Association between osteocalcin and residual ß-cell function in children and adolescents newly diagnosed with type 1 diabetes: a pivotal study.

PURPOSE: This pivotal study aimed to evaluate circulating levels of bone remodeling markers in children and adolescents at the onset of type 1 diabetes (T1D). Additionally, we assessed their correlation with glucose control, residual ß-cell function, and the severity of presentation. METHODS: In this single-center cross-sectional study, we recruited children and adolescents newly diagnosed with T1D at our tertiary-care Diabetes Centre. Anamnestic, anthropometric, clinical, and biochemical data at T1D diagnosis were collected. Basal and stimulated C-peptide levels were assessed, along with the following bone remodeling biomarkers: osteocalcin (OC), alkaline phosphatase (ALP), parathormone (PTH), 25-OH Vitamin D (25OH-D), and the C-terminal cross-linked telopeptide of type 1 collagen (CTX). RESULTS: We enrolled 29 individuals newly diagnosed with T1D, with a slight male prevalence (51.7%). The mean age was 8.4 ± 3.7 years. A positive correlation between OC and stimulated C-peptide (R = 0.538; p = 0.026) and between PTH and serum HCO3- (R = 0.544; p = 0.025) was found. No other correlations between bone remodeling biomarkers and clinical variables were detected. CONCLUSION: Our data showed a positive correlation between OC levels and residual ß-cell function in children and adolescents at T1D presentation. Further longitudinal studies evaluating OC levels in pediatric subjects with T1D are needed to better understand the complex interaction between bone and glucose metabolisms.

Global inequities in dietary calcium intake during pregnancy: a systematic review and meta-analysis.

BACKGROUND: Evidence shows that adequate calcium intake during pregnancy reduces the risk of hypertensive disorders of pregnancy. In most low- and middle-income countries (LMICs) the daily calcium intake is well below recommendations. Mapping calcium intake during pregnancy worldwide and identifying populations with low calcium intake will provide the evidence base for more targeted actions to improve calcium intake. OBJECTIVE: To assess dietary calcium intake during pregnancy worldwide. SEARCH STRATEGY: MEDLINE and EMBASE (from July 2004 to November 2017). SELECTION CRITERIA: Cross-sectional, cohort, and intervention studies reporting calcium intake during pregnancy. DATA COLLECTION AND ANALYSIS: Five reviewers working in pairs independently performed screening, extraction, and quality assessment. We reported summary measures of calcium intake and calculated the weighted arithmetic mean for high-income countries (HICs) and LMICs independently, and for geographic regions, among studies reporting country of recruitment, mean intake, and total number of participants. When available, inadequate intakes were reported. MAIN RESULTS: From 1880 citations 105 works met the inclusion criteria, providing data for 73 958 women in 37 countries. The mean calcium intake was 948.3 mg/day (95% CI 872.1-1024.4 mg/day) for HICs and 647.6 mg/day (95% CI 568.7-726.5 mg/day) for LMICs. Calcium intakes below 800 mg/day were reported in five (29%) countries from HICs and in 14 (82%) countries from LMICs. CONCLUSION: These results are consistent with a lack of improvement in calcium dietary intake during pregnancy and confirm the gap between HICs and LMICs, with alarmingly low intakes recorded for pregnant women in LMICs. From the public health perspective, in the absence of specific local data, calcium supplementation of pregnant women in these countries should be universal. TWEETABLE ABSTRACT: Despite dietary recommendations, women in LMICs face pregnancy with diets low in calcium.

Clinical approach on challenge and desensitization procedures with aspirin in patients with ischemic heart disease and nonsteroidal anti-inflammatory drug hypersensitivity.

BACKGROUND: Hypersensitivity to acetylsalicylic acid (ASA) constitutes a serious problem for subjects with coronary artery disease. In such subjects, physicians have to choose the more appropriate procedure between challenge and desensitization. As the literature on this issue is sparse, this study aimed to establish in these subjects clinical criteria for eligibility for an ASA challenge and/or desensitization. METHODS: Collection and analysis of data on ASA challenges and desensitizations from 10 allergy centers, as well as consensus among the related physicians and an expert panel. RESULTS: Altogether, 310 subjects were assessed; 217 had histories of urticaria/angioedema, 50 of anaphylaxis, 26 of nonimmediate cutaneous eruptions, and 17 of bronchospasm related to ASA/nonsteroidal anti-inflammatory drugs (NSAID) intake. Specifically, 119 subjects had index reactions to ASA doses lower than 300 mg. Of the 310 subjects, 138 had an acute coronary syndrome (ACS), 101 of whom underwent desensitizations, whereas 172 suffered from a chronic ischemic heart disease (CIHD), 126 of whom underwent challenges. Overall, 163 subjects underwent challenges and 147 subjects underwent desensitizations; 86 of the latter had index reactions to ASA doses of 300 mg or less. Ten subjects reacted to challenges, seven at doses up to 500 mg, three at a cumulative dose of 110 mg. The desensitization failure rate was 1.4%. CONCLUSIONS: In patients with stable CIHD and histories of nonsevere hypersensitivity reactions to ASA/NSAIDs, an ASA challenge is advisable. Patients with an ACS and histories of hypersensitivity reactions to ASA, especially following doses lower than 100 mg, should directly undergo desensitization.

The distribution of KIR-HLA functional blocks is different from north to south of Italy.

The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution.

Dropouts in sublingual allergen immunotherapy trials - a systematic review.

Participant dropouts can reduce the power of allergen immunotherapy clinical trials. Evaluation of the dropout rate and reasons for dropout are important not only in the planning of clinical studies but are also relevant for adherence to immunotherapy in daily clinical practice. A systematic review was carried out in order to establish the overall dropout rate among published double-blind, placebo-controlled randomized clinical trials of sublingual immunotherapy for respiratory allergic diseases. Dropouts were analysed in regards to allergen, formulation, treatment schedule, participant age, study size, number of centres and type of allergic disease. Relative dropout rates in placebo and active groups as well as reasons for dropout were also assessed. A total of 81 studies, comprising 9998 patients, were included. Dropout rates in sublingual immunotherapy controlled studies do not appear to be a major problem with a composite dropout percentage of 14% (95% CI:11.9-16). Furthermore, they are not different for active compared to placebo-treated participants. This lends support to the positive clinical outcomes seen in meta-analyses of these trials.

Association of serum triglyceride-to-HDL cholesterol ratio with carotid artery intima-media thickness, insulin resistance and nonalcoholic fatty liver disease in children and adolescents.

BACKGROUND AND AIMS: The triglyceride (TG)/high-density lipoprotein-cholesterol (HDL-C) ratio has been reported as a useful marker of atherogenic lipid abnormalities, insulin resistance, and cardiovascular disease. We evaluated in a large sample of children and adolescents the association of TG/HDL-C ratio with early signs of morphological vascular changes and cardiometabolic risk factors including nonalcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: The study population, including 548 children (aged 6-16 years), of whom 157 were normal-weight, 118 overweight, and 273 obese, had anthropometric, laboratory, liver and carotid ultrasonography (carotid artery intima-media thickness-cIMT) data collected. Subjects were stratified into tertiles of TG/HDL-C. There was a progressive increase in body mass index (BMI), BMI-SD score (SDS), waist circumference, blood pressure (BP), liver enzymes, glucose, insulin, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein (hsCRP), and cIMT values across TG/HDL-C tertiles. The odds ratios for central obesity, insulin resistance, high hsCRP, NAFLD, metabolic syndrome, and elevated cIMT increased significantly with the increasing tertile of TG/HDL-C ratio, after adjustment for age, gender, pubertal status, and BMI-SDS. In a stepwise multivariate logistic regression analysis, increased cIMT was associated with high TG/HDL-C ratio [OR, 1.81 (95% CI, 1.08-3.04); P < 0.05], elevated BP [5.13 (95% CI, 1.03-15.08); P < 0.05], insulin resistance [2.16 (95% CI, 1.30-3.39); P < 0.01], and NAFLD [2.70 (95% CI, 1.62-4.56); P < 0.01]. CONCLUSION: TG/HDL-C ratio may help identify children and adolescents at high risk for structural vascular changes and metabolic derangement.

Mastocytosis and allergic diseases.

Mastocytosis is a clonal disorder characterized by proliferation and accumulation of mast cells in various tissues, mainly skin and bone marrow. It can cause a wide variety of clinical manifestations-other than urticaria pigmentosa-that can lead to inappropriate release of mediators by mast cells. The most severe manifestation is anaphylaxis. The triggers of anaphylaxis in adults with mastocytosis are numerous, but Hymenoptera stings seem to be the most frequent, followed by foods and drugs. Therefore, to prevent severe reactions, it is very important to recognize and avoid potential triggers; in addition, venom-allergic patients must receive lifelong immunotherapy, which has proven very effective. Given that published data on drug anaphylaxis in patients with mast cell disorders are scarce, it is not currently possible to provide clear recommendations. The risk of systemic reactions during general anesthesia can be reduced by assessing risk on an individual basis (previous reaction to a drug or reaction during surgery) and by avoiding specific trigger factors (patient temperature changes, infusion of cold solution, tissue trauma, friction, and other mechanical factors).

Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper.

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.

SPINK3 modulates mouse sperm physiology through the reduction of nitric oxide level independently of its trypsin inhibitory activity.

Serine protease inhibitor Kazal-type (SPINK3)/P12/PSTI-II is a small secretory protein from mouse seminal vesicle which contains a KAZAL domain and shows calcium (Ca(2+))-transport inhibitory (caltrin) activity. This molecule was obtained as a recombinant protein and its effect on capacitated sperm cells was examined. SPINK3 inhibited trypsin activity in vitro while the fusion protein GST-SPINK3 had no effect on this enzyme activity. The inactive GST-SPINK3 significantly reduced the percentage of spermatozoa positively stained for nitric oxide (NO) with the specific probe DAF-FM DA and NO concentration measured by Griess method in capacitated mouse sperm; the same effect was observed when sperm were capacitated under low Ca(2+) concentration, using either intracellular (BAPTA-AM) or extracellular Ca(2+) (EDTA) chelators. The percentage of sperm showing spontaneous and progesterone-induced acrosomal reaction was significantly lower in the presence of GST-SPINK3 compared to untreated capacitated spermatozoa. Interestingly, this decrease was overcome by the exogenous addition of the NO donors, sodium nitroprusside (SNP), and S-nitrosoglutathione (GSNO). Phosphorylation of sperm proteins in tyrosine residues was partially affected by GST-SPINK3, however, only GSNO was able to reverse this effect. Sperm progressive motility was not significantly diminished by GST-SPINK3 or BAPTA-AM but enhanced by the addition of SNP. This is the first report that demonstrates that SPINK3 modulates sperm physiology through a downstream reduction of endogenous NO concentration and independently of SPINK3 trypsin inhibitory activity.

IgE to staphylococcal enterotoxins are undetectable in sera from patients with nasal polyposis.

Nasal polyposis is a frequent disease, sometime associated with asthma and non steroidal anti-inflammatory drugs intolerance. Staphylococcus aureus colonization can play a pathogenetic role in same cases by a severe eosinophilic inflammation, which can suggest new therapeutic approaches. Staphylococcus aureus colonization has been demonstrated by local specific enterotoxins IgE dosage in polyps homogenates. This study demonstrate lack of detection of serum enterotoxins specific IgE to staphylococcal in patients with nasal polyposis, compared with healthy subjects.

Body dissatisfaction among pre-adolescent girls is predicted by their involvement in aesthetic sports and by personal characteristics of their mothers.

Empirical evidence indicates that the dissatisfaction with one's body is widely present in the general population even at very early ages, and that it is predictive of future eating disorders. The family seem particularly influent for the development of body dissatisfaction while sports practice is associated to a higher prevalence of disordered eating. However the role of sports practice in the development of body dissatisfaction is still under debate and only few studies have evaluated together the influences of family and sport practice on body dissatisfaction. The present study aimed at evaluating both the singular and conjoint role of the type of sport and maternal influences in young female children. The sport influence was assessed comparing aesthetic and non-aesthetic disciplines; the mother's influence was evaluated considering her personal characteristics and her desire to have a thinner child. Results evidence that children involved in aesthetic sports, although thinner than those involved in non-aesthetic sports, report higher desire to be much thinner and have mothers who pressure them toward a greater thinness. Furthermore, children's body dissatisfaction in the sport groups is predicted by maternal characteristic like her habit to restrict her own eating and her perfectionism.

Tolerability of aztreonam in patients with cell-mediated allergy to ß-lactams.

BACKGROUND: Cross-reactivity between aztreonam and ß-lactams is poor, but tolerability of aztreonam has been assessed in a few groups of patients suffering from IgE-mediated allergy to ß-lactams. The aim of this study was to assess the cross-reactivity of aztreonam with other ß-lactams and its tolerability in patients with cell-mediated allergy to these drugs. METHODS: We studied 78 patients with cell-mediated allergy to ß-lactams who underwent skin prick, immediate and delayed-reading intradermal tests as well as patch tests with penicilloyl-polylysine, minor determinant mixture, semi-synthetic penicillins, cephalosporins, aztreonam and imipenem. Patients with negative allergy testing with aztreonam underwent an intramuscular test dosing and were observed for 3 h. RESULTS: Our patients experienced 94 non-immediate reactions; delayed-onset urticaria (34 cases), maculopapular exanthema (13 cases), urticaria/angioedema (15 cases) and itching erythema (13 cases) were the most reported symptoms. Amoxicillin (35 cases), ampicillin (28 cases) and bacampicillin (18 cases) were the most involved drugs. All patients had a positive patch test and/or a positive delayed-reading intradermal test to at least 1 ß-lactam antibiotic and none had a positive patch or delayed-reading intradermal test to aztreonam. Then, 65 patients underwent intramuscular test dosing with aztroenam, and none of them had a clinical reaction. CONCLUSIONS: Our data confirm the lack of cross-reactivity between ß-lactams and aztreonam in patients with cell-mediated allergy to these drugs. Delayed-reading intradermal tests and patch tests with aztreonam represent a simple and rapid diagnostic tool to establish tolerability in ß-lactam-allergic patients.

Anti-cancer activity of targeted pro-apoptotic peptides.

We have designed short peptides composed of two functional domains, one a tumor blood vessel 'homing' motif and the other a programmed cell death-inducing sequence, and synthesized them by simple peptide chemistry. The 'homing' domain was designed to guide the peptide to targeted cells and allow its internalization. The pro-apoptotic domain was designed to be nontoxic outside cells, but toxic when internalized into targeted cells by the disruption of mitochondrial membranes. Although our prototypes contain only 21 and 26 residues, they were selectively toxic to angiogenic endothelial cells and showed anti-cancer activity in mice. This approach may yield new therapeutic agents.

Concurrent validity of the Disordered Eating Questionnaire (DEQ) with the Eating Disorder Examination (EDE) clinical interview in clinical and non clinical samples.

OBJECTIVES: The aim of the present study was to evaluate the concurrent validity, specificity and sensitivity of the Disordered Eating Questionnaire (DEQ). The DEQ is a brief questionnaire (24 items), that can be used for epidemiological screenings. It addresses face valid questions to evaluate frequency and intensity of disordered eating attitudes and behaviors over a time frame of three months. DESIGN: The study was conducted using a cross-sectional design. METHODS: The DEQ was completed by 190 eating disordered patients (73 patients with Anorexia, 48 with Bulimia, 11 with Binge Eating Disorder, 48 with Eating Disorders Not Otherwise Specified, 10 recovered patients) and 88 healthy controls. RESULTS: In the whole group, DEQ scores were highly correlated with the scores of the Eating Disorder Examination (EDE 12.0D). Sensitivity and specificity were evaluated. In the female subsample, the ROC curves indicate that a cut-off score of 30 allows to obtain a sensitivity of 82% and a specificity of 68%. A formative approach of Structural Equationing Model confirm the construct validity of the instrument. CONCLUSIONS: The DEQ confirm to be a valid and reliable instrument, whose sensitivity and specificity is comparable to that of the EAT-40 even though it has fewer items.

A simple method to treat post-kydney transplantation lymphocele.

OBJECTIVE: To describe our experience with ultrasonic-guided instillation of povidone-iodine to treat post-kidney transplantation lymphocele. Patients and methods. We studied the safety and efficacy of this procedure for treatment of lymphocele in 6 male kidney transplanted recipients in which we assisted a progressive increase of creatinine and urinary proteins levels and color-Doppler ultrasonography demonstrated an increase (25,4%) of index of resistence (IR) Using eco-colorDoppler, the related-graft lymphocele location and the distance to the anterior abdominal wall were determined; then, a radiopaque double-lumen catheter was used to instillate 5% povidone-iodine 10 ml. Results. Percutaneous drainage achieved a resolution rate of 100%. Studying the rate of peripheral and internal vascularization of the kidney before and after treatment, eco-colorDoppler showed a significant decrease of the IR (24,6%). Conclusions. The US-guided povidone-iodine instillation for treatment of lymphocele following renal transplantation may be considered as first choice therapy in such disease.

Challenge tests in the diagnosis of latex allergy.

The aim of this study is to evaluate the sensitivity, specificity and safety of challenge tests and their usefulness in the diagnosis of latex allergy. Forty adult subjects (F/M = 34/6, aged 18-66 yrs) with a history of adverse reactions after latex exposure and positive prick test and/or specific IgE to latex were enrolled. They were compared with 20 control subjects. They underwent provocative (cutaneous, mucous-oral, sublingual, conjunctival, nasal, bronchial, vaginal) tests. Symptoms and drug scores were recorded for each patient during challenges. All patients reacted to at least one of the following: cutaneous, nasal and conjunctival tests. No systemic reactions requiring epinephrine occurred. Of the challenges, the vaginal test resulted as the safest, but it had low sensitivity and many limits related to the procedure. According to our data, bronchial and nasal tests had the highest sensitivity (76% and 82% respectively), and were more precise than other tests in determining latex exposure and symptoms, but the bronchial test also presented the highest rate of risk. Mucous and cutaneous tests resulted as the most reliable. For all the tests, specificity and positive predictive value were 100%. All control subjects resulted negative to all challenges. There were no statistically significant changes in skin and serologic tests between the first and second visits. Correlations between MIS and skin tests and between MIS and serum tests were not found. Challenges can be considered safe diagnostic procedures. Tests that most faithfully reproduce natural exposure, on the basis of a patient's history, are preferable.

Allergic and non-allergic drug hypersensitivity reactions in children.

Adverse drug reactions (ADR) are an important medical problem. The aim of this study is to investigate the clinical characteristics of children with ADR and to assess the tolerability of alternative drugs in children (under 16 yrs of age) with a history of ADR. We studied 278 children (132 males and 146 females). Patients were studied by recording personal history and performing in vivo skin testing, in vitro laboratory tests and challenge tests. Patients who had experienced mild adverse reactions underwent challenge tests without any premedication; patients with a clinical history of moderate reactions, received a premedication with sodium chromolyn 30 min before the oral challenge; patients with a clinical history of severe reactions or undergoing parenteral challenges, were given an antihistamine 30 minutes before. A total of 660 adverse events were reported with 126 different drugs involved. Antimicrobial agents were the most involved drugs (51.7%). Non-steroidal anti-inflammatory drugs were involved in 22.7% of episodes. The most reported symptoms were cutaneous. Allergy testing was negative in 272 patients. A diagnosis of drug allergy was reported for 6 patients. A total of 669 challenge tests were performed. 639 were negative at first attempt while 22 were positive. Eight were repeated using a different premedication and resulted negative. Hypersensitivity drug reactions in children are mainly non-allergic. A premedication with sodium cromolyn or with oral H1-antihistamines may be useful in preventing ADR.