Vascular endothelial growth factor (VEGF) levels in short, GH treated children: a distinct pattern of VEGF-C in Noonan syndrome.

CONTEXT: Noonan syndrome (NS) is characterized by short stature and elevated risk of lymphedema. The mechanism underlying lymphedema may be mediated by vascular endothelial growth factors (VEGFs). OBJECTIVE: To assess the effect of growth hormone (GH) treatment on plasma insulin-like growth factor (IGF)-1, VEGF-A and VEGF-C levels in patients with NS as compared to short GH-sufficient children. DESIGN: Retrospective, comparative. SETTING: Endocrinology department of a tertiary pediatric medical center. PATIENTS AND METHODS: Plasma IGF-1, VEGF-A and VEGF-C levels were measured before and during GH treatment in 6 patients with NS and 18 age-matched short subjects (Turner, idiopathic short stature and small for gestational age). MAIN OUTCOME MEASURES: Changes in plasma VEGF and IGF-1 levels. RESULTS: Baseline IGF-1 SDS levels were slightly lower in NS patients compared with controls; IGF-1 response to GH therapy was markedly lower in NS patients compared with controls (p = 0.017). Mean baseline VEGF-A levels were similar in NS patients and controls whilst mean baseline VEGF-C levels were significantly lower in the NS group as compared with controls (p = 0.022). Plasma VEGF-A and VEGF-C levels did not significantly change during GH treatment in the study cohort. No correlation was found between VEGF-C levels and levels of IGF-1, VEGF-A and auxological parameters, either before or during GH administration. CONCLUSION: Children with NS have a distinct growth factor profile including low basal VEGF-C and flattened IGF-1 response to GH. Further studies are needed to confirm our findings and to elucidate the interaction between VEGF-C levels and lymphedema.

A family with a novel termination mutation in hepatic nuclear factor 1α in maturity-onset diabetes of the young type 3 which is unresponsive to sulphonylurea therapy.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus. AIMS: To identify the genetic basis in a family with 3 generations of diabetes and to assess the concordance between the genotype and phenotype. METHODS: A molecular analysis was performed on genomic DNA using polymerase chain reaction, denaturing gradient gel electrophoresis, and sequencing. A mixed-meal tolerance test (MMTT) was performed with/without glibenclamide. Abdominal ultrasonography was performed on all family members with diabetes due to the location of the mutation. RESULTS: A novel c.618G>A, p.W206X termination mutation was identified in the hepatic nuclear factor 1α (HNF1α) gene. The mutation was identified in the proband and 8 of the 14 family members tested. An MMTT stimulus (±2.5 and 5 mg glibenclamide) produced a similar glucose profile and C-peptide graph in both the obese proband and her nonobese mother, showing no effect of the glibenclamide. No evidence of liver adenomas was found in the abdominal ultrasonography. CONCLUSIONS: We described a novel c.618G>A, p.W206X mutation in HNF1α associated with MODY 3 but not with hepatocellular adenoma. In contradistinction to most MODY 3 mutations, treatment with sulphonylurea was found to be a clinically ineffective alternative to insulin therapy.

Using the Internet-based upload blood glucose monitoring and therapy management system in patients with type 1 diabetes.

The aim of this study is to assess the impact of the internet-based upload blood glucose monitoring and therapy management system (Carelink(®)) in patients with type 1 diabetes. Diabetic patients treated with pump infusion for ≥3 months were prospectively randomized to use the CareLink(®) with (4 months) and without (4 months) diabetes-team initiated contact (n = 36, intervention group) or to continue standard care for 4 months and then transfer to the CareLink(®) without diabetes-team initiated contact (n = 34, control group). In the first 4 months, treatment was adjusted monthly by the same team in both groups. Main outcome measures were HbA1c level and scores on the Diabetes Treatment Satisfaction and Diabetes Quality of Life Questionnaires. Patients who submitted <3 times during each 4-month segment were considered noncompliant. Mean patient age was 14.02 ± 5.33 years; mean diabetes duration, 6.4 ± 4.7 years; median duration of pump treatment, 2.5 years. After 4 months, mean HbA1c level decreased from 8.75 ± 0.84 to 8.45 ± 0.90% in the intervention group (p = 0.013) and from 8.65 ± 0.57 to 8.37 ± 0.73% in the control group (p = 0.054). Within the intervention group, the difference in the change in HbA1c levels between compliant and noncompliant patients was significant (8.17 ± 0.81 vs. 8.99 ± 0.85%, p = 0.017). Only in the compliant subgroup was the decrease from baseline significant (p = 0.006). Similar findings were noted in the control group at 8 months (p < 0.05 and p = 0.018, respectively). There were no significant changes in questionnaire scores at 4 or 8 months in either group. Use of the CareLink(®) system is associated with significantly improved glycemic control in compliant patients, with no apparent effect on patient satisfaction or quality of life.

Changes in weight and BMI following the diagnosis of type 1 diabetes in children and adolescents.

The aim of this study was to study weight and body mass index (BMI) before, at, and after diagnosis of type 1 diabetes (T1D) and to identify factors associated with weight gain. Studied retrospectively were 209 children <18 years with T1D followed for 6 years. Data collected included clinical and laboratory data before diagnosis, at diagnosis, and during 6 years of follow-up. Anthropometric parameters of patients were compared along follow-up and with those of their parents and siblings. Mean BMI-standard deviation score (SDS) was below average at diagnosis (-0.66 ± 1.27), had increased to 0.37 ± 0.93 at 3 months, and decreased to a nadir at 6 months in females and 12 months in males; between 1 and 3 years, there was a slight increase and between 3 and 6 years a further increase only in the females. BMI-SDS at 6 years was significantly higher than pre-diabetes BMI-SDS (0.35 ± 0.83 vs. -0.04 ± 1.23, p < 0.001). Patients' BMI-SDS at 6 years was similar to that of their parents and siblings, was higher in the females (0.53 ± 0.74 vs. 0.27 ± 0.82, p = 0.02) and in those keeping diabetes a secret (0.66 ± 0.82 vs. 0.33 ± 0.78, p = 0.027), and was not associated with age or pubertal stage at diagnosis, ethnicity, or metabolic control. A longer duration of insulin pump therapy was associated with a lower BMI-SDS (r = -0.2375, p < 0.025). BMI-SDS increased during the 6 years following diagnosis of T1D in pediatric patients, especially in the females, but remained in the normal range and was similar to that of other family members.

Factors associated with diabetic ketoacidosis at onset of Type 1 diabetes in children and adolescents.

AIMS: To identify risk factors for diabetic ketoacidosis at diagnosis of Type 1 diabetes in children and adolescents. METHODS: In three time periods (1986-1987, 1996-1997 and 2006-2007) 75, 86 and 245 patients, respectively, aged < 20 years were newly diagnosed with Type 1 diabetes in one tertiary care centre. In this retrospective comparative study, data of clinical characteristics, laboratory evaluation at diagnosis, as well as demographic data were retrieved from the patients' files. Comparative analyses were performed between patients presenting with or without diabetic ketoacidosis and between the three time periods. RESULTS: Patients presenting with diabetic ketoacidosis were younger (9.2 ± 4.7 vs. 10.4 ± 4.7 years; P < 0.02), thinner (weight standard deviation score -0.59 ± 1.2 vs. -0.25 ± 1.1; P = 0.002) and less frequently had a first- and/or second-degree relative with Type 1 diabetes compared with those without diabetic ketoacidosis at presentation (16.0 vs. 31.2%, respectively; P = 0.001). Children with diabetic ketoacidosis were less likely to have had relevant testing before diagnosis than children without diabetic ketoacidosis. Children aged < 2 years presented more often with diabetic ketoacidosis than the older children (85 vs. 32%; P < 0.001). Children of Ethiopian origin had a higher rate of diabetic ketoacidosis at diagnosis than the rest of the cohort (57.8 vs. 33%; P = 0.04). CONCLUSIONS: Factors affecting the risk of developing diabetic ketoacidosis at diagnosis of Type 1 diabetes may be related to the degree of awareness of symptoms of diabetes among parents and primary care physicians. Prevention programmes should aim at increasing awareness and consider the application of special measures to avoid diabetic ketoacidosis in children aged < 2 years and high-risk ethnic groups.

Decrease in frequency of ketoacidosis at diabetes onset over the past two decades - perspectives of a paediatric tertiary care centre.

AIMS: To determine whether the frequency and severity of diabetic ketoacidosis and the clinical characteristics of children at diagnosis of Type 1 diabetes mellitus have changed over the past decades among patients under surveillance of a tertiary paediatric centre. METHODS: In three time-periods, 75 (1986-1987), 86 (1996-1997) and 245 (2006-2007) patients at mean age 10.1 ± 4.7 years (0.6-20.0) were diagnosed with new-onset Type 1 diabetes. Data on clinical characteristics and laboratory evaluation at diagnosis retrieved from the patients' files . Comparative analysis was performed between the three time periods. RESULTS: The frequency of diabetic ketoacidosis at diagnosis was 40% in 1986-1987, 41.8% in 1996-1997 and 29.4% in 2006-2007; the last rate was significantly lower (P=0.04). No significant differences in the proportions of patients with severe or moderate diabetic ketoacidosis were found over time. Mean weight standard deviation score significantly increased from -0.72 ± 1.8 in 1986-1987 to -0.27 ± 1.2 in 2006-2007 (P<0.05), while percentage weight loss (∼6.5%) before diagnosis remained unchanged. In 2006-2007 a higher proportion of children had glucose testing at the community clinic before diagnosis, than in the earlier years (73.1 vs. 59.6%, P=0.003). CONCLUSIONS: The overall frequency of diabetic ketoacidosis in children with newly diagnosed Type 1 diabetes has decreased in the past decade, although the degree of metabolic decompensation has remained unchanged.

Are treatment targets for hypercholesterolemia evidence based? Systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: Search for evidence supporting target age, level of intervention and target values for low-density lipoprotein (LDL) cholesterol levels in children with familial hypercholesterolemia. DESIGN: Systematic review and meta-analysis. PubMed, Medline, CINAHL and Cochrane Reviews databases from 1966 to 2007 were searched for articles reporting statin therapy in children and adolescents aged 8-18 years. Retrieved articles were screened for double-blind randomised controlled trials (RCTs). RESULTS: Seven trials involving 884 patients met inclusion criteria. Meta-analysis findings showed significantly reduced total cholesterol, LDL cholesterol and apolipoprotein B, whereas high-density lipoprotein cholesterol and apolipoprotein A1 were significantly increased by statin therapy. Evidence on target level in children was limited to one study attainment of LDL cholesterol treatment target in 60% of the subjects in the treatment group and none in the placebo group reached their target LDL cholesterol. Evidence on the effect of statins on surrogate markers of atherosclerosis was limited to two studies (one RCT on the effect upon the carotid intima-media thickness (n=211; mean difference (MD) -0.01; 95% CI -0.03 to -0.00), and one showing that the mean absolute change in flow-mediated dilation after 28 weeks of statin treatment was significantly higher in the simvastatin group compared to placebo group (MD 2.7%; 95% CI 0.42 to 4.98). CONCLUSIONS: There is no firm evidence regarding when to start statin treatment or what target LDL cholesterol level should be attained. Recent recommendations that favour statins as the first-line drug treatment for hypercholesterolemia are evidence based. Studying high-risk groups (obese or diabetic patients) and incorporating composite end points may help define treatment guidelines.

Effect of sex hormone administration on circulating ghrelin levels in peripubertal children.

BACKGROUND: Ghrelin levels gradually decrease throughout childhood and with advancing pubertal stage. The change during puberty is more pronounced in boys than girls. OBJECTIVE: The objective of the study was to investigate whether the pubertal drop in ghrelin secretion is modified by the increase in sex hormones. PATIENTS AND METHODS: Ghrelin levels were measured in 34 short peripubertal children (17 boys and 17 girls) aged 8-12.5 yr before and after sex hormone priming for GH stimulation testing. RESULTS: In boys, priming with testosterone increased testosterone to pubertal levels (23.7 +/- 7.1 nmol/liter), which in turn induced a marked decrease in ghrelin (from 1615.8 +/- 418.6 to 1390.0 +/- 352.0 pg/ml) and leptin (from 8.0 +/- 4.5 to 5.8 +/- 3.2 ng/ml) and an increase in IGF-I (from 162.7 +/- 52.8 to 291.1 +/- 101.6 ng/ml) (P < 0.001 for all parameters). In girls, priming with estrogen led to a supraphysiological increase in estradiol levels (1313.8 +/- 438.0 pmol/liter), which had no effect on ghrelin, leptin, or IGF-I. There was no correlation between ghrelin levels and levels of sex hormones, leptin, or body mass index in either boys or girls. CONCLUSIONS: A pharmacological increase in sex hormones is associated with a marked decline in circulating levels of ghrelin in boys but not girls. Additional longitudinal studies through puberty are needed to elucidate the physiological interaction between sex hormones and ghrelin.

[Probiotics: a therapeutic concept awaiting recognition]. / Probiotiki: kontseptsiia lechebnogo primeneniia, ozhidaiushchaia svoego priznaniia.

The history of emergence of the probiotics concept as well as basic knowledge on the mechanism of their action is described. The possibilities of the therapeutic use of probiotics, in particular for cases of Crohn's disease, viral gastroenteritis and travelers' diarrhea are discussed. The conclusion is made that the effectiveness of the use of probiotics has not yet been proved due to the fact that in clinical trials of these preparations many uncontrolled variables are not taken into consideration. For this reason at the present moment the prophylactic and curative use of probiotics is an idea whose constructive character has yet to be proved.

Leukocyte adhesiveness/aggregation test (LAAT) to discriminate between viral and bacterial infections in children.

OBJECTIVES: We previously noted that white blood cells (WBC) have increased adhesive properties during bacterial infections. Here, we aim to explore the possibility of using the different adhesive properties of WBC as a means of differentiating between viral and bacterial infections, a common problem in paediatrics. METHODS: The adhesive properties of WBC in the peripheral blood of 25 children with documented bacterial infections, 15 with documented viral infections and 36 with probable viral infections, were studied by means of a leukocyte adhesiveness/aggregation slide test (LAAT). The results of the LAAT were compared with those of the other acute phase reactants, namely WBC, differential count and erythrocyte sedimentation rate (ESR), which were taken in the same blood sample in each patient. RESULTS: The sensitivity, specificity and positive predictive value were 92%, 96%, and 92%, respectively for the LAAT; 83%, 87% and 80% for the ESR; 56%, 78% and 56% for the white blood cell count; and 54%, 74% and 50% for the differential count. CONCLUSIONS: The presence of bacterial infections in children can be tested using a simple slide test to reveal the increased state of leukocyte adhesiveness/aggregation in the peripheral blood. The LAAT is a reliable, rapid and inexpensive test, and it can be a useful laboratory tool for the paediatrician treating a child with acute febrile illness.

A pneumococcal protein that elicits interleukin-8 from pulmonary epithelial cells.

To understand how neutrophils are recruited to the lung in pneumococcal pneumonia, the ability of pneumococcal components to elicit the chemokine interleukin (IL)-8 from monolayers of cultured human type II cells was assessed. Heat-killed clinical and laboratory strains of Streptococcus pneumoniae and secreted proteins from exponentially growing pneumococci elicited significant quantities of IL-8 from A549 cells. All strains that elicited IL-8 production secreted a protein ( approximately 90 kDa) that comigrated on SDS-PAGE with a C3-binding protein previously identified in S. pneumoniae. As little as 7 pmol of the purified 90-kDa protein readily elicited levels of IL-8 production equivalent to those obtained with 1 U of IL-1alpha. Supernatant proteins and heat-killed cells of an isogenic mutant that failed to produce the C3-binding protein elicited significantly less IL-8 than did supernatant proteins or heat-killed cells of the parent strain. These results implicate the C3-binding protein of S. pneumoniae in a novel pathway of pulmonary inflammation.