High 1-h glucose in youths with obesity as marker of prediabetes and cardiovascular risk.

PURPOSE: Testing 1-h glucose (1HG) concentration during oral glucose tolerance test is cost-effective to identify individuals at risk of incident type 2 diabetes. Aim of the study was to define 1HG cutoffs diagnostic of incident impaired glucose tolerance (IGT) in youths with obesity, and to evaluate prevalence and association of cutoffs identified in the cohort and from the literature (133 and 155 mg/dl) to cardiovascular disease (CVD) in a population of youths with obesity. METHODS: This is a longitudinal study of 154 youths to identify 1HG cutoffs, and cross-sectional study of 2295 youths to estimate prevalence of high 1HG and association to CVD. Receiver-operating characteristic curves (ROC) were used to establish 1HG cutoffs, and univariate regression analyses to test association of 1HG to blood pressure, lipids and aminotransferases. RESULTS: ROC analysis identified the 1HG cutoff of 159 mg/dl as having diagnostic accuracy of IGT with area under the ROC 0.82 (95% CI 0.66-0.98), sensitivity 0.86% and specificity 0.79%. In the cross-sectional population, prevalence of high 1HG was 36% and 15% for 133 and 155 mg/dl cutoffs, respectively, and 17% for the 159 mg/dl value. All the examined cutoffs were significantly associated with worse lipid profile, liver function test, reduced insulin sensitivity, secretion and disposition index. CONCLUSION: High 1HG is marker of persistent IGT and increased risk of metabolic abnormalities in youths. The 155 mg/dl cutoff is a convenient estimate in young people but longitudinal studies with retinopathy and overt diabetes as end points are advised to verify the 1HG cutoff with the best diagnostic accuracy.

Exercise-induced GH secretion is related to puberty.

PURPOSE: Exercise represents a physiological stimulus that initiates the coordinated responses of hypothalamic-pituitary axis and sympathetic nervous system. Aims of the study were: 1) to analyze the response of GH, cortisol and prolactin to acute exercise in healthy children with normal GH response to stimulation tests 2) to evaluate the reliability of physical exercise as a screening test for GH secretion. METHODS: Forty-four children (mean age 9.35 ± 2.69 years, range 4-13.7) underwent standardized Bruce's test on treadmill. Twenty-nine children were pre-pubertal (nine females and 20 males) and 15 children were pubertal (ten females and five males). RESULTS: Exercise elicited a peak secretion of all the analyzed hormones. GH showed the highest mean percentage increase (558%), followed by prolactin (178%) and cortisol (23%). In 19/44 children (43.2%), GH peak did not reach the cut-off level of 8 ng/ml, considered as the normal GH response to stimulation tests. Despite a wide inter-individual variability, both GH peak and GH increase from baseline were higher in pubertal children than in pre-pubertal ones (GH peak: 13.49 ± 10.28 ng/ml versus 6.6 ± 4.09 ng/ml-p < 0.001; GH increase: 12.02 ± 10.30 ng/ml versus 5.28 ± 3.97 ng/ml-p < 0.001). The impact of puberty on both GH peak and GH increase was independent of sex, age, BMI SDS and VO2max. No differences related to sex or pubertal status were found in cortisol and prolactin responses. CONCLUSION: Exercise-induced GH secretion should not be considered a valuable screening tool in the diagnostic work-up of GH deficiency, due to the wide inter-individual variability in GH response. As described for standard GH stimulation tests, puberty represents the key factor that enhances GH secretion in healthy children.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Wrist circumference is a biomarker of adipose tissue dysfunction and cardiovascular risk in children with obesity.

PURPOSE: To evaluate the relationship between wrist circumference, markers of adipose dysfunction, and cardiovascular risk in youths with obesity. METHODS: In this cross-sectional study, we measured body mass composition by dual-energy X-ray absorptiometry, wrist circumference, waist-to-height ratio, fasting blood insulin, glucose, lipid profile, adiponectin, and leptin in 280 children with overweight/obesity and without diabetes (age: 7-18 years). Cardiovascular risk was estimated by "metabolic syndrome score" (MetS score). RESULTS: Study participants had median [25th-75th percentile] wrist circumference of 17.5 [16.7-18.5] cm and waist-to-height ratio of 0.62 [0.59-0.67]. Lower adiponectin-leptin ratio was found among subjects in the upper 50th percentiles of wrist circumference [0.17 (0.09-0.36) vs. 0.38 (0.16-0.79); p < 0.001]. Wrist circumference was independently associated with MetS score (r = 0.5 p < 0.001). Among MetS score components, an independent association between wrist circumference HDLc, triglycerides, and systolic blood pressure was found (r = - 0.253 p < 0.001; r =+ 0.204 p < 0.001; r = + 0.403 p = < 0.001, respectively). The coefficient of determination for MetS score was nominally higher when considering wrist circumference as independent variable (Adj-R2 = 0.30) then when considering body mass index SD (Adj-R2 = 0.28), waist-to-height ratio (Adj-R2 = 0.26) or truncal fat percentage (Adj-R2 = 0.01). The addition of wrist circumference in age and gender adjusted models, accounting to any other anthropometric parameters, resulted in a significant improvement of the Adj-R2 (p < 0.001 for all). CONCLUSIONS: Our study shows that wrist circumference independently relates to adiponectin-leptin ratio and to the prediction of cardiovascular risk, suggesting it as an efficient and adjunctive anthropometric marker of cardiometabolic risk in children with obesity.

25OH vitamin D levels in pediatric patients affected by Prader-Willi syndrome.

PURPOSE: Obesity, insulin resistance, and puberty seem to influence and been inversely associated with 25-hydroxy vitamin D (25OHD) levels. To our knowledge, a study on 25OHD in children and adolescents with Prader-Willi syndrome (PWS), a genetic form of obesity, is not yet available. OBJECTIVE: To analyze the 25OHD values in pediatric PWS subjects in comparison with a control group (CNT), highlighting the possible correlations with IR, BMD, body composition, pubertal stage, and GH therapy (GHT). METHODS: Auxological and laboratory parameters, HOMA-IR, Vitamin D status, and bone density and body composition by DEXA scan were analyzed in 52 PWS and 110 controls (CNT), gender-, age-, and BMI-SD matched. None of them was on calcium or vitamin D. 20 PWS were on growth hormone (GH) therapy and 32 were previously treated. RESULTS AND CONCLUSION: Altogether, PWS had similar values of 25OHD compared to CNT.16 PWS (30.7%) and 27 CNT (24.5%) had low 25OHD levels (< 20 ng/ml) (p = NS). 25OHD of PWS on GHT were comparable to those previously treated. In both groups, univariate analysis showed a negative correlation between 25OHD and fat mass% (FM%). GH therapy and pubertal stage were positively correlated with bone parameters analyzed by DXA. Multivariate regression confirmed only FM% as negative predictor of 25HOD in PWS patients, as previously described. GHT does not seem to influence 25OHD in PWS. CONCLUSION: Our data showed that PWS had similar values of 25OHD compared to CNT. As already described, FM seems to be the only parameter influencing 25OHD levels. Finally, GHT does not seem to influence 25OHD metabolism in PWS.

Growth hormone treatment improves final height and nutritional status of children with chronic kidney disease and growth deceleration.

PURPOSE: Growth retardation is a common complication of chronic kidney disease (CKD) in children. Treatment with recombinant human growth hormone (rhGH) has been used to help short children with CKD to attain a height more in keeping with their age group, but the scientific evidence regarding the effect of rhGH on final height is scarce. METHODS: Final heights of children with CKD receiving rhGH treatment (cases) were compared with final heights of a matched cohort of children with CKD that did not receive rhGH therapy (controls). RESULTS: Sixty-eight rhGH-treated cases (44 boys) were compared with 92 untreated controls (60 boys). Mean duration of rhGH therapy was 4.2 ± 0.9 years; rhGH dose was 0.3 ± 0.07 mg/kg/week. Height SDS at baseline was lower in rhGH-treated patients than in controls (-2.00 ± 1.02 versus -0.96 ± 1.11, p < 0.001). Baseline height SDS was significantly lower than target height SDS in both groups. Height SDS significantly improved from baseline to final height attainment in rhGH-treated patients, while it slightly decreased in controls (mean SDS variation 0.69 ± 1.05 in rhGH-treated cases versus -0.15 ± 1.2 in controls). Final height SDS was -1.25 ± 1.06 in rhGH-treated cases and -1.06 ± 1.17 in controls (p = 0.29). Target adjusted final height SDS was -0.91 ± 1.03 in rhGH-treated cases and -0.61 ± 1.17 in controls (p = 0.1). CONCLUSIONS: Long-term rhGH therapy is able to reduce the linear growth deceleration of children with CKD, and ultimately to improve their final height, reducing the difference with target height.

Family history and ethnicity influencing clinical presentation of type 1 diabetes in childhood.

BACKGROUND: A different clinical presentation of type 1 diabetes (T1DM) could be supposed in children belonging to different ethnicities, with or without family history of autoimmunity. OBJECTIVE: This study investigates the effect of ethnicity and family history of T1DM on clinical characteristics at presentation in a group of T1DM children. METHODS: One hundred ninety-six T1DM children <18 years, consecutively diagnosed during the years 2011-2014, were studied including 91 % of Caucasians of Italian ancestry and 9 % of non-Caucasian origin. RESULTS: Children with 1st or 2nd degree relatives affected by T1DM were younger at disease onset (p = 0.005) and showed lower HbA1C levels (p = 0.002), and higher IAA levels (p = 0.01). Non-Caucasian children were younger at disease onset (p = 0.029), and showed more severe hyperglycemia (p = 0.008) and ketoacidosis (pH p < 0.001). HbA1C levels were negatively related to positive family history of T1DM (p = 0.01), fasting C-peptide levels (p = 0.003), IAA levels (p = 0.03), and IA-2 levels (p = 0.003). The level of pH was positively influenced by fasting C-peptide (p = 0.004), and negatively impacted by C-reactive protein (p = 0.01) and non-Caucasian ethnicity (p = 0.03). CONCLUSION: The milder metabolic decompensation in children with a positive family history of T1DM is probably explained by the awareness of the families in terms of early symptoms of T1DM, while the younger age at onset and the higher levels of autoantibodies may suggest a stronger genetic susceptibility, associated with a more aggressive autoimmune process. The younger age in non-Caucasian children is probably explained by the higher genetic susceptibility in subjects belonging to ethnic groups with a low T1DM incidence. Social aspects and poor living conditions probably predominate in determining the increased severity of metabolic decompensation at onset in children from non-Caucasian ethnicities.

Early retesting by GHRH + arginine test shows normal GH response in most children with idiopathic GH deficiency.

PURPOSE: Most children with idiopathic isolated GH deficiency (IGHD) normalize GH response to stimulation tests when retested at the completion of growth. The objective of this study was to test the effectiveness of early retesting in challenging the diagnosis of idiopathic IGHD and critically review the diagnostic workup leading to this diagnosis in children with short stature. METHODS: We cross-sectionally retested 38 children with idiopathic IGHD and still on GH treatment. The initial diagnosis of idiopathic IGHD was based on subnormal GH responses to two stimulation tests and normal brain imaging or minor/nonspecific findings at magnetic resonance. The GH response normalization at retesting was considered as the main outcome measure. Clinical features of children who were falsely classified as idiopathic IGHD based on first GH testing were retrospectively analyzed. RESULTS: GH secretion was normal in 36/38 children (95%). Two children showed slightly reduced peak GH responses and normal IGF-I levels. Fourteen children underwent GH retesting before puberty, 24 children during puberty. CONCLUSION: The diagnostic process should be improved to minimize the rate of false positive at GH testing and, in case of unsatisfactory response to GH treatment, the diagnosis of isolated idiopathic GHD should be challenged with early retesting.

Metabolic syndrome and diabetes mellitus in childhood cancer survivors.

BACKGROUND: The survival of children with cancer has grown considerably in recent years resulting in a marked increase of endocrine complications. increasingly recognized problems are metabolic syndrome and diabetes mellitus. DATA SOURCES: We critically analysed the most recent literature about the prevalence and molecular mechanisms of metabolic dysregulation and long-term cardio-metabolic risk in this population. RESULTS: Hypothalamic irradiation determines growth hormone deficiency and hypogonadism; moreover it is able to disrupt the appetite regulating centre leading to hyperphagia and progressive obesity. These conditions determine an insulin resistant state, contributing to the development of metabolic syndrome and diabetes mellitus. Irradiation and/or chemotherapy may lead to an insulin secretory defect through a direct damage of pancreatic beta cells. CONCLUSION: Metabolic syndrome and diabetes mellitus represent increasingly recognized long-term complications of childhood cancer treatment. The different impact of insulin resistance and secretory defects on the onset and progression of metabolic syndrome and diabetes mellitus remains unclear.

Permanent diabetes during the first year of life: multiple gene screening in 54 patients.

AIMS/HYPOTHESIS: The aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age. METHODS: We studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009. RESULTS: In group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287. CONCLUSIONS/INTERPRETATION: Genetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes.

Is subclinical adrenal failure in adrenoleukodystrophy/adrenomyeloneuropathy reversible?

BACKGROUND: X-linked adrenoleukodystrophy/adrenomieloneuropathy (ALD/AMN) is a progressive neurodegenerative disorder due to mutations in the ABCD1 gene encoding the ABC transporter ALDP. Mutations in ALDP impair peroxisomal ß-oxidation of very long chain fatty acids (VLCFA), resulting in elevated levels of VLCFA in plasma, nervous system, and adrenals. Lorenzo's oil, combined with VLCFA- poor diet, normalizes plasma VLCFA within 1 month, but it does not prevent the progression of pre-existing neurological symptoms. No previous study analyzed the effect of Lorenzo's oil therapy on adrenal function. AIM: To investigate short-term effects of Lorenzo's oil, combined with VLCFA- poor diet, on adrenal function of AMN patients with early subclinical signs of adrenal failure. SUBJECTS AND METHODS: Seven AMN subjects underwent VLCFA-restricted diet combined with Lorenzo's oil (45 ml/day po), without steroid therapy, for 6 months. RESULTS: All patients had elevated ACTH at baseline, and a significant reduction was evident after 6 months (median ACTH at baseline: 1300 pg/ml, range: 720- 2100; median ACTH at 6 months: 186 pg/ml, range: 109-320, p: 0.0156). Cortisol was normal both at baseline and after 6 months. VLCFA dropped in all patients during the 6- month follow-up, and no patient required glucocorticoid replacement therapy. CONCLUSIONS: Adrenal insufficiency in ALD/AMN is probably due to a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of the adrenal cell membrane functions. In an early phase, Lorenzo's oil therapy may be able to improve VLCFA clearance and restore a normal ACTH receptor activity, and hypoadrenalism may be potentially reversible.

Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells.

Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase with a CXXC active site that can be released by various cell types upon activation. We show here that Trx is chemotactic for monocytes, polymorphonuclear leukocytes, and T lymphocytes, both in vitro in the standard micro Boyden chamber migration assay and in vivo in the mouse air pouch model. The potency of the chemotactic action of Trx for all leukocyte populations is in the nanomolar range, comparable with that of known chemokines. However, Trx does not increase intracellular Ca2+ and its activity is not inhibited by pertussis toxin. Thus, the chemotactic action of Trx differs from that of known chemokines in that it is G protein independent. Mutation of the active site cysteines resulted in loss of chemotactic activity, suggesting that the latter is mediated by the enzyme activity of Trx. Trx also accounted for part of the chemotactic activity released by human T lymphotropic virus (HTLV)-1-infected cells, which was inhibited by incubation with anti-Trx antibody. Since Trx production is induced by oxidants, it represents a link between oxidative stress and inflammation that is of particular interest because circulating Trx levels are elevated in inflammatory diseases and HIV infection.

Growth hormone response to physical exercise in growing patients with classic congenital adrenal hyperplasia.

Glucocorticoid over-treatment in children with congenital adrenal hyperplasia (CAH) may suppress GH secretion and growth. Aims of our study were: 1) to evaluate post-exercise GH response in patients affected by CAH due to 21-hydroxylase deficiency, in comparison with a group of healthy subjects; 2) to investigate the relationship between the hormonal markers of adequate steroid therapy and GH secretion. We evaluated GH secretion every 6 months in 20 young CAH patients (8 girls, 12 boys). Mean follow-up was 4.6+/-0.9 yr (107 tests performed, 5.35+/-2.05 repeated tests for each patient). Forty-four healthy subjects (25 boys, 19 girls) were selected as a control group. The range of post-exercise GH peak was very wide, but medians were not statistically different in cases and controls (p=0.570). Multivariate analysis showed that post-exercise GH peak was not related to age (p=0.743), gender (p=0.296) or pubertal status (p=0.440) in both groups. GH increase from baseline showed the same behavior (p=0.265, 0.639 and 0.105, respectively). In CAH patients, GH peak and GH increase were both directly related to 17-OH-progesterone levels [GH peak: p=0.032--95% confidence interval (CI): 0.01-0.34--beta=0.18; GH increase: p=0.008--95% CI: 0.06-0.35--beta=0.20]. The negative effect of glucocorticoid therapy on GH secretion seems to be dominant in CAH. The most effective approach to adjust treatment remains monitoring growth. Relying on hormonal markers to adequate steroid therapy may result in over-treatment, GH suppression, and finally poor linear growth.

Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats.

BACKGROUND AND PURPOSE: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. EXPERIMENTAL APPROACH: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. KEY RESULTS: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg(-1), twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1beta, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. CONCLUSIONS AND IMPLICATIONS: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.

Young elite athletes of different sport disciplines present with an increase in pulsatile secretion of growth hormone compared with non-elite athletes and sedentary subjects.

Acute exercise is a well-known stimulus for GH secretion but the effect of chronic training on GH secretion still remains equivocal. The aim of our study was to analyse spontaneous pulsatile GH secretion (during a period of 2 hours in the morning) in a group of young elite athletes (EA) compared with non-elite athletes (NEA), and sedentary subjects (SS). Mean and peak GH levels proved significantly higher in EA than in NEA and SS (p=0.0004 and p<0.0001, respectively). The same differences in mean and peak GH levels were also demonstrated in males and females when considered separately (males: p=0.0062 and p=0.0025; females: p=0.0056 and p=0.0032). In addition, GH levels (mean and peak) were higher in females than in males in SS while no differences were demonstrated between the 2 sexes in the EA and NEA groups. IGF-I levels were within the normal range for age in all the subjects with no difference between the 3 groups. Body mass index (BMI) exhibited no difference between groups, while EA showed higher lean mass (p=0.0063) and lower fat mass (p=0.0139) than NEA and SS measured by dual-energy x-ray absorptiometry. A strong positive correlation between GH levels (mean and peak) and hours of training a week was demonstrated (p=0.0101; r2=0.1184; p=0.0022; r2=0.1640, respectively). In conclusion, GH levels were higher in EA than NEA and SS without any modification of IGF-I levels; a strong positive correlation was present between GH levels and intensity of training. An increase in the knowledge of the effect of chronic training on GH secretion could improve the training programme to elicit the greatest exercise- induced GH response.

Basal insulin supplementation in Type 1 diabetic children: a long-term comparative observational study between continuous subcutaneous insulin infusion and glargine insulin.

No long-term data are available on the efficacy of glargine insulin in comparison with continuous sc insulin infusion (CSII) in children and adolescents affected by Type 1 diabetes (T1D). Our aim was to compare the 2-yr efficacy of the 2 insulin approaches, in order to know how to best supply basal insulin in these patients. Thirty-six 9 to 18-yr-old consecutive children with at least 3 yr previous T1D diagnosis were enrolled. As part of routine clinical care, the patients consecutively changed their previous insulin scheme (isophane insulin at bedtime and human regular insulin at meals) and were randomly selected in order to receive either multiple daily injections (MDI) treatment with once-daily glargine and human regular insulin at meals, or CSII with aspart or lispro insulin. Both groups showed a significant decrease in glycosylated hemoglobin (HbA1c) values during the 1st year of therapy, though only in the CSII treated children was the decrease also observed during the 2nd year. The overall insulin requirement significantly decreased only in the CSII group and exclusively during the 1st year, while no significant differences were observed concerning body mass index SD score, severe hypoglycemic episodes and basal insulin supplementation. The work illustrates the first long-term study comparing the efficacy of CSII to MDI using glargine as basal insulin in children. Only with CSII were better HbA1c values obtained for prolonged periods of time, so that CSII might be considered the gold standard of intensive insulin therapy also for long-term follow-ups.

Targeting C5a: recent advances in drug discovery.

Activation of complement via the innate and adaptive immune system is vital to the body's defences in fighting infections. Unregulated complement activation is likely to play a crucial role in the pathogenesis of several diseases including psoriasis, adult (acute) respiratory distress syndrome (ARDS), bullous pemphigoid (BP), rheumatoid arthritis (RA) and ischemia-reperfusion (I/R) injury. The 74 amino acid peptide C5a is released after complement activation at sites of inflammation and is a potent chemoattractant for neutrophils, basophils, eosinophils, leukocytes, monocytes and macrophages. Recombinant proteins and humanized anti-C5 antibodies have been recently developed for blocking specific proteins of the complement system bringing renewed attention towards complement inhibition. Pharmacological studies have been highlighting the complement fragment C5a as an interesting target for the management of complement mediated diseases. Specific inhibition of C5a biological activity could gain therapeutic benefit without affecting the protective immune response. In the last few years several peptide and non-peptide antagonists of C5a have been discovered and tested in relevant pharmacological models; the availability of orally active compounds is rapidly helping to delineate the precise role of C5a in immunoinflammatory disorders. Moreover, mutagenesis data for the C5a/C5a receptor (C5aR) couple make C5aR a valuable model for mechanistic studies of peptidergic G-protein coupled receptors (GPCRs). The aim of this review is to outline the recent advances in C5a inhibition, especially highlighting the value of a multidisciplinary integrated approach in drug discovery.

IL-1 beta primes IL-8-activated human neutrophils for elastase release, phospholipase D activity, and calcium flux.

Interleukin-8 (IL-8), the prototype of the alpha (e.i., C-X-C branch) chemokine family, induced elastase release in a concentration-dependent manner (50-1000 ng/mL) in cytochalasin B-treated human polymorphonuclear leukocytes (PMNs). This response was potentiated about twofold if PMNs were preexposed to interleukin-1 beta (IL-1 beta) at concentrations that were by themselves inactive. The effect of IL-1 beta was clearly observed after 5 min and was maximal after a 30-min preincubation of the cells. The effect was present over the whole active concentration range of IL-8 and was completely blocked by the presence of IL-1 receptor antagonist. Priming of elastase release by IL-1 beta was not associated with a change in receptor number or affinity for IL-8. On the contrary, it was correlated with priming of phospholipase D activity and calcium flux activated by IL-8. Preincubation of the cells with ethanol and/or La3+ inhibited IL-8-induced degranulations, suggesting that activation of phospholipase D and increase of [Ca2+]i were important for this response. In contrast, ethanol and La3+ did not decrease the priming effect of IL-1 beta. IL-8 and IL-1 beta have been shown to be released by the same cell types and may be concomitantly present at sites of inflammation, giving rise to an amplification of the inflammatory response.