Radical Scavenging Mechanisms of 1-Arylhydrazone Benzimidazole Hybrids with Neuroprotective Activity.

Benzimidazole-arylhydrazone hybrids showed promising potential as multifunctional drugs for the treatment of neurodegenerative disorders. The neuroprotection studies conducted using an in vitro model of H2O2-induced oxidative stress on the SH-SY5Y cell line revealed a remarkable activity of the compound possessing a vanilloid structural fragment. The cell viability was preserved up to 84% and this effect was significantly higher than the one exerted by the reference compounds melatonin and rasagiline. Another compound with a catecholic moiety demonstrated the second-best neuroprotective activity. Computational studies were further conducted to characterize in depth the antioxidant properties of both compounds. The possible radical scavenging mechanisms were estimated as well as the most reactive sites through which the compounds may deactivate a variety of free radicals. Both of the compounds are able to deactivate not only the highly reactive hydroxyl radicals but also alkoxyl and hydroperoxyl radicals, following hydrogen atom transfer or radical adduct formation mechanism. In nonpolar medium, 3e is predicted to react slightly faster than 3a with alkoxyl radicals and around two orders of magnitude faster than 3a with hydroperoxyl radicals. The most reactive sites for formal hydrogen atom transfer in 3a are the meta-hydroxy group in the phenyl ring in water and the amide N-H group in benzene; in 3e, the amide N-H group is more reactive in both solvents. The radical adduct formation can occur at several positions in 3a and 3e, the most active being C4, C6, and C14. The stability of the formed radicals was estimated by NBO calculations. The NBO calculations indicated that the spin density in the radicals formed by the abstraction of a hydrogen atom from the amide groups of both compounds is delocalized over the phenyl ring and the hydrazone chain. The obtained theoretical data for the better radical scavenging ability of the vanilloid hybrid corroborate its experimentally established better neuroprotective activity.

Pediatric endoscopy training across Europe: a survey of the ESPGHAN National Societies Network 2016-2019.

Background and study aims The ability to perform endoscopy procedures safely and effectively is a key aspect of quality clinical care in Pediatric Gastroenterology, Hepatology and Nutrition (PGHN). The aim of this survey, which was part of a global survey on PGHN training in Europe, was to assess endoscopy training opportunities provided across Europe. Methods Responses to standardized questions related to endoscopy training were collected from training centers across Europe through the presidents/representatives of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition National Societies from June 2016 to December 2019. Results A total of 100 training centers from 19 countries participated in the survey. In 57 centers, the endoscopy suit was attached to the PGHN center, while in 23, pediatric endoscopies were performed in adult endoscopy facilities. Ninety percent of centers reported the availability of specialized endoscopy nurses and 96 % of pediatric anesthetists. Pediatric endoscopies were performed by PGHN specialists in 55 centers, while 31 centers reported the involvement of an adult endoscopist and 14 of a pediatric surgeon. Dividing the number of procedures performed at the training center by the number of trainees, ≤ 20 upper, lower, or therapeutic endoscopies per trainee per year were reported by 0 %, 23 %, and 56 % of centers, respectively, whereas ≤ 5 wireless capsule endoscopies per trainee per year by 75 %. Only one country (United Kingdom) required separate certification of competency in endoscopy. Conclusions Differences and deficiencies in infrastructure, staffing, and procedural volume, as well as in endoscopy competency assessment and certification, were identified among European PGHN training centers limiting training opportunities in pediatric endoscopy.

Molecular screening for fragile X syndrome in children with unexplained intellectual disability and/or autistic behaviour.

INTRODUCTION: Fragile X syndrome (FXS, OMIM #300624) is the most common inherited form of intellectual disability and the leading monogenic cause of autism.

Variants of uncertain significance in the era of next-generation sequencing.

ABSTRACT: Next-generation sequencing (NGS) is now widely used in diagnosing rare diseases. However, it has some limitations, such as variants of uncertain significance (VUS). This can present difficulties even for nurse practitioners involved in clinical genetics. We present three cases from our clinical practice: two targeted panel testing and one exome sequencing. Whole blood samples were collected and sent for NGS analysis. In case 1, a VUS was found in the LITAF gene, which is associated with autosomal dominant Charcot-Marie-Tooth disease type 1C. In case 2, a VUS was reported in the MEFV gene, which is associated with autosomal recessive and autosomal dominant familial Mediterranean fever. In these cases, the reported VUS corresponded to the clinical diagnosis. In case 3, two variants in the heterozygous state were found in the ATP7B gene, which is associated with Wilson disease, and the disorder was later clinically recognized. According to the published guidelines, VUSs should not be discussed as a cause for an observed genetic condition. Nevertheless, if the reported variant is in a gene associated with the clinically diagnosed disorder, and there is a strong genotype-phenotype correlation, it could be suggestive of the etiological role of this variant.

Training in pediatric neurogastroenterology and motility across Europe: a survey of the ESPGHAN National Societies Network 2016-2019.

Background: Pediatric gastrointestinal motility disorders present significant challenges for diagnosis and management, emphasizing the need for appropriate training in Pediatric Neurogastroenterology and Motility (PNGM). The aim of this survey, part of a comprehensive survey on training in pediatric gastroenterology, hepatology and nutrition, was to evaluate training related to PNGM across European training centers. Method: Standardized questionnaires were collected from training centers through the National Societies Network of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), from June 2016 to December 2019. Results: In total, 100 training centers from 19 countries participated in the survey. Dedicated PNGM clinics were available in 22 centers; pH-monitoring in 60; pH/impedance in 66; standard manometry in 37; and high-resolution manometry in 33. If all motility studies were performed partially or fully by the trainees, the median (range) annual numbers/per trainee were as follows: pH-monitoring 30 (1-500); pH/impedance 17 (1-131); standard manometries 10 (1-150); and high-resolution manometries 8 (1-75). The motility assessment was performed by pediatric gastroenterologists (43 centers); adult gastroenterologists (10 centers); pediatric surgeons (5 centers); and both pediatric gastroenterologists and pediatric surgeons (9 centers). Annual numbers ≤10 for pH-monitoring, pH/impedance, standard manometries and high-resolution manometries were reported by 7 (12%), 15 (23%), 11 (30%) and 14 (42%) centers, respectively. Conclusions: Significant differences exist in PNGM-related infrastructure, staff and procedural volumes at training centers across Europe. ESPGHAN and the National Societies should take initiatives to ensure the acquisition of competence in PNGM-related knowledge and skills, and develop strategies for assessment and accreditation.An infographic is available for this article at: http://www.annalsgastro.gr/files/journals/1/earlyview/2022/Infographic-AG6486.pdf.

Association of training standards in pediatric gastroenterology, hepatology and nutrition in European training centers with formal national recognition of the subspecialty: a survey of the ESPGHAN National Societies Network 2016-2019.

Background: This survey evaluated the effects of the recognition of pediatric gastroenterology, hepatology and nutrition (PGHN) on European PGHN training centers. Method: Standardized questionnaires were collected from training centers via the presidents/representatives of the National Societies Network of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, from June 2016 to December 2019. Results: A total of 100 training centers from 19 countries participated in the survey: 55 from 12 countries where PGHN is formally recognized (Group 1) and 45 from 7 countries where it is not (Group 2). Training centers in Group 2 were less likely to have an integrated endoscopy suite, a written training curriculum and a training lead (P=0.059, P<0.001 and P=0.012, respectively). Trainees in Group 2 were less likely to be exposed to an adequate number of diagnostic endoscopies, while no differences were found in relation to liver biopsies. Half of the training centers in both Groups do not have dedicated beds for PGHN patients, while in 64% and 58%, respectively, trainees do not participate in on-call programs for PGHN emergencies. Research training is mandatory in 26% of the centers. The duration of training, as well as the assessment and accreditation policies, vary between countries. Conclusions: This study has revealed significant discrepancies and gaps in infrastructure and training programs, training leadership, and assessment of training and certification across European training centers in PGHN. Strategies to support the recognition of PGHN and to standardize and improve training conditions should be developed and implemented.An infographic is available for this article at: http://www.annalsgastro.gr/files/journals/1/earlyview/2022/Infographic_AG-6496.pdf.

Training in pediatric hepatology across Europe: a survey of the National Societies Network (2016-2019) of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

Background: The widely recognized burden of liver diseases makes training in pediatric hepatology (PH) imperative. The aim of this survey, which was part of a global survey on training in pediatric gastroenterology, hepatology and nutrition (PGHN) across Europe, was to assess the PH and liver transplantation (LT) infrastructure, staff and training programs in PGHN training centers. Method: Standardized questionnaires were collected from training centers via the presidents/representatives of the National Societies Network of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) from June 2016 to December 2019. Results: A total of 100 PGHN training centers participated in the survey (14/100 were national referral centers in PH and/or LT). Dedicated PH clinics were available in 75%, but LT clinics in only 11%. Dedicated beds for PGHN inpatients were available in 47/95 (49%) centers. Full-time or part-time specialists for PH care were available in 31/45 (69%) and 11/36 (31%) centers, respectively. Liver biopsies (LB) were performed in 93% of centers by: a PGHN specialist (35%); an interventional radiologist (26%); a pediatric surgeon (4%); or a combination of them (35%). Dividing the annual number of LBs in the centers performing LBs by the number of trainees gave a median (range) of 10 (1-125) per trainee. Transient elastography was available in 60/92 (65%) of centers. Conclusions: The survey highlighted the differences and shortcomings in PH training across Europe. ESPGHAN should take initiatives together with National Societies to ensure the acquisition of PH knowledge and skills according to the ESPGHAN curriculum.An infographic is available for this article at: http://www.annalsgastro.gr/files/journals/1/earlyview/2022/Infographic-Hepatology-training-paper.pdf.

Training in Paediatric Clinical Nutrition Across Europe: A Survey of the National Societies Network (2016-2019) of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

OBJECTIVES/BACKGROUND: Disease-related malnutrition is common in patients with chronic diseases and has detrimental effects, therefore, skills in nutrition care are essential core competencies for paediatric digestive medicine. The aim of this survey, conducted as part of a global survey of paediatric gastroenterology, hepatology and nutrition (PGHN) training in Europe, was to assess nutrition care-related infrastructure, staff, and patient volumes in European PGHN training centres. METHODS: Standardized questionnaires related to clinical nutrition (CN) care were completed by representatives of European PGHN training centres between June 2016 and December 2019. RESULTS: One hundred training centres from 17 European countries, Turkey, and Israel participated in the survey. Dedicated CN clinics exist in 66% of the centres, with fulltime and part-time CN specialists in 66% and 42%, respectively. Home tube feeding (HTF) andhome parenteral nutrition (HPN) programmes are in place in 95% and 77% of centres, respectively. Twenty-four percent of centres do not have a dedicated dietitian and 55% do not have a dedicated pharmacist attached to the training centre. Even the largest centres with >5000 outpatients reported that 25% and 50%, respectively do not have a dedicated dietitian or pharmacist. Low patient numbers on HTF and HPN of <5 annually are reported by 13% and 43% of centres, respectively. CONCLUSIONS: The survey shows clear differences and deficits in Clinical Nutrition training infrastructure, including staff and patient volumes, in European PGHN training centres, leading to large differences and limitations in training opportunities in Clinical Nutrition.

New 1H-benzimidazole-2-yl hydrazones with combined antiparasitic and antioxidant activity.

Parasitic infections, caused mainly by the species Trichinella spiralis (T. spiralis), are widespread around the world and lead to morbidity and mortality in the population. Meanwhile, some studies have showed that these parasites induce oxidative stress in the infected host. With the aim of developing a class of compounds combining anthelmintic with antioxidant properties, a series of new benzimidazolyl-2-hydrazones 5a-l, bearing hydroxyl- and methoxy-groups, were synthesized. The anthelmintic activity on encapsulated T. spiralis was studied in vitro thus indicating that all hydrazones were more active than the clinically used anthelmintic drugs albendazole and ivermectin. 5b and 5d killed the total parasitic larvae (100% effectiveness) after 24 hours incubation period at 37 °C in both concentrations (50 and 100 µg ml-1). The antioxidant activity of the target compounds was elucidated in vitro against stable free radicals DPPH and ABTS as well as iron induced oxidative damage in model systems containing biologically relevant molecules lecithin and deoxyribose. The two 2,3- and 3,4-dihydroxy hydrazones 5b and 5d were the most effective radical scavengers in all studied systems. DFT calculations were applied to calculate the reaction enthalpies in polar and nonpolar medium and estimate the preferred mechanism of antioxidant activity. The relative radical scavenging ability of compounds 5a-l showed a good correlation to the experimentally observed trends. It was found that the studied compounds are capable to react with various free radicals - ˙OCH3, ˙OOH and ˙OOCH3, through several possible reaction pathways - HAT in nonpolar medium, SPLET in polar medium and RAF in both media.

Nutritional Considerations in Pediatric Pancreatitis: A Position Paper from the NASPGHAN Pancreas Committee and ESPGHAN Cystic Fibrosis/Pancreas Working Group.

OBJECTIVES: Wide variations exist in how physicians manage the nutritional aspects of children affected by acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic (CP) pancreatitis. Better consensus for optimal management is needed. METHODS: This consensus statement on nutrition in pediatric pancreatic diseases was developed through a joint ESPGHAN-NASPGHAN working group that performed an evidence-based search of the literature on nutrition in AP, ARP, and CP with a focus on pediatrics. The literature was summarized, quality of evidence reviewed, and expert recommendations developed. The authorship met to discuss the evidence and statements. Voting on recommendations occurred over 2 rounds based on feedback. A consensus of at least 75% was required to approve a recommendation. Areas requiring further research were identified. RESULTS AND DISCUSSION: The literature on nutrition in pediatric pancreatitis is limited. Children with mild AP benefit from starting an early nutritional regimen in the course of the attack. Early nutrition should be attempted in severe AP when possible; enteral nutrition is preferred over parenteral nutrition. Children with ARP are likely to tolerate and benefit from a regular diet. Children with CP need ongoing assessment for growth and nutritional deficiencies, exocrine and endocrine insufficiencies. CONCLUSIONS: This document presents the first authoritative recommendations on nutritional considerations in pediatric pancreatitis. Future research should address the gaps in knowledge particularly relating to optimal nutrition for AP in children, role of diet or dietary supplements on recurrent attacks of pancreatitis and pain episodes, monitoring practices to detect early growth and nutritional deficiencies in CP and identifying risk factors that predispose children to these deficiencies.

In vivo confocal microstructural analysis of corneas presenting Kayser-Fleischer rings in patients with Wilson's disease.

PURPOSE: To evaluate microstructural differences between corneas with and without Kayser-Fleischer rings in age-matched subjects with Wilson's disease with neurological symptoms, using confocal laser scanning microscopy. METHODS: The study included 12 subjects with Wilson's disease with neurological symptoms. Twelve corneas presented clinically with classic Kayser-Fleischer rings, visible on slit lamp examination; the other 12 served as controls. The subjects underwent a comprehensive clinical examination. Microstructural analysis using confocal laser scanning microscopy evaluated increased corneal thickness, decreased number of cells, increased debris or specific deposits, and unusual microstructures. RESULTS: Clinically, the subjects with Kayser-Fleischer rings had similar corneal findings and normal intraocular pressure; two had typical sunflower cataracts and decreased visual acuity. The control eyes all presented normal visual acuity, intraocular pressure, and corneal appearance. The microstructural analysis demonstrated similar findings in all the affected corneas. Compared with the control corneas, there were fewer keratocytes in the anterior stroma (17.380 vs. 22.380/mm3). Round, "hollow" dark areas were observed between the keratocytes; these were universal and similar in appearance in all affected corneas and all cornea layers. In the peripheral posterior stroma, there were dust-like, bright, granular deposits that tended to increase in number and density toward Descemet's membrane, masking the peripheral endothelium. The control corneas presented a normal microstructure apart from dust-like granular deposits in the periphery. CONCLUSIONS: In vivo confocal microscopy is a useful tool for evaluating the corneal microstructure when a Kayser-Fleischer ring is clinically present. The ring consists of granular, bright particles that increase in density toward Descemet's membrane, and is associated with a decreased number of keratocytes and peculiar dark, round areas in all stromal layers, probably a sign of corneal damage. When the ring is not visible in subjects with Wilson's disease, changes to the corneal microstructure are insignificant.

In vivo confocal microstructural analysis of corneas presenting Kayser-Fleischer rings in patients with Wilson's disease / Análise microestrutural confocal in vivo de córneas apresentando anel de Kayser-Fleischer em pacientes com doença de Wilson

ABSTRACT Purpose: To evaluate microstructural differences between corneas with and without Kayser-Fleischer rings in age-matched subjects with Wilson's disease with neurological symptoms, using confocal laser scanning microscopy. Methods: The study included 12 subjects with Wilson's disease with neurological symptoms. Twelve corneas presented clinically with classic Kayser-Fleischer rings, visible on slit lamp examination; the other 12 served as controls. The subjects underwent a comprehensive clinical examination. Microstructural analysis using confocal laser scanning microscopy evaluated increased corneal thickness, decreased number of cells, increased debris or specific deposits, and unusual microstructures. Results: Clinically, the subjects with Kayser-Fleischer rings had similar corneal findings and normal intraocular pressure; two had typical sunflower cataracts and decreased visual acuity. The control eyes all presented normal visual acuity, intraocular pressure, and corneal appearance. The microstructural analysis demonstrated similar findings in all the affected corneas. Compared with the control corneas, there were fewer keratocytes in the anterior stroma (17.380 vs. 22.380/mm3). Round, "hollow" dark areas were observed between the keratocytes; these were universal and similar in appearance in all affected corneas and all cornea layers. In the peripheral posterior stroma, there were dust-like, bright, granular deposits that tended to increase in number and density toward Descemet's membrane, masking the peripheral endothelium. The control corneas presented a normal microstructure apart from dust-like granular deposits in the periphery. Conclusions: In vivo confocal microscopy is a useful tool for evaluating the corneal microstructure when a Kayser-Fleischer ring is clinically present. The ring consists of granular, bright particles that increase in density toward Descemet's membrane, and is associated with a decreased number of keratocytes and peculiar dark, round areas in all stromal layers, probably a sign of corneal damage. When the ring is not visible in subjects with Wilson's disease, changes to the corneal microstructure are insignificant.

RESUMO Objetivo: Avaliar, ao nível microestrutural, através de microscopia confocal in vivo a lazer, 12 córneas com anel de Kayser-Fleischer visível ao exame da lâmpada de fenda e compará-las com 12 córneas clinicamente normais de indivíduos com idades correspondentes aos pacientes com doença de Wilson e sintomas neurológicos. Métodos: O estudo incluiu 12 indivíduos com doença de Wilson e sintomas neurológicos (24 córneas). Doze córneas apresentavam clinicamente o anel clássico de Kayser-Fleischer e as outras 12 serviram como controle. Todos os pacientes foram submetidos a um exame clínico abrangente e a uma análise microestrutural subsequente utilizando microscopia confocal in vivo de varredura a laser. Os principais resultados observados foram: aumento da espessura da córnea, diminuição do número de células, aumento de resíduos/depósitos específicos e microestrutura atípica. Resultados: Clinicamente, todos os indivíduos com anel de Kayser-Fleischer (12 olhos) apresentaram achados similares da córnea e pressão intraocular normal. Dois indivíduos também apresentaram uma catarata de girassol típica e diminuição da acuidade visual. Todos os olhos do grupo controle apresentaram acuidade visual, pressão intraocular e aparência corneana normais. A microscopia confocal in vivo com varredura a laser revelou achados semelhantes em todas as córneas afetadas. O número de ceratócitos no estroma anterior era menor, 17.380/mm3 (22.380/mm3 no grupo controle), e entre eles foram identificadas áreas escuras arredondadas "vazias". Essas zonas escuras eram generalizadas e similares em todas as córneas examinadas e em todas as camadas da córnea. No estroma posterior periférico, havia presença de depósitos granulares brilhantes e com aparência de pó que tendiam a aumentar em número e densidade no sentido da membrana de Descemet, mascarando o endotélio periférico. As córneas controle apresentaram estrutura normal, com exceção de depósitos granulares com aparência de pó na periferia. Conclusões: A microscopia confocal in vivo é uma ferramenta útil para a avaliação da microestrutura da córnea quando o anel de Kayser-Fleischer está clinicamente presente. O anel é constituído de partículas granulares brilhantes com densidade aumentada no sentido da membrana de Descemet. Sua presença está associada com uma diminuição do número de ceratócitos e com áreas circulares escuras "peculiares" em todas as camadas estromais, que representam, provavelmente, um sinal de dano da córnea. Quando o anel não está clinicamente visível, a estrutura da córnea in vivo encontra-se insignificantemente alterada.

Chronic Treatment with Minoxidil Induces Elastic Fiber Neosynthesis and Functional Improvement in the Aorta of Aged Mice.

Normal arterial aging processes involve vascular cell dysfunction associated with wall stiffening, the latter being due to progressive elastin and elastic fiber degradation, and elastin and collagen cross-linking by advanced glycation end products (AGEs). These processes progressively lead to cardiovascular dysfunction during aging. Elastin is only synthesized during late gestation and childhood, and further degradation occurring throughout adulthood cannot be physiologically compensated by replacement of altered material. However, the ATP-dependent K+ channel opener minoxidil has been shown to stimulate elastin expression in vitro and in vivo in the aorta of young adult rats. Therefore, we have studied the effect of a 10-week chronic oral treatment with minoxidil (120 mg/L in drinking water) on the aortic structure and function in aged 24-month-old mice. Minoxidil treatment increased tropoelastin, fibulin-5, and lysyl-oxidase messenger RNA levels, reinduced a moderate expression of elastin, and lowered the levels of AGE-related molecules. This was accompanied by the formation of newly synthesized elastic fibers, which had diverse orientations in the wall. A decrease in the glycation capacity of aortic elastin was also produced by minoxidil treatment. The ascending aorta also underwent a minoxidil-induced increase in diameter and decrease in wall thickness, which partly reversed the age-associated thickening and returned the wall thickness value and strain-stress relation closer to those of younger adult animals. In conclusion, our results suggest that minoxidil presents an interesting potential for arterial remodeling in an antiaging perspective, even when treating already aged animals.

Directed electrostatic activation in enantioselective organocatalytic cyclopropanation reactions: a computational study.

Cyclopropane rings are versatile building blocks in organic chemistry. Their synthesis, by the reaction of sulfur ylides with α,ß-unsaturated carbonyl compounds, has recently aroused renewed interest after the discovery of efficient catalysis by using (S)-indoline-2-carboxylic acid. In order to rationalize the behavior of this catalyst, MacMillan proposed a directed electrostatic activation (DEA) mechanism, in which the negative carboxylate group interacts with the positive thionium moiety, thus reducing the activation energy and increasing the reaction rate. More recently, Mayr refuted some of MacMillan conclusions, but accepted the DEA mechanism as a justification for the experimental high reaction rates. In contrast, our results indicate that the selectivity obtained in the process seems to result from several strong hydrogen bond interactions between the two reacting species, while no strong evidence for a DEA mechanism was found. We also concluded that the hydrogen bonds don't improve the reaction rate by lowering the activation energy of the rate-determining step, but can do it by promoting efficient reaction trajectories due to long-range complexation of the reagents. Finally, our results confirm that the cyclopropanation reaction occurs by a two-step mechanism, and that the overall enantioselectivity depends on the relative energies of the two steps, averaged by the relative populations of the iminium intermediates that are initially formed in the reaction.

Effects of carob-bean gum thickened formulas on infants' reflux and tolerance indices.

AIM: To examine the effect of carob-bean gum (CBG) thickened-formulas on reflux and tolerance indices in infants with gastro-esophageal reflux (GER). METHODS: Fifty-six eligible infants (1-6 mo old) were randomly allocated to receive for two weeks a formula with either 0.33 g/100 mL (Formula A) or 0.45 g/100 mL (Formula B) of cold soluble CBG galactomannans respectively, or a formula with 0.45 g/100 mL of hot soluble CBG galactomannans (Formula C). No control group receiving standard formula was included in the study. Data on the following indices were obtained both at baseline and follow-up from all study participants: 24 h esophageal pH monitoring indices, anthropometrical indices (i.e., body weight and length) and tolerance indices (i.e., frequency of colics; type and frequency of defecations). From the eligible infants, forty seven were included in an intention-to-treat analysis to examine the effects of the two-week trial on esophageal 24 h pH monitoring, growth and tolerance indices. Repeated Measures ANOVA was used to examine the research hypothesis. RESULTS: Regarding changes in 24 h pH monitoring indices, significant decreases from baseline to follow-up were observed in the "Boix Ochoa Score" (i.e., an index of esophageal acid exposure), in the total number of visible refluxes and in all symptoms related indices due to acid reflux only for infants provided with Formula A, while no significant changes were observed for infants provided with Formulas B and C. In addition, the significant decreases observed in two symptoms related pH monitoring indices (i.e., "Symptom index for reflux" and "Percentage of all reflux") for infants provided with Formula A were also found to differentiate significantly compared to the changes observed in the other two groups (P = 0.048 and P = 0.014 respectively). Concerning changes in anthropometric indices, body weight significantly increased among infants provided with Formulas A and C, but not for infants provided with Formula B. As far as tolerance indices were concerned, the numbers of total and diarrheic defecations increased significantly only in infants provided with Formula B and these changes were significantly higher compared to the decreases observed in infants fed with Formulas A and C (P = 0.003 and P = 0.015 respectively. Lastly the number of colics significantly decreased in all infants, irrespective of the tested formula. CONCLUSION: Formula A (i.e., 0.33 g/100 mL of cold galactomannans) was effective in reducing certain pH-monitoring indices of uncomplicated GER, increased body weight and was well-tolerated by infants.

A computational study on Lewis acid-catalyzed diastereoselective acyclic radical allylation reactions with unusual selectivity dependence on temperature and epimer precursor.

In stereoselective radical reactions, it is accepted that the configuration of the radical precursor has no impact on the levels of stereoinduction, as a prochiral radical intermediate is planar, with two identical faces, independently of its origin. However, Sibi and Rheault (J. Am. Chem. Soc. 2000, 122, 8873-8879) remarkably obtained different selectivities in the trapping of radicals originated from two epimeric bromides, catalyzed by chelating Lewis acids. The selectivity rationalization was made on the basis of different conformational properties of each epimer. However, in this paper we show that the two epimers have similar conformational properties, which implies that the literature proposal is unable to explain the experimental results. We propose an alternative mechanism, in which the final selectivity is dependent on different reaction rates for radical formation from each epimer. By introducing a different perspective of the reaction mechanism, our model also allows the rationalization of different chemical yields obtained from each epimer, a result not rationalized by the previous model. Adaptation to other radical systems, under different reaction conditions, is also possible.

Catalytic asymmetric 5-enolexo aldolizations. A computational study.

The diastereo- and enantioselectivity obtained experimentally by Enders et all. (Enders, D.; Niemeier, O.; Straver, S. Synlett 2006, 3399-3402) in the amine-catalyzed intramolecular 5-enolexo aldolization of 1,6-dicarbonyl compounds were fully rationalized using density functional theory methods. A polarizable continuum model was used to describe solvent effects. While 6-enolexo aldolizations are well described by Houk's model on the basis of steric and electrostatic contacts, the main factors conditioning the final selectivity in 5-enolexo processes are calculated to be quite different. Thus, the selectivity results from the summation of several small electrostatic contacts with an unexpected HOMO electronic overlapping plus the ring strain of the five-membered ring, whereas steric effects seem to be unimportant. Our results indicate, in contrast with 6-enolexo processes, that high selectivities are not expected in this type of reaction and that the experimental selectivity shall be very dependent on the reaction conditions, as known experimental results seem to suggest. 7-enolendo products are not expected, as they are predicted to be formed by higher energetic transition states. Variable reaction rates, experimentally observed with different catalysts, are suggested to be mainly a result of different catalyst solubilities.

Effects of selenium on the vessel walls and anti-elastin antibodies in spontaneously hypertensive rats.

Selenium (Se) is an exogenous antioxidant that performs its role via expression of selenoproteins. Pathological changes of the structure of the vessel wall, elastin turnover and collagen production may lead to increased stiffness of the vessels with decreased blood flow to the peripheries. The level of anti-elastin antibodies (AEABs) may give information for elastin metabolism. The aim of the study is to investigate the influence of Se intake on the vessel wall changes and production of AEABs in spontaneously hypertensive rats (SHR). Twenty-four male, 32-week-old SHR were used, divided into three groups, G1, G2 and G3. Before blood and morphological testing, G1 received a low-Se diet for eight weeks, G2 received a diet with adequate Se content and G3 received a diet with Se supplementation. The Se nutritional status was assessed by determination of glutathione peroxidase-1 (GPx-1) activity in whole blood, using the 'Ransel' kit. The rats from group G3 showed higher GPx-1 activity and lower level of AEABs than the other groups (P = 0.021), and the aortic wall histology showed slight degenerative changes compared with other rats. A low-Se diet caused severe changes to the aortic wall's ultrastructure, whereas Se supplementation slowed the changes down. The morphometry revealed a thicker abdominal aortic wall in rats of G1 compared with the other groups, and reduced thickness of the wall of the left coronary artery in G3 compared with the other groups (P < 0.05). Our results have shown that low Se intake leads to severe changes in the vessel walls in SHR, whereas selenium supplementation slows down the elastin degradation and degenerative changes of the vessel walls.

Anti-fibrillin-1 autoantibodies in normal pregnancy and recurrent pregnancy loss.

PROBLEM: The aim of this study was to investigate anti-fibrillin-1 autoantibody in patients with a history of recurrent pregnancy loss (RPL) and during normal pregnancy. METHOD OF STUDY: Anti-fibrillin-1 IgG and IgM antibodies were measured by a home made ELISA in serum samples of 48 medically and obstetrically normal pregnant women, classified to three trimester groups, 15 female patients with RPL and 26 healthy non-pregnant women classified to two control subgroups: (a) women who had already had at least one previous successful pregnancy and (b) women who had never been pregnant. Differences in anti-fibrillin-1 autoantibodies between the groups were analyzed for statistical significance (P<0.05) with one-way analysis of variance (ANOVA) and multiple comparison test - Post Hoc test, Least Significant Difference method. RESULTS: Anti-fibrillin-1 IgM autoantibodies were significantly decreased in the second and third trimester pregnant women compared to the nulligravida controls. RPL patients had significantly increased anti-fibrillin-1 IgM antibody compared to control group (a). CONCLUSION: Fibrillin-1 degradation seems to be decreased during the second and third trimester of normal pregnancy. Increased anti-fibrillin-1 IgM antibodies in RPL patients may be a secondary phenomenon of increased fibrillin-1 degradation and contribute to the pathogenesis of pregnancy losses.

Age-related changes of anti-elastin antibodies in senescence-accelerated mice.

BACKGROUND: Antibodies recognizing the elastin precursor tropoelastin (ATEAb) or degradation products alpha-elastin (AEAb) are found in the serum of healthy human subjects, as a part of a homeostatic mechanism which assembles new or clears altered elastin structures. Serum ATEAb (reflecting elastin synthesis) and AEAb (reflecting elastin destruction) appear to correlate with the production and breakdown of the elastic tissue, respectively. OBJECTIVE: The aim of this study was to investigate plasma levels of AEAb and ATEAb in senescence-accelerated prone (SAMP8) and senescence-accelerated resistant (SAMR1) mice, compared with imprinting control region (ICR) mice in order to evaluate their age-related changes. METHODS: The levels of AEAb and ATEAb were measured by home-made ELISA in plasma of SAMP8, SAMR1, and ICR mice, grouped according to their age (3 and 9 months) and sex. The specificity of AEAb and ATEAb activity in mouse plasma, and elastin-derived peptides (EDP) in sera of ICR mice at 3 and 9 months of age were tested by competitive ELISA. RESULTS: The specificity of AEAb and ATEAb in mouse plasma was confirmed by the competitive investigations. The levels of AEAb in the plasma of SAMR1 and SAMP8 were increased compared to the levels measured in ICR on the matched ages (p < 0.001). Age-related increase of the levels of AEAb and ATEAb was established in the 3 strains (p < 0.001). Significantly higher levels of AEAb were established in female 9-month-old mice compared to males in all strains. The ATEAb:AEAb ratio was significantly lower in the SAM compared to the ICR strain. Positive correlation was established between the levels of serum AEAb and EDP in mouse sera of ICR mice. CONCLUSION: Variations with age in the plasma levels of AEAb and ATEAb were established in SAM compared with ICR, and in SAMP8 compared with SAMR1. Our findings suggest that increased anti-elastin IgG autoantibodies could be used as a marker of aging in SAM and possibly contribute to the processes of aging. The absence of a difference between SAMP8 and SAMR1 regarding the ATEAb:AEAb ratio raises the question if SAMR1 are an appropriate control of SAMP8 in terms of the senescence of the elastic tissues.