediating hyperfiltration and the increased vascular permeability induced by diabetes. Serum nitrite and nitrate (NO2-+ NO3-) concentrations were assessed as an index of NO production in 30 adolescents and young adults with type 1 diabetes, 15 with and 15 without microalbuminuria (albumin excretion rate [AER] between 20 and 200 microg/min), compared with a well-balanced group of healthy control subjects. In all subjects, glomerular filtration rate (GFR) was determined by radionuclide imaging. Our study showed that NO2- + NO3- serum content and GFR values were significantly higher in microalbuminuric diabetic patients than in the other 2 groups. GFR was significantly and positively related to AER levels (r2 = 0.75, P < 0.0001), whereas NO2- + NO3- serum content was independently associated with both AER and GFR values (beta = 2.086, P = 0.05, beta = 1.273, P = 0.0085, respectively), suggesting a strong link between circulating NO, glomerular hyperfiltration, and microalbuminuria in young type 1 diabetic patients with early nephropathy. Interestingly, mean HbA1c, serum concentration was significantly higher in microalbuminuric than in normoalbuminuric diabetic subjects (P < 0.05) and was independently associated with AER values, suggesting a role for chronic hyperglycemia in the genesis of diabetic nephropathy. Moreover, HbA1c serum concentration was significantly and positively related to NO2 + NO3 serum content (r2 = 0.45, P = 0.0063) and GFR values (r2 = 0.57, P = 0.0011), suggesting that chronic hyperglycemia may act through a mechanism that involves increased NO generation and/or action. In conclusion, we suggest that in young type 1 diabetic patients with early nephropathy, chronic hyperglycemia is associated with an increased NO biosynthesis and action that contributes to generating glomerular hyperfiltration and persistent microalbuminuria.