A large comparison of integrated SAR/QSAR models of the Ames test for mutagenicity$.

Results from the Ames test are the first outcome considered to assess the possible mutagenicity of substances. Many QSAR models and structural alerts are available to predict this endpoint. From a regulatory point of view, the recommendation from international authorities is to consider the predictions of more than one model and to combine results in order to develop conclusions about the mutagenicity risk posed by chemicals. However, the results of those models are often conflicting, and the existing inconsistency in the predictions requires intelligent strategies to integrate them. In our study, we evaluated different strategies for combining results of models for Ames mutagenicity, starting from a set of 10 diverse individual models, each built on a dataset of around 6000 compounds. The novelty of our study is that we collected a much larger set of about 18,000 compounds and used the new data to build a family of integrated models. These integrations used probabilistic approaches, decision theory, machine learning, and voting strategies in the integration scheme. Results are discussed considering balanced or conservative perspectives, regarding the possible uses for different purposes, including screening of large collection of substances for prioritization.

Results of a round-robin exercise on read-across.

A round-robin exercise was conducted within the CALEIDOS LIFE project. The participants were invited to assess the hazard posed by a substance, applying in silico methods and read-across approaches. The exercise was based on three endpoints: mutagenicity, bioconcentration factor and fish acute toxicity. Nine chemicals were assigned for each endpoint and the participants were invited to complete a specific questionnaire communicating their conclusions. The interesting aspect of this exercise is the justification behind the answers more than the final prediction in itself. Which tools were used? How did the approach selected affect the final answer?

Comparison of in silico tools for evaluating rat oral acute toxicity.

Different in silico models have been developed and implemented for the evaluation of mammalian acute toxicity, exploring acute oral toxicity data expressed as median lethal dose (LD(50)). We compared five software programs (TOPKAT, ACD/ToxSuite, TerraQSAR, ADMET Predictor and T.E.S.T.) using a dataset of 7417 chemicals. We tested the models' performance using the quantitative results and, in classification, the toxicity threshold defined within the Classifying, Labelling and Packaging (CLP) regulation. ACD gave the best results with r(2) of 0.79 and 0.66 accuracy. However, its performance dropped when considering the molecules not present in its training set, and the other models behaved similarly. We also considered the information on the applicability domain (AD), which improved the models' performance, but not enough for the molecules external to the models' training set. We also considered the chemical classes and found that all models gave high performance for certain classes (e.g. hydrazones and sulphides) while other classes were always badly predicted (e.g. aromatic secondary amides).

ToxRead: a tool to assist in read across and its use to assess mutagenicity of chemicals.

Life sciences, and toxicology in particular, are heavily impacted by the development of methods for data collection and data analysis; they are moving from an analytical approach to a modelling approach. The scarce availability of experimental data is a known bottleneck in assessing the properties of new chemicals. Even when a model is available, the resulting predictions have to be assessed by close scrutiny of the chemicals and the biological properties of the compounds concerned. To avoid unnecessary testing, a read across strategy is often suggested and used. In this paper we discuss how to improve and standardize read across activity using ad hoc visualization and data search methods which use similarity measures and fragment search to organize in a chart a picture of all the relevant information that the expert needs to make an assessment. We show in particular how to apply our system to the case of mutagenicity.

Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction.

This work proposes a new structure-activity relationship (SAR) approach to mine molecular fragments that act as structural alerts for biological activity. The entire process is designed to fit with human reasoning, not only to make the predictions more reliable but also to permit clear control by the user in order to meet customized requirements. This approach has been tested on the mutagenicity endpoint, showing marked prediction skills and, more interestingly, bringing to the surface much of the knowledge already collected in the literature as well as new evidence.

Increased large artery intima media thickness in adolescents with either classical or non-classical congenital adrenal hyperplasia.

BACKGROUND: Increased artery intima-media thickness (IMT) was found in adults with classical congenital adrenal hyperplasia (CAH). No data are available in patients with non-classical (NC) CAH. AIMS: To evaluate IMT in adolescents with classical and NC CAH and to compare the results with those recorded in a control population. PATIENTS AND METHODS: Eighteen adolescents with either classical (Subgroup A1) or NC CAH (Subgroup A2) were compared with 16 controls (Group B). All subjects underwent IMT ultrasonography measurement at different sites; results were correlated with clinical, metabolic, and insulin resistance (IR) data. RESULTS: When compared with Group B, both subgroups exhibited higher IMT values at all sites. No differences were found between classical and NC CAH. Univariate analysis of factors impacting on IMT of CAH patients demonstrated that: a) abdominal aorta (AA) IMT was positively correlated with cumulative glucocorticoid doses, triglyceride serum levels, and diastolic blood pressure SD score and negatively with androstenendione and ACTH levels; b) common carotid (CC) IMT was positively associated with triglycerides and triglyceride/HDL ratio. At multiple regression analysis, the independent positive predictors of AA and CC IMT were respectively triglyceride levels and triglyceride/HDL ratio. CONCLUSIONS: a) Even adolescents with NC CAH and not only those with classical form may be at higher risk of artery alterations; b) this risk is not necessarily associated with either obesity or waist/height ratio or dyslipidemia; c) an important role in the pathogenesis of artery alterations in CAH may be played by intermittent iatrogenic hypercortisolism and secondary IR.

Impacts of marine aquaculture at large spatial scales: evidences from N and P catchment loading and phytoplankton biomass.

While several studies point at off-shore aquaculture as a possible source of impacts on the local marine environment, very few have analysed its effects at large scales such as at the bay, gulf or basin levels. Similar analyses are hampered by the multiple sources of disturbance that may concomitantly affect a given area. The present paper addresses these issues taking the Gulf of Castellammare (Southern Tyrrhenian Sea) as an example. Nitrogen (N) and phosphorous (P) loads were calculated for the period 1970-2007, and compared to chlorophyll-a concentration as measured inside and outside the Gulf over the same period. Results indicate that N and P catchment loading has constantly decreased because of improved environmental management. Nevertheless, nutrient concentration in the Gulf has steadily increased since the establishment of aquaculture facilities in 1999. Chlorophyll-a concentration followed this trend, showing a marked increase from 2001 onwards. In the same period, chlorophyll-a concentrations measured inside and outside the Gulf have significantly diverged. As all the other possible causes can be ruled out, aquaculture remains the sole explanation for the observed situation. This paper demonstrates for the first time ever that off-shore aquaculture may affect the marine ecosystem well beyond the local scale and provides an additional element of concern to be kept into consideration when allocating oceans' space for new fish-farming activities.

QSAR modelling of the toxicity to Tetrahymena pyriformis by balance of correlations.

Balance of correlations is an approach to build up quantitative structure-property/activity relationships (QSPR/QSAR). This approach is based on a split into the subtraining, calibration and test sets instead of classic split into training and test sets. The function of the calibration set is the preliminary check up of the model. In other words, the calibration set is like a preliminary test set. Computational experiments (with the Monte Carlo method) have shown that the statistical characteristics of the prediction for the toxicity to Tetrahymena pyriformis (the 50% growth inhibition concentration, IGC(50)) based on the balance of correlations are better than the statistical characteristics of the prediction based on the classic scheme.

Canonical Measure of Correlation (CMC) and Canonical Measure of Distance (CMD) between sets of data. Part 1. Theory and simple chemometric applications.

So far, similarity/diversity of objects has been widely studied in different research fields and a number of distance measures to estimate diversity between objects have been proposed. However, not much interest has been addressed to analysis of how diverse are configurations of objects in two different multivariate spaces. Since computerisation and automation nowadays lead to a large availability of information, it is apparent that a system could be described in different ways and, consequently, methods for comparison of the different viewpoints are required. These methods, for instance, may be usefully applied to Quantitative Structure-Activity Relationship (QSAR) studies. In this field, several thousands of molecular descriptors have been proposed in the literature and different selections of descriptors define different chemical spaces that need to be compared. Moreover, variable selection techniques such as Genetic Algorithms, Simulated Annealing, and Tabu Search are widely used to process available information in order to select optimal QSAR models. When more than one optimal model results, the problem arising is how to compare these models to find out whether they are really diverse or based on descriptors explaining almost the same information. In this paper, novel indices are proposed to measure similarity/diversity between pairs of data sets by the aid of the variable cross-correlation matrix.

Canonical Measure of Correlation (CMC) and Canonical Measure of Distance (CMD) between sets of data Part 2. Variable reduction.

This paper proposes a new method for determining the subset of variables that reproduce as well as possible the main structural features of the complete data set. This method can be useful for pre-treatment of large data sets since it allows discarding variables that contain redundant information. Reducing the number of variables often allows one to better investigate data structure and obtain more stable results from multivariate modelling methods. The novel method is based on the recently proposed canonical measure of correlation (CMC index) between two sets of variables [R. Todeschini, V. Consonni, A. Manganaro, D. Ballabio, A. Mauri, Canonical Measure of Correlation (CMC) and Canonical Measure of Distance (CMD) between sets of data. Part 1. Theory and simple chemometric applications, Anal. Chim. Acta submitted for publication (2009)]. Following a stepwise procedure (backward elimination), each variable in turn is compared to all the other variables and the most correlated is definitively discarded. Finally, a key subset of variables being as orthogonal as possible are selected. The performance was evaluated on both simulated and real data sets. The effectiveness of the novel method is discussed by comparison with results of other well known methods for variable reduction, such as Jolliffe techniques, McCabe criteria, Krzanowski approach and its modification based on genetic algorithms, loadings of the first principal component, Key Set Factor Analysis (KSFA), Variable Inflation Factor (VIF), pairwise correlation approach, and K correlation analysis (KIF). The obtained results are consistent with those of the other considered methods; moreover, the advantage of the proposed CMC method is that calculation is very quick and can be easily implemented in any software application.

QSAR modelling of carcinogenicity by balance of correlations.

Optimal descriptors based on the simplified molecular input line entry system (SMILES) have been utilized in modeling of carcinogenicity. Carcinogenicity of 401 compounds has been modeled by means of balance of correlations for the training (n = 170) and calibration (n = 170) sets. The obtained models were evaluated with an external test set (n = 61). Comparison of models based on the balance of correlations and models which were obtained on the basis of the total training set (i.e., both training and calibration sets as the united training set) has shown that the balance of correlations improves the statistical quality for the external test set.

[Crossed renal ectopia. Report of two cases and literature review]. / Ectopia renale crociata. Descrizione di due casi e revisione della letteratura.

Renal ectopia is a malformative uropathy classified as simple and crossed. The authors report two patients with renal ectopia (one case of ERC without fusion and one case of ERC with fusion). The authors review the literature about crossed renal ectopia and discuss the importance of early diagnosis and the advantage of thorough investigation in order to exclude associated anomalies.

Sarcoglycan immunoreactivity is lacking in infantile hypertrophic pyloric stenosis. A confocal laser scanning microscopic study.

OBJECTIVES: The Dystrophin-Glycoprotein Complex (DGC) is a large multisubunit complex that plays a crucial role in maintaining the structural integrity and physiology of muscle fibers. Dystrophin has been reported to be absent in the pyloric muscle of infantile hypertrophic pyloric stenosis (IHPS) patients. The present study was designed to investigate the other two patterns of DGC (dystroglycan and sarcoglycan complexes) in normal pyloric muscle and their possible modifications in IHPS patients. METHODS: Ten pyloric muscle biopsies were obtained from babies operated for IHPS and five control pylorus biopsy taken at autopsy from cases without gastrointestinal disease. The DGC sub-complexes (beta-dystroglican and beta, delta- sarcoglycans) were localized immunohistochemically using specific monoclonal antibodies. The results were evaluated using a confocal laser scanning microscope. RESULTS: Positive immunolocalization of the two DGC sub complexes was demonstrated in the smooth muscle cells (SMCs) of the pyloric region of control patients. Similarly, a positive immune expression of beta-dystroglican was observed in the pyloric SMCs of IHPS patients. On the other hand a negative immunoreaction for sarcoglycans was recorded within the full thickness of the pyloric SMCs of these patients. CONCLUSIONS: The absence of sarcoglycans within the hypertrophied pyloric muscle may be a predisposing factor in the pathogenesis of IHPS since it could alter the normal physiology of SMCs through the modifications of structural integrity of sarcolemma and signaling between the extracellular and intracellular compartment.

[Conservative treatment of pediatric spleen trauma. Twenty years of experience]. / Trattamento conservativo dei traumi splenici in età pediatrica. Venti anni di esperienza.

OBJECTIVE: The spleen is the most frequently involved organ in abdominal blunt traumas. In the last decade the treatment has changed from an exclusive surgical approach to a conservative approach. We report our experience in the last twenty years. METHODS: Between 1983-2003, 54 patients with blunt abdominal traumas and isolated injury have been treated. The age at the time of diagnosis was 3 to 16 years (mean, 6.5). The diagnosis was made clinically and with imaging techniques (radiographic assessment, scintigraphy, US, CT). In all cases, a conservative treatment was started with continuous vital parameters monitoring, blood red cells count, hemoglobin, hematocrit; volume infusion and when necessary hemo-transfusion. Clinical follow-up and US monitoring were performed for six months after the trauma. RESULTS: In the period 1983-1993 a conservative treatment was tried in 23 patients; in 15 cases it was successfully, in 8 cases a laparotomy with splenectomy was necessary due to hemodinamic instability. In the second decade we observed 31 patients, all had been treated conservatively. The mean hospital stay was of 12 days with no deaths. CONCLUSIONS: Conservative treatment for splenic injuries in patients with hemodinamic stability is nowadays the treatment choice. Constantly monitoring of clinical, laboratory parameters and use of modern imaging techniques allows to follow the evolution of the lesion and to avoid, in most cases, a surgical treatment.

[Acute abdomen caused by Salmonella typhi acute appendicitis]. / Addome acuto da appendicite acuta secondaria a Salmonella typhi.

Salmonella infections can manifest themselves as acute abdominal problems and lead to emergency surgery. Some examples are: salmonella-related intestinal perforations, gallbladder involments, salpingitis, and peritonitis. Mesenteric lymphadenitis associated with salmonella mimics acute appendicitis and it is often difficult to establish a timely and tempestive diagnosis in children with right lower abdominal pain. Because of the difficult diagnostic process, a significant number of patients with salmonella infections present acute abdomen and undergo needless operations. Instead, in our case of salmonella-related acute abdomen, laparotomy was the right therapeutic choice. The conclusion is drawn that, even if there is not a precise diagnosis, in salmonella-related acute abdomen the surgical approach is the right choice, considering the high morbidity and mortality associated with untreated appendicitis and intestinal perforations.

[Preputioplasty in the treatment of phimosis in pediatric age. Indications and results]. / La prepuzioplastica nel trattamento della fimosi in età pediatrica. Indicazioni e risultati.

AIM: Phimosis is a common condition in the pediatric age. Circumcision has been the technique of choice for the surgical correction of this condition. As an alternative to circumcision different techniques of preputioplasty have been described in the last years. The aim of this paper was to report our experience with the preputioplasty technique in the treatment of phimosis in pediatric age. METHODS: A preputioplasty is performed for phimosis correction in 109 patients aged between 4 and 16 years. Patients with a sclerotic phimosis were not treated with preputioplasty. All the patients underwent frenulotomy with dorsal preputial plasty using a single dorsal incision. Only in 3 patients a double lateral incision was necessary. Patients were operated under general anesthesia with an average time of 8 min. RESULTS: Patients were followed-up at 8 days, 30 and 90 days postoperatively. The cosmetic result has been excellent in 90% of cases and good in 10%. The functional result has been excellent in all the patients. We observed 3 cases of infection and 8 cases of edema of the prepuce. These postoperative complications were all resolved with medical therapy. No recurrences have been observed. CONCLUSIONS: Preputioplasty is a safe and rapid technique that allows to obtain excellent cosmetic and functional results. In our opinion, preputioplasty should be the first choice technique for the treatment of phimosis in pediatric and adolescent age.

Surgical correction of penoscrotal transposition associated with hypospadias and bifid scrotum: our experience of two-stage repair.

OBJECTIVE: To assess the results of surgical correction of incomplete penoscrotal transposition and bifid scrotum using the Glenn-Anderson technique, and its impact on subsequent definitive urethroplasties and final outcome. PATIENTS AND METHODS: We retrospectively reviewed 31 children that underwent two-stage repair for incomplete penoscrotal transposition with severe hypospadias and bifid scrotum. Patient age at stage 1 ranged from 12 to 24 months (average 16 months). The operative principle was based on achieving a normal anatomical position of the penis and scrotum using the Glenn-Anderson technique. In cases with associated scrotal or perineal hypospadias this was transformed into a penoscrotal hypospadias. Final stage urethroplasty was performed after a period of 6 months with a modified Thiersch-Duplay technique. RESULTS: Cosmetic and functional results of the Glenn-Anderson operation were excellent. No major complications were observed. Of 31 patients, 12 (38%) had complications secondary to urethral repair. CONCLUSION: The Glenn-Anderson technique for reconstruction of penoscrotal transposition and bifid scrotum is a simple technique, free of major complications. The purpose of this intervention is to improve the cosmetic appearance and function of the penis. A minimum period of 6 months between consecutive urethroplasties is important. The final stage guarantees good functional and cosmetic results preserving the prepuce.

[Esophagoscopy in pediatric surgery]. / L'esofagoscopia in chirurgia pediatrica.

Esophagoscopy in pediatric surgery represents about 70% of examinations of upper digestive tract. The authors present their experience with pediatric surgical endoscopy. They show the importance of this procedure in pediatric population, which provides clear diagnostic answers and represents a good alternative to traditional surgical procedures.

Bilateral neonatal adrenal abscess. Report of two cases and review of the literature.

Neonatal adrenal abscess is an extremely rare condition. 32 cases, 4 bilateral, have been described in the world literature. We treated successfully other two bilateral cases. We report on this rare condition and review the world literature. In our Department we observed two patients in the neonatal period with abdominal distension, vomiting, irritability and fever. Abdominal ultrasound (US), plain x-ray of the abdomen, intravenous pyelography and computed tomography (CT) of the abdomen were performed. In both cases bilateral suprarenal cystic masses were identified. Vanilmandelic acid, Homovanillic acid and cathecolamines were normal. The two neonates underwent a surgical exploration. Abscesses were found and drained releasing a moderate amount of haemorrhagic and purulent materials from the adrenal glands. Post-operative histology on the surgical specimen showed in both cases an abscess in partial haemorrhagic adrenal glands. No neoplastic cells were observed. The recovery was uneventful and at six months follow-up both patients were well and without signs of adrenal insufficiency. Haematogenous bacteria seeding a normal gland or abscess formation in a previous haemorrhagic gland are the most accredited theories. Neuroblastoma, Wilm's tumor and renal duplication with dilatation of the upper segment must be considered in the differential diagnosis. Percutaneous drainage (+/- biopsy) under CT or US guide should be considered the treatment of choice, followed by surgical exploration when diagnosis is not clear.