Contribution of SNP arrays in diagnosis of deletion 2p11.2-p12. - Rocca, Maria Santa; Fabretto, Antonella; Faletra, Flavio; Carlet, Ombretta; Skabar, Aldo; Gasparini, Paolo; Pecile, Vanna (Gene, 2012)
Deletions of the short arm of chromosome 2 are exceedingly rare, having been reported in few patients. Furthermore most cases with deletion in 2p11.2-p12 have been studied using standard karyotype and so it is not possible to delineate the precise size of deletions. Here, we describe a 9-year-old girl with a 9.4 Mb de novo interstitial deletion of region 2p11.2-p12 identified by SNP array analysis. The deleted region encompasses over 40 known genes, including LRRTM1, CTNNA2 and REEP1, haploinsufficiency of which could explain some clinical features of this patient such as mental retardation, speech delay and gait abnormalities. A comparison of our case with previously reported patients who present deletions in 2p11.2-p12 was carried out. Our case adds new information to the deletion of 2p11.2-p12, improving the knowledge on this rearrangement.
Keywords: Abnormalities, Multiple; Child; Chromosomes, Human, Pair 2; Female; Humans; Intellectual Disability; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Sequence Deletion

A coughing spine. - Norbedo, Stefania; Perini, Roberto; Amaddeo, Alessandro (Emerg Med J, 2012)
Keywords: Cervical Vertebrae; Child; Dyspnea; Humans; Male; Mediastinal Emphysema; Spinal Diseases; Subcutaneous Emphysema; Tomography, X-Ray Computed

De novo 6.9 Mb interstitial deletion on chromosome 4q31.1-q32.1 in a girl with severe speech delay and dysmorphic features. - Fabretto, Antonella; Santa Rocca, Maria; Perrone, Maria Dolores; Skabar, Aldo; Pecile, Vanna; Gasparini, Paolo (Am J Med Genet A, 2012)
Deletion of the terminal part of long arm of chromosome 4 is a condition characterized by facial dysmorphisms, cardiac and limb defects, and developmental delay. Deletions usually involve the terminal part of the chromosome and most frequently are interstitial. Here, we report a de novo interstitial deletion resulting in a microdeletion of 6.9 Mb involving 4q31.3-q32.1 segment, detected by SNPs-Array technique in a 4-year-old female showing severe speech delay, mild facial dysmorphisms, and joint laxity. Phenotype-genotype relationships looking at the genes involved in this part of the chromosome were also carried out and data compared with those previously described.
Keywords: Abnormalities, Multiple; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 4; Developmental Disabilities; Female; Genotype; Humans; Language Development Disorders; Phenotype; Sequence Deletion

De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature. - Perrone, M D; Rocca, M S; Bruno, I; Faletra, F; Pecile, V; Gasparini, P (Eur J Med Genet, 2012)
Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42-1q44, the minimal chromosomal region involved has not yet defined. In this report, we describe a 7 years old male with mental retardation, cryptorchid testes, short stature and alopecia carrying only an interstitial de novo deletion of 911 Kb in the 1q43 region (239,597,095-240,508,817) encompassing three genes CHRM3, RPS7P5 and FMN2.
Keywords: Child; Chromosomes, Human, Pair 1; Dwarfism; Humans; Intellectual Disability; Male; Sequence Deletion

Dealing with abdominal pain in children affected by systemic lupus erythematosus. - Taddio, Andrea; Rosé, Carlos; Lepore, Loredana; Ventura, Alessandro (Semin Arthritis Rheum, 2012)
Keywords: Abdominal Pain; Female; Humans; Lupus Erythematosus, Systemic; Male

DEFB1 gene 5' untranslated region (UTR) polymorphisms in inflammatory bowel diseases. - Zanin, Valentina; Segat, Ludovica; Bianco, Anna Monica; Padovan, Lara; Tavares, Nathalia de Alencar Cunha; Crovella, Sergio (Clinics (Sao Paulo), 2012)
Keywords: 5' Untranslated Regions; Adult; Antimicrobial Cationic Peptides; beta-Defensins; Case-Control Studies; Colitis, Ulcerative; Crohn Disease; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Inflammatory Bowel Diseases; Male; Polymorphism, Genetic; Polymorphism, Single Nucleotide

Defective and excessive immunities in pediatric diseases. - Notarangelo, Luigi Daniele; Tommasini, Alberto (Curr Pharm Des, 2012)
Inflammatory and autoimmune diseases are classically considered as disorders arising from hyper-activation of immunity and hence are treated with drugs that suppress the lymphocyte activation and inflammation. Although this strategy has proven useful to cure symptoms, it rarely can heal the disease and long-term treatments are usually needed. Inflammatory and autoimmune diseases frequently occur also in patients with primary immune deficiency disease, proving that immune hyper-activation may paradoxically arise from defective function of immune genes. In these cases, the phenotype of hyper-activation is believed to reflect the attempts of the immune system to compensate for immune defects. Recent data suggest that similar mechanisms could be involved also in the pathogenesis of some multifactorial disorders, such as Crohn's disease and systemic lupus erythematosus. Based on these considerations, novel therapies could be developed to cure severe autoimmune and inflammatory disorders, not only by aiming to hyper-activation but as well by focusing on the possible underlying immune defects.
Keywords: Autoimmune Diseases; Child; Drug Design; Humans; Immunologic Deficiency Syndromes; Inflammation; Lymphocyte Activation; Severity of Illness Index

Delayed diagnosis of glycogen storage disease type III. - Minen, Federico; Cont, Gabriele; De Cunto, Angela; Martelossi, Stefano; Ventura, Alessandro; Maggiore, Giuseppe; Faletra, Flavio; Gasparini, Paolo; Cassandrini, Denise (J Pediatr Gastroenterol Nutr, 2012)
Keywords: Delayed Diagnosis; Diagnostic Errors; Glycogen Storage Disease Type I; Glycogen Storage Disease Type III; Humans; Infant; Liver; Male

Diagnosed child, treated child: food challenge as the first step toward tolerance induction in cow's milk protein allergy. - Longo, G; Berti, I; Barbi, E; Calligaris, L; Matarazzo, L; Radillo, O; Ronfani, L; Ventura, A (Eur Ann Allergy Clin Immunol, 2012)
BACKGROUND: Food challenge is required to assess tolerance in cow milk (CM) allergy. A positive challenge contraindicates the reintroduction of CM. Specific oral tolerance induction (SOTI) is a promising treatment. METHODS: All children admitted for a challenge were prospectively enrolled. To those tolerating between 2 and 150 ml a SOTI protocol was offered. Outcome, adverse reactions, parents' satisfaction were recorded. RESULTS: Out of 245 challenged patients, 175 reacted 122 out of 125, able to tolerate a minimum dose of 2 ml, underwent SOTI. After one year 75.4% were in an unrestricted diet, 16.1% tolerated between 5 and 150 ml, 8.5% stopped SOTI. Side effects were mild, parents' satisfaction was very high. CONCLUSIONS: The majority of children tolerating limited amounts of CM at the challenge acquires tolerance with SOTI without relevant side effects. Maintaining on an exclusion diet partially tolerant children should be considered debatable.
Keywords: Administration, Oral; Adolescent; Animals; Cattle; Child; Child, Preschool; Humans; Immune Tolerance; Infant; Milk Hypersensitivity; Milk Proteins; Self Administration

The dietary paradox in food allergy: yesterday's mistakes, today's evidence and lessons for tomorrow. - Badina, Laura; Barbi, Egidio; Berti, Irene; Radillo, Oriano; Matarazzo, Lorenza; Ventura, Alessandro; Longo, Giorgio (Curr Pharm Des, 2012)
During the last decades the prevalence of food allergy has significantly increased among children and antigen avoidance still remains the standard care for the management of this condition. Most reactions are IgE-mediated with a high risk of anaphylaxis requiring emergency medications in case of inadvertent ingestion. Recent studies showed that continuous administration of the offending food, rather than an elimination diet, could promote the development and maintenance of oral tolerance. Indeed, intestinal transit of food proteins and their interaction with gut-associated lymphoid tissue (GALT) is the essential prerequisite for oral tolerance. On the contrary, low-dose cutaneous exposure to environmental foods in children with atopic dermatitis and altered skin barrier facilitates allergic sensitization. The timing and the amount of cutaneous and oral exposure determine whether a child will have allergy or tolerance. Furthermore, previous preventive strategies such as the elimination diet during pregnancy and breastfeeding, prolonged exclusive breastfeeding and delayed weaning to solid foods did not succeed in preventing the development of food allergy. On the other hand, there could be an early narrow window of immunological opportunity to expose children to allergenic foods and induce natural tolerance. Finally, the gradual exposure to the offending food through special protocols of specific oral tolerance induction (SOTI) may be a promising approach to a proactive treatment of food allergy.
Keywords: Anaphylaxis; Antigens; Breast Feeding; Child; Dermatitis, Atopic; Female; Food Hypersensitivity; Humans; Immunoglobulin E; Pregnancy; Time Factors

Does the 1.5 Mb microduplication in chromosome band Xp22.31 have a pathogenetic role? New contribution and a review of the literature. - Faletra, Flavio; d'Adamo, Adamo Pio; Santa Rocca, Maria; Carrozzi, Marco; Perrone, Maria Dolores; Pecile, Vanna; Gasparini, Paolo (Am J Med Genet A, 2012)
Keywords: Chromosome Breakpoints; Chromosome Duplication; Chromosomes, Human, X; Hand Deformities, Congenital; Humans; Intellectual Disability; Karyotyping; Muscle Hypotonia; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatases

Does the LATCH score assessed in the first 24 hours after delivery predict non-exclusive breastfeeding at hospital discharge? - Tornese, Gianluca; Ronfani, Luca; Pavan, Carla; Demarini, Sergio; Monasta, Lorenzo; Davanzo, Riccardo (Breastfeed Med, 2012)
AIM: The aims of this study were to analyze the relationship between the LATCH score assessed in the first 24 hours after delivery and non-exclusive breastfeeding at discharge and to identify a cutoff for the LATCH score in order to identify women with higher risk of non-exclusive breastfeeding who may need additional breastfeeding support. SUBJECTS AND METHODS: We conducted a prospective observational study in the Maternity Ward of the Institute for Maternal and Child Health "Burlo Garofolo" (Trieste, Italy) and collected data from 299 mother-infant dyads. RESULTS: The rate of nonexclusive breastfeeding was inversely related to the LATCH score (p<0.001) with non-exclusive breastfeeding infants scoring less (6.9) than infants exclusively breastfed at discharge (7.6) (p=0.001). In multivariate analysis, non-exclusive breastfeeding was also associated with cesarean section, primiparity, and infant phototherapy. In order to support maternity staff in providing targeted interventions, we identified four LATCH score cutoffs associated with as many risk groups for non-exclusive breastfeeding at discharge. CONCLUSIONS: The LATCH score is a useful tool to identify mother-infant pairs who might benefit from additional skilled support in specific subgroups at risk of non-exclusive breastfeeding at discharge. Future research is needed to explore if the LATCH score assessed in the first days of life can also predict the duration of breastfeeding.
Keywords: Adult; Breast Feeding; Female; Health Promotion; Humans; Infant, Newborn; Italy; Logistic Models; Multivariate Analysis; Patient Care Planning; Patient Discharge; Prospective Studies; Risk Assessment; ROC Curve; Sensitivity and Specificity; Social Support

Editorial: innovative therapeutic approaches for the treatment of pediatric autoimmune and inflammatory diseases. - Zauli, Giorgio (Curr Pharm Des, 2012)
Keywords: Anti-Inflammatory Agents; Autoimmune Diseases; Child; Drug Design; Humans; Inflammation

The effect of clodronate on a mevalonate kinase deficiency cellular model. - Zanin, Valentina; Marcuzzi, Annalisa; Piscianz, Elisa; Vuch, Josef; Bianco, Anna Monica; Monasta, Lorenzo; Decorti, Giuliana; Crovella, Sergio (Inflamm Res, 2012)
BACKGROUND: A potential anti-inflammatory effect of clodronate--an aminobisphosphonate--was described to antagonize the pro-inflammatory effects of the block in the mevalonate pathway, the main feature of a rare auto-inflammatory disease called mevalonate kinase deficiency (MKD). OBJECTIVE: In this study we evaluated the potential anti-inflammatory effect of clodronate in MKD--a still orphan drug pediatric disease. METHODS: We studied some biological parameters, nitric oxide production using Griess reagents and programmed cell death by flow cytometry, as common inflammatory parameters in MKD, in the presence of different doses of clodronate (1, 10 and 100 μM). RESULTS: In our cellular model and in monocytes from patients with MKD, clodronate induced an increase in programed cell death and nitric oxide production in comparison with non-treated cells. CONCLUSION: Our findings suggest that clodronate does not have an anti-inflammatory effect as previously reported but that it increases the epiphenomena of this pediatric disease.
Keywords: Adolescent; Adult; Alendronate; Animals; Anti-Inflammatory Agents; Apoptosis; Cell Line; Cells, Cultured; Child; Clodronic Acid; Female; Humans; Inflammation; Lipopolysaccharides; Male; Mevalonate Kinase Deficiency; Mice; Models, Biological; Monocytes; Nitric Oxide; Young Adult

Effects of hormonal contraception on vaginal flora. - De Seta, Francesco; Restaino, Stefano; De Santo, Davide; Stabile, Guglielmo; Banco, Rubina; Busetti, Marina; Barbati, Giulia; Guaschino, Secondo (Contraception, 2012)
BACKGROUND: The sector of the market that deals with contraception offers a long list of different contraceptive methods. Within the estroprogestinic choice, the routes of administration are oral, transdermic and vaginal one. Even though efficacy is comparable with these methods, secondary and adverse effects are directly involved in the acceptability of the method. STUDY DESIGN: This was a prospective comparative study. During 1 year, we enrolled 60 asymptomatic women who voluntarily requested combined oral contraception (COC) or combined contraceptive vaginal ring (CCVR group). After a baseline study of vaginal milieu prior to starting hormonal contraception, we performed a follow-up. For each woman, we examined vaginal pH; quantification of leukocytes, lactobacilli, Candida and cocci on saline microscopy fluid; Gram stain with Nugent score and the presence of vaginal infection [culture for Trichomonas vaginalis, albicans and nonalbicans Candida, Group B Streptococcus (GBS)]. RESULTS: At the end of follow-up, there was a little change of vaginal milieu in both groups. We noted an increase of lactobacilli in the CCVR users and an increase of GBS in COC users. CONCLUSION: CCVR compared to COC users showed an increase of the number of lactobacilli in vaginal flora. It means that an increase of leukorrhea in that group could be protective in terms of prevention of vaginal imbalance/infection.
Keywords: Administration, Intravaginal; Adolescent; Adult; Bacterial Load; Candida; Candida albicans; Contraceptive Devices, Female; Contraceptives, Oral, Combined; Female; Humans; Hydrogen-Ion Concentration; Lactobacillus; Leukocyte Count; Middle Aged; Prospective Studies; Streptococcus agalactiae; Trichomonas vaginalis; Vagina

Effects of prone and supine position on cerebral blood flow in preterm infants. - Bembich, Stefano; Oretti, Chiara; Travan, Laura; Clarici, Andrea; Massaccesi, Stefano; Demarini, Sergio (J Pediatr, 2012)
We evaluated the effect of prone and supine position on cerebral blood flow (CBF) in stable preterm infants. CBF, PO(2), and PCO(2) were measured in the two positions. Peripheral oxygenation increased and CBF decreased in prone position. We speculate that CBF autoregulation may compensate for increased peripheral oxygenation, by decreasing CBF.
Keywords: Cerebrovascular Circulation; Female; Humans; Infant, Newborn; Infant, Premature; Male; Prone Position; Regional Blood Flow; Supine Position

The effects of uterine fundal pressure (Kristeller maneuver) on pelvic floor function after vaginal delivery. - Sartore, Andrea; De Seta, Francesco; Maso, Gianpaolo; Ricci, Giuseppe; Alberico, Salvatore; Borelli, Massimo; Guaschino, Secondo (Arch Gynecol Obstet, 2012)
PURPOSE: To evaluate the role of uterine fundal pressure during the second stage of labor (Kristeller maneuver) on pelvic floor dysfunction (urinary and anal incontinence, genital prolapse, pelvic floor strength). METHODS: 522 primiparous women, enrolled 3 months after vaginal delivery, were divided in two groups: group A (297 women) identifies the women who received Kristeller maneuvers with different indications (e.g. fetal distress, failure to progress, mother exhaustion), group B (225 women) the women without maneuver. Participants were questioned about urogynecological symptoms and examined by Q-tip test, digital test, vaginal perineometry and uroflowmetric stop test score. RESULTS: Mediolateral episiotomies, dyspareunia and perineal pain were significantly higher in Kristeller group, whereas urinary and anal incontinence, genital prolapse and pelvic floor strength were not significantly different between the groups. CONCLUSIONS: Kristeller maneuver does not modify puerperal pelvic floor function but increases the rate of episiotomies.
Keywords: Delivery, Obstetric; Dyspareunia; Dystocia; Episiotomy; Fatigue; Fecal Incontinence; Female; Fetal Distress; Humans; Labor Stage, Second; Pain, Postoperative; Pelvic Floor; Pelvic Organ Prolapse; Perineum; Pregnancy; Pressure; Puerperal Disorders; Urinary Incontinence; Uterus

Efficacy of rifaximin vaginal tablets in treatment of bacterial vaginosis: a molecular characterization of the vaginal microbiota. - Cruciani, Federica; Brigidi, Patrizia; Calanni, Fiorella; Lauro, Vittoria; Tacchi, Raffaella; Donders, Gilbert; Peters, Klaus; Guaschino, Secondo; Vitali, Beatrice (Antimicrob Agents Chemother, 2012)
Bacterial vaginosis (BV) is a common vaginal disorder characterized by an alteration of the vaginal bacterial morphotypes, associated with sexually transmitted infections and adverse pregnancy outcomes. The purpose of the present study was to evaluate the impact of different doses of rifaximin vaginal tablets (100 mg/day for 5 days, 25 mg/day for 5 days, and 100 mg/day for 2 days) on the vaginal microbiota of 102 European patients with BV enrolled in a multicenter, double-blind, randomized, placebo-controlled study. An integrated molecular approach based on quantitative PCR (qPCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) was used to investigate the effects of vaginal tablets containing the antibiotic. An increase in members of the genus Lactobacillus and a decrease in the BV-related bacterial groups after the antibiotic treatment were demonstrated by qPCR. PCR-DGGE profiles confirmed the capability of rifaximin to modulate the composition of the vaginal microbial communities and to reduce their complexity. This molecular analysis supported the clinical observation that rifaximin at 25 mg/day for 5 days represents an effective treatment to be used in future pivotal studies for the treatment of BV.
Keywords: Adolescent; Adult; Anti-Bacterial Agents; Double-Blind Method; Female; Humans; Lactobacillus; Metagenome; Middle Aged; Rifamycins; RNA, Ribosomal, 16S; Vagina; Vaginal Creams, Foams, and Jellies; Vaginosis, Bacterial; Young Adult

Endoscopic treatment of primary vesicoureteral reflux. - Pennesi, Marco; L'erario, Ines; Barbi, Egidio (N Engl J Med, 2012)
Keywords: Female; Humans; Ureteroscopy; Vesico-Ureteral Reflux

Endothelial cells obtained from patients affected by chronic venous disease exhibit a pro-inflammatory phenotype. - Tisato, Veronica; Zauli, Giorgio; Voltan, Rebecca; Gianesini, Sergio; di Iasio, Maria Grazia; Volpi, Ilaria; Fiorentini, Guido; Zamboni, Paolo; Secchiero, Paola (PLoS One, 2012)
BACKGROUND: The inflammatory properties of vein endothelium in relation to chronic venous disease (CVD) have been poorly investigated. Therefore, new insights on the characteristics of large vein endothelium would increase our knowledge of large vessel physiopathology. METHODOLOGY/PRINCIPAL FINDINGS: Surgical specimens of veins were obtained from the tertiary venous network (R3) and/or saphenous vein (SF) of patients affected by CVD and from control individuals. Highly purified venous endothelial cell (VEC) cultures obtained from CVD patients were characterized for morphological, phenotypic and functional properties compared to control VEC. An increase of CD31/PECAM-1, CD146 and ICAM-1 surface levels was documented at flow cytometry in pathological VEC with respect to normal controls. Of note, the strongest expression of these pro-inflammatory markers was observed in VEC obtained from patients with more advanced disease. Similarly, spontaneous cell proliferation and resistance to starvation was higher in pathological than in normal VEC, while the migratory response of VEC showed an opposite trend, being significantly lower in VEC obtained from pathological specimens. In addition, in keeping with a higher baseline transcriptional activity of NF-kB, the release of the pro-inflammatory cytokines osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF) was higher in pathological VEC cultures with respect to control VEC. Interestingly, there was a systemic correlation to these in vitro data, as demonstrated by higher serum OPG and VEGF levels in CVD patients with respect to normal healthy controls. CONCLUSION/SIGNIFICANCE: Taken together, these data indicate that large vein endothelial cells obtained from CVD patients exhibit a pro-inflammatory phenotype, which might significantly contribute to systemic inflammation in CVD patients.
Keywords: Adult; Antigens, CD146; Antigens, CD31; Body Mass Index; Cell Culture Techniques; Endothelial Cells; Female; Flow Cytometry; Humans; Inflammation; Intercellular Adhesion Molecule-1; Kinetics; Male; Microscopy, Electron, Scanning; Middle Aged; Phenotype; Saphenous Vein; Vascular Diseases

The energy balance positively regulates the levels of circulating TNF-related apoptosis inducing ligand in humans. - Biolo, Gianni; Secchiero, Paola; De Giorgi, Sara; Tisato, Veronica; Zauli, Giorgio (Clin Nutr, 2012)
BACKGROUND & AIMS: Although decreased levels of circulating TRAIL have been associated to cardiovascular risk and overall mortality, the mechanisms controlling TRAIL levels in physiopathological conditions are currently unknown. The aim of the present study was to investigate whether changes in the energy intake and insulin sensitivity may influence circulating TRAIL, and to analyze potential relationships between circulating TRAIL and changes in fat mass in healthy subjects receiving hypocaloric or hypercaloric diets. METHODS: Three distinct groups of participants were studied, at the end of a 14-day (n = 9), 35-day (n = 30) or 60-day (n = 16) period of experimental bed rest to induce insulin resistance and during controlled ambulation, after receiving eucaloric, hypocaloric or hypercaloric diets. RESULTS: After bed rest conditions, energy restriction significantly decreased circulating TRAIL, while overfeeding significantly increased TRAIL levels with respect to eucaloric control subjects. Moreover, a positive correlation was found between levels of circulating TRAIL and energy intake as well as between circulating TRAIL and energy balance, as determined by changes in fat mass in these subjects. CONCLUSIONS: Circulating levels of TRAIL exhibit a clear-cut positive correlation with the energy intake and balance in healthy subjects during experimental physical inactivity.
Keywords: Adult; Apoptosis; Bed Rest; Cross-Over Studies; Diet; Energy Intake; Energy Metabolism; Female; Humans; Insulin Resistance; Male; Motor Activity; Risk Factors; TNF-Related Apoptosis-Inducing Ligand; Young Adult

Establishing the Baby-Friendly Community Initiative in Italy: development, strategy, and implementation. - Bettinelli, Maria Enrica; Chapin, Elise M; Cattaneo, Adriano (J Hum Lact, 2012)
BACKGROUND: The Baby-Friendly Hospital Initiative (BFHI), developed by the World Health Organization and the United Nations Children's Fund (UNICEF) to promote breastfeeding in maternity facilities worldwide, has had a global impact on breastfeeding outcomes, but other interventions are needed both before and after hospital discharge to meet the recommended targets at 6 months. The Baby-Friendly Community Initiative (BFCI), a multifaceted program for community-based breastfeeding promotion that is complementary to the BFHI, addresses this challenge. OBJECTIVE: To describe the development, strategy, and implementation of the BFCI in Italy. METHODS: In 2006, UNICEF Italy created a working group to develop the BFCI for the Italian health system. A review of the different BFCI models worldwide was conducted. A preliminary adaptation of tools to Italian community health care settings was developed in 2007, when the Italian BFCI Seven Steps were published. Two years later, UNICEF Italy launched the Standards for Best Practice for both hospitals and communities, based on 2009 BFHI and UNICEF UK BFCI materials. OUTCOMES: The main outcome was to promote this process in Italian regional health systems and develop tools to assess compliance with the BFCI criteria. There is now one fully accredited Baby-Friendly Community in Italy, and 17 other communities are working on the various stages. CONCLUSIONS: The BFCI, a complex program that involves participation, training, audits, a continuous flow of feedback, and provision of resources for health workers and families, is now a reality in Italy.
Keywords: Breast Feeding; Continuity of Patient Care; Delivery Rooms; Female; Health Policy; Humans; Infant; Infant Care; Infant Welfare; Infant, Newborn; Italy; Maternal Health Services; Organizational Policy; Outcome and Process Assessment (Health Care); Practice Guidelines as Topic; Pregnancy; Program Development; Program Evaluation; United Nations; World Health Organization

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. - Husby, S; Koletzko, S; Korponay-Szabó, I R; Mearin, M L; Phillips, A; Shamir, R; Troncone, R; Giersiepen, K; Branski, D; Catassi, C; Lelgeman, M; Mäki, M; et al. (J Pediatr Gastroenterol Nutr, 2012)
OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.
Keywords: Adolescent; Celiac Disease; Child; Duodenum; HLA-DQ Antigens; Humans; Immunoglobulin A; Transglutaminases

Evidence of inbreeding depression on human height. - McQuillan, Ruth; Eklund, Niina; Pirastu, Nicola; Kuningas, Maris; McEvoy, Brian P; Esko, Tõnu; Corre, Tanguy; Davies, Gail; Kaakinen, Marika; Lyytikäinen, Leo-Pekka; Kristiansson, Kati; Havulinna, Aki S; et al. (PLoS Genet, 2012)
Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
Keywords: Adult; Aged; Body Height; Consanguinity; Databases, Genetic; Family; Female; Genes, Recessive; Genetic Heterogeneity; Genome-Wide Association Study; Homozygote; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable

Exhaled nitric oxide as a guide to management of asthma in pregnancy. - Bibalo, Chiara; Badina, Laura; Longo, Giorgio; Ventura, Alessandro (Lancet, 2012)
Keywords: Asthma; Breath Tests; Female; Glucocorticoids; Humans; Nitric Oxide; Pregnancy; Pregnancy Complications

Extra-large letter spacing improves reading in dyslexia. - Zorzi, Marco; Barbiero, Chiara; Facoetti, Andrea; Lonciari, Isabella; Carrozzi, Marco; Montico, Marcella; Bravar, Laura; George, Florence; Pech-Georgel, Catherine; Ziegler, Johannes C (Proc Natl Acad Sci U S A, 2012)
Although the causes of dyslexia are still debated, all researchers agree that the main challenge is to find ways that allow a child with dyslexia to read more words in less time, because reading more is undisputedly the most efficient intervention for dyslexia. Sophisticated training programs exist, but they typically target the component skills of reading, such as phonological awareness. After the component skills have improved, the main challenge remains (that is, reading deficits must be treated by reading more--a vicious circle for a dyslexic child). Here, we show that a simple manipulation of letter spacing substantially improved text reading performance on the fly (without any training) in a large, unselected sample of Italian and French dyslexic children. Extra-large letter spacing helps reading, because dyslexics are abnormally affected by crowding, a perceptual phenomenon with detrimental effects on letter recognition that is modulated by the spacing between letters. Extra-large letter spacing may help to break the vicious circle by rendering the reading material more easily accessible.
Keywords: Attention; Awareness; Child; Dyslexia; Form Perception; France; Humans; Italy; Language; Pattern Recognition, Visual; Phonetics; Reading; Vision, Ocular; Visual Fields

Febrile urinary tract infections in young children: recommendations for the diagnosis, treatment and follow-up. - Ammenti, Anita; Cataldi, Luigi; Chimenz, Roberto; Fanos, Vassilios; La Manna, Angela; Marra, Giuseppina; Materassi, Marco; Pecile, Paolo; Pennesi, Marco; Pisanello, Lorena; Sica, Felice; Toffolo, Antonella; et al. (Acta Paediatr, 2012)
UNLABELLED: We report the recommendations for the diagnosis, treatment, imaging evaluation and use of antibiotic prophylaxis in children with the first febrile urinary tract infection, aged 2 months to 3 years. They were prepared by a working group of the Italian Society of Pediatric Nephrology after careful review of the available literature and a consensus decision, when clear evidence was not available. CONCLUSION: These recommendations are endorsed by the Italian Society of Pediatric Nephrology. They can also be a tool of comparison with other existing guidelines in issues in which much controversy still exists.
Keywords: Anti-Bacterial Agents; Child, Preschool; Female; Fever; Follow-Up Studies; Humans; Infant; Male; Urinary Tract Infections

First trimester maternal serum PIGF, free β-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia. - Di Lorenzo, G; Ceccarello, M; Cecotti, V; Ronfani, L; Monasta, L; Vecchi Brumatti, L; Montico, M; D'Ottavio, G (Placenta, 2012)
OBJECTIVE: To evaluate the detection of pregnancy hypertensive disorders by integrating maternal history, serum biomarkers and uterine artery Doppler in the first trimester. METHODS: We prospectively recruited 2118 women that underwent an 11-13 weeks aneuploidy screening. We gathered information on maternal history, uterine artery Doppler and serum biomarkers (PAPP-A, PlGF, PP-13 and free β-hCG). Models were developed for the prediction of overall preeclampsia (PE), early-onset PE, late-onset PE and gestational hypertension (GH). For each outcome, we performed a multivariate logistic regression starting from the saturated model: adopting a step-down procedure we excluded all factors not statistically significant (p > 0.05). Sensitivity models only for statistically significant parameters were calculated from the ROC curves for fixed false-positive rates (FPR). RESULTS: Among 2118 women, 46 (2.17%) developed GH and 25 (1.18%) were diagnosed with PE, including 12 (0.57%) early-onset PE and 13 (0.61%) late-onset PE. For a fixed FPR of 10 and 5%, serum PlGF, free β-hCG and chronic hypertension identified respectively 67 and 75% of women who developed early-onset PE. In the model for the prediction of overall PE the combination of the uterine artery Doppler pulsatility index (UtA PI) with PlGF and chronic hypertension reached a sensitivity of 60% for a 20% of FPR. CONCLUSION: An integration of maternal characteristics and first trimester maternal serum biomarkers (free β-hCG and PlGF) provided a possible screening for early-onset PE. In the overall PE model, UtA PI turned out to be statistically significant but did not improve the detection rate.
Keywords: Adult; Biological Markers; Chorionic Gonadotropin, beta Subunit, Human; Cohort Studies; Female; Galectins; Humans; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Proteins; Pregnancy Trimester, First; Pregnancy-Associated Plasma Protein-A; Prospective Studies; Ultrasonography, Prenatal; Uterine Artery; Uterus

Formation of membrane-defined compartments by tick-borne encephalitis virus contributes to the early delay in interferon signaling. - Miorin, Lisa; Albornoz, Amelina; Baba, Marycelin M; D'Agaro, Pierlanfranco; Marcello, Alessandro (Virus Res, 2012)
Interferons are key mediators of the innate antiviral response of the cell against viral infections. Viruses on the other hand have evolved various strategies to delay innate immunity in order to establish a productive infection. In this work we analyzed the pathway of interferon induction by the tick-borne encephalitis virus. We initially observed a consistent delay of interferon induction following virus replication. RIG-I, but not MDA5, and nuclear translocation of IRF3 were eventually required for interferon activation pointing to a defect in pattern recognition receptor's signaling. However, viral proteins could not directly inhibit the pathway suggesting an indirect mechanism. We found that dsRNA replication intermediates and replicated viral RNA localized to membrane-defined perinuclear compartments that resisted RNAse treatment. Thus, initial escape from innate immunity involved the formation of replication vesicles that may function as a barrier to pattern recognition receptors.
Keywords: Cell Membrane; Encephalitis Viruses, Tick-Borne; Humans; Immune Evasion; Interferons; Receptors, Pattern Recognition; RNA, Viral; Signal Transduction

Frequency of human papillomavirus types 16, 18, 31, and 33 and sites of cervical lesions in gynecological patients from Recife, Brazil. - Baldez da Silva, M F P T; Guimarães, V; Silva, M A R; Medeiros do Amaral, C M; Beçak, W; Stocco, R C; Freitas, A C; Crovella, S (Genet Mol Res, 2012)
Human papilloma virus (HPV) is a well-established cause of cervical cancer. While many studies have been performed so far on HPV viral biology, mode of infection and prevention measures, scanty information is available on lesion sites of infected women and the incidence of viral types at specific locations. We looked for a possible relationship between the most common viral types (HPVs 16, 18, 31, 33) found in Recife, PE, Brazil, and lesion sites. We examined 396 HPV-positive women at the Gynecological Unit of the IMIP at Recife; 288 women were positive for HPV 16, 18, 31, or 33, present as a single-virus type or as co-infection. HPV 16 was the most frequent virus type found in the vulva, vagina, uterine cervix-vagina, and uterine cervix. HPV 31 was the second prevalent virus type in vulva, vagina, uterine cervix-vagina, uterine cervix, and mole. HPVs 18 and 33 were present with similar frequencies in the mole-vulva region. Among the co-infections, HPV 16/18 and HPV16/31 were the most frequent in our study group, followed by HPV 16/33.
Keywords: Adolescent; Adult; Brazil; Cervix Uteri; DNA, Viral; Female; Human papillomavirus 16; Human papillomavirus 18; Human papillomavirus 31; Humans; Papillomavirus Infections; Uterine Cervical Diseases; Young Adult

From bone marrow transplantation to cellular therapies: possible therapeutic strategies in managing autoimmune disorders. - Taddio, Andrea; Biondi, Andrea; Piscianz, Elisa; Valencic, Erica; Biagi, Ettore; Badolato, Raffaele (Curr Pharm Des, 2012)
Chronic inflammatory disorders occurring in childhood represent a serious therapeutic challenge. However, available therapies seem not to be targeted on the pathogenic mechanism of the disease and are often not actively affecting the natural history of the disease. Emerging treatments might be of some benefit to many patients who did not respond to conventional therapeutic options. Biological therapies with monoclonal antibodies and other recombinant proteins have been introduced in clinical practice. At the same time, mesenchymal stromal cells (MSC) have gained attention as a savage treatment in patients subjected to hematopoietic stem cell transplantation who develop severe graft versus host disease (GvHD); in addition, recent reports from clinical trials on larger cohorts of patients support their use as second-line treatment after failure of corticosteroid treatment. For analogy, they have been proposed for the treatment of intractable autoimmune disorders. Hematopoietic stem cell transplantation (HSCT) has been shown to be effective for treatment of rheumatic disorder cases that were resistant to traditional therapies especially if combined with cell manipulation techniques, such as selection of regulatory T cell and depletion of harmful lymphocytes. We herein present the rationale of different strategies, the preliminary data obtained in clinical trials, unsolved problems and possible next developments of novel treatment protocols of autoimmune disorders.
Keywords: Autoimmune Diseases; Bone Marrow Transplantation; Child; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Inflammation; Lymphocytes; Mesenchymal Stem Cell Transplantation; T-Lymphocytes, Regulatory; Treatment Outcome

Functional single-nucleotide polymorphisms in the DEFB1 gene are associated with systemic lupus erythematosus in Southern Brazilians. - Sandrin-Garcia, P; Brandão, L A C; Guimarães, R L; Pancoto, J A T; Donadi, E A; Lima-Filho, J L de; Segat, L; Crovella, S (Lupus, 2012)
Systemic lupus erythematosus (SLE) is an autoimmune disease that results in inflammation and tissue damage. The etiology of SLE remains unknown, but recent studies have shown that the innate immune system may have a role in SLE pathogenesis through the secretion of small cationic peptides named defensins. The aim of the study was to determine the possible involvement in SLE of three functional single nucleotide polymorphisms (SNPs) (c.-52G>A, c.-44C>G and c.-20G>A) in the 5'UTR region of DEFB1 gene, by analyzing them in a population of 139 SLE patients and 288 healthy controls. The c.-52G>A SNP showed significant differences in allele and genotype frequency distribution between SLE patients and controls (p = 0.01 and p = 0.02 respectively) indicating protection against SLE (A allele, OR = 0.68, AA genotype OR = 0.51). Significant differences were also observed for c.-44C>G SNP, the C/G genotype being associated with susceptibility to SLE (OR = 1.60, p = 0.04). Moreover, statistically significant differences between patients and controls were found for two DEFB1 haplotypes (GCA and GGG, p = 0.01 and p = 0.02 respectively). When considering DEFB1 SNPs and SLE clinical and laboratory manifestations, significant association was found with neuropsychiatric disorders, immunological alterations and anti-DNA antibodies. In conclusion, our results evidence a possible role for the c.-52G>A and c.-44C>G DEFB1 polymorphisms in SLE pathogenesis, that can be considered as possible risk factors for development of disease and disease-related clinical manifestations. Additional studies are needed, to corroborate these results as well as functional studies to understand the biological role of these SNPs in the pathogenesis of SLE.
Keywords: Adolescent; Adult; Aged; beta-Defensins; Brazil; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Young Adult

Genetics of food preferences: a first view from silk road populations. - Pirastu, Nicola; Robino, Antonietta; Lanzara, Carmela; Athanasakis, Emmanouil; Esposito, Laura; Tepper, Beverly J; Gasparini, Paolo (J Food Sci, 2012)
Food preferences are the main factor driving food intake and choice. There are good reasons to suspect some genetic influence on food acceptance, not least because genetic factors are implicated in a number of factors that are likely to be related to food choice. In addition, some food dislikes show themselves early in life, before there is any evidence for aversive experiences. Although taste has been widely studied in regards of pure tastes such as bitter or sweet perception, the relationship between taste-related genes and food preferences has seldom been explored. In this work we investigated relationship of 37 taste-related genes with food preferences. The study was carried out during a scientific expedition through Caucasus and Central Asia (Silk Road) analyzing more than 400 samples from 5 different countries. A food preference questionnaire was administered to each participant and a DNA sample was obtained. Other information, such as age, sex, life style and anthropometrical measures, were also collected. We found significant associations with variants of: (1) TAS1R2 [Correction added after initial online publication on 27 Aug 2012. TAS1R3 was changed to TAS1R2.] gene and liking of Vodka (P= 1.6 × 10(-3)), white wine (P= 4.0 × 10(-4)) and lamb meat (P= 1.6 × 10(-3)); (2) PCLB2 gene and preference for Hot Tea (P= 8.0 × 10(-4)); (3) TPRV1 gene and beet liking (P= 3.8 × 10(-5)); and (4) ITPR3 gene and liking of both lamb meat (5.8 × 10(-4)) and sheep cheese (8.9×10(-4)). These findings give a new insight on a better understanding, of genetic factors influencing food preferences which is critical to the development of effective dietary interventions, especially for people that may be genetically not predisposed for liking specific nutrients.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Azerbaijan; Child; Choice Behavior; Cohort Studies; Female; Food Habits; Food Preferences; Gene Frequency; Genotype; Georgia; Humans; Kazakhstan; Linear Models; Male; Middle Aged; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Questionnaires; Tajikistan; Taste; Uzbekistan; Young Adult

Genome-wide association and functional follow-up reveals new loci for kidney function. - Pattaro, Cristian; Köttgen, Anna; Teumer, Alexander; Garnaas, Maija; Böger, Carsten A; Fuchsberger, Christian; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; et al. (PLoS Genet, 2012)
Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Keywords: African Americans; Aged; Animals; Caspase 9; Cyclin-Dependent Kinases; DEAD-box RNA Helicases; DNA Helicases; European Continental Ancestry Group; Female; Follow-Up Studies; Gene Knockdown Techniques; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Phosphoric Diester Hydrolases; Zebrafish

Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse. - Perotti, Daniela; Spreafico, Filippo; Torri, Federica; Gamba, Beatrice; d'Adamo, Pio; Pizzamiglio, Sara; Terenziani, Monica; Catania, Serena; Collini, Paola; Nantron, Marilina; Pession, Andrea; Bianchi, Maurizio; et al. (Genes Chromosomes Cancer, 2012)
Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (≤ 24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations.
Keywords: Adolescent; Allelic Imbalance; Child; Child, Preschool; Chromosome Aberrations; DNA Copy Number Variations; Female; Genetic Markers; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Infant; Kaplan-Meier Estimate; Male; Polymorphism, Single Nucleotide; Prospective Studies; Recurrence; Wilms Tumor

Gluten-dependent intestinal autoimmune response. - Korponay-Szabó, Ilma Rita; Simon-Vecsei, Zsafia; De Leo, Luigina; Not, Tarcisio (Curr Pharm Des, 2012)
Celiac disease is a multi-systemic autoimmune disease of the small bowel induced by gluten in genetically predisposed subjects. Highly specific and gluten-dependent production of auto-antibodies targeting self-proteins of the transglutaminase family occurs in the intestinal mucosa. These anti-transglutaminase antibodies are found deposited in intestinal and extra-intestinal tissue where they might exert biological effects, together with the intestinal mucosal gliadin-specific T lymphocytes. We conducted a brief review on antitransglutaminase antibodies effects, discussing their roles in the pathogenesis of several clinical manifestations of celiac disease.
Keywords: Animals; Autoantibodies; Celiac Disease; Genetic Predisposition to Disease; Gliadin; Glutens; Humans; Intestinal Mucosa; T-Lymphocytes; Transglutaminases

Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. - Snowden, J A; Saccardi, R; Allez, M; Ardizzone, S; Arnold, R; Cervera, R; Denton, C; Hawkey, C; Labopin, M; Mancardi, G; Martin, R; Moore, J J; et al. (Bone Marrow Transplant, 2012)
In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.
Keywords: Autoimmune Diseases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; European Union; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Risk Factors; Safety; Severity of Illness Index

High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma. - Mazzoni, Elisa; Corallini, Alfredo; Cristaudo, Alfonso; Taronna, Angelo; Tassi, Gianfranco; Manfrini, Marco; Comar, Manola; Bovenzi, Massimo; Guaschino, Roberto; Vaniglia, Francesca; Magnani, Corrado; Casali, Ferruccio; et al. (Proc Natl Acad Sci U S A, 2012)
Human malignant pleural mesothelioma (MPM) is considered a rare tumor, but recent estimations indicate that one-quarter million people will die of this neoplasm in Europe in the next three decades. The mineral asbestos is considered the main causative agent of this neoplasm. MPM is largely unresponsive to conventional chemotherapy/radiotherapy. In addition to asbestos exposure, genetic predisposition to asbestos carcinogenesis and to simian virus (SV)40 infection has also been suggested. SV40 is a DNA tumor virus found in some studies to be associated at high prevalence with MPM. SV40 sequences have also been detected, although at a lower prevalence than in MPM, in blood specimens from healthy donors. However, some studies have failed to reveal SV40 footprints in MPM and its association with this neoplasm. These conflicting results indicate the need for further investigations with new approaches. We report on the presence of antibodies in serum samples from patients affected by MPM that specifically react with two different SV40 mimotopes. The two SV40 peptides used in indirect ELISAs correspond to viral capsid proteins. ELISA with the two SV40 mimotopes gave overlapping results. Our data indicate that in serum samples from MPM-affected patients (n = 97), the prevalence of antibodies against SV40 viral capsid protein antigens is significantly higher (26%, P = 0.043) than in the control group (15%) represented by healthy subjects (n = 168) with the same median age (66 y) and sex. Our results suggest that SV40 is associated with a subset of MPM and circulates in humans.
Keywords: Amino Acid Sequence; Antibodies, Viral; Capsid Proteins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mesothelioma; Molecular Sequence Data; Pleural Neoplasms; Pregnancy; Simian virus 40

HIV-1 induces NALP3-inflammasome expression and interleukin-1β secretion in dendritic cells from healthy individuals but not from HIV-positive patients. - Pontillo, Alessandra; Silva, Lais T; Oshiro, Telma M; Finazzo, Claudia; Crovella, Sergio; Duarte, Alberto J S (AIDS, 2012)
OBJECTIVE: NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals. DESIGN AND METHODS: Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1β (IL-1β) secretion. RESULTS: In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1β secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients' immune cells. CONCLUSION: HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines.
Keywords: Acquired Immunodeficiency Syndrome; Adult; Brazil; Carrier Proteins; Caspase 1; Cells, Cultured; Dendritic Cells; DNA, Viral; Female; HIV-1; Humans; Immunity, Innate; Inflammasomes; Interleukin-1beta; Male; Tumor Necrosis Factor-alpha

HLA-G 14bp del/ins genetic variation: association with susceptibility to human immunodeficiency virus-1 vertical transmission but not with human immunodeficiency virus-1 infection through horizontal transmission. - Segat, L; Crovella, S (Tissue Antigens, 2012)
Keywords: Ethnic Groups; Genetic Association Studies; Genetic Predisposition to Disease; HIV Infections; HIV-1; HLA-G Antigens; Humans; INDEL Mutation; Infectious Disease Transmission, Vertical; Polymorphism, Genetic

How the newly introduced compression, airway, and breathing sequence affects the training in pediatric cardiopulmonary resuscitation. - Lubrano, Riccardo; Messi, Gianni; Elli, Marco (Am J Emerg Med, 2012)
Keywords: Cardiopulmonary Resuscitation; Clinical Competence; Feedback; Female; Heart Massage; Humans; Inservice Training; Male

Hydrogen sulfide down-regulates the expression and release of osteoprotegerin (OPG) by vascular endothelial cells. - Rimondi, Erika; di Iasio, Maria Grazia; Gonelli, Arianna; Celeghini, Claudio; Secchiero, Paola; Zauli, Giorgio (Invest New Drugs, 2012)
Keywords: Cell Death; Cytostatic Agents; Down-Regulation; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen Sulfide; Osteoprotegerin; Tumor Necrosis Factor-alpha

Identification of a New Mutation (L46P) in the Human NOG Gene in an Italian Patient with Symphalangism Syndrome. - Athanasakis, E; Biarnés, X; Bonati, M T; Gasparini, P; Faletra, F (Mol Syndromol, 2012)
Proximal symphalangism (SYM1) is a joint morphogenesis disorder characterized by stapes ankylosis, proximal interphalangeal joint fusion, skeletal anomalies and conductive hearing loss. Noggin is a bone morphogenetic protein (BMP) antagonist essential for normal bone and joint development in humans and mice. Autosomal dominant mutations have been described in the NOG gene, encoding the noggin protein. We analyzed an Italian sporadic patient with SYM1 due to a novel NOG mutation (L46P) based on a c.137T>C transition. A different pathogenic mutation in the same codon (L46D) has been previously described in an in vivo chicken model. An in silico model shows a decreased binding affinity between noggin and BMP7 for both L46D and L46P compared to the wild type. Therefore, this codon should play an important role in BMP7 binding activity of the noggin protein and consequently to the joint morphogenesis.

Immunomodulatory drugs in autoimmune lymphoproliferative syndrome (ALPS). - Tommasini, Alberto; Valencic, Erica; Piscianz, Elisa; Rabusin, Marco (Pediatr Blood Cancer, 2012)
Keywords: Antineoplastic Agents; Autoimmune Lymphoproliferative Syndrome; Diseases in Twins; Humans; Male; Pentostatin

Importance of bladder bowel dysfunction in patients with urinary tract infection. - Giurici, Nagua; Pennesi, Marco (J Pediatr, 2012)
Keywords: Cystoscopy; Female; Fever; Humans; Male; Ureteroscopy; Urinary Tract Infections; Vesico-Ureteral Reflux

In vivo anti-lymphoma activity of an agonistic human recombinant anti-TRAIL-R2 minibody. - Zauli, Giorgio; Corallini, Federica; Zorzet, Sonia; Grill, Vittorio; Marzari, Roberto; Secchiero, Paola (Invest New Drugs, 2012)
A new single-chain fragment variable (scFv) to TRAIL-R2 receptor produced as minibody (MB2.23) was characterized for anti-lymphoma activity in vivo. For this purpose, a disseminated lymphoma model was generated by intraperitoneal inoculation of BJAB cells in severe combined immunodeficiency mice. Two weekly injections with MB2.23 (10 mg/kg) were able to significantly increase the median survival time of lymphoma-bearing animals with respect to the vehicle-treated control mice, providing a rationale for further investigating the use of MB2.23 in anticancer therapy.
Keywords: Animals; Humans; Immunotherapy; Injections, Intraperitoneal; Lymphoma, B-Cell; Mice; Mice, SCID; Receptors, TNF-Related Apoptosis-Inducing Ligand; Single-Chain Antibodies; Time Factors; Xenograft Model Antitumor Assays

Inflammation profile of four early onset Crohn patients. - Marcuzzi, Annalisa; Girardelli, Martina; Bianco, Anna Monica; Martelossi, Stefano; Magnolato, Andrea; Tommasini, Alberto; Crovella, Sergio (Gene, 2012)
Crohn disease (CD) is a multifactorial disorder affecting mainly young adults. Sometimes, however, it can present in the first year of life (Early onset Crohn disease (EOCD)) showing an unpredictable course and can often be more severe than at older ages. Some cases have been associated to an underlying primary immunodeficiency such as IL10R deficiency. We studied the functional response to IL-10 and the genotype of IL-10 receptor in four patients with early onset crohn-like colitis. We found an IL10R variant, which may be associated with a decreased response to the cytokine in one patient. Further studies to determine its pathogenic effect should be performed. In addition IL-10 mediated inhibition of LPS-induced TNFα expression was measured in patient's monocytes.
Keywords: Crohn Disease; Cytokines; Humans; Inflammation; Monocytes; Nod2 Signaling Adaptor Protein; Polymorphism, Genetic; Receptors, Interleukin-10; Tumor Necrosis Factor-alpha

Influence of age, sex and ethnicity on platelet count in five Italian geographic isolates: mild thrombocytopenia may be physiological. - Biino, Ginevra; Gasparini, Paolo; d'Adamo, Pio; Ciullo, Marina; Nutile, Teresa; Toniolo, Daniela; Sala, Cinzia; Minelli, Cosetta; Gögele, Martin; Balduini, Carlo L (Br J Haematol, 2012)
Keywords: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Humans; Infant; Italy; Male; Middle Aged; Platelet Count; Reference Values; Sex Distribution; Thrombocytopenia; Young Adult

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. - Chasman, Daniel I; Fuchsberger, Christian; Pattaro, Cristian; Teumer, Alexander; Böger, Carsten A; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; et al. (Hum Mol Genet, 2012)
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Keywords: Amino Acid Transport Systems, Basic; Antigens, CD98 Heavy Chain; Genetic Predisposition to Disease; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Inhibin-beta Subunits; Intracellular Signaling Peptides and Proteins; Low Density Lipoprotein Receptor-Related Protein-2; Membrane Proteins; Polymorphism, Single Nucleotide

International collaboration as a tool for diagnosis of patients with inherited thrombocytopenia in the setting of a developing country. - Glembotsky, A C; Marta, R F; Pecci, A; De Rocco, D; Gnan, C; Espasandin, Y R; Goette, N P; Negro, F; Noris, P; Savoia, A; Balduini, C L; Molinas, F C; et al. (J Thromb Haemost, 2012)
BACKGROUND: Inherited thrombocytopenias (ITs) are heterogeneous genetic disorders that frequently represent a diagnostic challenge. The requirement of highly specialized tests for diagnosis represents a particular problem in resource-limited settings. To overcome this difficulty, we applied a diagnostic algorithm and developed a collaboration program with a specialized international center in order to increase the diagnostic yield in a cohort of patients in Argentina. METHODS: Based on the algorithm, initial evaluation included collection of clinical data, platelet size, blood smear examination and platelet aggregation tests. Confirmatory tests were performed according to diagnostic suspicion, which included platelet glycoprotein expression, immunofluorescence for myosin-9 in granulocytes and platelet thrombospondin-1 and molecular screening of candidate genes. RESULTS: Thirty-one patients from 14 pedigrees were included; their median age was 32 (4-72) years and platelet count 72 (4-147)×10(9) L(-1). Autosomal dominant inheritance was found in nine (64%) pedigrees; 10 (71%) had large platelets and nine (29%) patients presented with syndromic forms. A definitive diagnosis was made in 10 of 14 pedigrees and comprised MYH9-related disease in four, while classic and monoallelic Bernard-Soulier syndrome, gray platelet syndrome, X-linked thrombocytopenia, thrombocytopenia 2 (ANKRD26 mutation) and familial platelet disorder with predisposition to acute myelogenous leukemia were diagnosed in one pedigree each. CONCLUSIONS: Adoption of an established diagnostic algorithm and collaboration with an expert referral center proved useful for diagnosis of IT patients in the setting of a developing country. This initiative may serve as a model to develop international networks with the goal of improving diagnosis and care of patients with these rare diseases.
Keywords: Adolescent; Adult; Aged; Algorithms; Argentina; Biological Markers; Child; Child, Preschool; Cooperative Behavior; Developing Countries; DNA Mutational Analysis; Feasibility Studies; Female; Flow Cytometry; Fluorescent Antibody Technique; Genetic Predisposition to Disease; Genetic Testing; Health Services Accessibility; Hematologic Tests; Heredity; Humans; International Cooperation; Italy; Male; Middle Aged; Molecular Motor Proteins; Myosin Heavy Chains; Pedigree; Phenotype; Platelet Count; Platelet Function Tests; Predictive Value of Tests; Prognosis; Referral and Consultation; Thrombocytopenia; Thrombospondin 1; Young Adult

Involuntary movements after correction of vitamin B12 deficiency: a video-case report. - Zanus, Caterina; Alberini, Elena; Costa, Paola; Colonna, Franco; Zennaro, Floriana; Carrozzi, Marco (Epileptic Disord, 2012)
Involuntary movements can appear before and after initiation of vitamin B12 treatment. The pathogenesis of involuntary movements in vitamin B12 deficiency and their relationship with cobalamin injection remain unclear due to a lack of video-EEG documentation making the electroclinical correlation difficult to ascertain. Here, we report video-EEG and neuroimaging findings of an 11-month-old girl with vitamin B12 deficiency, who acutely developed involuntary movements a few days after initiation of vitamin B12 treatment with normal vitamin plasmatic levels. Abnormal movements were a combination of tremor and myoclonus involving the face, mouth, and left arm, which disappeared after discontinuation of therapy. [Published with video sequences].
Keywords: Atrophy; Brain; Dyskinesias; Electroencephalography; Female; Humans; Infant; Magnetic Resonance Imaging; Myelin Sheath; Myoclonus; Tremor; Video Recording; Vitamin B 12; Vitamin B 12 Deficiency; Vitamins

JCV+ Patients with Inflammatory bowel disease show elevated plasma levels of MIG and SCF. - Comar, Manola; Secchiero, Paola; De Lorenzo, Elisa; Martelossi, Stefano; Tommasini, Alberto; Zauli, Giorgio (Inflamm Bowel Dis, 2012)
Keywords: Adolescent; Adult; Chemokine CXCL9; Child; DNA, Viral; Female; Humans; Inflammatory Bowel Diseases; JC Virus; Leukoencephalopathy, Progressive Multifocal; Male; Stem Cell Factor; Young Adult

Letter: inflammatory bowel disease, complementary and alternative medicine, and genetics. - Bianco, A M; Vuch, J; Girardelli, M; Zanin, V; Marcuzzi, A; Crovella, S (Aliment Pharmacol Ther, 2012)
Keywords: Complementary Therapies; Female; Humans; Inflammatory Bowel Diseases; Male; Medication Adherence

Letter: TPMT activity and age in IBD patients. - Stocco, G; De Iudicibus, S; Cuzzoni, E; Decorti, G; Martelossi, S; Ventura, A (Aliment Pharmacol Ther, 2012)
Keywords: Azathioprine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Thioguanine

Lingual schwannoma in pediatric patients. - Manna, Francesco; Barbi, Egidio; Murru, Flora; Bussani, Rossana (J Craniofac Surg, 2012)
We present the case of a 15-year-old boy who presented to our emergency department because of a soft lesion growing on the back of his tongue. On examination, a vegetant mass on the posteromidline lingual part of the body of the tongue was noticed: it was not painful, even if the boy reported discomfort because of its size; there was no bleeding or signs of infection. The magnetic resonance imaging showed the lesion as trilobated and capsulated, but was not diriment to define a diagnosis; excisional biopsy was performed under general anesthesia, and the mass was identified as a schwannoma. Schwannoma, or neurilemmoma, is a benign tumor originating from Schwann cells of the nerve sheath surrounding peripheral nerves. It is slow-growing, usually solitary, and encapsulated. Intraoral schwannomas are rare and account for 1% of lesions of the head and neck region. There is no sex predilection. The symptoms depend on size and location of the tumor. Recurrence is rare after complete surgical resection. The present study aimed to retrospectively describe our experience with a case of neurilemmoma of the tongue presenting in childhood, the diagnostic methods used, the surgical decision, and the treatment outcome and to analyze the data and review the literature available on this type of tumor. The etiology, clinical presentation, differential diagnosis, and management are discussed.
Keywords: Adolescent; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Male; Neurilemmoma; Tongue Neoplasms

Lovastatin-induced apoptosis is modulated by geranylgeraniol in a neuroblastoma cell line. - Marcuzzi, Annalisa; Zanin, Valentina; Piscianz, Elisa; Tricarico, Paola Maura; Vuch, Josef; Girardelli, Martina; Monasta, Lorenzo; Bianco, Anna Monica; Crovella, Sergio (Int J Dev Neurosci, 2012)
Mevalonic aciduria (MA), the most severe form of mevalonate kinase deficiency (MKD), is still an orphan drug disease and the pathogenetic mechanisms underlying neuronal dysfunction is still poorly understood. In our study we have investigated the apoptotic mechanism mediated by the exposure of the cultured neuroblastoma cell line, SH-SY5Y, to lovastatin in absence or in presence of the isoprenoid, geranylgeraniol, with the aim of unraveling the pathogenesis of MA. Lovastatin, blocks the mevalonate pathway inhibiting the 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR), an enzyme of the mevalonate pathway upstream the mevalonate kinase enzyme, reproducing biochemical features similar to those found in MKD. We demonstrate that apoptosis in neuronal lovastatin treated-cells is induced by the mitochondrial pathway, with caspase-9 as the initiator and caspase-3 as the effector caspase. The presence of geranylgeraniol modulates both the caspase-9 and caspase-3 activity in a dose-dependent way, confirming that this isoprenoid enters the mevalonate pathway, is metabolized and finally is able to by-pass the statin biochemical block reconstituting the mevalonate pathway. According to our findings, it should not be the time course adopted that modulates the apoptotic response but rather the isoprenoid itself. Being aware that our results have been obtained using a biochemical model of MKD, and not cells from patients with the disease, we believe our findings increase the knowledge of MA pathogenesis, and may possibly contribute to the development of novel therapeutic strategies.
Keywords: Analysis of Variance; Apoptosis; Caspases; Cell Line, Tumor; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Neuroblastoma; Time Factors

Lutein and zeaxanthin supplementation in preterm infants to prevent retinopathy of prematurity: a randomized controlled study. - Dani, Carlo; Lori, Ilaria; Favelli, Federica; Frosini, Saverio; Messner, Hubert; Wanker, Petra; De Marini, Sergio; Oretti, Chiara; Boldrini, Antonio; Massimiliano, Ciantelli; Bragetti, Patrizia; Germini, Cristiana (J Matern Fetal Neonatal Med, 2012)
OBJECTIVES: Lutein and its isomer zeaxanthin (L/Z) function in the eye as antioxidant agents and blue-light filters. Our aim was to evaluate whether their administration could help decrease the occurrence of retinopathy of prematurity (ROP) in preterm infants. METHODS: Infants with gestational age ≤32 weeks were randomly assigned to receive a daily dose of L/Z (0.14 + 0.006 mg) or placebo until discharge. RESULTS: ROP occurrence was similar in the L/Z (11/58; 19%) and placebo (15/56; 27%) groups, as the occurrence of ROP at each stage and the need of eye surgery. CONCLUSION: L/Z supplementation was ineffective in preventing ROP in preterm infants and did not affect the outcome at discharge of our patients.
Keywords: Antioxidants; Drug Administration Schedule; Drug Combinations; Female; Humans; Infant, Newborn; Infant, Premature; Logistic Models; Lutein; Male; Retinopathy of Prematurity; Risk Factors; Treatment Outcome; Xanthophylls; Zeaxanthins

Management of cryptorchidism: a survey of clinical practice in Italy. - Marchetti, Federico; Bua, Jenny; Tornese, Gianluca; Piras, Gianni; Toffol, Giacomo; Ronfani, Luca (BMC Pediatr, 2012)
BACKGROUND: An evidence-based Consensus on the treatment of undescended testis (UT) was recently published, recommending to perform orchidopexy between 6 and 12 months of age, or upon diagnosis and to avoid the use of hormones. In Italy, current practices on UT management are little known. Our aim was to describe the current management of UT in a cohort of Italian children in comparison with the Consensus guidelines. As management of retractile testis (RT) differs, RT cases were described separately. METHODS: Ours is a retrospective, multicenter descriptive study. An online questionnaire was filled in by 140 Italian Family Paediatricians (FP) from Associazione Culturale Pediatri (ACP), a national professional association of FP. The questionnaire requested information on all children with cryptorchidism born between 1/01/2004 and 1/01/2006. Data on 169 children were obtained. Analyses were descriptive. RESULTS: Overall 24% of children were diagnosed with RT, 76% with UT. Among the latter, cryptorchidism resolved spontaneously in 10% of cases at a mean age of 21.6 months. Overall 70% of UT cases underwent orchidopexy at a mean age of 22.8 months (SD 10.8, range 1.2-56.4), 13% of whom before 1 year. The intervention was performed by a paediatric surgeon in 90% of cases, with a success rate of 91%. Orchidopexy was the first line treatment in 82% of cases, while preceded by hormonal treatment in the remaining 18%. Hormonal treatment was used as first line therapy in 23% of UT cases with a reported success rate of 25%. Overall, 13 children did not undergo any intervention (mean age at last follow up 39.6 months). We analyzed the data from the 5 Italian Regions with the largest number of children enrolled and found a statistically significant regional difference in the use of hormonal therapy, and in the use of and age at orchidopexy. CONCLUSIONS: Our study showed an important delay in orchidopexy. A quarter of children with cryptorchidism was treated with hormonal therapy. In line with the Consensus guidelines, surgery was carried out by a paediatric surgeon in the majority of cases, with a high success rate.
Keywords: Child, Preschool; Chorionic Gonadotropin; Cryptorchidism; Gonadotropin-Releasing Hormone; Guideline Adherence; Humans; Infant; Italy; Male; Middle Aged; Orchiopexy; Pediatrics; Physician's Practice Patterns; Practice Guidelines as Topic; Questionnaires; Retrospective Studies; Treatment Outcome

Managing children under 36 months of age with febrile urinary tract infection: a new approach. - Pennesi, Marco; L'erario, Ines; Travan, Laura; Ventura, Alessandro (Pediatr Nephrol, 2012)
BACKGROUND: Recent guidelines on urinary tract infection (UTI) agree on reducing the number of invasive procedures. None of these has been validated by a long-term study. We describe our 11-years experience in the application of a diagnostic protocol that uses a reduced number of invasive procedures. METHODS: We reviewed retrospectively the records of 406 children aged between 1 and 36 months at their first UTI. All patients underwent renal ultrasound (RUS). Children with abnormal RUS and those with UTI recurrences underwent voiding cystourethrography (VCUG) and dimercaptosuccinic acid (DMSA) renal scans. RESULTS: RUS after the first UTI was pathological in 7.4% children; 4.4 % had a second UTI. We performed 48 VCUG: 14 patients (29%) had vesicoureteral reflux (VUR), 12 of which showed an abnormal RUS while 2 had recurrent UTI. After DMSA renal scan renal damage appeared in only 6 of them (12.5%); all these children showed grade IV VUR. CONCLUSIONS: The application of our guidelines leads to a decrease in invasive examinations without missing any useful diagnoses or compromising the child's health.
Keywords: Anti-Bacterial Agents; Child, Preschool; Female; Humans; Infant; Male; Pediatrics; Recurrence; Retrospective Studies; Urinary Tract Infections

Mannose-binding lectin and MBL-associated serine protease-2 gene polymorphisms in a Brazilian population from Rio de Janeiro. - Ferraroni, N R; Segat, L; Guimarães, R L; Brandão, L A C; Crovella, S; Constantino-Silva, R N; Loja, C; da Silva Duarte, A J; Grumach, A S (Int J Immunogenet, 2012)
Mannose-binding lectin (MBL) is a protein able to bind to carbohydrate patterns on pathogen membranes; upon MBL binding, its' associated serine protease MBL-associated serine protease type 2 (MASP2) is autoactivated, promoting the activation of complement via the lectin pathway. For both MBL2 and MASP2 genes, the frequencies of polymorphisms are extremely variable between different ethnicities, and this aspect has to be carefully considered when performing genetic studies. While polymorphisms in the MBL-encoding gene (MBL2) have been associated, depending upon ethnicity, with several diseases in different populations, little is known about the distribution of MASP2 gene polymorphisms in human populations. The aim of our study was thus to determine the frequencies of MBL2 (exon 1 and promoter) and MASP2 (p.D371Y) polymorphisms in a Brazilian population from Rio de Janeiro. A total of 294 blood donor samples were genotyped for 27 polymorphisms in the MBL2 gene by direct sequencing of a region spanning from the promoter polymorphism H/L rs11003125 to the rs1800451 polymorphism (at codon 57 in the first exon of the gene). Genotyping for MASP2 p.D371Y was carried out using fluorogenic probes. To our knowledge, this is the first study reporting the prevalence of the MASP2 p.D371Y polymorphism in a Brazilian population. The C allele frequency 39% is something intermediate between the reported 14% in Europeans and 90% in Sub-Saharan Africans. MBL2 polymorphisms frequencies were quite comparable to those previously reported for admixed Brazilians. Both MBL2 and MASP2 polymorphisms frequencies reported in our study for the admixed Brazilian population are somehow intermediate between those reported in Europeans and Africans, reflecting the ethnic composition of the southern Brazilian population, estimated to derive from an admixture of Caucasian (31%), African (34%) and Native American (33%) populations. In conclusion, our population genetic study describes the frequencies of MBL2 and MASP2 functional SNPs in a population from Rio de Janeiro, with the aim of adding new information concerning the distribution of these SNPs in a previously unanalysed Brazilian population, thus providing a new genetic tool for the evaluation of the association of MBL2 and MASP2 functional SNPs with diseases in Brazil, with particular emphasis on the state of Rio de Janeiro.
Keywords: Adolescent; Adult; Brazil; Ethnic Groups; Exons; Female; Fluorescent Dyes; Gene Frequency; Genetics, Population; Genome, Human; HapMap Project; Humans; Male; Mannose-Binding Lectin; Mannose-Binding Protein-Associated Serine Proteases; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Sequence Analysis, DNA; Young Adult

MBL interferes with endovascular trophoblast invasion in pre-eclampsia. - Agostinis, Chiara; Bossi, Fleur; Masat, Elisa; Radillo, Oriano; Tonon, Maddalena; De Seta, Francesco; Tedesco, Francesco; Bulla, Roberta (Clin Dev Immunol, 2012)
The spiral arteries undergo physiologic changes during pregnancy, and the failure of this process may lead to a spectrum of pregnancy disorders, including pre-eclampsia. Our recent data indicate that decidual endothelial cells (DECs), covering the inner side of the spiral arteries, acquire the ability to synthesize C1q, which acts as a link between endovascular trophoblast and DECs favouring the process of vascular remodelling. In this study, we have shown that sera obtained from pre-eclamptic patients strongly inhibit the interaction between extravillous trophoblast (EVT) and DECs, preventing endovascular invasion of trophoblast cells. We further demonstrated that mannose-binding lectin (MBL), one of the factor increased in pre-eclamptic patient sera, strongly inhibits the interaction of EVT with C1q interfering with the process of EVT adhesion to and migration through DECs. These data suggest that the increased level of MBL in pre-eclampsia may contribute to the failure of the endovascular invasion of trophoblast cells.
Keywords: Cell Communication; Decidua; Endothelial Cells; Female; Humans; Mannose-Binding Lectin; Pre-Eclampsia; Pregnancy; Transendothelial and Transepithelial Migration; Trophoblasts

MCL1 down-regulation plays a critical role in mediating the higher anti-leukaemic activity of the multi-kinase inhibitor Sorafenib with respect to Dasatinib. - Secchiero, Paola; Melloni, Elisabetta; Voltan, Rebecca; Norcio, Alessia; Celeghini, Claudio; Zauli, Giorgio (Br J Haematol, 2012)
Keywords: Antineoplastic Agents; Benzenesulfonates; Cell Line, Tumor; Down-Regulation; Humans; Leukemia, Myeloid, Acute; Myeloid Cell Leukemia Sequence 1 Protein; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyridines; Pyrimidines; Thiazoles

The MDM2 inhibitor Nutlin-3 modulates dendritic cell-induced T cell proliferation. - Gasparini, Chiara; Tommasini, Alberto; Zauli, Giorgio (Hum Immunol, 2012)
Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, has been recently taken into consideration as a promising therapeutic tool for tumor treatment based on its ability to stabilize and activate the p53 transcription factor pathway. Since Nutlin-3 displays non cell-autonomous tumor-suppressor activities, we wanted to investigate its effect on dendritic cell functions, given the central role of these cells in the modulation of the immune response. We found that Nutlin-3 alone slightly affected the levels of major histocompatibility complex and costimulatory molecules and significantly promoted the ability of dendritic cells to stimulate T cells in the mixed lymphocyte reaction. Taken together, our findings suggest that the ability of Nutlin-3 to modulate dendritic cell functions and therefore lymphocyte proliferation might represent an additional important mechanism by which Nutlin-3 exerts its non cell-autonomous tumor-suppression function.
Keywords: Dendritic Cells; Humans; Imidazoles; Immunologic Factors; Immunophenotyping; Lymphocyte Activation; Piperazines; Proto-Oncogene Proteins c-mdm2; T-Lymphocytes

Merkel-cell polyomavirus (MCPyV) is rarely associated to B-chronic lymphocytic leukemia (1 out of 50) samples and occurs late in the natural history of the disease. - Comar, Manola; Cuneo, Antonio; Maestri, Iva; Melloni, Elisabetta; Pozzato, Gabriele; Soffritti, Olga; Secchiero, Paola; Zauli, Giorgio (J Clin Virol, 2012)
BACKGROUND: Previous studies have reported conflicting results on the frequency and potential pathogenetic role of Merkel-cell polyomavirus (MCPyV) in B-chronic lymphocytic leukemia (B-CLL). OBJECTIVES: To evaluate the association of MCPyV to B-CLL and to investigate the occurrence of MCPyV infection in relationship to the natural history of B-CLL. STUDY DESIGN: Samples of primary B-CLL peripheral blood mononuclear cells were obtained from two distinct University Hospitals of Italy from January 2010. For one B-CLL patient, it was possible to retrospectively examine the blood sample at diagnosis of B-CLL (March 2004) and several pathological tissues of cutaneous tumors occurring during the course of the disease. RESULTS: Only one out of 50 B-CLL blood samples examined was positive for MCPyV DNA. Retrospective analysis revealed that MCPyV DNA was absent in peripheral blood sample at diagnosis, becoming present only in advanced disease stages also in tonsil tissue as well as in a biopsy of differentiated squamous cell carcinoma. CONCLUSIONS: The association with MCPyV seems to represent a rare and late event during the natural history of B-CLL.
Keywords: Aged; Aged, 80 and over; Blood; Female; Humans; Italy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Merkel cell polyomavirus; Middle Aged; Palatine Tonsil; Polyomavirus Infections; Prevalence; Skin; Tumor Virus Infections

Mesenchymal stem cells display hepato-protective activity in lymphoma bearing xenografts. - Secchiero, Paola; Corallini, Federica; Zavan, Barbara; Tripodo, Claudio; Vindigni, Vincenzo; Zauli, Giorgio (Invest New Drugs, 2012)
A disseminated model of non-Hodgkin's lymphoma with prevalent liver metastasis was generated by intraperitoneal (i.p.) injection of EBV(+) B lymphoblastoid SKW6.4 in nude-SCID mice. The survival of SKW6.4 xenografts (median survival = 27 days) was significantly improved when hyaluronan scaffolds embedded with mesenchimal stem cells (MSC) were implanted in the abdominal area 4 days after SKW6.4 injection (median survival = 39.5 days). Mice implanted with MSC showed a significant improvement of hepatic functionality in lymphoma xenografts, as demonstrated by measurement of serum ALT/AST levels. Co-culture of MSC with lymphoma cells enhanced the release of hepatocyte growth factor (HGF) by MSC. These data suggest that hyaluronan-embedded MSC exert anti-lymphoma activity by ameliorating hepatic functionality.
Keywords: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biological Markers; Cell Communication; Cell Line, Tumor; Cell Survival; Coculture Techniques; Hepatocyte Growth Factor; Humans; Hyaluronic Acid; Liver; Liver Neoplasms; Lymphoma, Non-Hodgkin; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells; Mice; Mice, Nude; Mice, SCID; Time Factors; Tissue Scaffolds; Xenograft Model Antitumor Assays

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. - Stolk, Lisette; Perry, John R B; Chasman, Daniel I; He, Chunyan; Mangino, Massimo; Sulem, Patrick; Barbalic, Maja; Broer, Linda; Byrne, Enda M; Ernst, Florian; Esko, Tõnu; Franceschini, Nora; et al. (Nat Genet, 2012)
To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
Keywords: Age Factors; DNA Helicases; DNA Primase; DNA Repair; DNA Repair Enzymes; DNA-Directed DNA Polymerase; European Continental Ancestry Group; Exodeoxyribonucleases; Female; Genetic Loci; Genome-Wide Association Study; Humans; Immunity; Menopause; Polymorphism, Single Nucleotide; Proteins

Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations. - Okada, Yukinori; Sim, Xueling; Go, Min Jin; Wu, Jer-Yuarn; Gu, Dongfeng; Takeuchi, Fumihiko; Takahashi, Atsushi; Maeda, Shiro; Tsunoda, Tatsuhiko; Chen, Peng; Lim, Su-Chi; Wong, Tien-Yin; et al. (Nat Genet, 2012)
Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.
Keywords: Asian Continental Ancestry Group; Blood Urea Nitrogen; Cohort Studies; Creatinine; Genetic Predisposition to Disease; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Uric Acid

Mevalonate kinase deficiency: disclosing the role of mevalonate pathway modulation in inflammation. - Marcuzzi, Annalisa; Crovella, Sergio; Monasta, Lorenzo; Vecchi Brumatti, Liza; Gattorno, Marco; Frenkel, Joost (Curr Pharm Des, 2012)
Inflammation is a highly regulated process involved both in the response to pathogens as well as in tissue homeostasis. In recent years, a complex network of proteins in charge of inflammation control has been revealed by the study of hereditary periodic fever syndromes. Most of these proteins belong to a few families and share the capability of sensing pathogen-associated and damageassociated molecular patterns. By interacting with each other, these proteins participate in the assembly of molecular platforms, called inflammasomes, which ultimately lead to the activation of cytokines, to the transcription of inflammatory genes or to the induction of cell apoptosis. Among hereditary periodic fever syndromes, mevalonate kinase deficiency (MKD) is the sole in which the phenotype did not directly associate with a deficiency of these proteins, but with a metabolic defect of the mevalonate pathway, highlighting the importance of this metabolic pathway in the inflammation control. Noteworthy, drugs acting on this pathway can greatly influence the inflammatory response. The modulation of inflammation by mevalonate pathway is of interest, since it may involve mechanisms not directly referable to inflammasomes. MKD provides a model to study these mechanisms and possibly to develop new classes of anti-inflammatory drugs.
Keywords: Animals; Anti-Inflammatory Agents; Apoptosis; Cytokines; Drug Design; Hereditary Autoinflammatory Diseases; Humans; Inflammasomes; Inflammation; Mevalonate Kinase Deficiency; Mevalonic Acid

miR-EdiTar: a database of predicted A-to-I edited miRNA target sites. - Laganà, Alessandro; Paone, Alessio; Veneziano, Dario; Cascione, Luciano; Gasparini, Pierluigi; Carasi, Stefania; Russo, Francesco; Nigita, Giovanni; Macca, Valentina; Giugno, Rosalba; Pulvirenti, Alfredo; Shasha, Dennis; et al. (Bioinformatics, 2012)
MOTIVATION: A-to-I RNA editing is an important mechanism that consists of the conversion of specific adenosines into inosines in RNA molecules. Its dysregulation has been associated to several human diseases including cancer. Recent work has demonstrated a role for A-to-I editing in microRNA (miRNA)-mediated gene expression regulation. In fact, edited forms of mature miRNAs can target sets of genes that differ from the targets of their unedited forms. The specific deamination of mRNAs can generate novel binding sites in addition to potentially altering existing ones. RESULTS: This work presents miR-EdiTar, a database of predicted A-to-I edited miRNA binding sites. The database contains predicted miRNA binding sites that could be affected by A-to-I editing and sites that could become miRNA binding sites as a result of A-to-I editing. AVAILABILITY: miR-EdiTar is freely available online at http://microrna.osumc.edu/mireditar. CONTACT: alessandro.lagana@osumc.edu or carlo.croce@osumc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Keywords: Adenosine; Binding Sites; Databases, Genetic; Gene Expression Regulation; Humans; Inosine; Internet; MicroRNAs; Nucleic Acid Conformation; RNA Editing

Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. - Zampieri, Stefania; Montalvo, Annalisa; Blanco, Mariana; Zanin, Irene; Amartino, Hernan; Vlahovicek, Kristian; Szlago, Marina; Schenone, Andrea; Pittis, Gabriela; Bembi, Bruno; Dardis, Andrea (Gene, 2012)
Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.
Keywords: Child; Cohort Studies; Female; Hexosaminidase A; Humans; Infant; Male; Mutation; Tay-Sachs Disease

Molecular diagnosis of Usher syndrome: application of two different next generation sequencing-based procedures. - Licastro, Danilo; Mutarelli, Margherita; Peluso, Ivana; Neveling, Kornelia; Wieskamp, Nienke; Rispoli, Rossella; Vozzi, Diego; Athanasakis, Emmanouil; D'Eustacchio, Angela; Pizzo, Mariateresa; D'Amico, Francesca; Ziviello, Carmela; et al. (PLoS One, 2012)
Usher syndrome (USH) is a clinically and genetically heterogeneous disorder characterized by visual and hearing impairments. Clinically, it is subdivided into three subclasses with nine genes identified so far. In the present study, we investigated whether the currently available Next Generation Sequencing (NGS) technologies are already suitable for molecular diagnostics of USH. We analyzed a total of 12 patients, most of which were negative for previously described mutations in known USH genes upon primer extension-based microarray genotyping. We enriched the NGS template either by whole exome capture or by Long-PCR of the known USH genes. The main NGS sequencing platforms were used: SOLiD for whole exome sequencing, Illumina (Genome Analyzer II) and Roche 454 (GS FLX) for the Long-PCR sequencing. Long-PCR targeting was more efficient with up to 94% of USH gene regions displaying an overall coverage higher than 25×, whereas whole exome sequencing yielded a similar coverage for only 50% of those regions. Overall this integrated analysis led to the identification of 11 novel sequence variations in USH genes (2 homozygous and 9 heterozygous) out of 18 detected. However, at least two cases were not genetically solved. Our result highlights the current limitations in the diagnostic use of NGS for USH patients. The limit for whole exome sequencing is linked to the need of a strong coverage and to the correct interpretation of sequence variations with a non obvious, pathogenic role, whereas the targeted approach suffers from the high genetic heterogeneity of USH that may be also caused by the presence of additional causative genes yet to be identified.
Keywords: Child, Preschool; Exome; Genome, Human; High-Throughput Nucleotide Sequencing; Humans; Molecular Diagnostic Techniques; Pilot Projects; Sequence Analysis, DNA; Usher Syndromes

More on professionals' attitudes on blood-tinged milk: a survey from Italy. - Bua, J; Travan, L; Davanzo, R; Demarini, S (J Perinatol, 2012)
Keywords: Attitude of Health Personnel; Breast Feeding; Clinical Protocols; Female; Humans; Intensive Care Units, Neonatal; Intensive Care, Neonatal; Male; Milk, Human; Professional Practice

MYH9-related disorders: report on a patient of Greek origin presenting with macroscopic hematuria and presenile cataract, caused by an R1165C mutation. - Economou, Marina; Batzios, Spyros P; Pecci, Alessandro; Printza, Nikoletta; Savoia, Anna; Barozzi, Serena; Theodoridou, Stamatia; Teli, Aikaterini; Psillas, Georgios; Zafeiriou, Dimitrios I (J Pediatr Hematol Oncol, 2012)
Myosin heavy chain-9 (MYH9)-related disorders represent a heterogenous group of hereditary diseases caused by mutations in the gene encoding the heavy chain of nonmuscle myosin IIA. May-Hegglin anomaly and Fechtner, Sebastian, and Epstein syndromes are the four phenotypes of the disease, characterized by congenital macrothrombocytopenia and distinguished by different combinations of clinical signs that may include glomerulonephritis, sensorineural hearing loss, and presenile cataract. The spectrum of mutations responsible for the disease is wide and the existence of genotype-phenotype correlation remains a critical issue. We report the first case of an MYH9-RD in a patient of Greek origin presenting with macroscopic hematuria and presenile cataract caused by a p.R1165C mutation. The same mutation was present in the patient's father, who exhibited no extrahematological features of the disease. The p.R1165C mutation is one of the MYH9 alterations whose prognostic significance is still poorly defined. Thus, the patients described add to the limited existing data on the MYH9 mutations and their resultant phenotypes.
Keywords: Adolescent; Cataract; Diagnosis, Differential; DNA Mutational Analysis; Greece; Hematuria; Humans; Male; Molecular Motor Proteins; Myosin Heavy Chains; Point Mutation

NALP1/NLRP1 genetic variants are associated with Alzheimer disease. - Pontillo, Alessandra; Catamo, Eulalia; Arosio, Beatrice; Mari, Daniela; Crovella, Sergio (Alzheimer Dis Assoc Disord, 2012)
Alzheimer disease (AD) is a complex neurodegenerative disease. Genetic and molecular studies have confirmed that in the human brain, amyloid-β fibrils can induce, through the activation of NALP1 inflammosome, inflammatory and apoptotic responses involved in the pathogenesis of AD. Considering that AD pathogenesis is multifactorial, we hypothesized that NALP1/NLRP1 could be a susceptibility gene involved in the devolvement of the disease. The possible association between 9 selected polymorphisms in the NALP1/NLRP1 gene and AD was evaluated by comparing their frequency distribution in an Italian cohort of AD patients (AD, n = 276) and in a group of Italian sex-matched and age-matched healthy controls without dementia (HC, n = 266). Our study, evidences the association of 4 nonsynonymous polymorphisms in the NLRP1 gene (rs2137722, rs34733791, rs11657747, rs11651595) with AD. The major alleles of all 4 single nucleotide polymorphisms and the corresponding homozygote genotypes were more frequent in AD patients than in healthy controls, suggesting an association of these variants in the predisposition versus the development of the disease. These findings seem to support the previously reported role of NALP1 in neuronal damage, and provide evidence of an association between single nucleotide variations in the NLRP1 gene and AD.
Keywords: Adaptor Proteins, Signal Transducing; Aged, 80 and over; Alzheimer Disease; Apoptosis Regulatory Proteins; Female; Genetic Predisposition to Disease; Genotype; Humans; Italy; Male; Polymerase Chain Reaction; Polymorphism, Single Nucleotide

The negative prognostic value of TRAIL overexpression in oral squamous cell carcinomas does not preclude the potential therapeutic use of recombinant TRAIL. - Carinci, Francesco; Monasta, Lorenzo; Rubini, Corrado; Stramazzotti, Daniela; Palmieri, Annalisa; Melloni, Elisabetta; Knowles, Alex; Ronfani, Luca; Zauli, Giorgio; Secchiero, Paola (Invest New Drugs, 2012)
Keywords: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Female; Flow Cytometry; HL-60 Cells; Humans; Immunohistochemistry; Male; Middle Aged; Mouth Neoplasms; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Recombinant Proteins; Risk Assessment; Risk Factors; Survival Analysis; TNF-Related Apoptosis-Inducing Ligand; Tumor Markers, Biological; Up-Regulation; Young Adult

New insights in the sugarcane transcriptome responding to drought stress as revealed by superSAGE. - Kido, Éderson Akio; Ferreira Neto, José Ribamar Costa; Silva, Roberta Lane de Oliveira; Pandolfi, Valesca; Guimarães, Ana Carolina Ribeiro; Veiga, Daniela Truffi; Chabregas, Sabrina Moutinho; Crovella, Sergio; Benko-Iseppon, Ana Maria (ScientificWorldJournal, 2012)
In the scope of the present work, four SuperSAGE libraries have been generated, using bulked root tissues from four drought-tolerant accessions as compared with four bulked sensitive genotypes, aiming to generate a panel of differentially expressed stress-responsive genes. Both groups were submitted to 24 hours of water deficit stress. The SuperSAGE libraries produced 8,787,315 tags (26 bp) that, after exclusion of singlets, allowed the identification of 205,975 unitags. Most relevant BlastN matches comprised 567,420 tags, regarding 75,404 unitags with 164,860 different ESTs. To optimize the annotation efficiency, the Gene Ontology (GO) categorization was carried out for 186,191 ESTs (BlastN against Uniprot-SwissProt), permitting the categorization of 118,208 ESTs (63.5%). In an attempt to elect a group of the best tags to be validated by RTqPCR, the GO categorization of the tag-related ESTs allowed the in silico identification of 213 upregulated unitags responding basically to abiotic stresses, from which 145 presented no hits after BlastN analysis, probably concerning new genes still uncovered in previous studies. The present report analyzes the sugarcane transcriptome under drought stress, using a combination of high-throughput transcriptome profiling by SuperSAGE with the Solexa sequencing technology, allowing the identification of potential target genes during the stress response.
Keywords: Droughts; Gene Expression Profiling; Heat-Shock Response; Plant Proteins; Saccharum; Transcriptome

NF-κB as a target for modulating inflammatory responses. - Gasparini, Chiara; Feldmann, Marc (Curr Pharm Des, 2012)
The inflammatory response is of major importance in host defence, but is involved in all acute and chronic diseases. Multiple inflammatory cells and molecules are involved. Among the latter, the Nuclear Factor -κB (NF-κB) has been found to be most important and present in all cell types. NF-B regulates the expression of a large number of genes involved in inflammation. NF-κB plays a key role in the orchestration of the multifaceted inflammatory response, not only in the first pro-inflammatory phase, but also later in the regulation of the resolution of inflammation, when anti-inflammatory genes are expressed and apoptosis is induced. The review describes NF-κB and its two pathways: the canonical, mediated by the p65 and p50 subunits, and the non-canonical, mediated by the subunits RelB, p52 and p50. The relevance of the kinases and interactions leading to NF-κB activation is considered in different primary cells (i.e. macrophages, dendritic cells, fibroblasts, cells from inflammatory tissues), together with the response induced and the ligand involved. Then we overview the different steps to NF-B activation that can be targeted (IKKs, IκBα or NF-κB subunits themselves) with various technologies available i.e. small molecules peptides or nucleic acids. A rationale is provided for possible targets to consider, in the light that NF-κB signaling pathways regulates both pro-inflammatory and anti-inflammatory responses. The possibility of using NF-κB targeted dendritic cells in immunotherapy is considered.
Keywords: Acute Disease; Animals; Chronic Disease; Dendritic Cells; Gene Expression Regulation; Humans; Immunotherapy; Inflammation; NF-kappa B; Signal Transduction

NLRP1 polymorphisms in patients with asbestos-associated mesothelioma. - Girardelli, Martina; Maestri, Iva; Rinaldi, Rosa R; Tognon, Mauro; Boldorini, Renzo; Bovenzi, Massimo; Crovella, Sergio; Comar, Manola (Infect Agent Cancer, 2012)
UNLABELLED: BACKGROUND: An increasing incidence of malignant mesothelioma (MM) cases in patients with low levels of asbestos exposure suggests the interference of alternative cofactors. SV40 infection was detected, as co-morbidity factor, only in 22% of asbestos-MM patients from a North-Eastern Italy area. An additional mechanism of injury related to asbestos exposure in MM development has been recently associated to inflammatory responses, principally driven by interleukin (IL)-1 beta (ß) activated within the inflammasome complex.NLRP3 inflammosome has been described as the intracellular sensor for asbestos able to induce inflammasome activation and IL-1ß secretion while NLRP1 is expressed in lung epithelial cells and alveolar macrophages and contributes to the immune response and to survival/apoptosis balance. This study proposes to evaluate the impact of known NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos-induced mesothelioma in subjects from a hyperendemic area for MM. METHODS: 134 Italian patients with diagnosis of mesothelioma due (MMAE, n=69) or not (MMAF, n=65) to asbestos, 256 healthy Italian blood donors and 101 Italian healthy subjects exposed to asbestos (HCAE) were genotyped for NLRP1 (rs2670660 and rs12150220) and NLRP3 (rs35829419 and rs10754558) polymorphisms. RESULTS: While NLRP3 SNPs were not associated to mesothelioma, the NLRP1 rs12150220 allele T was significantly more frequent in MMAE (0.55) than in HCAE (0.41) (p=0.011; OR=1.79) suggesting a predisponent effect of this allele on the development of mesothelioma. This effect was amplified when the NLRP1 rs2670660 allele was combined with the NLRP1 rs12150220 allele (p=0.004; OR=0.52). CONCLUSION: Although NLRP3 SNPs was not involved in mesothelioma predisposition, these data proposed NLRP1 as a novel factor possibly involved in the development of mesothelioma.

Nutlin-3 differentially modulates miRNA34a and miRNA181 versus miR26a and miR155 in p53 proficient and p53 deficient B chronic lymphocytic leukemia (B-CLL) samples. - di Iasio, Maria Grazia; Addobbati, Riccardo; Radillo, Oriano; Voltan, Rebecca (Invest New Drugs, 2012)
Keywords: Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Piperazines; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53

Oral rehabilitation of children with ectodermal dysplasia. - Montanari, Marco; Callea, Michele; Battelli, Filippo; Piana, Gabriela (BMJ Case Rep, 2012)
The aim of this study was to describe the clinical treatment of young patients, affected by ectodermal dysplasia (ED), and to possibly establish clinical guidelines. The study design was case series. ED syndromes (EDs) are a heterogeneous group of inherited diseases characterised by abnormal development of tissues of ectodermal origin. The most common form of EDs is X linked hypohidrotic ED (HED). Characteristic triad of HED is oligo-anodontia, hypotricosis, hypo-anhydrosis. Oligo-anodontia is one of the most severe impairment, since it affects chewing, swallowing, speech, esthetics and social relation. Early prosthetic rehabilitation (at 2-3 years of age), with partial or complete dentures, is essential to improve oral function and reduce the social impairment.
Keywords: Child; Child, Preschool; Denture, Complete; Denture, Partial; Ectodermal Dysplasia 1, Anhidrotic; Esthetics, Dental; Humans; Male; Mastication; Speech

Oral zinc for treating diarrhoea in children. - Lazzerini, Marzia; Ronfani, Luca (Cochrane Database Syst Rev, 2012)
BACKGROUND: In developing countries, diarrhoea causes around two million child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization and UNICEF. OBJECTIVES: To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea. SEARCH METHODS: In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2011, Issue 11), MEDLINE, EMBASE, LILACS, CINAHL, mRCT, and reference lists. We also contacted researchers. SELECTION CRITERIA: Randomized controlled trials comparing oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery. DATA COLLECTION AND ANALYSIS: Both authors assessed trial eligibility and risk of bias, extracted and analysed data, and drafted the review. Diarrhoea duration and severity were the primary outcomes. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using the fixed- or random-effects model) and assessed heterogeneity.The quality of evidence has been assessed using the GRADE methods MAIN RESULTS: Twenty-four trials, enrolling 9128 children, met our inclusion criteria. The majority of the data is from Asia, from countries at high risk of zinc deficiency, and may not be applicable elsewhere.Acute diarrhoeaThere is currently not enough evidence from well conducted randomized controlled trials to be able to say whether zinc supplementation during acute diarrhoea reduces death or hospitalization (very low quality evidence).In children aged greater than six months with acute diarrhoea, zinc supplementation may shorten the duration of diarrhoea by around 10 hours (MD -10.44 hours, 95% CI -21.13 to 0.25; 2091 children, five trials, low quality evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95% CI 0.61 to 0.88; 3865 children, six trials, moderate quality evidence). In children with signs of moderate malnutrition the effect appears greater, reducing the duration of diarrhoea by around 27 hours (MD -26.98 hours, 95% CI -14.62 to -39.34; 336 children, three trials, high quality evidence).Conversely, In children aged less than six months, the available evidence suggests zinc supplementation may have no effect on mean diarrhoea duration (MD 5.23 hours, 95% CI -4.00 to 14.45; 1334 children, two trials, low quality evidence), and may even increase the proportion of children whose diarrhoea persists until day seven (RR 1.24, 95% CI 0.99 to 1.54; 1074 children, one trial, moderate quality evidence).No trials reported serious adverse events, but zinc supplementation during acute diarrhoea causes vomiting in both age groups (RR 1.59, 95% 1.27 to 1.99; 5189 children, 10 trials, high quality evidence).Persistent diarrhoeaIn children with persistent diarrhoea, zinc supplementation probably shortens the duration of diarrhoea by around 16 hours (MD -15.84 hours, 95% CI -25.43 to -6.24; 529 children, five trials, moderate quality evidence). AUTHORS' CONCLUSIONS: In areas where the prevalence of zinc deficiency or the prevalence of moderate malnutrition is high, zinc may be of benefit in children aged six months or more.The current evidence does not support the use of zinc supplementation in children below six months of age.
Keywords: Acute Disease; Age Factors; Child; Child, Preschool; Diarrhea; Humans; Infant; Randomized Controlled Trials as Topic; Time Factors; Trace Elements; Zinc

Pathergy as a cause of false-positive tuberculin skin test. - Pastore, Serena; Naviglio, Samuele; Ventura, Alessandro (Pediatr Infect Dis J, 2012)
Keywords: Adolescent; Behcet Syndrome; False Positive Reactions; Female; Humans; Hypersensitivity; Needles; Skin; Skin Tests; Tuberculin Test; Tuberculosis, Gastrointestinal

Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. - de Vries, E (Clin Exp Immunol, 2012)
Members of the European Society for Immunodeficiencies (ESID) and other colleagues have updated the multi-stage expert-opinion-based diagnostic protocol for non-immunologists incorporating newly defined primary immunodeficiency diseases (PIDs). The protocol presented here aims to increase the awareness of PIDs among doctors working in different fields. Prompt identification of PID is important for prognosis, but this may not be an easy task. The protocol therefore starts from the clinical presentation of the patient. Because PIDs may present at all ages, this protocol is aimed at both adult and paediatric physicians. The multi-stage design allows cost-effective screening for PID of the large number of potential cases in the early phases, with more expensive tests reserved for definitive classification in collaboration with a specialist in the field of immunodeficiency at a later stage.
Keywords: Adult; Age of Onset; Child; Clinical Protocols; Cytotoxicity Tests, Immunologic; Early Diagnosis; General Practice; Granulocytes; Humans; Immunologic Deficiency Syndromes; Immunophenotyping; Incidence; Infection; Lymphocyte Subsets; Mass Screening; Medical History Taking; Patient-Centered Care; Pediatrics; Phenotype; Physical Examination; Recurrence

Pegylated TRAIL retains anti-leukemic cytotoxicity and exhibits improved signal transduction activity with respect to TRAIL. - Gonelli, Arianna; Radillo, Oriano; Drioli, Sara; Rimondi, Erika; Secchiero, Paola; Maria Bonora, Gian (Invest New Drugs, 2012)
To improve the pharmacokinetic profile of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) an N-terminal specific pegylation was performed to generate pegylated TRAIL (PEG-TRAIL). In in vitro experiments, we found that although PEG-TRAIL was slightly less efficient than recombinant TRAIL in promoting leukemic cell apoptosis, it showed an improved ability to promote migration of bone-marrow mesenchymal stem cells and to elicit the ERK1/2 intracellular signal transduction pathway. Overall, these data suggest that TRAIL pegylation retains, or even enhances, the biological activities of TRAIL relevant for its therapeutic applications.
Keywords: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Movement; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Leukemia; Mesenchymal Stromal Cells; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Polyethylene Glycols; Recombinant Fusion Proteins; Signal Transduction; Time Factors; TNF-Related Apoptosis-Inducing Ligand

Pelvic inflammatory disease (PID) from Chlamydia trachomatis versus PID from Neisseria gonorrhea: from clinical suspicion to therapy. - De Seta, F; Banco, R; Turrisi, A; Airoud, M; De Leo, R; Stabile, G; Ceccarello, M; Restaino, S; De Santo, D (G Ital Dermatol Venereol, 2012)
Pelvic inflammatory disease (PID) is the most significant complication of sexually transmitted infections in childbearing-age women and it represents an important public health problem because of its long-term sequelae (chronic pelvic pain, tubal infertility, ectopic pregnancy). Prior to the mid 1970s PID was considered a monoetiologic infection, due primarily to Neisseria gonorrhea. Now it is well documented as a polymicrobial process, with a great number of microrganisms involved. In addition to Neisseria gonorrhea and Chlamydia trachomatis, other vaginal microrganisms (anaerobes, Gardnerella vaginalis, Haemophilus influenzae, enteric Gram negative rods, Streptococco agalactie, Mycoplasma genitalium) also have been associated with PID. There is a wide variation in PID clinical features; the type and severity of symptoms vary by microbiologic etiology. Women who have chlamydial PID seem more likely than women who have gonococcal PID to be asymptomatic. Since clinical diagnosis is imprecise, the suspicion of PID should be confirmed by genital assessment for signs of inflammation or infection, blood test and imaging evaluation. Laparoscopic approach is considered the gold standard. According to the polymicrobial etiology of PID, antibiotic treatment must provide broad spectrum coverage of likely pathogens. Early administration of antibiotics is necessary to reduce the risk of long-term sequelae.
Keywords: Chlamydia Infections; Chlamydia trachomatis; Female; Gonorrhea; Humans; Neisseria gonorrhoeae; Pelvic Inflammatory Disease

Peroxidase-like activity of ferruginous bodies isolated by exploiting their magnetic property. - Borelli, Violetta; Trevisan, Elisa; Vita, Francesca; Bottin, Cristina; Melato, Mauro; Rizzardi, Clara; Zabucchi, Giuliano (J Toxicol Environ Health A, 2012)
Ferruginous bodies (FB) are polymorphic structures whose formation is macrophage dependent, and are composed of a core, which may consist of an asbestos fiber coated with proteins, among which ferritin is the main component. Within ferritin, the ferric and ferrous ions are coordinated as ferrihydrite, which is the main iron (Fe) storage compound. However, when ferritin accumulates in some tissues following Fe overload it also contains magnetite along with ferrihydrite, which endows it with magnetic properties. Recently studies showed that magnetite exerts peroxidase-like activity, and since ferruginous bodies display magnetic properties, it was postulated that these particular structures may also contain magnetite within the ferritin coating, and thus may also exert peroxidase-like activity. Histochemical analysis for peroxidase of isolated FB smears demonstrated positive staining. Samples isolated from 4 different autopsy lung fragments were also able to oxidize 3,3',5,5'-tetramethyl-benzidine to a blue colored compound that absorbs at 655 nm. This activity was (1) azide and heat insensitive with optimal pH from 5 to 6, and (2) highly variable, changing more than 25-fold from one sample to another. These findings, together with evidence that the peroxidase-like activity of ferruginous bodies has a hydrogen peroxide and substrate requirement different from that of human myeloperoxidase, can exclude that this enzyme gives a significant contribution to the formation of FB. Standard Fe-rich asbestos fibers also express a peroxidase-like activity, but this appears negligible compared to that of ferruginous bodies. Strong acidification of standard Fe-containing asbestos fibers or magnetically isolated ferruginous bodies liberates a high amount of peroxidase-like activity, which is probably accounted for by the release of Fe ions. Further, FB also damage mesothelial cells in vitro. Data suggest that FB exert peroxidase-like activity and cytotoxic activity against mesothelial cells, and hence may be an important factor in pathogenesis of asbestos-related diseases.
Keywords: Air Pollutants, Occupational; Asbestos; Asbestosis; Benzidines; Catalysis; Cell Line; Chromogenic Compounds; Cytotoxins; Ferric Compounds; Ferritins; Ferrosoferric Oxide; Humans; Hydrogen-Ion Concentration; Lung; Magnetic Phenomena; Mesothelioma; Mineral Fibers; Oxidation-Reduction; Peroxidases; Respiratory Mucosa

Personalized therapies in pediatric inflammatory and autoimmune diseases. - Stocco, Gabriele; De Iudicibus, Sara; Franca, Raffaella; Addobbati, Riccardo; Decorti, Giuliana (Curr Pharm Des, 2012)
Pediatric inflammatory and autoimmune diseases are a wide array of systemic or organ-specific conditions, characterized by an exaggerated immune reactivity, which generally occurs in immunogenetically predisposed children. Among the most important ones, in terms of their diffusion and morbidity in the population worldwide, pediatric inflammatory bowel disease (IBD) and juvenile rheumatoid arthritis (JRA) have to be considered. The aim of personalized therapy is to give to each patient the most appropriate drug and dose regimen, in order to maximize treatment response and reduce the risk of adverse events. In general, several therapeutic options exist for pediatric inflammatory and autoimmune conditions, therefore the perspective of pharmacological tools that allow identification of patients with increased risk of treatment issues related to a particular medication, in terms of lack of efficacy or increased probability of adverse events, is particularly desirable and promising. The present review will be focused on the personalized therapy approaches already available or in development for pediatric patients with IBD or JRA, comprising pharmacokinetic, pharmacodynamic and pharmacogenetic assays.
Keywords: Arthritis, Rheumatoid; Autoimmune Diseases; Child; Genetic Predisposition to Disease; Humans; Immunogenetic Phenomena; Individualized Medicine; Inflammation; Inflammatory Bowel Diseases; Pharmacogenetics

Phylloid pattern of hypomelanosis closely related to chromosomal abnormalities in the 13q detected by SNP array analysis. - Faletra, F; Berti, I; Tommasini, A; Pecile, V; Cleva, L; Alberini, E; Bruno, I; Gasparini, P (Dermatology, 2012)
Phylloid hypomelanosis is a distinct type of pigmentary mosaicism characterized by congenital hypochromic macules resembling a floral ornament with various elements such as round or oval patches, asymmetrical macules similar to begonia leaves, or oblong lesions. It has been found to be predominantly associated with abnormalities in chromosome 13 and sometimes as-sociated with different extracutaneous abnormalities. Here, we report 2 new cases of phylloid hypomelanosis due to mosaicism involving chromosome 13. The first one is a mosaicism for a supernumerary marker belonging to chromosome 13 and the second one is the first report of phylloid hypomelanosis associated with a mosaic deletion of 13q. Because of the extremely low level of mosaicism in these 2 cases, SNP array analysis on skin fibroblasts was carried out, showing a 13q21.33-q34 duplication (71,024,411-115,103,529) and a 13q13.3-q34 (38,368,012-115,103,529) deletion. Both cases underline on the one hand the strict connection between phylloid hypomelanosis and anomalies of chromosome 13, and on the other hand the relevance of the SNP array analysis on skin fibroblasts in the detection of low-level mosaicism.
Keywords: Chromosomes, Human, Pair 13; Humans; Hypopigmentation; Male; Mosaicism; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide

Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. - Pontillo, Alessandra; Girardelli, Martina; Kamada, Anselmo J; Pancotto, Joao A T; Donadi, Eduardo A; Crovella, Sergio; Sandrin-Garcia, Paula (Autoimmunity, 2012)
Recent findings provide evidence of inflammasome critical role in the predisposition to autoimmune disorders. The involvement of inflammasome in the pathogenesis of systemic lupus erythematosus (SLE) has been hypothesized even if no significant association within inflammasome genes mutations or polymorphisms and lupus has been reported yet. We analyzed 14 single nucleotide polymorphisms (SNPs) within 7 inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1, IL1B) in 144 patients affected by systemic lupus erythematosus and in 158 healthy controls from Southern Brazilian (state of São Paulo) with the aim of disclosing the possible role of inflammasome genes in the susceptibility of SLE. Our results demonstrated that NLRP1 rs2670660 SNP and the NLRP1 rs12150220-rs2670660 A-G haplotype were associated with SLE in our study population, and in particular with the development of nephritis, rash and arthritis. These findings are concordant with previously reported association of NLRP1 with vitiligo and type-1 diabetes underlining once more the involvement of NALP1 inflammasome in the pathogenesis of autoimmune disorders.
Keywords: Adaptor Proteins, Signal Transducing; Adult; Alleles; Apoptosis Regulatory Proteins; Brazil; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Inflammasomes; Lupus Erythematosus, Systemic; Male; Middle Aged; Polymorphism, Single Nucleotide

Polymorphisms in DC-SIGN and L-SIGN genes are associated with HIV-1 vertical transmission in a Northeastern Brazilian population. - da Silva, Ronaldo Celerino; Segat, Ludovica; Zanin, Valentina; Arraes, Luiz Claudio; Crovella, Sergio (Hum Immunol, 2012)
DC-SIGN and L-SIGN are receptors expressed on specialized macrophages in decidua, (Hofbauer and placental capillary endothelial cells), known to interact with several pathogens, including HIV-1. To disclose the possible involvement of these molecules in the susceptibility to HIV vertical transmission, we analyzed DC-SIGN and L-SIGN gene single nucleotide polymorphisms (SNPs) in 192 HIV-1 positive children and 58 HIV-1 negative children all born to HIV-1 positive mothers, as well as 96 healthy uninfected children not exposed to HIV-1, all from Northeast Brazil. The frequency of three SNPs in the DC-SIGN promoter (-139G>A, -201G>T and -336A>G) were significantly different when comparing HIV positive children with HIV-1 exposed uninfected children, indicating an association with susceptibility to HIV-1 vertical transmission. This genetic association suggests that DC-SIGN molecule may play a role in susceptibility to HIV-1 infection through vertical transmission.
Keywords: Alleles; Brazil; Cell Adhesion Molecules; Child; Child, Preschool; Exons; Female; Gene Frequency; Genotype; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lectins, C-Type; Male; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Cell Surface; Tandem Repeat Sequences

Polymorphisms in inflammasome' genes and susceptibility to HIV-1 infection. - Pontillo, Alessandra; Oshiro, Telma M; Girardelli, Martina; Kamada, Anselmo J; Crovella, Sergio; Duarte, Alberto J S (J Acquir Immune Defic Syndr, 2012)
The involvement of inflammasome genes in the susceptibility to HIV-1 infection was investigated. Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects and 158 healthy controls. The 2 polymorphisms rs10754558 in NLRP3 and rs1143634 in IL1B were significantly associated to the HIV-1 infection. These findings supported the previously hypothesized involvement of NALP3-inflammasome in HIV-1 pathogenesis, underlining once more the key role of inflammation and innate immunity in the susceptibility to HIV-1 infection.
Keywords: Adaptor Proteins, Signal Transducing; Adult; Apoptosis Regulatory Proteins; Brazil; Calcium-Binding Proteins; CARD Signaling Adaptor Proteins; Carrier Proteins; Caspase 1; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; HIV Infections; HIV-1; Humans; Inflammasomes; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Neoplasm Proteins; Polymorphism, Single Nucleotide

Potential role of TRAIL in the management of autoimmune diabetes mellitus. - Bernardi, Stella; Norcio, Alessia; Toffoli, Barbara; Zauli, Giorgio; Secchiero, Paola (Curr Pharm Des, 2012)
Type 1 diabetes mellitus (T1DM) is an autoimmune disease, due to the immune-mediated destruction of pancreatic β-cells, whose incidence has been steadily increasing during the last decades. Insulin replacement therapy can treat T1DM, which, however, is still associated with substantial morbidity and mortality. For this reason, great effort is being put into developing strategies that could eventually prevent and/or cure this disease. These strategies are mainly focused on blocking the immune system from attacking β-cells together with functional islet restoration either by regeneration or transplantation. Recent experimental evidences suggest that TNFrelated apoptosis-inducing ligand (TRAIL), which is an immune system modulator protein, could represent an interesting candidate for the cure for T1DM and/or its complications. Here we review the evidences on the potential role of TRAIL in the management of T1DM.
Keywords: Animals; Autoimmunity; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Islets of Langerhans; TNF-Related Apoptosis-Inducing Ligand

A real-time polymerase chain reaction-based protocol for low/medium-throughput Y-chromosome microdeletions analysis. - Segat, Ludovica; Padovan, Lara; Doc, Darja; Petix, Vincenzo; Morgutti, Marcello; Crovella, Sergio; Ricci, Giuseppe (Genet Test Mol Biomarkers, 2012)
PURPOSE: We describe a real-time polymerase chain reaction (PCR) protocol based on the fluorescent molecule SYBR Green chemistry, for a low- to medium-throughput analysis of Y-chromosome microdeletions, optimized according to the European guidelines and aimed at making the protocol faster, avoiding post-PCR processing, and simplifying the results interpretation. METHODS: We screened 156 men from the Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Institute for Maternal and Child Health IRCCS Burlo Garofolo (Trieste, Italy), 150 not presenting Y-chromosome microdeletion, and 6 with microdeletions in different azoospermic factor (AZF) regions. For each sample, the Zinc finger Y-chromosomal protein (ZFY), sex-determining region Y (SRY), sY84, sY86, sY127, sY134, sY254, and sY255 loci were analyzed by performing one reaction for each locus. RESULTS: AZF microdeletions were successfully detected in six individuals, confirming the results obtained with commercial kits. CONCLUSION: Our real-time PCR protocol proved to be a rapid, safe, and relatively cheap method that was suitable for a low- to medium-throughput diagnosis of Y-chromosome microdeletion, which allows an analysis of approximately 10 samples (with the addition of positive and negative controls) in a 96-well plate format, or approximately 46 samples in a 384-well plate for all markers simultaneously, in less than 2 h without the need of post-PCR manipulation.
Keywords: Azoospermia; Chromosome Deletion; Chromosomes, Human, Y; Female; Humans; Kruppel-Like Transcription Factors; Male; Real-Time Polymerase Chain Reaction; Sex Chromosome Aberrations; Sex Chromosome Disorders of Sex Development

Recurrent fever and fitful abdominal pain in a child. - Zanchi, Chiara; Paloni, Giulia; Marchetti, Federico (Gastroenterology, 2012)
Keywords: Abdominal Pain; Child; Female; Fever; Giant Lymph Node Hyperplasia; Humans; Recurrence

A red baby should not be taken too lightly. - Faletra, Flavio; Bruno, Irene; Berti, Irene; Pastore, Serena; Pirrone, Angela; Tommasini, Alberto (Acta Paediatr, 2012)
AIM: To identify clinical and laboratory features that can drive the differential diagnosis of a primary immunodeficiency diseases in patients with ectodermal defects. METHODS: Analysis of selected teaching cases. RESULTS: We identified four exemplary cases that allowed to point out specific clues. CONCLUSIONS: A careful evaluation of immune and ectodermal signs is the key to the diagnosis. Therefore, a multidisciplinary approach can lead to diagnosis and to an appropriate treatment in most of the cases.
Keywords: Child, Preschool; Dermatitis; Ectodermal Dysplasia; Female; Humans; Immunologic Deficiency Syndromes; Infant; Male; Netherton Syndrome; Severe Combined Immunodeficiency; Skin

Relation between maternal thrombophilia and stillbirth according to causes/associated conditions of death. - Monari, F; Alberico, S; Avagliano, L; Cetin, I; Cozzolino, S; Gargano, G; Marozio, L; Mecacci, F; Neri, I; Tranquilli, A L; Venturini, P; Facchinetti, F (Early Hum Dev, 2012)
OBJECTIVE: To investigate maternal thrombophilia in cases of Stillbirth (SB), also an uncertain topic because most case series were not characterised for cause/associated conditions of death. STUDY DESIGN: In a consecutive, prospective, multicentre design, maternal DNA was obtained in 171 cases of antenatal SB and 326 controls (uneventful pregnancy at term, 1:2 ratio). Diagnostic work-up of SB included obstetric history, neonatologist inspection, placenta histology, autopsy, microbiology/chromosome evaluations. Results audited in each centre were classified by two of us by using CoDAC. Cases were subdivided into explained SB where a cause of death was identified and although no defined cause was detected in the remnants, 64 cases found conditions associated with placenta-vascular disorders (including preeclampsia, growth restriction and placenta abruption - PVD). In the remnant 79 cases, no cause of death or associated condition was found. Antithrombin activity, Factor V Leiden, G20210A Prothrombin mutation (FII mutation) and acquired thrombophilia were analysed. RESULTS: Overall, the presence of a thrombophilic defect was significantly more prevalent in mothers with SBs compared to controls. In particular, SB mothers showed an increased risk of carrying Factor II mutation (OR=3.2, 95% CI: 1.3-8.3, p=0.01), namely in unexplained cases. Such mutation was significantly associated also with previous SB (OR=8.9, 95%CI 1.2-70.5). At multiple logistic regression, Factor II mutation was the only significantly associated variable with SB (adj OR=3.8, 95% CI: 1.3-13.5). CONCLUSION: These data suggest that Factor II mutation is the only condition specifically associated with unexplained SB and could represents a risk of recurrence. PVD-associated condition is unrelated to thrombophilia.
Keywords: Adult; Case-Control Studies; Cause of Death; Female; Fetal Diseases; Fetal Mortality; Humans; Infant, Newborn; Male; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Socioeconomic Factors; Stillbirth; Thrombophilia; Young Adult

Review of the scientific literature on the health of the Roma and Sinti in Italy. - Monasta, Lorenzo; Erenbourg, Anna; Restaino, Stefano; Lutje, Vittoria; Ronfani, Luca (Ethn Dis, 2012)
BACKGROUND: Roma and Sinti in Italy are excluded from the rest of society, often live in precarious housing conditions and have poor access to health services. In Italy, the Roma and Sinti minority (.3% of the overall population) is scarcely represented if compared with other European countries. METHODS: To establish what is known and how Roma and Sinti health is studied in Italy, we conducted a review of the scientific literature, including articles published between 2000 and 2010, found in Medline, Embase and Web of Science. RESULTS: We analyzed 15 relevant articles out of 32 references. Four papers describe rare autosomal recessive disorders. Four illustrate outbreaks of measles. The remaining papers describe health conditions suffered by this minority. All but two, however, are based on data collected at health services. CONCLUSIONS: The lack of prevalence data and analysis of determinants is a detriment to the health of the Roma and Sinti populations in Italy. Participatory research and evidence-based interventions are needed to improve health outcomes and living conditions of the Roma and Sinti people.
Keywords: Gypsies; Health Services Accessibility; Health Status; Housing; Humans; Italy; Minority Groups; Prejudice

RICH (rapidly involuting congenital hemangioma): not only a definition of wealth. - Abate, Maria Valentina; Davanzo, Riccardo; Bibalo, Chiara; Zennaro, Floriana; Berti, Irene (J Pediatr, 2012)
Keywords: Female; Hemangioma; Humans; Infant, Newborn; Skin Neoplasms

Role of high molecular weight hyaluronic acid in postmenopausal vaginal discomfort. - Grimaldi, E F; Restaino, S; Inglese, S; Foltran, L; Sorz, A; Di Lorenzo, G; Guaschino, S (Minerva Ginecol, 2012)
AIM: Aim of the present study was to quantify the intensity of vulvovaginal symptoms before and after treatment with high molecular weight hyaluronic acid (HA), to test the tolerability and safety of the product, to evaluate the effect on the quality of life and the compliance to the treatment. METHODS: This was a double-blind randomized placebo-controlled study. In seven months we enrolled 36 post-menopausal women, equally distributed in placebo and active group. The evaluation was based on at least three atrophy-related signs and on the patient reported symptoms. After the written informed consent, the participants were instructed to apply the gel (drug or placebo) daily. Three days after the end of the treatment the patients received a final examination to evaluate the progress of symptoms, the presence of any adverse events and their correlation with the treatment. RESULTS: Self-evaluation scales and investigator evaluation showed that the vaginal dryness was significantly reduced both in placebo and in the active group; however, high molecular weight HA was the only active treatment in reducing significantly itching and burning (P<0.02 and <0.04 respectively). Both treatments significantly reduced vaginal atrophy (P<0.001), erythema (P<0.01 placebo and P<0.001 HA) and vaginal dryness (P<0.001), but HA treatment was significantly more effective on the first two symptoms. Both treatments were very well tolerated and compliance of the treatment was very high. CONCLUSION: High molecular weight HA could be effective in subjective and objective improvement of postmenopausal vaginal atrophy providing a good compliance. No adverse events occurred during the entire period of the study.
Keywords: Atrophy; Double-Blind Method; Female; Humans; Hyaluronic Acid; Middle Aged; Molecular Weight; Postmenopause; Vagina; Vaginal Diseases

Sedation with intranasal midazolam of Angolan children undergoing invasive procedures. - Kawanda, Lumana; Capobianco, Ivan; Starc, Meta; Felipe, Daniel; Zanon, Davide; Barbi, Egidio; Munkela, Nadine; Rodrigues, Verónica; Malundo, Lúis; Not, Tarcisio (Acta Paediatr, 2012)
AIM: Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient's pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures. METHODS: Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay's reactivity score, we gave a score to four different types of children's behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty). RESULTS: Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001). CONCLUSION: These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon's job easier.
Keywords: Administration, Intranasal; Adolescent; Ambulatory Surgical Procedures; Angola; Child; Child Behavior; Child, Preschool; Conscious Sedation; Crying; Female; Humans; Hypnotics and Sedatives; Infant; Male; Midazolam; Prospective Studies

Serum amyloid A and cholesterol: a pivotal role on inflammation. - Tricarico, Paola Maura; Marcuzzi, Annalisa; Zanin, Valentina; Kleiner, Giulio; Bianco, Anna Monica; Crovella, Sergio (Amyloid, 2012)
Keywords: Animals; Humans; Serum Amyloid A Protein

Sexually transmitted infections and diseases: old and new challenges - part I - Introduction. - Guaschino, S; Zuccati, G (G Ital Dermatol Venereol, 2012)
Keywords: Humans; Sexually Transmitted Diseases

Should cardiac involvement be included in the criteria for diagnosis of Churg Strauss syndrome? - Amaddeo, Alessandro; Ventura, Alessandro; Marchetti, Federico; Benettoni, Alessandra; Londero, Margherita (J Pediatr, 2012)
Keywords: Adolescent; Churg-Strauss Syndrome; Heart Diseases; Humans; Male

Simian virus 40 efficiently infects human T lymphocytes and extends their lifespan. - Mazzoni, Elisa; Rigolin, Gian Matteo; Alaribe, Franca Nneka; Pancaldi, Cecilia; Maniero, Stefania; Comar, Manola; Martini, Fernanda; Tognon, Mauro (Exp Hematol, 2012)
The relevance of viral infections to the onset and progression of human hematologic malignancies and other blood diseases is still a matter of active investigation. Purified human T lymphocytes isolated from the peripheral blood mononuclear cells of healthy blood donors were experimentally infected with simian virus 40 (SV40), a small DNA tumor virus. SV40-positive T lymphocytes extended their lifespan up to day 80 postinfection (PI). Expression of viral antigens, such as the large T antigen and the viral capsid protein VP1 from the early and late regions, respectively, was detected up to day 40 PI. SV40 viral progeny were continuously produced from day 10 to 40 PI. SV40 DNA sequences were detected in infected T cells for up to 80 days. Our data indicate that human T lymphocytes can be efficiently infected with SV40. Although T cells infected by SV40 were not immortalized, 30% of these lymphocytes appeared to be morphologically transformed with an enlarged T-cell shape. Our investigation provides a simple model for studying the interactions of human T lymphocytes with this small DNA tumor virus and it might represent an experimental tool for investigating new biomarkers and targets for innovative therapeutic approaches.
Keywords: Antigens, Polyomavirus Transforming; Cell Line, Transformed; Cell Survival; Humans; Microscopy, Electron, Transmission; Simian virus 40; T-Lymphocytes

Simultaneous determination of multiple cytokines reveals a pro-inflammatory and pro-angiogenic signature after major cardiothoracic surgery: potential role of C-reactive protein. - Tisato, Veronica; Monasta, Lorenzo; Biolo, Gianni; Donatelli, Francesco; Secchiero, Paola; Zauli, Giorgio (Cytokine, 2012)
Keywords: C-Reactive Protein; Coronary Artery Bypass; Cytokines; Humans; Inflammation; Macrophages; Neovascularization, Physiologic; Risk Factors

Slow growth: do not forget the thyroid. - Tornese, Gianluca; Tonini, Giorgio; Ventura, Alessandro (J Pediatr Gastroenterol Nutr, 2012)
Keywords: Constipation; Female; Humans; Hypothyroidism; Male; Thyroid Function Tests

SOCS1 is significantly up-regulated in Nutlin-3-treated p53wild-type B chronic lymphocytic leukemia (B-CLL) samples and shows an inverse correlation with miR-155. - di Iasio, Maria Grazia; Norcio, Alessia; Melloni, Elisabetta; Zauli, Giorgio (Invest New Drugs, 2012)
The basal SOCS1 mRNA levels were significantly lower in p53(mutated) BJAB and MAVER leukemic cell lines with respect to p53(wild-type) SKW6.4 and JVM-2 leukemic cell lines, p53(wild-type) primary B chronic lymphocytic leukemia (B-CLL) cells and primary normal peripheral blood mononuclear cells (PBMC). Moreover, the MDM2 small molecule inhibitor Nutlin-3 significantly increased the levels of SOCS1 mRNA in both primary p53(wild-type) B-CLL cells as well as in p53(wild-type) B leukemic cell lines, but not in p53(mutated) B leukemic cell lines nor in primary PBMC. Of note, a significant inverse correlation was observed between SOCS1 mRNA and miR-155 levels in Nutlin-3-treated primary B-CLL cells and PBMC, suggesting that the miRNA-155/SOCS1 axis represents a potentially important therapeutic target of Nutlin-3 in B-CLL.
Keywords: Cell Line, Tumor; Cells, Cultured; Down-Regulation; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; MicroRNAs; Piperazines; Suppressor of Cytokine Signaling Proteins; Tumor Suppressor Protein p53; Up-Regulation

Soluble TRAIL is elevated in recurrent miscarriage and inhibits the in vitro adhesion and migration of HTR8 trophoblastic cells. - Agostinis, Chiara; Bulla, Roberta; Tisato, Veronica; De Seta, Francesco; Alberico, Salvatore; Secchiero, Paola; Zauli, Giorgio (Hum Reprod, 2012)
STUDY QUESTION: What is the potential physiopathological role of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in recurrent miscarriage (RM), characterized by at least three consecutive pregnancy losses. SUMMARY ANSWER: The levels of serum TRAIL immediately after miscarriage in RM patients are significantly elevated with respect to that in first-trimester normal pregnant women, and recombinant TRAIL inhibits the adhesion and migration of HTR8 trophoblastic cells in vitro. WHAT IS KNOWN ALREADY: Both TRAIL and its trans-membrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3 and TRAIL-R4) have been documented in the placenta, but their physiopathological role is incompletely understood. STUDY DESIGN, SIZE, DURATION: The study populations consisted of RM patients (n = 80) and first-trimester normal pregnant women (n = 80). Blood samples were obtained within 24 h after abortion (RM) or at gestational 12-week (normal pregnant women). As additional controls, third-trimester normal pregnant women (n = 28) were examined before (within 72 h) and after (within 24 h) partum. PARTICIPANTS/MATERIALS, SETTING, METHODS: The concentrations of TRAIL were analysed in serum samples by ELISA. In parallel, the effect of soluble recombinant TRAIL (0.1-1000 ng/ml) was analysed on the survival of primary extravillus trophoblasts (EVTs) and on the survival, proliferation, adhesion and migration of trophoblastic HTR8 cells. MAIN RESULTS AND THE ROLE OF CHANCE: The circulating levels of TRAIL in RM women (median: 52.5 pg/ml; mean and SD: 55.5 ± 24.4 pg/ml) were significantly higher with respect to first-trimester normal pregnant women (median: 44.9 pg/ml; mean and SD: 47 ± 15.1 pg/ml) and third-trimester normal pregnant women, as assessed before (median: 45.1 pg/ml; mean and SD: 46 ± 12.4 pg/ml) and after partum (median: 35.4 pg/ml; mean and SD: 38 + 17.5 pg/ml). Both primary EVT and HTR8 cells expressed detectable levels of TRAIL death receptors, but exposure to soluble recombinant TRAIL did not induce cell death of trophoblastic cells. On the other hand, TRAIL dose-dependently inhibited the adhesion of HTR8 cells to decidual endothelial cells (DEC) as well as the migration of HTR8 in transwell assays using either fibronectin or DEC. LIMITATIONS, REASONS FOR CAUTION: Although this study suggests that TRAIL might have a pathogenic role in RM by inhibiting both the adhesion and migration capabilities of first trimester trophoblastic cells, there is a possibility that the elevated serum levels of TRAIL in RM are not cause but rather the result of RM. WIDER IMPLICATIONS OF THE FINDINGS: Our current findings together with data of other authors suggest that circulating TRAIL should be further analysed as a potential important biomarker in different physiopathological settings. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by FIRB projects (RBAP11Z4Z9_002 to Giorgio Zauli and RBAP10447J_002 to Paola Secchiero). The authors have no competing interests to declare.
Keywords: Abortion, Habitual; Apoptosis; Cell Adhesion; Cell Line; Cell Movement; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Humans; Pregnancy; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Trophoblasts

The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status. - Zauli, Giorgio; Celeghini, Claudio; Melloni, Elisabetta; Voltan, Rebecca; Ongari, Manuele; Tiribelli, Mario; di Iasio, Maria Grazia; Lanza, Francesco; Secchiero, Paola (Haematologica, 2012)
BACKGROUND: Both the multi-kinase inhibitor sorafenib and the small molecule inhibitor of the MDM2/p53 interaction, nutlin-3, used alone, have shown promising anti-leukemic activity in acute myeloid leukemia cells. Thus, in this study we investigated the effect of the combination of sorafenib plus nutlin-3 in acute myeloid leukemia. DESIGN AND METHODS: Primary acute myeloid leukemia blasts (n=13) and FLT3(wild-type)/p53(wild-type) (OCI-AML3), FLT3(mutated)/p53(wild-type) (MOLM), FLT3(mutated)/p53(mutated) (MV4-11), FLT3(wild-type)/p53(deleted) (HL60) or FLT3(wild-type)/p53(mutated) (NB4) acute myeloid cell lines were exposed to sorafenib, used alone or in association with nutlin-3 at a 1:1 ratio, in a range of clinically achievable concentrations (1-10 μM). Induction of apoptosis and autophagy was evaluated by transmission electron microscopy and by specific flow cytometry analyses. The levels of Mcl-1, p53 and Bak proteins were analyzed by western blotting. Knock-down of Bax and Bak gene expression was performed in transfection experiments with specific short interfering RNA. RESULTS: The sorafenib+nutlin-3 drug combination exhibits synergistic cytotoxicity in primary acute myeloid leukemia blasts and in acute myeloid leukemia cell lines with maximal cytotoxicity in FLT3(mutated) MV4-11 and MOLM, followed by the FLT3(wild-type) OCI-AML3, HL60 and NB4 cell lines. The cytotoxic activity of sorafenib+nutlin-3 was characterized by an increase of both apoptosis and autophagy. Moreover, Bax and Bak showed prominent roles in mediating the decrease of cell viability in response to the drug combination in p53(wild-type) OCI-AML3 and p53(deleted) HL-60 cells, respectively, as demonstrated in transfection experiments performed with specific short interfering RNA. CONCLUSIONS: Our data demonstrate that acute myeloid leukemia cells show a variable but overall good susceptibility to the innovative therapeutic combination of sorafenib+nutlin-3, which differentially involves the pro-apoptotic Bcl-2 family members Bax and Bak in p53(wild-type) and p53(deleted) cells.
Keywords: Antineoplastic Agents; Drug Synergism; Female; fms-Like Tyrosine Kinase 3; HL-60 Cells; Humans; Imidazoles; Leukemia, Myeloid, Acute; Male; Niacinamide; Phenylurea Compounds; Piperazines; Tumor Suppressor Protein p53

Specific protein profile in cerebrospinal fluid from HIV-1-positive cART-treated patients affected by neurological disorders. - Zanin, Valentina; Delbue, Serena; Marcuzzi, Annalisa; Tavazzi, Eleonora; Del Savio, Rossella; Crovella, Sergio; Marchioni, Enrico; Ferrante, Pasquale; Comar, Manola (J Neurovirol, 2012)
Cytokines/chemokines are involved in the immune response of infections, including HIV-1. We defined the profile of 48 cytokines/chemokines in cerebrospinal fluid from 18 cART patients with chronic HIV-1 infection by Luminex technology. Nine patients were affected with leukoencephalopathies: five with John Cunningham virus (JCV) + progressive multifocal leukoencephalopathy (PML) and four with JCV-not determined leukoencephalopathy (NDLE). In addition, nine HIV-1-positive patients with no neurological signs (NND) and five HIV-1-negative patients affected with acute disseminated encephalomyelitis (ADEM) were enrolled. Ten cytokines (IL-15, IL-3, IL-16, IL-18, CTACK, GRO1, SCF, MCP-1, MIF, SDF) were highly expressed in HIV-1-positive patients while IL-1Ra and IL-17 were present at a lower level. In addition, the levels of IL-17, IL-9, FGF-basic, MIP-1β, and MCP-1 were significantly higher (p < 0.05) in patients with neurological diseases (PML, NDLE, ADEM) with respect to NND. Focusing the attention to the cytokine profile in JCV + PML patients with respect to JCV-NDLE patients, only TNF-β was significantly downregulated (p < 0.05) in JCV + PML patients. This pilot study emphasized the role of immunoregulation in HIV-1-related neurological disorders during cART treatment.
Keywords: Adult; Aged; Anti-HIV Agents; Cytokines; Encephalomyelitis, Acute Disseminated; Female; HIV Infections; HIV-1; Humans; Leukoencephalopathy, Progressive Multifocal; Male; Middle Aged; Pilot Projects

State of art and recent developments of anti-cancer strategies based on TRAIL. - Bernardi, Stella; Secchiero, Paola; Zauli, Giorgio (Recent Pat Anticancer Drug Discov, 2012)
Multicellular organisms require apoptosis whereby the human body eliminates unnecessary and/or damaged cells. Apoptosis, or programmed cell death, can indeed be considered as a constitutive anti-cancer mechanism that seems to be defective in more than 50% of cancers. Molecular insights on the biology of the apoptotic process have led to the development of new anti-cancer strategies aiming at recovering and stimulating this process. Preclinical and clinical studies of our and other groups have demonstrated that targeting the extrinsic apoptotic pathway by various death receptors agonists is a safe and effective anti-cancer strategy, which thus may become a new cornerstone of cancer therapy. Here, we review the most recent acquisitions and patents on TRAIL or TRAIL mimetics, as well as the combination therapies that could be used with them.
Keywords: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Clinical Trials as Topic; Humans; Mice; Neoplasms; Receptors, Death Domain; TNF-Related Apoptosis-Inducing Ligand

State of the art of the therapeutic perspective of sorafenib against hematological malignancies. - Zauli, G; Voltan, R; Tisato, V; Secchiero, P (Curr Med Chem, 2012)
The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti-neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the growing evidences for the role of Mcl-1 in mediating the anti-leukemic activity of Sorafenib will be discussed in relationship with promising therapeutic perspectives.
Keywords: Apoptosis; Clinical Trials as Topic; fms-Like Tyrosine Kinase 3; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Myeloid Cell Leukemia Sequence 1 Protein; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Receptors, Vascular Endothelial Growth Factor; TNF-Related Apoptosis-Inducing Ligand

Stem cell ageing and apoptosis. - Fulle, Stefania; Centurione, Lucia; Mancinelli, Rosa; Sancilio, Silvia; Manzoli, Francesco Antonio; Di Pietro, Roberta (Curr Pharm Des, 2012)
Ageing has been defined as the process of deterioration of many body functions over the lifespan of an individual. In spite of the number of different theories about ageing, there is a general consensus in identifying ageing effects in a reduced capacity to regenerate injured tissues or organs and an increased propensity to infections and cancer. In recent years the stem cell theory of ageing has gained much attention. Adult stem cells residing in mammalian tissues are essential for tissue homeostasis and repair throughout adult life. With advancing age, the highly regulated molecular signalling necessary to ensure proper cellular, tissue, and organ homeostasis loses coordination and leads, as a consequence, to a compromised potential of regeneration and repair of damaged cells and tissues. Although a complete comprehension of the molecular mechanisms involved in stem cell ageing and apoptosis is far to be reached, recent studies are beginning to unravel the processes involved in stem cell ageing, particularly in adult skeletal muscle stem cells, namely satellite cells. Thus, the focus of this review is to analyse the relationship between stem cell ageing and apoptosis with a peculiar attention to human satellite cells as compared to haematopoietic stem cells. Undoubtedly, the knowledge of age-related changes of stem cells will help in understanding the ageing process itself and will provide novel therapeutic challenges for improved tissue regeneration.
Keywords: Adult; Apoptosis; Cell Aging; Humans; Stem Cells

Stem cells in severe infantile spinal muscular atrophy (SMA1). - Carrozzi, Marco; Amaddeo, Alessandro; Biondi, Andrea; Zanus, Caterina; Monti, Fabrizio; Alessandro, Ventura (Neuromuscul Disord, 2012)
Keywords: Humans; Spinal Muscular Atrophies of Childhood; Stem Cell Transplantation; Stem Cells; Treatment Outcome

The submerged dyslexia iceberg: how many school children are not diagnosed? Results from an Italian study. - Barbiero, Chiara; Lonciari, Isabella; Montico, Marcella; Monasta, Lorenzo; Penge, Roberta; Vio, Claudio; Tressoldi, Patrizio Emanuele; Ferluga, Valentina; Bigoni, Anna; Tullio, Alessia; Carrozzi, Marco; Ronfani, Luca (PLoS One, 2012)
BACKGROUND: Although dyslexia is one of the most common neurobehavioral disorders affecting children, prevalence is uncertain and available data are scanty and dated. The objective of this study is to evaluate the prevalence of dyslexia in an unselected school population using clearly defined and rigorous diagnostic criteria and methods. METHODS: Cross sectional study. We selected a random cluster sample of 94 fourth grade elementary school classes of Friuli Venezia Giulia, a Region of North Eastern Italy. We carried out three consecutive levels of screening: the first two at school and the last at the Neuropsychiatry Unit of a third level Mother and Child Hospital. The main outcome measure was the prevalence of dyslexia, defined as the number of children positive to the third level of screening divided by the total number of children enrolled. RESULTS: We recruited 1774 children aged 8-10 years, of which 1528 received parents' consent to participate. After applying exclusion criteria, 1357 pupils constituted the final working sample. The prevalence of dyslexia in the enrolled population ranged from 3.1% (95% CI 2.2-4.1%) to 3.2% (95% CI 2.4-4.3%) depending on different criteria adopted. In two out of three children with dyslexia the disorder had not been previously diagnosed. CONCLUSIONS: This study shows that dyslexia is largely underestimated in Italy and underlines the need for reliable information on prevalence, in order to better allocate resources both to Health Services and Schools.
Keywords: Area Under Curve; Child; Cross-Sectional Studies; Delayed Diagnosis; Dyslexia; Female; Humans; Italy; Male; Neuropsychological Tests; Prevalence; Questionnaires; ROC Curve

Successful induction of oral tolerance in Netherton syndrome. - Pastore, Serena; Gorlato, Gaia; Berti, Irene; Barbi, Egidio; Ventura, Alessandro (Allergol Immunopathol (Madr), 2012)
Keywords: Allergens; Alopecia; Child, Preschool; Desensitization, Immunologic; Disease-Free Survival; Eczema; Female; Food Hypersensitivity; Hair Follicle; Humans; Immune Tolerance; Immunoglobulin E; Infant, Newborn; Mouth; Netherton Syndrome; Treatment Outcome

Thoracoscopic removal of a bulky cystic mediastinal mature teratoma in a 4-year-old child: report of one case and few surgical tricks. - Codrich, Daniela; Lembo, Maria Antonietta; Schleef, Jurgen (Eur J Pediatr Surg, 2012)
Keywords: Child, Preschool; Female; Humans; Mediastinal Neoplasms; Teratoma; Thoracoscopy; Tomography, X-Ray Computed

TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation. - Bernardi, Stella; Zauli, Giorgio; Tikellis, Christos; Candido, Riccardo; Fabris, Bruno; Secchiero, Paola; Cooper, Mark E; Thomas, Merlin C (Clin Sci (Lond), 2012)
TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).
Keywords: Adiposity; Animals; Apoptosis; Calorimetry; Cytokines; Dietary Fats; Energy Intake; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Palmitic Acid; Real-Time Polymerase Chain Reaction; TNF-Related Apoptosis-Inducing Ligand

TRAIL, a new weapon against neointimal hyperplasia. - Secchiero, Paola; Zauli, Giorgio (Cardiology, 2012)
Keywords: Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Male; Neointima; TNF-Related Apoptosis-Inducing Ligand

TRAIL administration down-modulated the acute systemic inflammatory response induced in a mouse model by muramyldipeptide or lipopolysaccharide. - Marcuzzi, Annalisa; Secchiero, Paola; Crovella, Sergio; Zauli, Giorgio (Cytokine, 2012)
The potent inducer of apoptosis TRAIL/Apo2 ligand is now under considerations in clinical trials for the treatment of different types of cancer. Since the natural history of cancer is often characterized by microbial infections, we have investigated the effect of recombinant human TRAIL in a mouse model of systemic acute inflammation of microbial origin represented by BALB/c mice treated with either bacterial muramyldipeptide (MDP) or lipopolysaccharide (LPS). When administered intraperitoneally (i.p.), these inflammatory bacterial compounds triggered a severe systemic inflammatory response within 2h, represented by body temperature elevation, increase of circulating serum amyloid-A (SAA) and of the number of leukocytes in the peritoneal cavity. Moreover, both MDP and LPS induced a significant elevation of the circulating levels of several inflammatory cytokines and chemokines. Noteworthy, pre-treatment with recombinant human TRAIL 48 and 72 h before administration of either MDP or LPS, significantly counteracted all acute inflammatory responses, including the elevation of key pro-inflammatory cytokines/chemokines such as IL-1α, IL-6, G-CSF, MCP-1. These data demonstrate for the first time that TRAIL has a potent anti-inflammatory activity, which might be beneficial for the anti-tumoral activity of TRAIL.
Keywords: Acetylmuramyl-Alanyl-Isoglutamine; Acute Disease; Animals; Chemokine CCL2; Cytokines; Disease Models, Animal; Down-Regulation; Granulocyte Colony-Stimulating Factor; Humans; Immunoassay; Inflammation; Inflammation Mediators; Interleukin-1alpha; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Recombinant Proteins; Serum Amyloid A Protein; TNF-Related Apoptosis-Inducing Ligand

TRAIL as biomarker and potential therapeutic tool for cardiovascular diseases. - Bernardi, Stella; Milani, Daniela; Fabris, Bruno; Secchiero, Paola; Zauli, Giorgio (Curr Drug Targets, 2012)
This review focuses on TNF-related apoptosis-inducing ligand (TRAIL), also called Apo2 ligand, a protein belonging to the TNF superfamily. TRAIL can be found either in its transmembrane or circulating form, and its mostly studied peripheral effect is the induction of cellular apoptosis. Here, we discuss the evidences supporting the use of TRAIL as biomarker of cardiovascular diseases as well as the evidences showing the potential beneficial therapeutic effects of TRAIL on cardiovascular diseases and diabetes.
Keywords: Biological Markers; Cardiovascular Diseases; Humans; Prognosis; TNF-Related Apoptosis-Inducing Ligand

TRAIL shows potential cardioprotective activity. - Toffoli, Barbara; Bernardi, Stella; Candido, Riccardo; Zacchigna, Serena; Fabris, Bruno; Secchiero, Paola (Invest New Drugs, 2012)
Recent clinical trials carried out in patients with advanced cancer have shown that recombinant TRAIL administration is usually safe and well tolerated when used either alone or in association with chemotherapeutic drugs. Notably, anticancer chemotherapy can be associated to cardiomiopathy. We have here demonstrated that TRAIL (administrated as either recombinant soluble TRAIL or as AAV-TRAIL expression viral vector) reduced the development of cardiomyopathy in the ApoE(-/-) diabetic mouse model. These data suggest, for the first time, that therapeutically administration of TRAIL might have a cardioprotective effect.
Keywords: Animals; Apolipoproteins E; Apoptosis; Cardiotonic Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Fibrosis; Male; Mice; Mice, Knockout; Recombinant Proteins; TNF-Related Apoptosis-Inducing Ligand

Treatment with pamidronate for osteoporosis complicating long-term intestinal failure. - Pastore, S; Londero, M; Barbieri, F; Di Leo, G; Paparazzo, R; Ventura, A (J Pediatr Gastroenterol Nutr, 2012)
Long-term home parenteral nutrition (PN) is a potential risk for developing osteoporosis. Various attempts have been made to treat bone disease both by modifying the composition of PN and by administering hormones, such as calcitonin, parathyroid hormone, and sexual hormones. Bisphosphonates are recognized as a medication useful for the treatment of several bone disorders associated with excessive reabsorption. Nevertheless, there have been no paediatric studies on bisphosphonates use for intestinal failure-associated bone disease. Our study includes 6 paediatric patients receiving extremely long-term home PN (at least 3 years) who showed radiological and clinical signs of osteoporosis. Diagnosis of bone disease was made after a median period of 127.5 PN months. Treatment consisted in 2 cycles of intravenous pamidronate, 30 mg/m once per month for 6 months consecutively. They all showed a significant improvement in bone mineral density, evaluated after 6 and 12 months of pamidronate treatment. In our sample anthropometrical variables (weight, height, and body mass index) are not related with the z-score trend. Our patients had normal levels of calcium, phosphorus, and vitamin D, and proper nutrient intake. At the last follow-up, dual-energy x-ray absorptiometry scan showed that no patients had a z-score lower than -2.5; moreover, nobody developed bone fractures during the 108-month follow-up. The patients did not have any prominent adverse effect. Finally, in our experience, pamidronate is effective for improving bone mineral density and safe in patients with intestinal failure-associated bone disease.
Keywords: Absorptiometry, Photon; Adolescent; Bone Density; Bone Density Conservation Agents; Child; Child, Preschool; Diphosphonates; Female; Humans; Intestinal Diseases; Male; Osteoporosis; Parenteral Nutrition, Home

Two Novel COH1 Mutations in an Italian Patient with Cohen Syndrome. - Athanasakis, E; Fabretto, A; Faletra, F; Mocenigo, M; Morgan, A; Gasparini, P (Mol Syndromol, 2012)
Cohen syndrome (CS) is an autosomal recessive disease caused by mutations in the COH1 gene. It is characterized by intellectual disability, hypotonia, joint hyperlaxity, severe myopia, characteristic facial dysmorphisms and, in some cases, intermittent isolated neutropenia. We investigated an Italian patient with CS together with his family. Genetic analysis disclosed 2 novel mutations: the first is an intronic mutation (c.8697-9A>G) creating a new splice site 8 nucleotides upstream, and the second is a duplication of 1 base (c.10156dupA) generating a premature stop codon. The compound heterozygous mutations explain the proband's phenotype and improved the knowledge of genotype-phenotype correlation.

Upper gastrointestinal involvement in paediatric onset Crohn's disease: prevalence and clinical implications. - Crocco, S; Martelossi, S; Giurici, N; Villanacci, V; Ventura, A (J Crohns Colitis, 2012)
BACKGROUND AND AIMS: Our study evaluated the prevalence, the characteristics and implications of the upper gastrointestinal localisation (UGI+) in paediatric Crohn's Disease (CD) patients. METHODS: This prospective study evaluated 45 newly diagnosed CD patients at diagnosis and follow up with respect to CD localisation. RESULTS: All patients presented CD at the colon and/or ileum. In 24/45 patients (53.3%, 12 F and 12 M) an UGI+ involvement was also found. UGI+ patients had a younger age of onset (10.9 years versus 12.6 years; P<0.05). PCDAI at diagnosis was significantly higher in the UGI+ (41 vs. 25 P<0.01). UGI+ patients were overall more symptomatic. Pancolitis and extraintestinal manifestations were also more frequent (19/24 (80%) vs. 12/21 (57%) P<0.01). Growth was more impaired at diagnosis in UGI+ patients. By the end of the follow-up (mean 3 years, range 2 to 4) no significant difference was found in PCDAI (17 in UGI+ patients vs. 11 in UGI- P=NS), or the number of relapses. Weight and growth catch-up in UGI+ patients were comparable to UGI- ones. However, UGI+ patients required a more aggressive therapeutic approach. CONCLUSION: At least half of paediatric onset CD patients have an upper gastrointestinal localisation. UGI+ patients present an earlier onset and a more severe disease. The final outcome does not differ, but UGI+ patients require a more aggressive therapeutic approach.
Keywords: Adolescent; Age of Onset; Child; Crohn Disease; Female; Humans; Male; Prospective Studies; Upper Gastrointestinal Tract

Use of specific antiretroviral regimens among HIV-infected women in Italy at time of conception: 2001-2011. - Floridia, Marco; Ravizza, Marina; Guaraldi, Giovanni; Pinnetti, Carmela; Martinelli, Pasquale; Tamburrini, Enrica (AIDS Patient Care STDS, 2012)
Keywords: Anti-HIV Agents; Drug Administration Schedule; Female; Fertilization; HIV Protease Inhibitors; HIV Seropositivity; Humans; Infectious Disease Transmission, Vertical; Italy; Pregnancy; Reverse Transcriptase Inhibitors; Sentinel Surveillance

Videogame playing as distraction technique in course of venipuncture. - Minute, M; Badina, L; Cont, G; Montico, M; Ronfani, L; Barbi, E; Ventura, A (Pediatr Med Chir, 2012)
BACKGROUND: Needle-related procedures (venipuncture, intravenous cannulation) are the most common source of pain and distress for children. Reducing needle related pain and anxiety could be important in order to prevent further distress, especially for children needing multiple hospital admissions. The aim of the present open randomized controlled trial was to investigate the efficacy of adding an active distraction strategy (videogame) to EMLA premedication in needle-related pain in children. METHODS: One-hundred and nine children (4 -10 years of age) were prospectively recruited to enter in the study. Ninety-seven were randomized in two groups: CC group (conventional care: EMLA only) as control group and AD group (active distraction: EMLA plus videogame) as intervention group. Outcome measures were: self-reported pain by mean of FPS-R scale (main study outcome), observer-reported pain by FLACC scale, number of attempts for successful procedure. RESULTS: In both groups FPS-R median rate was 0 (interquartile range: 0-2), with significant pain (FPS-R > 4) reported by 9% of subjects. FLACC median rate was 1 in both groups (interquartile range 0-3 in CC group; 0-2 in AD group). The percentage of children with major pain (FLACC > 4) was 18% in CC group and 9% in AD group (p = 0.2). The median of necessary attempts to succeed in the procedures was 1 (interquartile range 1-2) in both groups.. CONCLUSION: Active distraction doesn't improve EMLA analgesia for iv cannulation and venipuncture. Even though, it resulted in an easily applicable strategy appreciated by children. This technique could be usefully investigated in other painful procedures.
Keywords: Anesthetics, Local; Child; Child, Preschool; Female; Humans; Lidocaine; Male; Pain; Phlebotomy; Prilocaine; Prospective Studies; Video Games

Young girl with apical ballooning heart syndrome. - Berton, E; Vitali-Serdoz, L; Vallon, P; Maschio, M; Gortani, G; Benettoni, A (Int J Cardiol, 2012)
Keywords: Child; Diagnosis, Differential; Electrocardiography; Female; Humans; Takotsubo Cardiomyopathy

Β-hexosaminidase over-expression affects lysosomal glycohydrolases expression and glycosphingolipid metabolism in mammalian cells. - Tancini, Brunella; Magini, Alessandro; Bortot, Barbara; Polchi, Alice; Urbanelli, Lorena; Sonnino, Sandro; Severini, Giovanni Maria; Emiliani, Carla (Mol Cell Biochem, 2012)
Lysosomes are not only degrading organelles but also involved in other critical cellular processes. In addition, active lysosomal glycohydrolases have been detected in an extra-lysosomal compartment: the presence of glycohydrolases on the plasma membrane (PM) has been widely demonstrated, and a possible role on the modification of the cell surface glycosphingolipids (GSL) participating in the modulation of cell functions such as cell-to-cell interactions and signal transduction pathways has been proposed. On this basis, the coordinated expression of lysosomal glycohydrolases and their translocation to the PM appear to be crucial for many cellular events. In this paper, we report evidence for the existence of a coordinated mechanism regulating the expression/activity of both lysosomal and PM-associated glycohydrolases. We show that the over-expression of the acidic glycohydrolase β-hexosaminidase α-subunit in mouse NIH/3T3 fibroblasts induces the increased expression of the Hex β-subunit necessary to form the active isoenzyme dimers as well as of other glycohydrolases participating in the GSL catabolism, such as β-galactosidase and β-glucocerebrosidase. More interestingly, this regulatory effect was also extended to the PM-associated hydrolases. In addition, transfected cells displayed a rearrangement of the GSL expression pattern that cannot be simply explained by the increased activity of a single enzyme. These observations clearly indicate that the expression level of metabolically related glycohydrolases is regulated in a coordinated manner and this regulation mechanism also involves the PM-associated isoforms.
Keywords: Animals; beta-Hexosaminidase alpha Chain; Cell Membrane; Exocytosis; Fibroblasts; Glycoside Hydrolases; Glycosphingolipids; Humans; Lysosomes; Mice; NIH 3T3 Cells; Transfection

The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation. - Goldblum, Simeon E; Rai, Usha; Tripathi, Amit; Thakar, Manjusha; De Leo, Luigina; Di Toro, Nicola; Not, Tarcisio; Ramachandran, Rithwik; Puche, Adam C; Hollenberg, Morley D; Fasano, Alessio (FASEB J, 2011)
Vibrio cholerae-derived zonula occludins toxin (Zot) is a multifunctional protein that reversibly disassembles intestinal tight junctions (tjs). Zot structure-function analysis has mapped this activity to aa 288-293, named AT1002. AT1002 reduced transepithelial electrical resistance across rat small intestine, ex vivo, as did Zot and its processed mature form, ΔG. AT1002 increased in vivo permeability to sugar tracers, whereas scrambled control peptides did not. Binding and barrier assays in proteinase activated receptor (PAR)(2)-expressing and PAR(2)-null cells established AT1002 activity to be PAR(2) dependent. Coincident with the increased intestinal permeability, confocal microscopy of AT1002-exposed rat intestinal IEC6 cells revealed displacement of ZO-1 and occludin from intercellular boundaries. In coimmunoprecipitation assays, AT1002 decreased ZO-1-occludin and ZO-1-claudin 1 interactions coincident with PKCα-dependent ZO-1 serine/threonine phosphorylation. Further, AT1002 increased serine phosphorylation of myosin 1C and, at the same time, transiently diminished its association with ZO-1. The COOH-terminal domain of ZO-1 was required for its association with myosin 1C. These data indicate that the NH(2)-terminal portion of active Zot contains a PAR(2)-activating motif, FCIGRL, that increases PKCα-dependent ZO-1 and myosin 1C serine/threonine phosphorylation. These modifications provoke selective disengagement of ZO-1 from its binding partners, occludin, claudin 1, and myosin 1C, coincident with opening of tjs.
Keywords: Amino Acid Sequence; Animals; Caco-2 Cells; Cell Line; Cells, Cultured; Cholera Toxin; Epithelial Cells; Humans; Immunoblotting; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Myosins; Oligopeptides; Phosphoproteins; Phosphorylation; Protein Binding; Protein Kinase C-alpha; Rats; Rats, Wistar; Receptor, PAR-2; RNA Interference; Serine; Threonine; Tight Junctions; Zonula Occludens-1 Protein

Acute cardiac valvular involvement in Kawasaki Disease. - Pellegrin, Maria Chiara; Taddio, Andrea; Lepore, Loredana (Clin Exp Rheumatol, 2011)
Keywords: Adrenal Cortex Hormones; Child, Preschool; Female; Heart Valve Diseases; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infant; Male; Mucocutaneous Lymph Node Syndrome; Treatment Outcome

Adam's rib and the origin of stem cells. - Callea, Francesco; Callea, Michele (Am J Hematol, 2011)
Keywords: Humans; Ribs; Stem Cell Transplantation; Stem Cells

Ages of celiac disease: from changing environment to improved diagnostics. - Tommasini, Alberto; Not, Tarcisio; Ventura, Alessandro (World J Gastroenterol, 2011)
From the time of Gee's landmark writings, the recent history of celiac disease (CD) can be divided into many ages, each driven by a diagnostic advance and a deeper knowledge of disease pathogenesis. At the same time, these advances were paralleled by the identification of new clinical patterns associated with CD and by a continuous redefinition of the prevalence of the disease in population. In the beginning, CD was considered a chronic indigestion, even if the causative food was not known; later, the disease was proven to depend on an intolerance to wheat gliadin, leading to typical mucosal changes in the gut and to a malabsorption syndrome. This knowledge led to curing the disease with a gluten-free diet. After the identification of antibodies to gluten (AGA) in the serum of patients and the identification of gluten-specific lymphocytes in the mucosa, CD was described as an immune disorder, resembling a chronic "gluten infection". The use of serological testing for AGA allowed identification of the higher prevalence of this disorder, revealing atypical patterns of presentation. More recently, the characterization of autoantibodies to endomysium and to transglutaminase shifted the attention to a complex autoimmune pathogenesis and to the increased risk of developing autoimmune disorders in untreated CD. New diagnostic assays, based on molecular technologies, will introduce new changes, with the promise of better defining the spectrum of gluten reactivity and the real burden of gluten related-disorders in the population. Herein, we describe the different periods of CD experience, and further developments for the next celiac age will be proposed.
Keywords: Autoantibodies; Celiac Disease; Diet, Gluten-Free; Gliadin; Glutens; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; History, Medieval; Humans; Transglutaminases

Antibiotics in severely malnourished children: systematic review of efficacy, safety and pharmacokinetics. - Lazzerini, Marzia; Tickell, David (Bull World Health Organ, 2011)
OBJECTIVE: To systemically review the evidence in support of World Health Organization guidelines recommending broad-spectrum antibiotics for children with severe acute malnutrition (SAM). METHODS: CENTRAL, MEDLINE, EMBASE, LILACS, POPLINE, CAB Abstracts and ongoing trials registers were searched. Experts were contacted. Conference proceedings and reference lists were manually searched. All study types, except single case reports, were included. FINDINGS: Two randomized controlled trials (RCTs), one before-and-after study and two retrospective reports on clinical efficacy and safety were retrieved, together with 18 pharmacokinetic studies. Trial quality was generally poor and results could not be pooled due to heterogeneity. Oral amoxicillin for 5 days was as effective as intramuscular ceftriaxone for 2 days (1 RCT). For uncomplicated SAM, amoxicillin showed no benefit over placebo (1 retrospective study). The introduction of a standardized regimen using ampicillin and gentamicin significantly reduced mortality in hospitalized children (odds ratio, OR: 4.0; 95% confidence interval, CI: 1.7-9.8; 1 before-and-after study). Oral chloramphenicol was as effective as trimethoprim-sulfamethoxazole in children with pneumonia (1 RCT). Pharmacokinetic data suggest that normal doses of penicillins, cotrimoxazole and gentamicin are safe in malnourished children, while the dose or frequency of chloramphenicol requires adjustment. Existing evidence is not strong enough to further clarify recommendations for antibiotic treatment in children with SAM. CONCLUSION: Large RCTs are needed to define optimal antibiotic treatment in children with SAM with and without complications. Further research into gentamicin and chloramphenicol toxicity and into the pharmacokinetics of ceftriaxone and ciprofloxacin is also required.
Keywords: Anti-Bacterial Agents; Child; Child Nutrition Disorders; Child, Preschool; Humans; Severity of Illness Index; Treatment Outcome

Antidepressant drugs and breastfeeding: a review of the literature. - Davanzo, Riccardo; Copertino, Marco; De Cunto, Angela; Minen, Federico; Amaddeo, Alessandro (Breastfeed Med, 2011)
The use of antidepressants in breastfeeding mothers is controversial: Manufacters often routinely discourage breastfeeding for the nursing mother despite the well-known positive impact that breastfeeding carries on the health of the nursing infant and on his or her family and society. We conducted a systematic review of drugs commonly used in the treatment of postpartum depression. For every single drug two sets of data were provided: (1) selected pharmacokinetic characteristics such as half-life, milk-to-plasma ratio, protein binding, and oral bioavailability and (2) information about lactational risk, according to some authoritative sources of the literature: Drugs in Pregnancy and Lactation edited by Briggs et al. (Lippincott Williams, Philadelphia, 2008), Medications and Mothers' Milk by Hale (Hale Publishing, Amarillo, TX, 2010), and the LactMed database of TOXNET ( www.pubmed.gov ; accessed June 2010). Notwithstanding a certain variability of advice, we found that (1) knowledge of pharmacokinetic characteristics are scarcely useful to assess safety and (2) the majority of antidepressants are not usually contraindicated: (a) Selective serotinin reuptake inhibitors and nortryptiline have a better safety profile during lactation, (b) fluoxetine must be used carefully, (c) the tricyclic doxepine and the atypical nefazodone should better be avoided, and (d) lithium, usually considered as contraindicated, has been recently rehabilitated.
Keywords: Adrenergic Uptake Inhibitors; Antidepressive Agents; Antidepressive Agents, Tricyclic; Biological Availability; Breast Feeding; Depression, Postpartum; Directive Counseling; Drug Monitoring; Female; Humans; Infant, Newborn; Lactation; Lithium Compounds; Maternal Exposure; Milk, Human; Monoamine Oxidase Inhibitors; Pregnancy; Serotonin Uptake Inhibitors

Anti-α-enolase Antibodies in Serum from Pediatric Patients Affected by Inflammatory Diseases: Diagnostic and Pathogenetic Insights. - Pontillo, Alessandra; Di Toro, Nicola; Edomi, Paolo; Shadlow, A; Ammadeo, A; Gattorno, M; Not, T; Lepore, L; Crovella, S (Int J Rheumatol, 2011)
Human glycolytic enzyme α-enolase was associated with human diseases and with inflammation. An ELISA test was developed to measure anti-α-enolase AAE IgG and AAE IgA in the serum from patients affected by inflammatory diseases with the purpose to evaluate it as a novel diagnostic marker. 80 healthy blood donors and 194 paediatric patients affected by Juvenile idiopathic arthritis (JIA), celiac disease (CD), Crohn's Disease (CrD), hereditary periodic fever (HPF), and PFAPA syndrome were included in the study. HPF patients showed high levels of AAE antibodies, whereas JIA, CD, and CrD presented only partial results. Benign fevers such as PFAPA were almost negative for AAE Abs. These findings suggested that the genetic dysfunction of inflammasome associated with HPF could lead to the formation of AAE Abs that could be used for an early and easy diagnosis.

Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population. - Sorice, Rossella; Bione, Silvia; Sansanelli, Serena; Ulivi, Sheila; Athanasakis, Emmanouil; Lanzara, Carmela; Nutile, Teresa; Sala, Cinzia; Camaschella, Clara; d'Adamo, Pio; Gasparini, Paolo; Ciullo, Marina; et al. (Eur J Hum Genet, 2011)
Large-scale population studies have established that genetic factors contribute to individual differences in smoking behavior. Linkage and genome-wide association studies have shown many chromosomal regions and genes associated with different smoking behaviors. One study was the association of single-nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 gene cluster to nicotine addiction. Here, we report a replication of this association in the Italian population represented by three genetically isolated populations. One, the Val Borbera, is a genetic isolate from North-Western Italy; the Cilento population, is located in South-Western Italy; and the Carlantino village is located in South-Eastern Italy. Owing to their position and their isolation, the three populations have a different environment, different history and genetic structure. The variant A of the rs1051730 SNP was significantly associated with smoking quantity in two populations, Val Borbera and Cilento, no association was found in Carlantino population probably because difference in LD pattern in the variant region.
Keywords: Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Italy; Multigene Family; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Receptors, Nicotinic; Smoking; Tobacco Use Disorder

Association of tumor necrosis factor-related apoptosis-inducing ligand with total and cardiovascular mortality in older adults. - Volpato, Stefano; Ferrucci, Luigi; Secchiero, Paola; Corallini, Federica; Zuliani, Giovanni; Fellin, Renato; Guralnik, Jack M; Bandinelli, Stefania; Zauli, Giorgio (Atherosclerosis, 2011)
OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits biological activity on vascular cells in vitro. Rapid variation of circulating TRAIL levels occurs during acute coronary ischemia, suggesting that biological pathways involving TRAIL may be activated during ischemic heart disease. However, whether differential levels of soluble TRAIL in normal individuals are associated with adverse health outcomes has not been investigated. We tested the hypothesis that TRAIL levels predict mortality in a population based sample of community dwelling men and women. METHODS: Plasma TRAIL level was measured by ELISA at baseline in 1282 adults (mean age 68 years) enrolled in the InCHIANTI study. Vital status was ascertained over the six-year follow-up. RESULTS: In multivariable Cox regression analysis adjusted for potential confounders including prevalent cardiovascular diseases (CVD), ankle-brachial index, electrocardiogram abnormalities, and inflammatory markers, baseline TRAIL levels were inversely related to all-cause mortality (p=0.008). In stratified analyses, the prognostic effect of TRAIL level was strong and highly significant in participants with prevalent CVD (N=321), (lowest versus highest quartile: HR 3.1; 95% CI 1.5-6.5) while it was negligible in those free of CVD (p value for the interaction term between CVD status and TRAIL levels=0.038). Similar findings were obtained when CVD mortality was considered as the outcome of interest. CONCLUSIONS: In older patients with CVD, low levels of TRAIL were associated with increased risk of death over a period of 6 years. Lower concentration of circulating TRAIL may be related to the clinical evolution of older adults with CVD.
Keywords: Adult; Aged; Ankle Brachial Index; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Italy; Male; Middle Aged; TNF-Related Apoptosis-Inducing Ligand

Atlanto-axial joint involvement as exclusive manifestation of juvenile idiopathic arthritis (JIA). - Taddio, A; Pellegrin, M C; Gregori, M; Wientroub, S; Padeh, S; Lepore, L (Clin Exp Rheumatol, 2011)
Keywords: Antirheumatic Agents; Arthritis, Juvenile; Atlanto-Axial Joint; Child; Dislocations; Female; Glucocorticoids; Humans; Magnetic Resonance Imaging; Pulse Therapy, Drug; Torticollis; Treatment Outcome; Uveitis

Breastfeeding to 24 months of age in the northeast of Italy: a cohort study. - Carletti, Claudia; Pani, Paola; Knowles, Alessandra; Monasta, Lorenzo; Montico, Marcella; Cattaneo, Adriano (Breastfeed Med, 2011)
AIM: This study assessed the prevalence and duration of breastfeeding up to 24 months and the associated socioeconomic determinants in a birth cohort of children. METHODS: Four hundred infants born in a hospital in the north east of Italy were enrolled at birth and followed up for 36 months. Data on infant feeding were gathered through a feeding diary compiled at fixed intervals. Data were also gathered on type of delivery and weight, length, and health status at birth, as well as on selected socioeconomic indicators of the mothers. A multivariate logistic regression analysis was used to determine any association that exclusivity and duration of breastfeeding may have with selected socioeconomic variables and with health conditions of the infants at birth. RESULTS: Ninety-eight percent of mothers initiated breastfeeding, 69% of them exclusively. This rate, however, had declined to 6% by 6 months. There was a remarkable endurance of breastfeeding at 24 months (12%). The variables significantly associated with exclusive breastfeeding at 3 months and any form of breastfeeding at 12 months are mother's age (p=0.007 at 3 months, p=0.026 at 12 months) and postdischarge hospital admission (p=0.029 at 3 months). CONCLUSIONS: In this population, breastfeeding rates are higher than previously reported, but lower than recommended, especially as far as exclusivity is concerned. Full implementation of the World Health Organization-UNICEF Baby Friendly Initiatives in hospitals and communities is needed to improve them further. Monitoring systems should include the collection of data on breastfeeding beyond 12 months of age.
Keywords: Adult; Age Factors; Birth Weight; Breast Feeding; Cohort Studies; Family Characteristics; Female; Gestational Age; Guideline Adherence; Health Promotion; Humans; Infant; Infant, Newborn; Italy; Neonatal Screening; Prevalence; Socioeconomic Factors; Time Factors

Celiac disease and immigration in Northeastern Italy: the "drawn double nostalgia" of "cozonac" and "panettone" slices. - Parco, Sergio; Città, Angelo; Vascotto, Fulvia; Tamaro, Giorgio (Clin Exp Gastroenterol, 2011)
Many investigators consider children's drawings to be an important test in the evaluation of stress and anxiety, but few studies have examined the reliability and validity of indicators of emotional distress in children's projective drawings. In this report, we describe screening tests in children coming to the Friuli Venezia Giulia region in Northeastern Italy from non-European Union regions and suspected to have celiac disease, the problems involved in diagnosis of the disease, and the "drawn double nostalgia" of Romanian children for both Italian food and traditional Romanian foods. Of 3150 Western European cases, we found 712 with positive antibodies for IgA/IgG antitransglutaminase, 174 with a positive antiendomysium antibody confirmation test, and 20 with an IgA deficit. Of the children examined, 93% were children native to Western Europe, 4% were immigrants from Eastern Europe, and 1.6% originated from Africa. Among these, four Romanian children with celiac disease brought in their drawings, as requested in a hospital questionnaire. The prevalence of celiac disease is destined to increase among immigrants. Economic problems are common, and the twin nostalgia of immigrant children for foods and tastes that are "cozonac" (from the native country) and "panettone" (Italian cake flavor) represents a problem that will be difficult to resolve. Only some children's hospitals in Italy, ie, Burlo Garofolo and Gaslini, public and private foundations, or volunteer associations would be able to deal with this problem.

Childhood chronic anterior uveitis associated with vernal keratoconjunctivitis (VKC): successful treatment with topical tacrolimus. Case series. - Taddio, Andrea; Cimaz, Rolando; Caputo, Roberto; de Libero, Cinzia; Di Grande, Laura; Simonini, Gabriele; Mori, Francesca; Novembre, Elio; Pucci, Neri (Pediatr Rheumatol Online J, 2011)
Uveitis treatment involves topical corticosteroids along with cycloplegic-mydriatics. Particularly severe cases may require systemic corticosteroids and immunosuppressive drugs. Vernal keratoconjunctivitis (VKC) treatment consists of a brief period of topical corticosteroids and/or cyclosporine. In patients refractory to traditional treatment, the use of 0.1% topical ophtalmic FK- 506 (tacrolimus) ointment has been occasionally reported.This is the first report of the coexistence of uveitis and VKC. The documented response to topical tacrolimus eyedrop of uveitis and VKC is also of interest, in particular since to our knowledge there are no published reports on its clinical use in uveitis.

Circulating TRAIL shows a significant post-partum decline associated to stressful conditions. - Zauli, Giorgio; Monasta, Lorenzo; Rimondi, Erika; Vecchi Brumatti, Liza; Radillo, Oriano; Ronfani, Luca; Montico, Marcella; D'Ottavio, Giuseppina; Alberico, Salvatore; Secchiero, Paola (PLoS One, 2011)
BACKGROUND: Since circulating levels of TNF-related apoptosis inducing ligand (TRAIL) may be important in the physiopathology of pregnancy, we tested the hypothesis that TRAIL levels change at delivery in response to stressful conditions. METHODS/PRINCIPAL FINDINGS: We conducted a longitudinal study in a cohort of 73 women examined at week 12, week 16, delivery and in the corresponding cord blood (CB). Serum TRAIL was assessed in relationship with maternal characteristics and to biochemical parameters. TRAIL did not vary between 12 (67.6±27.6 pg/ml, means±SD) and 16 (64.0±16.2 pg/ml) weeks' gestation, while displaying a significant decline after partum (49.3±26.4 pg/ml). Using a cut-off decline >20 pg/ml between week 12 and delivery, the subset of women with the higher decline of circulating TRAIL (41.7%) showed the following characteristics: i) nullipara, ii) higher age, iii) operational vaginal delivery or urgent CS, iv) did not receive analgesia during labor, v) induced labor. CB TRAIL was significantly higher (131.6±52 pg/ml) with respect to the corresponding maternal TRAIL, and the variables significantly associated with the first quartile of CB TRAIL (<90 pg/ml) were higher pre-pregnancy BMI, induction of labor and fetal distress. With respect to the biochemical parameters, maternal TRAIL at delivery showed an inverse correlation with C-reactive protein (CRP), total cortisol, glycemia and insulin at bivariate analysis, but only with CRP at multivariate analysis. CONCLUSIONS: Stressful partum conditions and elevated CRP levels are associated with a decrease of circulating TRAIL.
Keywords: Adult; Biological Markers; C-Reactive Protein; Female; Fetal Blood; Fetal Distress; Humans; Labor, Obstetric; Logistic Models; Multivariate Analysis; Postpartum Period; Pregnancy; Pregnancy Outcome; Statistics, Nonparametric; Stress, Physiological; TNF-Related Apoptosis-Inducing Ligand

Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. - Savoia, Anna; Pastore, Annalisa; De Rocco, Daniela; Civaschi, Elisa; Di Stazio, Mariateresa; Bottega, Roberta; Melazzini, Federica; Bozzi, Valeria; Pecci, Alessandro; Magrin, Silvana; Balduini, Carlo L; Noris, Patrizia (Haematologica, 2011)
BACKGROUND: Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center. DESIGN AND METHODS: Thirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses. RESULTS: Patients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies. CONCLUSIONS: Regardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.
Keywords: Adolescent; Adult; Amino Acid Sequence; Bernard-Soulier Syndrome; Blood Platelets; Cell Shape; Child; Child, Preschool; Female; Genetic Association Studies; Genetic Markers; Hemorrhage; Homozygote; Humans; Italy; Male; Membrane Glycoproteins; Middle Aged; Molecular Sequence Data; Platelet Aggregation; Platelet Count; Platelet Glycoprotein GPIb-IX Complex; Point Mutation; Polymerase Chain Reaction; Ristocetin; Thrombocytopenia; von Willebrand Factor; Young Adult

Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. - Mazza, Cinzia; Buzi, Fabio; Ortolani, Federica; Vitali, Alberto; Notarangelo, Lucia D; Weber, Giovanna; Bacchetta, Rosa; Soresina, Annarosa; Lougaris, Vassilios; Greggio, Nella A; Taddio, Andrea; Pasic, Srdjan; et al. (Clin Immunol, 2011)
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED.
Keywords: Adolescent; Adult; Child; Child, Preschool; Heterozygote; Homozygote; Humans; Middle Aged; Mutation; Polyendocrinopathies, Autoimmune; Time Factors; Young Adult

Comments on ''Geranylgeraniol--a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw" by Ziebart T et al. (2011). - Marcuzzi, Annalisa; Zanin, Valentina; Crovella, Sergio; Pontillo, Alessandra (Oral Oncol, 2011)
Keywords: Bone Density Conservation Agents; Diphosphonates; Diterpenes; Humans; Jaw Diseases; Osteonecrosis

Comparison of propofol versus propofol-ketamine combination in pediatric oncologic procedures performed by non-anesthesiologists. - Chiaretti, Antonio; Ruggiero, Antonio; Barbi, Egidio; Pierri, Filomena; Maurizi, Palma; Fantacci, Claudia; Bersani, Giulia; Riccardi, Riccardo (Pediatr Blood Cancer, 2011)
BACKGROUND: Limited data are available on the best option (short acting sedatives, opioids, or ketamine) in oncologic procedural sedation performed by non-anesthesiologists. The aim of the present prospective study is to compare the safety and efficacy of propofol-ketamine versus propofol alone, managed by trained pediatricians, in children with cancer undergoing painful procedures. PROCEDURES: Data on 121 children with acute lymphatic leukemia (ALL) undergoing procedural sedations (lumbar punctures and bone marrow aspirations) were prospectively collected and included drug doses, side effects, pain assessment, and sedation degree. Children were randomly assigned to one of the two groups: P (n = 62) receiving propofol alone and K (n = 59) in whom a ketamine-propofol combination was used. RESULTS: In group K, the total dose of propofol required was significantly lower than in group P (3.9 ± 3.6 mg/kg vs. 5.1 ± 3.6 mg/kg; P < 0.001). The incidence of hypotension was also significantly lower (11% vs. 39%; P < 0.001). Major O(2) desaturations (defined as SatO(2) < 88%) occurred principally in group P (7 vs. 1; P = 0.05). Both best analgesia and shorter recovery time were obtained with the propofol-ketamine association. No differences were observed in the degree of sedation and in the awakening quality score between the two groups. CONCLUSIONS: The combination of propofol and ketamine produced statistically significant clinical advantages combined with a higher profile of safety in children with cancer undergoing painful procedures.
Keywords: Biopsy, Needle; Bone Marrow Examination; Child; Conscious Sedation; Female; Humans; Hypnotics and Sedatives; Ketamine; Male; Neoplasms; Pediatrics; Physicians; Propofol; Spinal Puncture

Compliance with the gluten-free diet: the role of locus of control in celiac disease. - Bellini, Anna; Zanchi, Chiara; Martelossi, Stefano; Di Leo, Grazia; Not, Tarcisio; Ventura, Alessandro (J Pediatr, 2011)
OBJECTIVES: To verify whether subjects with celiac disease (CD) have a different locus of control (LoC) compared with healthy subjects, and to evaluate the relationship between LoC and compliance with a prescribed gluten-free diet (GFD) and quality of life (QoL). STUDY DESIGN: We studied 156 subjects on a GFD (mean age, 10 years) and 353 healthy controls (mean age, 12 years). All subjects completed tests on the Nowicki-Strickland Locus of Control Scale; the subjects with CD also completed a questionnaire to measure compliance with dietary treatment and the disease's impact on QoL. RESULTS: There was no difference in LoC values between patients with CD and controls. Subjects with CD with good dietary compliance had a more internal LoC compared with those who were not compliant (P = .01). Patients who reported a satisfactory QoL had a more internal LoC compared with those who reported negative affects on QoL due to CD (P = .01). CONCLUSIONS: Our study confirms the usefulness of the LoC concept for identifying those patients who might be at risk for dietary transgression. Given the enhanced, psychological, and social well being that can result from adherence to a GFD, educational and psychological support can help internalize the LoC in those patients at risk for dietary transgression.
Keywords: Adolescent; Age Factors; Case-Control Studies; Celiac Disease; Child; Diet, Gluten-Free; Female; Humans; Internal-External Control; Italy; Male; Patient Compliance; Quality of Life

Concentrated midazolam for intranasal administration: a pilot study. - Calligaris, Lorenzo; Davide, Zanon; Alessandra, Maestro; De Bortoli, Romina; Chiaretti, Antonio; Barbi, Egidio (Pediatr Emerg Care, 2011)
Keywords: Administration, Intranasal; Child; Child, Preschool; Conscious Sedation; Dose-Response Relationship, Drug; Female; Humans; Hypnotics and Sedatives; Infant; Male; Midazolam; Pain; Pilot Projects; Preoperative Care

Congenital aplasia of the optic chiasm and esophageal atresia: a case report. - Pensiero, Stefano; Cecchini, Paolo; Michieletto, Paola; Pelizzo, Gloria; Madonia, Maurizio; Parentin, Fulvio (J Med Case Rep, 2011)
INTRODUCTION: The complete absence of the chiasm (chiasmal aplasia) is a rare clinical condition. Hypoplasia of the optic nerve and congenital nystagmus are almost invariably associated characteristics. Microphthalmos or anophthalmos are common features in chiasmal aplasia, while central nervous system abnormalities are less frequent. Esophageal atresia can be isolated or syndromic. In syndromic cases, it is frequently associated with cardiac, limb, renal or vertebral malformations and anal atresia. More rarely, esophageal atresia can be part of anophthalmia-esophageal-genital syndrome, which comprises anophthalmia or microphthalmia, genital abnormalities, vertebral defects and cerebral malformations. Here, a previously unreported case of chiasmal aplasia presenting without microphthalmos and associated with esophageal atresia is described. CASE PRESENTATION: Aplasia of the optic chiasm was identified in a Caucasian Italian 8-month-old boy with esophageal atresia. An ultrasound examination carried out at 21 weeks' gestation revealed polyhydramnios. Intrauterine growth retardation, esophageal atresia and a small atrial-septal defect were subsequently detected at 28 weeks' gestation. Repair of the esophageal atresia was carried out shortly after birth. A jejunostomy was carried out at four months to facilitate enteral feeding. The child was subsequently noted to be visually inattentive and to be neurodevelopmentally delayed. Magnetic resonance imaging revealed chiasmal aplasia. No other midline brain defects were found. His karyotype was normal. CONCLUSION: If achiasmia is a spectrum, our patient seems to depict the most severe form, since he appears to have an extremely severe visual impairment. This is in contrast to most of the cases described in the literature, where patients maintain good--or at least useful-- visual function. To the best of our knowledge, the association of optic nerve hypoplasia, complete chiasmal aplasia, esophageal atresia and atrial-septal defect, choanal atresia, hypertelorism and psychomotor retardation has never been described before.

Consensus on diagnosis and empiric antibiotic therapy of febrile neutropenia. - Giurici, Nagua; Zanazzo, Giulio A (Pediatr Rep, 2011)
Controversial issues on the management of empiric therapy and diagnosis of febrile neutropenia (FN) were faced by a Consensus Group of the Italian Association of Pediatric Hematology-Oncology (AIEOP). In this paper we report the suggestions of the consensus process regarding the role of aminoglycosides, glycopeptides and oral antibiotics in empiric therapy of FN, the rules for changing or discontinuing the therapy as well as the timing of the blood cultures.

Corneal curvature and thickness development in premature infants. - De Silva, Silvana; Parentin, Fulvio; Michieletto, Paola; Pensiero, Stefano (J Pediatr Ophthalmol Strabismus, 2011)
PURPOSE: Analysis of postnatal changes in central corneal thickness (CCT) and corneal curvature (CC) in premature infants, their relation, and their possible influence on eye growth and intraocular pressure (IOP) evaluation. METHODS: CCT and CC were assessed in both eyes of 56 premature infants, born at 24 to 32 weeks of gestational age (GA), and then two or three times at post-conceptional ages (PCAs) of 28 to 42 weeks. RESULTS: CC changed from 65.83 diopters at 28 weeks of PCA to 49.38 diopters at 42 weeks of PCA. CCT decreased from 794 to 559 μm at the same ages. The reductions of these two corneal parameters seem to be related to each other and begin immediately after birth. CONCLUSION: In light of the few data available in the literature, these data provide more certainty about the CCT values of premature infants. The importance of CCT and CC fast variations after premature birth concerns both the knowledge of anterior segment development and the correct evaluation of IOP in immature eyes; the influence of these two parameters on the methods of IOP evaluation could be more remarkable at the lowest PCAs.
Keywords: Child Development; Cornea; Corneal Pachymetry; Eye; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Intraocular Pressure; Male; Premature Birth

Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet. - Not, Tarcisio; Ziberna, Fabiana; Vatta, Serena; Quaglia, Sara; Martelossi, Stefano; Villanacci, Vincenzo; Marzari, Roberto; Florian, Fiorella; Vecchiet, Monica; Sulic, Ana-Marija; Ferrara, Fortunato; Bradbury, Andrew; et al. (Gut, 2011)
BACKGROUND AND OBJECTIVE: Antitransglutaminase (anti-TG2) antibodies are synthesised in the intestine and their presence seems predictive of future coeliac disease (CD). This study investigates whether mucosal antibodies represent an early stage of gluten intolerance even in the absence of intestinal damage and serum anti-TG2 antibodies. METHODS: This study investigated 22 relatives of patients with CD genetically predisposed to gluten intolerance but negative for both serum anti-TG2 antibodies and intestinal abnormalities. Fifteen subjects were symptomatic and seven were asymptomatic. The presence of immunoglobulin A anti-TG2 antibodies in the intestine was studied by creating phage-antibody libraries against TG-2. The presence of intestinal anti-TG2 antibodies was compared with the serum concentration of the intestinal fatty acid-binding protein (I-FABP), a marker for early intestinal mucosal damage. The effects of a 12-month gluten-free diet on anti-TG2 antibody production and the subjects' clinical condition was monitored. Twelve subjects entered the study as controls. RESULTS: The intestinal mucosa appeared normal in 18/22; 4 had a slight increase in intraepithelial lymphocytes. Mucosal anti-TG2 antibodies were isolated in 15/22 subjects (68%); in particular symptomatic subjects were positive in 13/15 cases and asymptomatic subjects in 2/7 cases (p=0.01). No mucosal antibodies were selected from the controls' biopsies. There was significant correlation between the presence of intestinal anti-TG2 antibodies and positive concentrations of I-FABP (p=0.0008). After a gluten-free diet, 19/22 subjects underwent a second intestinal biopsy, which showed that anti-TG2 antibodies had disappeared in 12/15 (p=0.002), while I-FABP decreased significantly (p<0.0001). The diet resolved both extraintestinal and intestinal symptoms. CONCLUSIONS: A new form of genetic-dependent gluten intolerance has been described in which none of the usual diagnostic markers is present. Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms. Clinical trial number NCT00677495.
Keywords: Adolescent; Adult; Antibodies, Anti-Idiotypic; Asymptomatic Diseases; Celiac Disease; Child; Child, Preschool; Diet, Gluten-Free; Fatty Acid-Binding Proteins; Female; Genetic Predisposition to Disease; GTP-Binding Proteins; Health Status; Humans; Intestinal Mucosa; Male; Middle Aged; Peptide Library; Transglutaminases; Young Adult

Daily practice of mechanical ventilation in Italian pediatric intensive care units: a prospective survey. - Wolfler, Andrea; Calderoni, Edoardo; Ottonello, Giancarlo; Conti, Giorgio; Baroncini, Simonetta; Santuz, Pierantonio; Vitale, Pasquale; Salvo, Ida (Pediatr Crit Care Med, 2011)
OBJECTIVES: To assess how children requiring endotracheal intubation are mechanically ventilated in Italian pediatric intensive care units (PICUs). DESIGN: A prospective, national, observational, multicenter, 6-month study. SETTING: Eighteen medical-surgical PICUs. PATIENTS: A total of 1943 consecutive children, aged 0-16 yrs, admitted between November 1, 2006 and April 30, 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data on cause of respiratory failure, length of mechanical ventilation (MV), mode of ventilation, use of specific interventions were recorded for all children requiring endotracheal intubation for >24 hrs. Children were stratified for age, type of patient, and cause of respiratory failure. A total of 956 (49.2%) patients required MV via an endotracheal tube; 673 (34.6%) were ventilated for >24 hrs. The median length of MV was 4.5 days for all patients. If postoperative patients were excluded, the median time was 5 days. Bronchiolitis (6.7%), pneumonia (6.7%), and upper airway obstruction (5.3%) were the most frequent causes of acute respiratory failure, and altered mental status (9.2%) was the most frequent reason for MV. The overall mortality was 6.7% with highest rates for heart disease (nonoperative), sepsis, and acute respiratory distress syndrome (26.1%, 22.2%, and 16.7% respectively). Length of stay, associated chronic disease, severity score on admission, and PICU mortality were significantly higher in children who received MV (p < .05) than in children who did not. Controlled MV and pressure support ventilation + synchronized intermittent mandatory ventilation were the most frequently used modes of ventilatory assistance during PICU stay. CONCLUSIONS: Mechanical ventilation is frequently used in Italian PICUs with almost one child of two requiring endotracheal intubation. Children treated with MV represent a more severe category of patients than children who are breathing spontaneously. Describing the standard care and how MV is performed in children can be useful for future clinical studies.
Keywords: Adolescent; Child; Child, Preschool; Clinical Protocols; Female; Humans; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Intubation, Intratracheal; Italy; Male; Prospective Studies; Respiration, Artificial; Respiratory Insufficiency

Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. - Zauli, Giorgio; Voltan, Rebecca; Bosco, Raffaella; Melloni, Elisabetta; Marmiroli, Sandra; Rigolin, Gian Matteo; Cuneo, Antonio; Secchiero, Paola (Clin Cancer Res, 2011)
PURPOSE: To analyze the effect of the combination of Dasatinib, a multikinase inhibitor, plus Nutlin-3, a nongenotoxic activator of the p53 pathway, in primary B chronic lymphocytic leukemia (B-CLL) patient samples and B leukemic cell line models. EXPERIMENTAL DESIGN: The induction of cytotoxicity was evaluated in both primary B-CLL cell samples (n = 20) and in p53(wild-type) (EHEB, JVM-2) and p53(deleted/mutated) (MEC-2, BJAB) B leukemic cell lines. The role of Akt in modulating leukemic cell survival/apoptosis in response to Dasatinib or Dasatinib + Nutlin-3 was documented by functional experiments carried out using specific pharmacological inhibitors and by overexpression of membrane-targeted constitutively active form of Akt. RESULTS: The combination of Dasatinib + Nutlin-3 exhibited a synergistic cytotoxicity in the majority (19 out of 20) of B-CLL samples, including patients carrying 17p- (n = 4), and in both p53(wild-type) and p53(deleted/mutated) B leukemic cell lines. At the molecular level, Dasatinib significantly counteracted the Nutlin-3-mediated induction of the p53 transcriptional targets MDM2 and p21 observed in p53(wild-type) leukemic cells. Conversely, Nutlin-3 did not interfere with the ability of Dasatinib to decrease the phosphorylation levels of ERK1/2, p38/MAPK, and Akt in both p53(wild-type) and p53(deleted/mutated) B leukemic cell lines. A critical role of Akt downregulation in mediating the antileukemic activity of Dasatinib and Dasatinib + Nutlin-3 was demonstrated in experiments carried out by specifically modulating the Akt pathway. CONCLUSIONS: These findings suggest that Dasatinib + Nutlin-3 might represent an innovative therapeutic combination for both p53(wild-type) and p53(deleted/mutated) B-CLL.
Keywords: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Piperazines; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Thiazoles; Transcription, Genetic; Tumor Suppressor Protein p53

Decreased levels of soluble TNF-related apoptosis-inducing ligand (TRAIL) in the conjunctival sac fluid of patients with diabetes affected by proliferative retinopathy. - Secchiero, P; Perri, P; Melloni, E; Martini, A; Lamberti, G; Sebastiani, A; Zauli, G (Diabet Med, 2011)
Keywords: Apoptosis Regulatory Proteins; Body Fluids; Conjunctiva; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand

Diagnosis and treatment of pediatric chronic osteomyelitis in developing countries: prospective study of 96 patients treated in Kenya. - Mantero, E; Carbone, M; Calevo, M G; Boero, S (Musculoskelet Surg, 2011)
The authors carried out a prospective study on 96 patients they treated in Kenya for chronic osteomyelitis from 2000 to 2009. All the patients received orthopedic surgery and antibiotic therapy, when possible based on the antibiotic sensitivity test. Among the 90 patients with at least 12 months' follow-up, 11 had osteomyelitis relapse (12.2%) and recovery rate was therefore 87.8% with no resulting disability. Risk factors for osteomyelitis relapse were investigated and previous treatment with beta-lactamines, predisposing to onset of methycillin-resistant Staphylococcus aureus (MRSA) infections (P = 0.03, OR = 5.74), and onset of osteomyelitis in the metaepiphyseal region (P < 0.0001) resulted statistically significant. Aim of the study was to evaluate the validity of our treatment of chronic osteomyelitis in Kenya on the basis of outcome.
Keywords: Adolescent; Algorithms; Anti-Bacterial Agents; Child; Chronic Disease; Developing Countries; Female; Follow-Up Studies; Humans; Kenya; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Osteomyelitis; Prospective Studies; Recurrence; Reproducibility of Results; Risk Factors; Staphylococcal Infections; Treatment Outcome

Differential action of 3-hydroxyanthranilic acid on viability and activation of stimulated lymphocytes. - Piscianz, Elisa; Cuzzoni, Eva; De Iudicibus, Sara; Valencic, Erica; Decorti, Giuliana; Tommasini, Alberto (Int Immunopharmacol, 2011)
Lymphocytes proliferation after antigen-driven activation leads to an increase in cell count, which could last some week, until apoptosis mechanisms allow the homeostatic control of the system. During the first days of this stimulation, activated lymphocytes display high resistance to apoptosis and to most immunosuppressive drugs. According to the literature, few compounds have been described to kill recently activated cells, by inhibiting metabolic processes fundamental to proliferation. The aim of our work was to evaluate comparatively these different compounds, in order to identify the best strategy to kill cells that have undergone proliferation, while sparing the repertoire of resting cells. After preliminary experiments, 3-HAA and bortezomib were selected as the most suitable compounds for our purposes. The possible synergic effect of 3-HAA with bortezomib or with manganese ions was also assessed. 3-HAA was confirmed to be the most reliable pharmacologic approach to inhibit proliferation with acceptable toxicity on resting cells. While in the case of PHA stimulation 3-HAA led to death of most lymphocytes, only a minor percentage of cells were killed after allo-stimulation, suggesting that the effect is proportional to the percentage of stimulated lymphocytes. Manganese ions further enhanced this effect, while results with bortezomib seemed to be less consistent. These results deserve further investigations to develop new procedures for targeting activated cells with pharmacological approaches.
Keywords: 3-Hydroxyanthranilic Acid; Boronic Acids; Cell Survival; Cells, Cultured; Humans; Lymphocyte Activation; Lymphocytes; Manganese; Pyrazines

Echocardiographic detection of early myocardial calcification in acute neonatal myocarditis due to Coxsackie virus type B. - Benettoni, Alessandra; Berton, Emanuela (Pediatr Cardiol, 2011)
Keywords: Coronary Vessels; Electrocardiography; Humans; Male; Myocardial Infarction; Myocarditis

Endothelial progenitor cells, bronchopulmonary dysplasia and other short-term outcomes of extremely preterm birth. - Paviotti, Giulia; Fadini, Gian Paolo; Boscaro, Elisa; Agostini, Carlo; Avogaro, Angelo; Chiandetti, Lino; Baraldi, Eugenio; Filippone, Marco (Early Hum Dev, 2011)
AIM: To evaluate the impact of endothelial progenitor cells (EPCs), a subset of committed circulatory stem cells, on the development of bronchopulmonary dysplasia (BPD) and other short term outcomes in a cohort of extremely premature newborns. METHODS: Progenitor cells were quantified by flow cytometry at birth in 36 neonates born <=28 weeks of gestation and at 36 postmenstrual weeks in 18 of them. Cells expressing the stemness markers CD34, CD133, or both were defined as circulating progenitor cells (CPCs). EPCs were defined as CPCs co-expressing the endothelial marker KDR. RESULTS: Mean (SD) gestational age and birth weight of the infants studied were 26.2(1.5) weeks and 761.6(171.8) grams, respectively. EPC levels at birth did not differ between infants who subsequently developed BPD (n=9) and those who did not (n=24) [CD34(+)KDR(+) EPCs: 81(34-41) vs 80(56-110), p=0.7] and were not correlated with the duration of mechanical ventilation or O2-dependence, nor with the need of surfactant replacement. Infants with a hemodynamically significant patent ductus arteriosus (PDA) (n=22) had significantly lower EPC levels at birth than those with no PDA (n=11) [CD34(+)KDR(+) cells: 47(34-92) vs 142(84.5-221), p=0.008]. Data from the 18 infants studied both at birth and at 36 postmenstrual weeks showed that, while CPCs sharply decline over time, levels of all EPCs phenotypes are preserved after delivery. CONCLUSIONS: Levels of EPCs at birth did not affect the risk of developing BPD in our group of extremely premature neonates. However, the association between low EPC counts at birth and PDA may be clinically relevant, and deserves further studies.
Keywords: Blood Cell Count; Bronchopulmonary Dysplasia; Cohort Studies; Ductus Arteriosus, Patent; Endothelial Cells; Female; Flow Cytometry; Humans; Infant, Newborn; Infant, Premature; Italy; Pregnancy; Prospective Studies; Regression Analysis; Stem Cells

Epidemiological and molecular assessment of a measles outbreak in a highly vaccinated population of northeast Italy. - D'Agaro, P; Molin, G Dal; Gallo, T; Rossi, T; Santon, D; Busetti, M; Comar, M; Campello, C (Epidemiol Infect, 2011)
Two distinct measles outbreaks, unrelated from the epidemiological point of view but caused by genetically related strains, occurred in the Friuli Venezia Giulia region of northeastern Italy. Forty-two cases were reported during the period April-May 2008. In the first outbreak the index case was a teacher who introduced the virus into the Pordenone area, involving eight adolescents and young adults. The other concomitant outbreak occurred in the city of Trieste with 33 cases. The containment of the epidemics can be explained by the high MMR vaccine coverage in an area where the first dose was delivered to 93·4% and the second dose to 88·3% of the target children. Phylogenetic analysis of 14 measles virus strains showed that they belonged to a unique D4 genotype indistinguishable from the MVs/Enfield.GBR/14.07 strain, probably introduced from areas (i.e. Piedmont and Germany) where this genotype was present or had recently caused a large epidemic.
Keywords: Adolescent; Adult; Chi-Square Distribution; Child; Child, Preschool; Community-Acquired Infections; Disease Outbreaks; Female; Humans; Immunization Schedule; Infant; Italy; Male; Measles; Measles Vaccine; Measles virus; Middle Aged; Molecular Epidemiology; Phylogeny

ESPGHAN's 2008 recommendation for early introduction of complementary foods: how good is the evidence? - Cattaneo, Adriano; Williams, Carol; Pallás-Alonso, Carmen Rosa; Hernández-Aguilar, Maria Teresa; Lasarte-Velillas, Juan José; Landa-Rivera, Leonardo; Rouw, Elien; Pina, Mónica; Volta, Alessandro; Oudesluys-Murphy, Anne Marie (Matern Child Nutr, 2011)
Since 2002, the World Health Organization and many governments and professional associations have recommended exclusive breastfeeding for 6 months followed by complementary feeding (giving solid foods alongside breast milk) as optimal infant feeding practice. Several articles have been published challenging this recommendation. Arguably, the most influential has been the 2008 commentary of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition, which recommended that complementary foods should be introduced to all infants between 17 and 26 weeks. We challenge the validity of ESPGHAN's position, questioning the adequacy of the literature search, the interpretation and evidence used to reach their conclusions and the balance of an approach that focuses on disease prevention, with scant consideration of growth and neuromotor development. We contend that ESPGHAN's position should be understood as an expert opinion that may be influenced by conflicts of interest. In our view, the ESPGHAN position paper is not evidence based and does not justify a change of the current public health recommendation for 6 months of exclusive breastfeeding. At an individual level, health professionals should understand that developmental readiness for starting solid foods has an age range like other developmental milestones; that fewer infants will probably be ready to start complementary feeding before, rather than after, 6 months; and that their role is to equip parents with the confidence and skills to recognise the signs of developmental readiness. This empowerment process for infants and parents should be preferred over the prescriptive ESPGHAN approach.
Keywords: Breast Feeding; Evidence-Based Practice; Humans; Infant; Infant Food; Infant Nutritional Physiological Phenomena; Milk, Human; Nutritional Status; Public Health; Reproducibility of Results; World Health Organization

The farnesyltransferase inhibitors tipifarnib and lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency. - Marcuzzi, Annalisa; De Leo, Luigina; Decorti, Giuliana; Crovella, Sergio; Tommasini, Alberto; Pontillo, Alessandra (Pediatr Res, 2011)
The shortage of geranylgeranyl-pyrophosphate (GGPP) was associated to an increased IL-1β release in the autoinflammatory syndrome mevalonate kinase deficiency (MKD), a rare inherited disease that has no specific therapy. Farnesyltransferase inhibitors (FTIs) act at the end of mevalonate pathway. Two FTIs, tipifarnib (Tip) and lonafarnib (Lon), were therefore evaluated as possible therapeutical choices for the treatment of MKD. FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. The effect of Tip and Lon on intracellular cholesterol level (ICL) and on proinflammatory cytokines secretion was evaluated in a cellular model of MKD, chemically obtained treating RAW 264.7 cells with lovastatin (Lova) and alendronate (Ald). The combination of FTIs with the isoprenoid geraniol (GOH) was also tested both in this model and in monocytes isolated from MKD patients. Tip and Lon proved to revert the ICL lowering and to significantly reduce the lipopolysaccharide-induced cytokines secretion in Ald-Lova -RAW 264.7 cells. This anti-inflammatory effect was amplified combining the use of GOH with FTIs. The effect of GOH and Tip was successfully replicated in MKD patients' monocytes. Tip and Lon showed a dramatic anti-inflammatory effect in monocytes where mevalonate pathway was chemically or genetically impaired.
Keywords: Alendronate; Animals; Anti-Inflammatory Agents; Cell Line; Child; Child, Preschool; Cholesterol; Cytokines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Inflammation Mediators; Lovastatin; Male; Mevalonate Kinase Deficiency; Mice; Monocytes; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Polyenes; Polyisoprenyl Phosphates; Polyunsaturated Alkamides; Pyridines; Quinolones; Terpenes

Fine tuning of protein kinase C (PKC) isoforms in cancer: shortening the distance from the laboratory to the bedside. - Bosco, R; Melloni, E; Celeghini, C; Rimondi, E; Vaccarezza, M; Zauli, G (Mini Rev Med Chem, 2011)
The serine/threonine protein kinase C (PKC) family was first identified as intracellular receptor(s) for the tumor promoting agents phorbol esters. Thirty years after the discovery of PKC, the role of specific PKC isoforms has been described in relationship with an altered pattern of expression in different types of cancer and a good number of small molecule inhibitors (inhibitory peptides, antisense oligonucleotides or natural compounds) targeting PKC are now available. Despite all these achievements and a huge amount of basic research studies on the biochemical regulation of PKC, there has been a delay in clinical trials with drugs targeting PKC function. This delay is easily explained taking into account the extreme biological complexity of the PKC family of isoforms and the incomplete understanding of the specific role of each PKC isozyme in different types of cancers. Some of the difficulties in developing pharmacological compounds selectively tuning the different PKCs have started to be overcome. In this review, the growing evidences of the role of the PKC isoforms α, βII, δ, ε, ζ and ι is in promoting or counteracting tumor progression will be discussed in relationship with promising therapeutic perspectives.
Keywords: Antineoplastic Agents; Biological Products; Enzyme Inhibitors; Humans; Isoenzymes; Neoplasms; Oligonucleotides, Antisense; Peptides; Protein Kinase C

Foreign children with cancer in Italy. - Rondelli, Roberto; Dini, Giorgio; De Rosa, Marisa; Quarello, Paola; Bisogno, Gianni; Aricò, Maurizio; Vasconcelos, Carivaldo; Tamaro, Paolo; Casazza, Gabriella; Zecca, Marco; De Laurentis, Clementina; Porta, Fulvio; et al. (Ital J Pediatr, 2011)
BACKGROUND: There has been a noticeable annual increase in the number of children coming to Italy for medical treatment, just like it has happened in the rest of the European Union. In Italy, the assistance to children suffering from cancer is assured by the current network of 54 centres members of the Italian Association of Paediatric Haematology and Oncology (AIEOP), which has kept records of all demographic and clinical data in the database of Mod.1.01 Registry since 1989. METHODS: We used the information stored in the already mentioned database to assess the impact of immigration of foreign children with cancer on centres' activity, with the scope of drawing a map of the assistance to these cases. RESULTS: Out of 14,738 cases recorded by all centres in the period from 1999 to 2008, 92.2% were born and resident in Italy, 4.1% (608) were born abroad and living abroad and 3.7% (538) were born abroad and living in Italy. Foreign children cases have increased over the years from 2.5% in 1999 to. 8.1% in 2008.Most immigrant children came from Europe (65.7%), whereas patients who came from America, Asia and Oceania amounted to 13.2%, 10.1%, 0.2%, respectively. The immigrant survival rate was lower compared to that of children who were born in Italy. This is especially true for acute lymphoblastic leukaemia patients entered an AIEOP protocol, who showed a 10-years survival rate of 71.0% vs. 80.7% (p < 0.001) for immigrants and patients born in Italy, respectively. CONCLUSIONS: Children and adolescents are an increasingly important part of the immigration phenomenon, which occurs in many parts of the world. In Italy the vast majority of children affected by malignancies are treated in AIEOP centres. Since immigrant children are predominantly treated in northern Italy, these centres have developed a special expertise in treating immigrant patients, which is certainly very useful for the entire AIEOP network.
Keywords: Adolescent; Africa; Asia; Child; Child, Preschool; Databases, Factual; Emigrants and Immigrants; Ethnic Groups; Europe, Eastern; European Union; Female; Humans; Incidence; Infant; Infant, Newborn; Italy; Male; Neoplasms; North America; Oceania; Prevalence; Retrospective Studies; South America; Survival Rate

Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability. - Passerini, Laura; Olek, Sven; Di Nunzio, Sara; Barzaghi, Federica; Hambleton, Sophie; Abinun, Mario; Tommasini, Alberto; Vignola, Silvia; Cipolli, Marco; Amendola, Mario; Naldini, Luigi; Guidi, Luisa; et al. (J Allergy Clin Immunol, 2011)
Keywords: Forkhead Transcription Factors; Gene Expression Regulation; Genetic Diseases, X-Linked; Humans; Immunologic Deficiency Syndromes; Intestinal Diseases; Male; Mutation; Polyendocrinopathies, Autoimmune

Frequency distribution of HLA DQ2 and DQ8 in celiac patients and first-degree relatives in Recife, northeastern Brazil. - Castro-Antunes, Margarida Maria; Crovella, Sergio; Brandão, Lucas André Cavalcanti; Guimarães, Rafael Lima; Motta, Maria Eugênia Farias Almeida; Silva, Giselia Alves Pontes da (Clinics (Sao Paulo), 2011)
AIMS: The aim of this study was to evaluate the frequencies of the HLA genotypes DQ2 and DQ8 and the alleles A1*05, A1*0201, B1*0201 and B1*0302 in individuals with celiac disease in Recife, northeastern Brazil. METHODS: HLA DQ2 and DQ8 genotyping was performed for 73 individuals with celiac disease and 126 first-degree relatives with negative transglutaminase serology. The alleles DQA1*05, DQA1*0201, DQB1*02 and DQB1*0302 were identified by sequencing using specific primers and the EU-DQ kit from the Eurospital Laboratory, Trieste, Italy and double-checked by the All Set SPP kit (Dynal). RESULTS: Among the 73 cases, 50 (68.5%) had the genotype DQ2, 13 (17.8%) had DQ8, 5 (6.8%) had DQ2 and DQ8, and 5 did not have any of these genotypes. Among the 5 negative individuals, four had the B1*02 allele and one did not have any of the alleles studied. B1*02 was the most frequent allele in both groups (94% in the patients and 89% in the control relatives). CONCLUSIONS: In this study, celiac disease was associated with the genotypes DQ2 and DQ8. DQ2 predominated, but the distribution of the frequencies was different from what has been found in European populations and was closer to what has been found in the Americas. The high frequencies of the HLA genotypes DQ2 and DQ8 that were found in first-degree relatives would make it difficult to use these HLA genotypes for routine diagnosis of celiac disease in this group.
Keywords: Adolescent; Adult; Brazil; Celiac Disease; Chi-Square Distribution; Child; Child, Preschool; Cross-Sectional Studies; Europe; Family; Female; Gene Frequency; Genetic Predisposition to Disease; HLA-DQ Antigens; Humans; Infant; Male; Middle Aged; Young Adult

Frequency of HLA B*5701 allele carriers in abacavir treated-HIV infected patients and controls from northeastern Brazil. - Crovella, Sergio; Biller, Lara; Santos, Sergio; Salustiano, Ana; Brandão, Lucas; Guimarães, Rafael; Segat, Ludovica; Lima Filho, Jose Luiz de; Arraes, Luiz Claudio (Clinics (Sao Paulo), 2011)
Keywords: Adolescent; Adult; Anti-HIV Agents; Brazil; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Young Adult

Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. - Passerini, Laura; Di Nunzio, Sara; Gregori, Silvia; Gambineri, Eleonora; Cecconi, Massimiliano; Seidel, Markus G; Cazzola, Giantonio; Perroni, Lucia; Tommasini, Alberto; Vignola, Silvia; Guidi, Luisa; Roncarolo, Maria G; et al. (Eur J Immunol, 2011)
Mutations of forkhead box p3 (FOXP3), the master gene for naturally occurring regulatory T cells (nTregs), are responsible for the impaired function of nTregs, resulting in an autoimmune disease known as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The relevance of other peripheral tolerance mechanisms, such as the presence and function of type 1 regulatory T (Tr1) cells, the major adaptive IL-10-producing Treg subset, in patients with IPEX syndrome remains to be clarified. FOXP3(mutated) Tr1-polarized cells, differentiated in vitro from CD4(+) T cells of four IPEX patients, were enriched in IL-10(+) IL-4(-) IFN-γ(+) T cells, a cytokine production profile specific for Tr1 cells, and expressed low levels of FOXP3 and high levels of Granzyme-B. IPEX Tr1 cells were hypoproliferative and suppressive, thus indicating that FOXP3 mutations did not impair their function. Furthermore, we isolated Tr1 cell clones from the peripheral blood of one FOXP3(null) patient, demonstrating that Tr1 cells are present in vivo and they can be expanded in vitro in the absence of WT FOXP3. Overall, our results (i) show that functional Tr1 cells differentiate independently of FOXP3, (ii) confirm that human Tr1 and nTregs are distinct T-cell lineages, and (iii) suggest that under favorable conditions Tr1 cells could exert regulatory functions in IPEX patients.
Keywords: Cell Differentiation; Cell Lineage; Cells, Cultured; Enteritis; Forkhead Transcription Factors; Genetic Diseases, X-Linked; Humans; Immunity, Innate; Interleukin-2 Receptor alpha Subunit; Mutation; Polyendocrinopathies, Autoimmune; Syndrome; T-Lymphocytes, Regulatory

Gastroesophageal reflux disease at any cost: a dangerous paediatric attitude. - Taddio, Andrea; Bersanini, Chiara; Basile, Lucio; Fontana, Massimo; Ventura, Alessandro (Acta Paediatr, 2011)
Keywords: Diagnostic Errors; Gastroesophageal Reflux; Humans; Inappropriate Prescribing; Infant; Infant, Newborn; Male; Proton Pump Inhibitors; Spasms, Infantile

Gastrointestinal Foxp3 expression in normal, inflammatory and neoplastic conditions. - Villanacci, Vincenzo; Not, Tarcisio; Nascimbeni, Riccardo; Ferrara, Fortunato; Tommasini, Alberto; Manenti, Stefania; Antonelli, Elisabetta; Bassotti, Gabrio (Pathology, 2011)
BACKGROUND: Foxp3(+) regulatory T lymphocytes (T-regs) represent an important regulatory cell subset in inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract. METHODS: Inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract (189 cases) were studied with the evaluation of Foxp3 regulatory T cells based on immunohistochemistry. RESULTS: Few Foxp3(+) cells were found in controls and inflammatory conditions (oesophagitis, gastritis, coeliac disease, inflammatory bowel disease); in preneoplastic and neoplastic conditions the number of Foxp3(+) cells was significatively increased. CONCLUSIONS: In normal conditions the number of mucosal lymphocytes is very low throughout the gastro-intestinal tract; in active coeliac disease patients or on a gluten-free diet, only a slight increase in Foxp3(+) cells may be found. Gastrointestinal cancers are associated with higher Foxp3(+) cell proportion, compared with microscopically normal tissue and with precancerous conditions. However, it is uncertain whether the increase in these regulatory cells is a cause or a consequence of tumour progression.
Keywords: Adult; Aged; Celiac Disease; Cell Count; Disease Progression; Esophagitis; Female; Forkhead Transcription Factors; Gastric Mucosa; Gastritis; Humans; Inflammatory Bowel Diseases; Lymphocytes; Male; Middle Aged; Precancerous Conditions; Stomach Diseases; Stomach Neoplasms; Young Adult

Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases. - De Iudicibus, Sara; Stocco, Gabriele; Martelossi, Stefano; Londero, Margherita; Ebner, Egle; Pontillo, Alessandra; Lionetti, Paolo; Barabino, Arrigo; Bartoli, Fiora; Ventura, Alessandro; Decorti, Giuliana (J Clin Gastroenterol, 2011)
BACKGROUND: Glucocorticoids (GCs) are used in moderate-to-severe inflammatory bowel diseases (IBD) but their effect is often unpredictable. AIM: To determine the influence of 4 polymorphisms in the GC receptor [nuclear receptor subfamily 3, group C, member 1 (NR3C1)], interleukin-1β (IL-1β), and NACHT leucine-rich-repeat protein 1 (NALP1) genes, on the clinical response to steroids in pediatric patients with IBD. METHODS: One hundred fifty-four young IBD patients treated with GCs for at least 30 days and with a minimum follow-up of 1 year were genotyped. The polymorphisms considered are the BclI in the NR3C1 gene, C-511T in IL-1β gene, and Leu155His and rs2670660/C in NALP1 gene. Patients were grouped as responder, dependant, and resistant to GCs. The relation between GC response and the genetic polymorphisms considered was examined using univariate, multivariate, and Classification and Regression Tree (CART) analysis. RESULTS: Univariate analysis showed that BclI polymorphism was more frequent in responders compared with dependant patients (P=0.03) and with the combined dependant and resistant groups (P=0.02). Moreover, the NALP1 Leu155His polymorphism was less frequent in the GC responsive group compared with resistant (P=0.0059) and nonresponder (P=0.02) groups. Multivariate analysis comparing responders and nonresponders confirmed an association between BclI mutated genotype and steroid response (P=0.030), and between NALP1 Leu155His mutant variant and nonresponders (P=0.033). An association between steroid response and male sex was also observed (P=0.034). In addition, Leu155His mutated genotype was associated with steroid resistance (P=0.034). Two CART analyses supported these findings by showing that BclI and Leu155His polymorphisms had the greatest effect on steroid response (permutation P value=0.046). The second CART analysis also identified age of disease onset and male sex as important variables affecting response. CONCLUSIONS: These results confirm that genetic and demographic factors may affect the response to GCs in young patients with IBD and strengthen the importance of studying high-order interactions for predicting response.
Keywords: Adolescent; Child; Drug Resistance; Female; Follow-Up Studies; Genotype; Glucocorticoids; Humans; Inflammatory Bowel Diseases; Male; Multivariate Analysis; Polymorphism, Genetic; Receptors, Glucocorticoid; Regression Analysis; Retrospective Studies; Sex Factors; Treatment Outcome

A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. - Chen, S-H; Yang, W; Fan, Y; Stocco, G; Crews, K R; Yang, J J; Paugh, S W; Pui, C-H; Evans, W E; Relling, M V (Leukemia, 2011)
Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (inhibitory concentration (IC)(50)). In CEU lines, we tested 2,390,203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P<0.001) and gene level (P<0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC(50). The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P=8.1 × 10(-3)), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P=5.5 × 10(-5)). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity.
Keywords: Antineoplastic Agents; Asparaginase; Aspartic Acid; Cell Line; Genome-Wide Association Study; Humans; Multivariate Analysis; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. - Wain, Louise V; Verwoert, Germaine C; O'Reilly, Paul F; Shi, Gang; Johnson, Toby; Johnson, Andrew D; Bochud, Murielle; Rice, Kenneth M; Henneman, Peter; Smith, Albert V; Ehret, Georg B; Amin, Najaf; et al. (Nat Genet, 2011)
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Keywords: Arteries; Blood Pressure; Case-Control Studies; Follow-Up Studies; Genetic Loci; Genome-Wide Association Study; Humans; Hypertension; Linkage Disequilibrium; Polymorphism, Single Nucleotide

Geraniol rescues inflammation in cellular and animal models of mevalonate kinase deficiency. - Marcuzzi, Annalisa; Crovella, Sergio; Pontillo, Alessandra (In Vivo, 2011)
BACKGROUND/AIM: The inhibition of the mevalonate pathway through genetic defects such as mevalonate kinase deficiency (MKD) or pharmacological drugs such as aminobisphosphonates causes a shortage of intermediate compounds, in particular geranylgeranyl-pyrophosphate (GGPP), which is associated with the consequent augmented IL-1β release in monocytes. Considering that, due to its biochemical structure, isoprenoid geraniol enters the mevalonate pathway and may revert the genetic or pharmacological inhibition, the present study tested isoprenoid geraniol in cellular and animal MKD models obtained through the use of aminobisphosphonate pamidronate. MATERIALS AND METHODS: The effect of natural isoprenoid geraniol on bacterial induced-inflammation was evaluated in a monocytic cell line (Raw 264.7) and in Balb/c mice treated with pamidronate. RESULTS: Geraniol diminished the levels of inflammatory markers induced by pamidronate stimuli in vitro and in vivo. CONCLUSION: Geraniol may be proposed as a novel therapeutic approach for the orphan disease MKD, and may also be considered for the evaluation of possible inflammatory side-effects of aminobisphosphonates.
Keywords: Animals; Anti-Inflammatory Agents; Cell Line; Diphosphonates; Disease Models, Animal; Inflammation; Lipopolysaccharides; Mevalonate Kinase Deficiency; Mice; Mice, Inbred BALB C; Monocytes; Nitric Oxide; Terpenes

"GINEXMAL RCT: Induction of labour versus expectant management in gestational diabetes pregnancies". - Maso, Gianpaolo; Alberico, Salvatore; Wiesenfeld, Uri; Ronfani, Luca; Erenbourg, Anna; Hadar, Eran; Yogev, Yariv; Hod, Moshe (BMC Pregnancy Childbirth, 2011)
BACKGROUND: Gestational diabetes (GDM) is one of the most common complications of pregnancies affecting around 7% of women. This clinical condition is associated with an increased risk of developing fetal macrosomia and is related to a higher incidence of caesarean section in comparison to the general population. Strong evidence indicating the best management between induction of labour at term and expectant monitoring are missing. METHODS/DESIGN: Pregnant women with singleton pregnancy in vertex presentation previously diagnosed with gestational diabetes will be asked to participate in a multicenter open-label randomized controlled trial between 38+0 and 39+0 gestational weeks. Women will be recruited in the third trimester in the outpatient clinic or in the Day Assessment Unit according to local protocols. Women who opt to take part will be randomized according to induction of labour or expectant management for spontaneous delivery. Patients allocated to the induction group will be admitted to the obstetric ward and offered induction of labour via use of prostaglandins, Foley catheter or oxytocin (depending on clinical conditions). Women assigned to the expectant arm will be sent to their domicile where they will be followed up until delivery, through maternal and fetal wellbeing monitoring twice weekly. The primary study outcome is the Caesarean section (C-section) rate, whilst secondary measurements are maternal and neonatal outcomes. A total sample of 1760 women (880 each arm) will be recruited to identify a relative difference between the two arms equal to 20% in favour of induction, with concerns to C-section rate. Data will be collected until mothers and newborns discharge from the hospital. Analysis of the outcome measures will be carried out by intention to treat. DISCUSSION: The present trial will provide evidence as to whether or not, in women affected by gestational diabetes, induction of labour between 38+0 and 39+0 weeks is an effective management to ameliorate maternal and neonatal outcomes. The primary objective is to determine whether caesarean section rate could be reduced among women undergoing induction of labour, in comparison to patients allocated to expectant monitoring. The secondary objective consists of the assessment and comparison of maternal and neonatal outcomes in the two study arms. .
Keywords: Adolescent; Adult; Cesarean Section; Diabetes, Gestational; Female; Gestational Age; Humans; Intention to Treat Analysis; Labor, Induced; Patient Selection; Pregnancy; Pregnancy Outcome; Research Design; Watchful Waiting; Young Adult

Glutamine-enriched nutrition does not reduce mucosal morbidity or complications after stem-cell transplantation for childhood malignancies: a prospective randomized study. - Uderzo, Cornelio; Rebora, Paola; Marrocco, Emanuela; Varotto, Stefania; Cichello, Francesca; Bonetti, Maurizio; Maximova, Natalia; Zanon, Davide; Fagioli, Franca; Nesi, Francesca; Masetti, Riccardo; Masetti, Roberto; et al. (Transplantation, 2011)
BACKGROUND: Intravenous glutamine-enriched solution seems to be effective in posttransplant period in decreasing the severity and duration of mucositis. The aim of this randomized study was to determine the benefit of glutamine supplementation both on mucosal morbidity and in posttransplant associated complications. METHODS: Children undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) for malignant hematological diseases were randomly assigned to standard total parenteral nutrition (S-TPN) or glutamine-enriched (GE)-TPN solution consisting of 0.4 g/kg/day of l-alanine-glutamine dipeptide. This treatment started on the day of HSCT and ended when the patients could orally cover more than 50% of their daily energy requirements. The severity and the rate of post-HSCT mucositis were based on World Health Organization criteria. All the analyses were conducted on intention-to-treat principle. RESULTS: One hundred twenty consecutive patients (83 men; median age, 8.1 years) were enrolled. The mean duration of treatment was 23.5 and 23 days in the two treatment arms. The mean calorie intake was 1538 kcal/d in the S-TPN group and 1512 kcal/d in GE-TPN group. All patients were well nourished before and after HSCT. Mucositis occurred in 91.4% and 91.7% of patients in S-TPN and GE-TPN arm, respectively (P=0.98). Odds ratio adjusted by type of HSCT was 0.98 (95% confidence interval, 0.26-2.63). Type and duration of analgesic treatment, clinical outcome (engraftment, graft versus host disease, early morbidity, and mortality, relapse rate up to 180 days post-HSCT) were not significantly different in the two treatment arms. CONCLUSION: GE-TPN solution does not affect mucositis and outcome in well-nourished HSCT allogeneic patients.
Keywords: Adolescent; Analgesia; Child; Child, Preschool; Double-Blind Method; Female; Glutamine; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Mucositis; Mucous Membrane; Neoplasms; Odds Ratio; Parenteral Nutrition; Prospective Studies; Recurrence; Stem Cells; Treatment Outcome

Hearing function and thresholds: a genome-wide association study in European isolated populations identifies new loci and pathways. - Girotto, Giorgia; Pirastu, Nicola; Sorice, Rossella; Biino, Ginevra; Campbell, Harry; d'Adamo, Adamo P; Hastie, Nicholas D; Nutile, Teresa; Polasek, Ozren; Portas, Laura; Rudan, Igor; Ulivi, Sheila; et al. (J Med Genet, 2011)
BACKGROUND: Hearing is a complex trait, but until now only a few genes are known to contribute to variability of this process. In order to discover genes and pathways that underlie auditory function, a genome-wide association study was carried out within the International Consortium G-EAR. METHODS: Meta-analysis of genome-wide association study's data from six isolated populations of European ancestry for an overall number of 3417 individuals. RESULTS: Eight suggestive significant loci (p<10(-7)) were detected with a series of genes expressed within the inner ear such as: DCLK1, PTPRD, GRM8, CMIP. Additional biological candidates marked by a single nucleotide polymorphism (SNP) with a suggestive association (p<10(-6)) were identified, as well as loci encompassing 'gene desert regions'-genes of unknown function or genes whose function has not be linked to hearing so far. Some of these new loci map to already known hereditary hearing loss loci whose genes still need to be identified. Data have also been used to construct a highly significant 'in silico' pathway for hearing function characterised by a network of 49 genes, 34 of which are certainly expressed in the ear. CONCLUSION: These results provide new insights into the molecular basis of hearing function and may suggest new targets for hearing impairment treatment and prevention.
Keywords: Adaptor Proteins, Signal Transducing; Animals; Auditory Threshold; Carrier Proteins; Databases, Genetic; Europe; European Continental Ancestry Group; Female; Founder Effect; Genetic Linkage; Genome-Wide Association Study; Hearing; Hearing Loss; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Phenotype; Polymorphism, Single Nucleotide; Protein-Serine-Threonine Kinases; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Receptors, Metabotropic Glutamate

High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. - Tanaka, Naoko; Izawa, Kazushi; Saito, Megumu K; Sakuma, Mio; Oshima, Koichi; Ohara, Osamu; Nishikomori, Ryuta; Morimoto, Takeshi; Kambe, Naotomo; Goldbach-Mansky, Raphaela; Aksentijevich, Ivona; de Saint Basile, Geneviève; et al. (Arthritis Rheum, 2011)
OBJECTIVE: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. METHODS: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations. RESULTS: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. CONCLUSION: Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.
Keywords: Adolescent; Adult; Carrier Proteins; Case-Control Studies; Child; Child, Preschool; Cryopyrin-Associated Periodic Syndromes; Female; Genetic Association Studies; Humans; Infant; Male; Mosaicism

High prevalence of BK polyomavirus sequences in human papillomavirus-16-positive precancerous cervical lesions. - Comar, Manola; Bonifacio, Daniela; Zanconati, Fabrizio; Di Napoli, Michela; Isidoro, Erica; Martini, Fernanda; Torelli, Lucio; Tognon, Mauro (J Med Virol, 2011)
High- and low-grade cervical lesions were analyzed for the presence of polyomavirus (PYV) and human papillomavirus (HPV) sequences. In precancerous cervical lesions, the overall prevalence of PYV sequences was 44% (41/93). Specifically, among the PYV-positive samples, 83% (34/41) tested positive for BK polyomavirus (BKV) sequences, whereas 17% (7/41) were positive for JC-virus. None of the samples were positive for simian virus 40. The presence of BKV DNA in high-grade squamous intraepithelial lesions was confirmed by in situ PCR. BKV sequences were detected more frequently in high-grade squamous intraepithelial lesions, together with the genotype HPV-16. The association of BKV with precancerous cervical lesions suggests that this polyomavirus participates with HPV-16 in the cell transformation process. Alternatively, BKV might multiply better in HPV-16-positive cells from precancerous cervical lesions than in HPV-16-negative cells.
Keywords: Adult; BK Virus; Cervical Intraepithelial Neoplasia; Cervix Uteri; DNA, Viral; Female; Human papillomavirus 16; Human papillomavirus 18; Human papillomavirus 31; Humans; JC Virus; Middle Aged; Oncogene Proteins, Viral; Papillomavirus Infections; Precancerous Conditions; Simian virus 40; Uterine Cervical Diseases

High-throughput genotyping robot-assisted method for mutation detection in patients with hypertrophic cardiomyopathy. - Bortot, Barbara; Athanasakis, Emmanouil; Brun, Francesca; Rizzotti, Diego; Mestroni, Luisa; Sinagra, Gianfranco; Severini, Giovanni Maria (Diagn Mol Pathol, 2011)
Hypertrophic cardiomyopathy (HCM) is the most frequent autosomal dominant genetic heart muscle disease and the most common cause of sudden cardiac death in young people (under 30 y of age), who are often unaware of their underlying condition. Genetic screening is now considered a fundamental tool for clinical management of HCM families. However, the high genetic heterogeneity of HCM makes genetic screening very expensive. Here, we propose a new high-throughput genotyping method based on a HCM 96-well sequencing plate for the analysis of 8 of the most frequent HCM-causing sarcomeric genes by automating several processes required for direct sequencing, using a commercially available robotic systems and routinely used instruments. To assess the efficiency of the robot-assisted method, we have analyzed the entire coding sequence and flanking intronic sequences of the 8 sarcomeric genes in samples from 18 patients affected by HCM and their relatives, which revealed 9 different mutations, 3 of which were novel. The automated, robot-assisted assembling of polymerase chain reaction, purification of polymerase chain reaction products, and assembly of sequencing reactions resulted in a substantial saving of time, reagent costs, and reduction of human errors, and can therefore be proposed as a primary strategy for mutation identification in HCM genetic screening in many medical genetic laboratories.
Keywords: Cardiomyopathy, Hypertrophic; DNA Mutational Analysis; Genetic Predisposition to Disease; Genetic Testing; Genotyping Techniques; High-Throughput Nucleotide Sequencing; Humans; Muscle Proteins; Mutation; Robotics

HLA-G 14 bp deletion/insertion polymorphism in celiac disease. - Fabris, Annalisa; Segat, Ludovica; Catamo, Eulalia; Morgutti, Marcello; Vendramin, Anna; Crovella, Sergio (Am J Gastroenterol, 2011)
OBJECTIVES: Nonclassical major histocompatibility class I HLA-G antigen is a tolerogenic molecule that inhibits lytic activity of natural killer (NK) cells and cytotoxic T lymphocytes. Because of its immunomodulatory and tolerogenic properties, HLA-G molecules may have a role in celiac disease (CD). We analyzed the HLA-G 14 bp deletion/insertion polymorphism, known to have a functional effect on mRNA stability, in a group of 522 CD patients, stratified for the presence of HLA-DQ2 genotype, and 400 healthy individuals to evaluate the possible effect of the polymorphism on the risk to develop the disease. METHODS: HLA-G 14 bp deletion/insertion polymorphism (rs1704) was detected by polymerase chain reaction and double-checked by direct sequencing. RESULTS: The 14 bp inserted (I) allele and the homozygous I/I genotype were significantly more frequent in CD patients than in healthy controls. The presence of I allele was associated with an increased risk of CD (OR 1.35) and the effect of I allele was consistent with a recessive genetic model (P<0.001). CONCLUSIONS: Our results also indicate that the effect of the HLA-G D/I polymorphism is restricted for HLA-DQ2, and not simply due to the presence of linkage disequilibrium with the major known risk factor; moreover we found that the presence of the I allele confers an increased risk of CD in addition to the risk conferred by HLA-DQ2 alone and that subjects that carry both DQ2 and HLA-G I alleles have an increased risk of CD than subjects that carry DQ2 but not the I allele.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Case-Control Studies; Celiac Disease; Child; Child, Preschool; Confidence Intervals; Female; Genetic Predisposition to Disease; Genotype; Histocompatibility Antigens Class I; HLA Antigens; HLA-DQ Antigens; HLA-G Antigens; Humans; Male; Middle Aged; Mutagenesis, Insertional; Odds Ratio; Polymerase Chain Reaction; Polymorphism, Genetic; Reference Values; RNA Stability; Sequence Deletion; Young Adult

Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations. - Abu-Amero, Khaled K; Faletra, Flavio; Gasparini, Paolo; Parentin, Fulvio; Pensiero, Stefano; Alorainy, Ibrahim A; Hellani, Ali M; Catalano, Dario; Bosley, Thomas M (Ophthalmic Genet, 2011)
BACKGROUND: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene. MATERIALS AND METHODS: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s). RESULTS: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities. CONCLUSIONS: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.
Keywords: Child; Humans; Kyphosis; Magnetic Resonance Imaging; Male; Mutation; Ocular Motility Disorders; Oculomotor Nerve Diseases; Pedigree; Receptors, Immunologic; Scoliosis

In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions. - Agostinis, Chiara; Biffi, Stefania; Garrovo, Chiara; Durigutto, Paolo; Lorenzon, Andrea; Bek, Alpan; Bulla, Roberta; Grossi, Claudia; Borghi, Maria O; Meroni, Pierluigi; Tedesco, Francesco (Blood, 2011)
In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes.
Keywords: Animals; beta 2-Glycoprotein I; Complement C1q; Complement C3; Complement C9; Endothelial Cells; Endothelium, Vascular; Female; Fetal Death; Humans; Mice; Mice, Inbred BALB C; Pregnancy; Trophoblasts; Uterus

Interventions for the prevention of overweight and obesity in preschool children: a systematic review of randomized controlled trials. - Monasta, L; Batty, G D; Macaluso, A; Ronfani, L; Lutje, V; Bavcar, A; van Lenthe, F J; Brug, J; Cattaneo, A (Obes Rev, 2011)
The objective of this study was to analyse interventions for the prevention of overweight and obesity in children under 5 years of age. We carried out a systematic review focusing exclusively on randomized controlled trials (RCTs). Data sources include Medline, Cochrane Library, EMBASE, CINHAL, PsychInfo and Web of Science. Data were extracted from seventeen articles describing seven RCTs identified through electronic search, screening of references in systematic reviews, own files and contact with authors. RCTs were assessed with the Jadad scale. Four trials were carried out in preschool settings, one with an exclusive educational component, two with an exclusive physical activity component and one with both. Two trials were family-based, with education and counselling for parents and children. The remaining trial was carried out in maternity hospitals, with a training intervention on breastfeeding. None of the interventions had an effect in preventing overweight and obesity. The failure to show an effect may be due to the choice of outcomes, the quality of the RCTs, the suboptimal implementation of the interventions, the lack of focus on social and environmental determinants. More rigorous research is needed on interventions and on social and environmental factors that could impact on lifestyle.
Keywords: Child Nutrition Sciences; Child Nutritional Physiological Phenomena; Child, Preschool; Exercise; Female; Health Promotion; Humans; Life Style; Male; Obesity; Overweight; Randomized Controlled Trials as Topic

Intranasal lidocaine and midazolam for procedural sedation in children. - Chiaretti, Antonio; Barone, Giuseppe; Rigante, Donato; Ruggiero, Antonio; Pierri, Filomena; Barbi, Egidio; Barone, Giovanni; Riccardi, Riccardo (Arch Dis Child, 2011)
OBJECTIVE: To evaluate the safety and efficacy of a sedation protocol based on intranasal lidocaine spray and midazolam (INM) in children who are anxious and uncooperative when undergoing minor painful or diagnostic procedures, such as peripheral line insertion, venipuncture, intramuscular injection, echocardiogram, CT scan, audiometry testing and dental examination and extractions. PATIENTS AND DESIGN: 46 children, aged 5-50 months, received INM (0.5 mg/kg) via a mucosal atomiser device. To avoid any nasal discomfort a puff of lidocaine spray (10 mg/puff) was administered before INM. The child's degree of sedation was scored using a modified Ramsay sedation scale. A questionnaire was designed to evaluate the parents' and doctors' opinions on the efficacy of the sedation. Statistical analysis was used to compare sedation times with children's age and weight. RESULTS: The degree of sedation achieved by INM enabled all procedures to be completed without additional drugs. Premedication with lidocaine spray prevented any nasal discomfort related to the INM. The mean duration of sedation was 23.1 min. The depth of sedation was 1 on the modified Ramsay scale. The questionnaire revealed high levels of satisfaction by both doctors and parents. Sedation start and end times were significantly correlated with age only. No side effects were recorded in the cohort of children studied. CONCLUSIONS: This study has shown that the combined use of lidocaine spray and atomised INM appears to be a safe and effective method to achieve short-term sedation in children to facilitate medical care and procedures.
Keywords: Administration, Intranasal; Anesthetics, Local; Anxiety; Child, Preschool; Conscious Sedation; Diagnostic Techniques and Procedures; Female; Humans; Hypnotics and Sedatives; Infant; Lidocaine; Male; Midazolam; Minimally Invasive Surgical Procedures; Nebulizers and Vaporizers; Nose Diseases; Prospective Studies

Letter to the editor: acute effects of intravenous administration of pamidronate in patients with osteoporosis. - Marcuzzi, Annalisa; Zanin, Valentina; Vuch, Josef; Pontillo, Alessandra; Crovella, Sergio (J Korean Med Sci, 2011)
Keywords: Anti-Inflammatory Agents; Cytokines; Diphosphonates; Humans; Injections, Intravenous; Osteoporosis

Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene. - Pelagatti, M A; Meini, A; Caorsi, R; Cattalini, M; Federici, S; Zulian, F; Calcagno, G; Tommasini, A; Bossi, G; Sormani, M P; Caroli, F; Plebani, A; et al. (Arthritis Rheum, 2011)
OBJECTIVE: To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA). METHODS: The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL). RESULTS: The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations. CONCLUSION: Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.
Keywords: Adolescent; Antirheumatic Agents; Biological Therapy; Child; Child, Preschool; Familial Mediterranean Fever; Female; Fever; Follow-Up Studies; Genotype; Health Surveys; Humans; Infant; Interleukin 1 Receptor Antagonist Protein; Longitudinal Studies; Lymphadenitis; Male; Mutation; Pharyngitis; Quality of Life; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Recurrence; Retrospective Studies; Steroids; Syndrome

Management of immigration and pregnancy screening in northeastern Italy. - Tamaro, Giorgio; Parco, Sergio (Risk Manag Healthc Policy, 2011)
This study assesses the impact of immigration in Friuli Venezia Giulia, a region of northeastern Italy, on the epidemiological features of hemoglobin patterns and on prothrombotic and trisomy risk in pregnancy for patients of non-Italian origin. This study follows a series of studies on the incidence of thalassemia and other hemoglobinopathies with reduced globin chain synthesis, that were performed during the postwar (1939-45) period in Friuli Venezia Giulia following immigration into the region from Istria and Sardinia (regions of northern and central Italy). Current data show that today's constantly growing immigration into the region differs from previous decades, in terms of origin and quantity of migrants, who mainly come from third world countries. This has a significant impact on health care issues, and more specifically on prospective health screening for foreigners. The authors conclude that scholastic education and hospital services, either public or private, and voluntary associations, may contribute to solving the problem, but only in terms of training and organization, for non-European Union citizens arriving in northern Italy and neighboring areas, especially those from Africa, Asia, Latin America, and eastern Europe.

Management of the adnexal mass. - Ricci, Giuseppe; Zito, Gabriella; Fischer-Tamaro, Leo (Obstet Gynecol, 2011)
Keywords: Female; Humans; Ovarian Neoplasms

Mannose binding lectin gene (MBL2) functional polymorphisms are associated with systemic lupus erythematosus in southern Brazilians. - Sandrin-Garcia, Paula; Brandão, Lucas André Cavalcanti; Coelho, Antônio Victor Campos; Guimarães, Rafael Lima; Pancoto, João Alexandre Trés; Segat, Ludovica; Donadi, Eduardo Antônio; de Lima-Filho, José Luiz; Crovella, Sergio (Hum Immunol, 2011)
Susceptibility to systemic lupus erythematosus (SLE) has been associated with immunologic, environmental, and genetic factors. To uncover a possible association between MBL2 gene polymorphisms and SLE, we analyzed functional polymorphisms in the promoter and first exon of the MBL2 gene in 134 Brazilian SLE patients and 101 healthy controls. Genotype and allele frequencies of MBL2 A/O polymorphism were significantly different between patients and controls, and the O allele was associated with an increased risk of SLE. An association between low mannose binding lectin (MBL) producer combined genotypes and increased risk for SLE was also reported. Furthermore, when stratifying SLE patients according to clinical and laboratory data, an association between the A/O genotype and nephritic disorders and between the X/Y genotype and antiphospholipid syndrome was evident. Combined genotypes responsible for low MBL production were more frequently observed in SLE patients with nephritis. Our results indicate MBL2 polymorphisms as possible risk factors for SLE development and disease-related clinical manifestations.
Keywords: Adolescent; Adult; Aged; Brazil; DNA Mutational Analysis; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Lupus Erythematosus, Systemic; Male; Mannose-Binding Lectin; Middle Aged; Polymorphism, Genetic; Population Groups; Promoter Regions, Genetic

Mannose-binding lectin gene (MBL-2) polymorphism in oral lichen planus. - Barkokebas, Andreza; de Albuquerque T Carvalho, Alessandra; de Souza, Paulo Roberto Eleutério; Gomez, Ricardo Santiago; Xavier, Guilherme Machado; Ribeiro, Camila Maria Beder; Crovella, Sergio; Porter, Stephen Ross; Leão, Jair Carneiro (Clin Oral Investig, 2011)
TNF-α may be associated with the etiopathogenesis of oral lichen planus (OLP), and it has been suggested that polymorphism of mannose-binding lectin (MBL) increases the in vitro production of TNF- α. The aim of the present study was to assess the relevance of genetic diversity of MBL in OLP. The study sample comprised 90 individuals, 45 OLP patients and 45 healthy volunteers. MBL-2 gene was amplified using real-time PCR. Frequency of A/A genotype was 55.6% in OLP and 53.3% in healthy volunteers. Likewise, A/0 heterozygote genotype was found in 42.2% and 35.6%; 2.2% and 11.1%, had the recessive 0/0 genotype respectively. Frequencies of the "A" and "0" alleles were 77% and 23% in the OLP group and 71.2% in control group. There were no statistically significant differences regarding genotype frequency (p = 0.546) or allele frequency (p = 0.497). In conclusion, no significant association was found between polymorphism of MBL-2 gene and OLP.
Keywords: Adolescent; Adult; Aged; Female; Gene Expression Regulation; Gene Frequency; Genes, Recessive; Genetic Variation; Genotype; Heterozygote; Homozygote; Humans; Lichen Planus, Oral; Male; Mannose-Binding Lectin; Middle Aged; Mutation; Polymorphism, Genetic; Real-Time Polymerase Chain Reaction; Tumor Necrosis Factor-alpha; Young Adult

Marriage and parenthood among childhood cancer survivors: a report from the Italian AIEOP Off-Therapy Registry. - Pivetta, Emanuele; Maule, Milena M; Pisani, Paola; Zugna, Daniela; Haupt, Riccardo; Jankovic, Momcilo; Aricò, Maurizio; Casale, Fiorina; Clerico, Anna; Cordero di Montezemolo, Luca; Kiren, Valentina; Locatelli, Franco; et al. (Haematologica, 2011)
BACKGROUND: The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology. DESIGN AND METHODS: We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios. RESULTS: During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51-0.61) and 0.70 (95% CI: 0.65-0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53-0.62) overall, and 1.08 (95% CI: 0.99-1.17) when analyses were restricted to married/cohabiting women CONCLUSIONS: Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood.
Keywords: Adult; Child; Child, Preschool; Cohort Studies; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Infant; Infant, Newborn; Italy; Male; Marriage; Middle Aged; Parents; Registries; Survivors

Mast cells are critically involved in serum-mediated vascular leakage in chronic urticaria beyond high-affinity IgE receptor stimulation. - Bossi, F; Frossi, B; Radillo, O; Cugno, M; Tedeschi, A; Riboldi, P; Asero, R; Tedesco, F; Pucillo, C (Allergy, 2011)
BACKGROUND: Chronic urticaria (CU) is one of the most common skin disorders whose pathogenic mechanisms are not fully clarified. Autoimmune aetiology can be ascribed to 45% of patients with CU, and basophil histamine release is positive in 40% of cases. Our aim was to use a novel approach to evaluate the serum permeabilizing effect to identify the mediators of endothelial cell (EC) leakage and to define the role of mast cells (MCs) in the process. METHODS: Permeabilizing activity of sera from 19 patients with CU and 11 healthy blood donors was evaluated by measuring serum-induced degranulation of two MC lines, expressing (LAD2) or lacking (HMC-1) the IgE receptor. Mast cell supernatant (SN) was then incubated with an EC monolayer, and endothelial permeability was evaluated by Fluorescein isothiocyanate-bovine serum albumin leakage in a transwell system. RESULTS: All 19 patient sera failed to induce direct EC leakage, but 15/19 and 17/19 promoted degranulation of HMC-1 and LAD2, respectively. Interestingly, 85% of autologous serum skin test-negative sera were able to cause MC degranulation. Also, 17/19 SNs from HMC-1 and all SNs from LAD2 incubated with CU sera increased endothelial permeability. Endothelial cell leakage remained unchanged after Ig depletion and was prevented by antihistamine, platelet-activating factor or leukotriene antagonist. CONCLUSIONS: Our study shows that CU sera are able to degranulate MCs through an IgE- and IgG-independent mechanism. The nature of histamine-releasing factors involved is still unclear, but our finding opens new ways to the understanding of the pathogenesis of CU, particularly in patients not showing circulating autoantibodies to FcεRI or IgE.
Keywords: Adult; Aged; Capillary Permeability; Chronic Disease; Endothelial Cells; Female; Histamine Release; Humans; Male; Mast Cells; Middle Aged; Receptors, IgE; Serum; Urticaria; Young Adult

Maternal height should be considered in the evaluation of macrosomia related risk of infant injuries at birth. - Monasta, Lorenzo (Acta Obstet Gynecol Scand, 2011)
Keywords: Birth Injuries; Body Height; Female; Fetal Macrosomia; Humans; Infant, Newborn; Pregnancy; Risk Assessment

MBL1 gene in nonhuman primates. - Segat, Ludovica; Crovella, Sergio (Hum Immunol, 2011)
With the aim of investigating the evolution of MBL1P1 (MBL1) gene, we analyzed the MBL1 coding region sequences in several specimens of two species of great apes, two species of Hylobatidae, four species of Cercopithecidae, and one Platyrrhine species, and in human beings. An indication for a progressive silencing of the molecule has been found. We found a ∼300 bp insertion in the first intron of MBL1 in the Cercopithecidae that could explain the different splicing between primates species and possibly why Macaca mulatta is able to produce a complete protein, whereas in human beings the protein product is truncated. Based on our genetic findings, we could speculate that all the Cercopithecidae (presenting the 300-bp insertion) may express MBL1 mature protein like the M mulatta, whereas the lesser and great apes, which lack this insertion as do human beings, may have only the truncated pseudogene.
Keywords: Animals; Base Sequence; Evolution, Molecular; Gene Silencing; Genome; Humans; Mannose-Binding Lectin; Molecular Sequence Data; Multigene Family; Phylogeny; Polymorphism, Genetic; Primates; Pseudogenes; Sequence Alignment; Sequence Analysis, DNA; Sequence Deletion; Species Specificity

MBL2 polymorphisms and the choice of controls for association studies: just another story? - Segat, L; Crovella, S (Int J Immunogenet, 2011)
Keywords: Antibodies; Brazil; Control Groups; Gene Frequency; Genetic Association Studies; Genetic Heterogeneity; Genetic Predisposition to Disease; Hepatitis C; Humans; Mannose-Binding Lectin; Polymorphism, Genetic; Thyroid Gland

Merkel cell polyomavirus DNA sequences in the buffy coats of healthy blood donors. - Pancaldi, Cecilia; Corazzari, Valentina; Maniero, Stefania; Mazzoni, Elisa; Comar, Manola; Martini, Fernanda; Tognon, Mauro (Blood, 2011)
Merkel cell polyomavirus (MCPyV), a DNA tumor virus, has been found to be associated with Merkel cell carcinoma and chronic lymphocytic leukemia. MCPyV sequences have also been detected in various normal tissues in tumor-affected patients. Immunologic studies have detected MCPyV antibodies in as many as 80% of healthy blood donors. This high seroprevalence suggests that MCPyV infection is widespread in humans. In our study, buffy coats, which were examined for MCPyV DNA Tag sequences, showed a prevalence of 22%. Viral DNA load was revealed in blood samples from 10 to 100 molecules/100 000 cells. DNA sequencing confirmed that polymerase chain reaction amplicons belong to the MCPyV strain, MKL-1. To interpret the putative role of MCPyV in chronic lymphocytic leukemia, we may infer that, during a long period of viral persistence in blood cells, this DNA tumor virus may generate mutants, which are able to participate as cofactors in the multistep process of cell transformation.
Keywords: Adult; Aged; Base Sequence; Blood Buffy Coat; Carcinoma, Merkel Cell; Databases, Nucleic Acid; DNA, Viral; Expressed Sequence Tags; Humans; Italy; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polyomavirus; Polyomavirus Infections; Prevalence; Reverse Transcriptase Polymerase Chain Reaction; Sequence Alignment; Sequence Analysis, DNA; Tumor Virus Infections; Viral Load; Young Adult

miR-34a induces the downregulation of both E2F1 and B-Myb oncogenes in leukemic cells. - Zauli, Giorgio; Voltan, Rebecca; di Iasio, Maria Grazia; Bosco, Raffaella; Melloni, Elisabetta; Sana, Maria Elena; Secchiero, Paola (Clin Cancer Res, 2011)
PURPOSE: To elucidate new molecular mechanisms able to downregulate the mRNA levels of key oncogenes, such as B-Myb and E2F1, in a therapeutic perspective. EXPERIMENTAL DESIGN: B-Myb and E2F1 mRNA levels were evaluated in primary B chronic lymphocytic leukemia (B-CLL, n = 10) and acute myeloid leukemia (AML, n = 5) patient cells, in a variety of p53(wild-type) and p53(mutated/deleted) leukemic cell lines, as well as in primary endothelial cells and fibroblasts. Knockdown experiments with siRNA for p53 and E2F1 and overexpression experiments with miR34a were conducted to elucidate the role of these pathways in promoting B-Myb downregulation. RESULTS: In vitro exposure to Nutlin-3, a nongenotoxic activator of p53, variably downregulated the expression of B-Myb in primary leukemic cells and in p53(wild-type) myeloid (OCI, MOLM) and lymphoblastoid (SKW6.4, EHEB) but not in p53(mutated) (NB4, BJAB, MAVER) or p53(deleted) (HL-60) leukemic cell lines. The transcriptional repression of B-Myb was also observed in primary normal endothelial cells and fibroblasts. B-Myb downregulation played a critical role in the cell-cycle block in G(1) phase induced by Nutlin-3, as shown by transfection experiments with specific siRNA. Moreover, we have provided experimental evidence suggesting that miR-34a is a central mediator in the repression of B-Myb both directly and through E2F1. CONCLUSIONS: Owing to the role of B-Myb and E2F1 transcription factors in controlling cell-cycle progression of leukemic cells, the downregulation of these oncogenes by miR-34a suggests the usefulness of therapeutic approaches aimed to modulate the levels of miR-34a.
Keywords: Base Sequence; Cell Cycle Proteins; Cell Line, Tumor; Cells, Cultured; Down-Regulation; E2F1 Transcription Factor; Gene Expression Regulation, Leukemic; HCT116 Cells; HL-60 Cells; Humans; Imidazoles; Leukemia; MicroRNAs; Models, Biological; Oncogenes; Piperazines; Sequence Homology, Nucleic Acid; Trans-Activators; Transfection

The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease. - Pontillo, Alessandra; Vendramin, Anna; Catamo, Eulalia; Fabris, Annalisa; Crovella, Sergio (Am J Gastroenterol, 2011)
OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD. METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls. RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42). CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.
Keywords: Adaptor Proteins, Signal Transducing; Adolescent; Apoptosis Regulatory Proteins; Carrier Proteins; Celiac Disease; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genotype; Glutamine; Haplotypes; Humans; Inflammasomes; Italy; Lysine; Male; Mutation, Missense; Polymorphism, Single Nucleotide