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Seasonal sampling was carried out at three Argentinian salterns, Salitral Negro (SN), Colorada Grande (CG) and Guatraché (G), to analyze abiotic parameters and microbial diversity and dynamics. Microbial assemblages were correlated to environmental factors by statistical analyses. Principal component analysis of the environmental data grouped SN and CG samples separately from G samples owing to G's higher pH values and sulfate concentration. Differences in microbial assemblages were also found. Many archaeal sequences belonged to uncultured members of Haloquadratum and Haloquadratum-related genera, with different environmental optima. Notably, nearly half of the archaeal sequences were affiliated to the recently described 'Candidatus Haloredividus' (phylum Nanohaloarchaeota), not previously detected in salt-saturated environments. Most bacterial sequences belonged to Salinibacter representatives, while sequences affiliated to the recently described genus Spiribacter were also found. Seasonal analysis showed at least 40% of the microbiota from the three salterns was prevalent through the year, indicating they are well adapted to environmental fluctuations. On the other hand, a minority of archaeal and bacterial sequences were found to be seasonally distributed. Five viral morphotypes and also eukaryal predators were detected, suggesting different mechanisms for controlling prokaryotic numbers. Notably, Guatraché was the saltern that harbored the highest virus-to-cell ratios reported to date for hypersaline environments., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ1 receptor (σ1R) ligands are reported. The compounds were prepared using a 4-5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ1R, and the selectivity over the σ2R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ1R potency a minimum lipophilicity was required, while limiting to a defined range of cLogP avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.

Introduction: The sigma-1 receptor (σ1R) is a ligand-regulated molecular chaperone that interacts with other proteins, including NMDA and opioid receptors, to modulate their activity. Convergent evidence indicates that σ1R antagonists exert inhibitory effects (and agonists stimulatory effects) on pain by stepping down the intracellular signaling cascades involved in transduction of noxious stimuli and plastic changes (i.e., sensitization phenomena) associated with chronic pain states., Areas Covered: This review addresses three primary domains. The first focuses on mechanisms underlying the antinociceptive effects of σ1R antagonists. The second addresses evidence gained using pharmacological tools and experimental drugs in the discovery phase and clinical development. Finally, the article outlines the potential benefits of σ1R antagonists, alone or in combination, in the context of available pain therapeutics., Expert Opinion: There is a critical need for new analgesics based on new mechanisms of action. Target identification requires convincing evidence relating targets to function. In turn, target validation requires confirmation of therapeutic benefits, ideally in humans. Current preclinical evidence provides strong rationale for σ1R antagonists in pain. The outcome of clinical studies with the most advanced investigational σ1R antagonist, S1RA (E-52862), will be of great interest to ascertain the potential of this new therapeutic approach to pain management.

Background: Discriminating neoplastic from non-neoplastic polyps can significantly reduce the cost of colonoscopy. The American Society for Gastrointestinal Endoscopy (ASGE) recently set threshold levels for optical diagnostic accuracy to be acceptable for clinical use., Objective: In this study, we compare a novel colonoscope capable of dual-focus imaging with standard colonoscopy with respect to the ASGE guidelines., Setting: An academic medical center ambulatory surgical center., Patients and Interventions: Patients at average risk were randomized to standard colonoscopy (Olympus CF-H180 and Exera II 180 colonoscopes, Olympus America, Center Valley, Pa) or dual-focus colonoscopy (Olympus CF-HQ190 and Exera III 190 colonoscopes, Olympus America). All polyps were given an optical diagnosis and compared with histology., Results: A total of 600 patients were consented and 522 completed all aspects of the procedure. A total of 927 polyps were analyzed. Optical diagnostic accuracy was 79% (95% confidence interval, 74%-83%) for the 190 and 77% (95% confidence interval, 73%-81%) for the 180 colonoscope. Adenoma detection rates were also similar between the 2 groups (50% for the 190 vs 52% for the 180 colonoscope). For small distal rectosigmoid polyps with a high confidence diagnosis, the negative predictive value for adenoma was 96% (range 89%-99%) for the 180 in the narrow-band imaging (NBI) mode and 97% (range 88%-99%) for the 190 colonoscope in NBI mode. Agreement of surveillance intervals by using optical diagnosis was 94% to 95% for all modalities (180 and 190 colonoscopes, white light imaging, NBI)., Limitations: Our study evaluated the accuracy of the 180 and 190 colonoscopes at a center with already-established expertise in endoscopic imaging., Conclusions: Both traditional and new dual-focus colonoscopes provide highly accurate optical polyp discrimination. There was no difference between the 2 systems in terms of discrimination or adenoma detection. Both systems are consistent with ASGE guidelines for optical diagnosis of selected colorectal polyps without histological confirmation., (Copyright © 2014. Published by Elsevier Inc.)

Background: Bowel cleansing is paramount for colonoscopy quality. Unfortunately, an adequate bowel preparation is often limited by side effects and/or patient's intolerance to bowel preparation solutions. Comparisons among different preparations are limited by the lack of validated instruments designed to assess patient's tolerability., Aim: To develop and validate a simple, comprehensive instrument to assess bowel preparation tolerability in patients undergoing colonoscopy., Methods: Development and validation by phases: Phase I (bibliographic search and questionnaire design); Phase II (assessment of content validity and modification of the questionnaire); Phase III (assessment of reproducibility, final validation, and definitive version of the questionnaire)., Results: The initial draft of the questionnaire was generated based on a systematic literature review and feedback from a panel of consultants. Content validity was tested in a focus group of 25 patients undergoing colonoscopy. Patients' suggestions were reviewed by the research team and a second draft of the questionnaire was generated. Final validation and reproducibility were successfully tested (agreement: 86-100%, kappa: 0.77-1.00) in a convenience sample of 100 patients undergoing bowel preparation with different cleansing solutions., Conclusion: The Mayo Clinic Bowel Prep Tolerability Questionnaire is a simple, comprehensive instrument suitable to evaluate the tolerability of various types of bowel preparations., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The sigma-1 receptor (σ1R) is located in areas of the CNS key for pain control and belongs to a unique target class with chaperoning functions over different molecular targets involved in transmission and amplification of nociceptive messages. Preclinical evidence supports a role for σ1R antagonists in the treatment of pain states where hypersensitivity develops as hyperalgesia and allodynia, two common symptoms encountered in neuropathic and other chronic pain conditions. Additionally, σ1R antagonists increase opioid analgesia without increasing opioid-related unwanted effects, which point to their potential use as opioid adjuvant therapy. This review summarizes the structure and function of the σ1R as well as the medicinal chemistry and pharmacological studies directed to the identification of σ1R antagonists for the treatment of pain.

Objectives: The prevalence of irritable bowel syndrome (IBS) around the world is variable, ranging from as little as 1.1 to 45%. Limited studies have been carried out in Arab populations. The aim of this study was to determine the prevalence of IBS and its subtypes in the West Bank, Palestine, and to assess variation by locality of residence., Methods: We conducted a population-based, cross-sectional study. Participants were randomly selected from all districts of the West Bank, including cities, villages, and refugee camps, and they were at least 50 years of age. Participants completed the Rome III IBS questionnaire along with demographic data. The primary outcome was the effect of location of residence on the prevalence of IBS. A multivariable logistic regression model was used to assess the difference in IBS prevalence based on locality of residence., Results: A total of 1,601 people were approached for interview, of which 1,352 agreed to participate (response rate 84%). Most participants (53%; n=637) lived in urban centers. The overall prevalence of IBS was 30% (28-33%). IBS was more common in refugee camps (34%) and in villages (34%) compared with urban centers (27%) (P<0.05). Mixed IBS (IBS-M) was the most common of IBS subtypes (55%, n=244). In a multivariable logistic regression analysis, living in refugee camps (odds ratio (OR) 1.68 (95% confidence interval (CI) 1.14-2.40), P=0.005) and in villages (OR 1.33 (1.02-1.72), P=0.033) was associated with increased odds of having IBS when compared with residents of urban centers. IBS, IBS with constipation, and IBS-M were more common in women than in men (P<0.05)., Conclusions: The prevalence of IBS among middle-aged and elderly residents of Palestine is high. Residents in refugee camps and rural areas have a higher incidence of IBS than those in urban areas.

The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.

Objective: To analyze the clinical situations that leads us to carry out curettage after cesarean section, the ultrasound prior surgery, intraoperative, and pathological findings., Methods: A retrospective study of all cases of postpartum curettage after cesarean section in a level 3 maternity unit., Results: There were 42 curettages to women with cesarean sections (1.6% of all cesarean sections). The indications for curettage were: fever: 21, methrorraghia: 11, and residual trophoblastic tissue: 10. In the previous ultrasound, all indicated curettages for retained trophoblastic tissue showed it, and in a lower proportion those indicated for fever (66.6%) or methrorraghia (22.2%). A total of fourteen curettages (35%) were performed without suspect image of retained tissue, and in all cases the surgeon described to obtain small amount of tissue. From material submitted to pathologic evaluation trophoblastic tissue was found in 64.7%, and there were no differences as curettage indication., Conclusions: When the previous ultrasound do not showed retained tissue, the surgeon did not remove retained material. When extracted there were always in small amounts. Therefore, it could be concluded that after cesarean section the curettage should be indicated only in the presence of evident ultrasound image of retained products.

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.

The microbial community inhabiting Sfax solar salterns on the east coast of Tunisia has been studied by means of different molecular and culture-dependent tools that have unveiled the presence of novel microbial groups as well as a community structure different from that of other coastal hypersaline environments. We have focused on the study of the viral assemblages of these salterns and their changes along the salinity gradient and over time. Viruses from three ponds (C4, M1, and TS) encompassing salinities from moderately hypersaline to saturated (around 14, 19, and 35%, respectively) were sampled in May and October 2009 and analyzed by transmission electron microscopy (TEM) and pulsed-field gel electrophoresis (PFGE). Additionally, for all three October samples and the May TS sample, viral metagenomic DNA was cloned in fosmids, end sequenced, and analyzed. Viral concentration, as well as virus-to-cell ratios, increased along the salinity gradient, with around 10(10) virus-like particles (VLPs)/ml in close-to-saturation ponds, which represents the highest viral concentration reported so far for aquatic systems. Four distinct morphologies could be observed with TEM (spherical, tailed, spindled, and filamentous) but with various proportions in the different samples. Metagenomic analyses indicated that every pond harbored a distinct viral assemblage whose G+C content could be roughly correlated with that of the active part of the microbial community that may have constituted the putative hosts. As previously reported for hypersaline metaviromes, most sequences did not have matches in the databases, although some were conserved among the Sfax metaviromes. BLASTx, BLASTp, and dinucleotide frequency analyses indicated that (i) factors additional to salinity could be structuring viral communities and (ii) every metavirome had unique gene contents and dinucleotide frequencies. Comparison with hypersaline metaviromes available in the databases indicated that the viral assemblages present in close-to-saturation environments located thousands of kilometers apart presented some common traits among them in spite of their differences regarding the putative hosts. A small core metavirome for close-to-saturation systems was found that contained 7 sequences of around 100 nucleotides (nt) whose function was not hinted at by in silico search results, although it most likely represents properties essential for hyperhalophilic viruses.

Probiotic agents have received growing attention in recent years as an alternative therapeutic tool in the management of irritable bowel syndrome. In this article, we will discuss the rationale that support this indication, including the role of intestinal microbiota in gastrointestinal function in both human and animal models, potential links between an impaired microbiota imbalance and the psycho-immunopathophysiology of irritable bowel syndrome, and the results of the available clinical trials to date.

Background: the Irritable Bowel Syndrome Severity Score (IBSSS) is a questionnaire only available in English that classifies IBS patients according to the severity of their symptoms and can be used to guide and monitor the treatment., Aims: to adapt and validate into Spanish the English version of the IBSSS questionnaire., Methods: the Spanish version of the questionnaire was obtained through a process of translation-evaluation of the comprehensibility and back translation. In a later phase we evaluated the applicability(n = 15), reproducibility (n = 31) and sensitivity to change (n = 40) of the Spanish version of the questionnaire. Finally we evaluated an alternative version of the ISBSS using a numerical scoring system instead of the original analog visual scale (n = 40)., Results: the Spanish version of the IBSSS showed an excellent reproducibility (r = 0.81 for global score) and an adequate sensitivity to change: a decrease of 45 points or more identified worsening of IBS with a 70.6% sensitivity and 87.5% specificity; an increase of 45 points or more identified improvement of IBS with a 85.7% sensitivity and 87.5% specificity. The severity score was practically the same regardless of the scoring system used (r = 0.96)., Conclusions: the Spanish version of the IBSSS is a reproducible tool that is able to identify relevant changes over the course of the disease. The use of a numerical scoring system is a valid alternative to the visual scale that improves the applicability of the questionnaire to situations when the written communication is limited or not possible.

Backgrounds: irritable bowel syndrome (IBS) is a common and complex disorder. Though it is estimated that IBS constitutes an important part of the gastroenterology (GI) practice, the burden of this problem in the GI outpatients clinics in Spain is unclear., Aim: the aim of this study is to obtain a "shot" of the burden and management of this syndrome in the daily GI practice., Methods: 508 general gastroenterologists from all over the country were approached and asked to complete a survey that included questions about their daily practice and the definition, diagnosis and treatment of IBS., Results: 55% of the surveyed physicians estimate that IBS constitute between a quarter and a half of all their consultations; and pointed out that most of these patients were referred from primary care. Overall, the Spanish gastroenterologists show an adequate knowledge of the different diagnostic criteria, though they do not always follow the current guidelines. Up to 55% of the physicians always perform a complementary test to support their diagnosis and 40% order a diagnostic test only in older patients (> 50 years) or in presence of alarm symptoms. Interestingly, 80% of the gastroenterologists start empirical treatment based on the patients' symptoms., Conclusions: though Spanish gastroenterologists seem to have an adequate theoretical knowledge of the disease, they do not systematically follow current guidelines and tend to manage IBS symptoms based on their own criteria.

Objectives: Eye gaze tracking (EGT) technology follows a person's gaze and records the resulting visual gaze pattern (VGP). Adenoma detection rate (ADR) is a validated measure of colonoscopy quality. Higher ADRs are associated with prolonged withdrawal times and other endoscopic maneuvers that allow a better visualization of the mucosa; however, the influence of VGP has yet to be explored. We aim to quantify the VGP for endoscopists observing colonoscopy videos and describe the association between VGP and ADR. Furthermore, we will evaluate the relationship between VGP and the endoscopists' years of experience., Methods: Eleven endoscopists watched three videos while their VGP was recorded. The videos corresponded to 3 min of three different colonoscopy withdrawals. We divided the screen into a 3 × 3 grid of nine segments: eight peripheral and one central. We compared percent of gaze time (GT) in the central vs. peripheral segments using a paired t-test. VGP with ADR and years of practice were evaluated using Pearson's test., Results: Subjects spent more GT in the screen's central segment (65 vs. 33%, P<0.001). ADR was significantly associated with increased percentage of central GT (r = 0.67, P = 0.024) and increased mean GT in the central segment (r = 0.70, P = 0.017). There was negative correlation between endoscopists' years of practice and the percentage of central GT (r = -0.67, P = 0.025), but no correlation between years of practice and percentage of peripheral GT (r = 0.24, P = 0.47)., Conclusions: This reveals an association between a centrally focused VGP and ADR. Future steps include confirming in a larger sample and exploring if VGP can retrain low ADR endoscopists to perform higher quality colonoscopies.

Introduction: Doppler transabdominal ultrasound is a validated screening test for chronic mesenteric ischaemia, but gas and obesity are limitations. Endoscopic ultrasound has been proposed as a comprehensive test to evaluate chronic upper abdominal pain and is capable of Doppler measurement. We aim to evaluate the accuracy of Doppler endoscopic ultrasound (D-EUS) as a single screening test to rule out chronic mesenteric ischaemia in patients with abdominal pain and compare it with Doppler transabdominal ultrasound (D-TUS)., Methods: We enrolled all patients ≥50 years with chronic upper abdominal pain and vascular risk referred for endoscopic ultrasound. All were scheduled for D-EUS and D-TUS plus a confirmatory test if one of the previous resulted positive. We estimated the accuracy of both techniques comparing them using McNemar test., Results: 68 patients completed the study. Fifty-three (78%) underwent D-EUS, D-TUS, and a confirmatory test. Fifteen (38%) underwent follow-up after negative results. Three (4%) in the D-EUS group and 14 in the D-TUS (21%) were excluded due to artefacts. D-EUS presented a sensitivity of 63%, specificity of 84%, whilst D-TUS presented a sensitivity of 80% and a specificity of 78%. Specificity of D-EUS was not significantly different to D-TUS., Conclusions: These results support the role of Doppler endoscopic ultrasound to exclude chronic mesenteric ischaemia as cause of chronic abdominal pain., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Cost-benefit analysis is a standard methodological platform for public investment evaluation. In high environmental impact projects, with a long-term effect on future generations, the choice of discount rate and time horizon is of particular relevance, because it can lead to very different profitability assessments. This paper describes some recent approaches to environmental discounting and applies them, together with a number of classical procedures, to the economic evaluation of a plant for the desalination of irrigation return water from intensive farming, aimed at halting the degradation of an area of great ecological value, the Mar Menor, in South Eastern Spain. A Monte Carlo procedure is used in four CBA approaches and three time horizons to carry out a probabilistic sensitivity analysis designed to integrate the views of an international panel of experts in environmental discounting with the uncertainty affecting the market price of the project's main output, i.e., irrigation water for a water-deprived area. The results show which discounting scenarios most accurately estimate the socio-environmental profitability of the project while also considering the risk associated with these two key parameters. The analysis also provides some methodological findings regarding ways of assessing financial and environmental profitability in decisions concerning public investment in the environment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Fibromyalgia (FM) remains an enigmatic and challenging clinical entity to manage, given its far-reaching spectrum of symptoms, chronicity, associated psychopathology, and lack of clinically available diagnostic tests. However, recent insights into the pathophysiology of FM offer hope that this condition, as with all members of the central sensitization syndromes, can be more readily diagnosed, measured, and treated. This paper presents the epidemiology features and pathogenesis of FM in the context of evaluating NCCP as a prototype among central pain sensitization syndromes. Evidence for the multimodality approach to treatment of this condition is also presented.

Objectives: The etiology of eosinophilic esophagitis (EoE) is not well understood. It has been proposed that eosinophils migrate to the esophagus in response to various ingested and inhaled allergens. Recent reports in children found an increased proportion of cases of EoE during months with higher outdoor aeroallergens. To our knowledge, this has not been evaluated in adults. We aimed to determine whether there is a seasonal distribution in the number of newly diagnosed cases of EoE in an adult population., Methods: We conducted a retrospective review of consecutive adult cases newly diagnosed with EoE in 1 year. Cases were grouped based on the index month when the diagnosis was made at endoscopy. To test the consistency of the observations, a second cohort of consecutive cases of similar sample size diagnosed at a different period in time was also analyzed., Results: In total, 41 patients were diagnosed with EoE at our center during the study period, providing an annual prevalence of 0.98%. More cases were diagnosed with EoE during the months of April and May than any other month (P<0.001). When patients were grouped seasonally, there was a significant increase of EoE cases in spring and summer months (n=28) when compared with the fall and winter months (n=13) (P=0.019). Analysis of the second cohort of cases (n=37) from 2002 to 2006 confirmed a similar seasonal diagnostic pattern for EoE during the outdoor seasons., Conclusions: Our data demonstrate that EoE has a seasonal prevalence in adults. The seasonal variation pattern found in newly diagnosed EoE cases in adults supports the potential role of aeroallergens in the pathogenesis of EoE.

Background & Aims: Fibromyalgia is a rheumatologic disorder associated with somatic and psychologic conditions. Although fibromyalgia is associated with irritable bowel syndrome, its relationship with other functional gastrointestinal disorders (FGID) is unclear. We evaluated the prevalence of FGID in patients with fibromyalgia and the role of psychologic factors in this relationship., Methods: From a Spanish population, 100 patients with fibromyalgia and 100 matched controls completed the Rome II Integrative Questionnaire to assess the prevalence of FGID and the Symptom Checklist-90 Revised (SCL-90R) to evaluate psychologic distress. Patients completed the Fibromyalgia Impact Questionnaire to evaluate the overall impact of fibromyalgia and controls filled out the Chronic Widespread Pain Questionnaire to detect potential cases of fibromyalgia., Results: Ninety-three percent of the total study population was female, with a mean age of 50 years. We identified 6 cases of widespread pain among controls. The average Fibromyalgia Impact Questionnaire score for patients was 67.28 +/- 14.25. All gastrointestinal symptoms except for vomiting were more frequent in patients. Ninety-eight percent of patients with fibromyalgia had at least one FGID, compared with only 39% of controls. Fibromyalgia was correlated most highly with irritable bowel syndrome. Patients presented with significantly higher scores of psychologic distress than controls, especially those with fecal incontinence., Conclusions: There is a prevalence of FGID in patients with fibromyalgia and a wider distribution of such symptoms along the gastrointestinal tract compared with controls. We propose that an increased degree of psychologic distress in these patients predisposes them to FGID, especially significant for anorectal syndromes.

Unlabelled: A link between gastroesophageal reflux disease (GERD) and psychological distress has been suggested; psychological factors may modulate the characteristics of symptoms. Besides, irritable bowel syndrome (IBS) frequently coexists with GERD so it may be hypothesized that psychological distress in GERD might be an epiphenomenon of IBS comorbidity., Aims: Evaluate the association of psychological distress with GERD, the influence of psychological factors on symptoms, whether psychological distress is explained by a subset of GER patients, and if coexistence with IBS would be a surrogate marker., Methods: We performed a prospective case-control study. Cases were patients diagnosed with GERD reporting heartburn at least 2 days per week as the main complaint. Controls were matched healthy subjects without or occasional symptoms. All individuals completed a set of validated questionnaires to evaluate GERD and IBS symptoms and psychological distress (SCL-90R)., Results: Ninety-two patients and 92 controls were included. Fifty-seven patients and six controls fulfilled Rome II criteria for IBS. Body mass index (BMI), somatization, and IBS were independently related to GERD. Patients with and without IBS were not different in any measure of psychological distress. Characteristics of symptoms did not correlate to psychological measures. Cluster analysis isolated a cluster of nondistressed from distressed subjects. A higher proportion of GERD patients than controls were classified as distressed (29.7% versus 7.7%). No variable (including IBS) distinguished nondistressed from distressed GERD patients, except for sex., Conclusions: Nearly one-third of GERD patients attending a gastroenterologist office are psychological distressed; they cannot be identified by features of symptoms or IBS comorbidity so a specific anamnesis under the scope of a biopsychosocial model is warranted.

Diffuse esophageal spasm is a motility disorder of undetermined cause. The optimal treatment remains controversial, and evidence-based data are lacking. Several medical treatment modalities have been proposed, but none has emerged as the treatment of choice. Patients who do not respond to medical therapy may be considered for surgical treatment. The surgical treatment of diffuse esophageal spasm is based on similar principles to the treatment of achalasia. A long esophageal myotomy is done to divide the hypertrophied circular muscle that is frequently noted in diffuse esophageal spasm. To protect against postoperative reflux, an antireflux procedure may be added. However, the surgical treatment of diffuse esophageal spasm has not been subjected to randomized clinical trials. The purpose of this article is to provide a review of the available literature regarding the surgical management of the diffuse esophageal spasm. In particular, we offer an appraisal of surgical outcomes, the effects of surgery on manometric and radiologic parameters (when available), complications, and mortality.

Diffuse esophageal spasm (DES) is a motility disorder of undetermined etiology, typically presenting with chest pain, dysphagia or both. The aim of this paper is to provide a critical review of the prevalence, pathogenesis, diagnosis and therapy of DES. Data from referral centers indicates that this is a rare disorder with a prevalence of 4-7%. The diagnosis is based on the combination of typical symptoms, radiological findings and manometry (simultaneous contractions (SC) in the distal esophagus in > or = 20% of wet swallows mixed with normal peristalsis). The pathogenesis remains poorly understood. Recent evidence suggests that nitric oxide deficiency may explain the SC that characterizes this condition at manometry. Gastroesophageal reflux (GER) can coexist in DES and GER has also been implied in the pathogenesis of DES. Whether patients with DES and GER represent a subtype of DES with a different prognosis or outcome is unknown. We present a critical appraisal regarding different therapeutic approaches available for DES and conclude suggesting a management algorithm based on current available literature.

Introduction: lack of evidence in most clinical situations regarding irritable bowel syndrome (IBS) enhances the importance of an expert s opinion, which will guide management and even the concept underlying the disease., Objective: to delve into the knowledge and degree of agreement on main clinical skills for this syndrome among physicians involved in its management., Material and Method: two rounds of a Delphi survey were conducted on 100 physicians: general practitioners (GPs) and gastroenterologists. The questionnaire evaluated agreement among participants in some aspects regarding the definition, diagnosis, and treatment of IBS., Results: fifty-five percent of participants completed the two-round survey. Agreement was achieved regarding the definition of typical symptoms and red flags characterizing IBS. Although there was no consensus regarding the appropriate management of patients without alarm symptoms, the performance of a colonoscopy on any patient presenting red flags was suggested. Patients were thought to require a wider examination when older than 40. A well defined line of IBS treatment was not found, albeit most physicians tended to choose it depending on the main complaint., Conclusion: interviewed physicians showed adequate theoretical knowledge of IBS, but lack of uniformity on diagnosis and treatment approach reflects the controversial day-by-day management of this syndrome.

The main recognition characteristics of the ATP binding site of p38 mitogen activated protein kinase alpha (p38alpha MAPK) have been explored by a combination of modeling and bioinformatics techniques, making special emphasis in the characteristics of the site that justifies binding specificity with respect to other MAP kinases. Particularly, we have analyzed the binding mode of a new family of p38 MAPK inhibitors based on the pyridinyl-heterocycle core. This family of compounds has a marked pseudosymmetry and can exist in different tautomeric forms, which makes the determination of the binding mode especially challenging. A combination of homology modeling, quantum mechanics, classical docking, and molecular dynamics calculations allowed us to determine the main characteristics defining the binding mode of this new scaffold in the ATP binding site of p38alpha. A set of free energy calculations allowed us to verify the binding mode proposed, giving an overall excellent agreement with the experimental values. Finally, the binding mode of this new family of compounds was compared to that of other members of the pyridinyl and pyrimidinyl heterocycle class.

The adsorption isotherms of N(2) at -196 degrees C, CO(2) at 0 degrees C, and CH(4) at 25 degrees C on 35 activated carbons with a wide range of micropore volumes and pore size distributions have been compared to evaluate the density of adsorbed methane. Results indicate that methane is adsorbed in the micropores of the activated carbon with a density that is a function of the carbon porosity because methane is packed more compactly in narrow than in wide micropores. An experimental procedure is proposed to evaluate the density in both types of micropores as a function of pressure. Its application to these porous carbons indicates that density of adsorbed methane increases rapidly with pressure on narrow micropores, the increase becoming slower above 1.5 MPa. The value reached at 3 MPa is 0.21 g/cm(3), near that estimated as the limiting value, 0.23 g/cm(3). Density in wide micropores is low, 0.09 g/cm(3) at 3 MPa, but it continuously increases with pressure.

The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.

The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l] methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.

UR-7280 (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT1-selective receptor antagonist. Binding studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagonized the angiotensin II-induced contractile response in an insurmountable way, causing a significant reduction of the maximal response. Additional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit aorta. The results obtained with a series of structural analogues of UR-7280 demonstrated a relationship between the size of the pyrazole 3-substituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction between the antagonist and the angiotensin AT1 receptor.

A series of [(3-pyridylalkyl)piperidylidene]- and (nicotinoylpiperidylidene)benzocycloheptapyridine derivatives, Ia,b, were prepared and evaluated for PAF antagonist and H1 antihistamine activity. PAF antagonist activity was investigated by the in vitro PAF-induced platelet aggregation assay (PPA) and the in vivo PAF-induced hypotension test in rats (PH) and mortality test in mice (PM). For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) and the in vivo histamine-induced hypotension test (HH) in normotensive rats were used. The potential antiallergic activity of the compounds was evaluated using the active anaphylactic shock test in mice. These compounds are structurally related to loratadine (1) and were generated by replacement of the ethoxycarbonyl group of 1 with substituted 3-pyridylmethyl and nicotinoyl moieties. Both anti-PAF and H1 antihistamine activities have shown a high dependence on the exact nature and position of the substituent in the pyridine ring. Optimum structure 19 (UR-12592) incorporating a (5-methyl-3-pyridyl)methyl radical displayed an unique dual activity inhibiting both PAF-induced effects (PPA, IC50 = 3.7 microM; PH, ID50 = 0.44 mg/kg iv; PM, ID50 = 1.9 mg/kg po) and histamine-induced effects (HC, IC50 = 3.9 nM; HH, ID50 = 1.4 mg/kg iv). Furthermore, 19 was highly active in the passive cutaneous anaphylactic shock in rats (ID50 = 1.2 mg/kg po) and strongly protected mice and rats from mortality induced by endotoxin (ID50 = 1.2 and 0.5 mg/kg iv, respectively). Compound 19 showed itself to be devoid of CNS depressant effects, neither modifying spontaneous motor activity nor prolonging barbiturate-sleeping time in mice at a dose of 100 mg/kg po, and is now under development.

A second generation of (cyanomethyl)piperazines, 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)-piperazines, with increased oral activity was prepared and evaluated in vitro in a PAF-induced platelet aggregation assay (PAG) and in vivo in a PAF-induced hypotension test in normotensive rats (HYP). Oral activity was ascertained through a PAF-induced mortality test in mice (MOR). Attachment of a methyl group at position 2 of our earlier pyridine derivatives resulted in an improvement of 1 order of magnitude or greater in the ID50 of the oral test. Three different types of acyl substituents of similar potency emerge from this work: N-(diphenylmethylamino)acetyl, 3-substituted 3-hydroxy-3-phenylpropionyl, and N-substituted 3-amino-3-phenylpropionyl groups. The most interesting compounds, 26 (UR-12460, PAG IC50 = 0.040 microM, HYP, ID50 = 0.021 mg/kg i.v., MOR, ID50 = 0.30 mg/kg po) and 58 (UR-12519, PAG IC50 = 0.041 microM, HYP, ID50 = 0.015 mg/kg i.v., MOR, ID50 = 0.044 mg/kg po), compare favorably with WEB-2086. Compounds 26 and 58 were also tested in active anaphylactic shock (AAS) and endotoxin-induced mortality (EIM) tests. On the basis of these data, compounds 26 and 58 have been selected for further pharmacological development.

A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.

A series of (pyridylcyanomethyl)piperazines was prepared and evaluated for PAF-antagonist activity. Compounds were tested in vitro in a PAF-induced platelet aggregation assay and in vivo in a PAF-induced hypotension test in normotensive rats. Oral activity was ascertained through a PAF-induced mortality test in mice. The main structure-activity trends of the series were established. Activity was mainly found in four skeletons: 1-acyl-4-(3-pyridylcyanomethyl)piperazine, 1-acyl-4-(4-pyridylcyanomethyl)piperazine, 1-acyl-4-(3-pyridylcyanomethyl)piperidine, and 1-acyl-4-cyano-4-(3-pyridylamino)piperidine. The acyl substituents, diphenylacetyl and 3,3-diphenylpropionyl, provided the most active compounds, and the introduction of an amine or hydroxy group in the 3,3-diphenylpropionyl substituent led to further improvement in oral activity. As a result, three of the most active compounds (100, 114, and 115) have been selected for further pharmacological development.