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Goals We aimed to evaluate the efficacy and safety of PB+S (pinaverium bromide 100 mg plus simethicone 300 mg) in patients with irritable bowel syndrome (IBS). Background IBS is a multifactorial disorder; thus, combination therapy with different mechanisms of action is expected to be useful. PB+S has shown effectiveness in an open-label clinical study in IBS. However, there are no placebo-controlled trials. Materials and methods IBS-Rome III patients with abdominal pain/discomfort for at least 2 days within the week prior to baseline assessment were included in this 12-week, randomized, double-blind, placebo-controlled study of PB+S versus placebo, bid. The primary endpoint was overall symptom improvement, evaluated weekly by the patient (Likert Scale). Secondary endpoints included the weekly improvement in the severity of abdominal pain and bloating assessed both by patients (10-cm Visual Analogue Scale) and investigators (Likert Scale); frequency of Bristol Scale stool types (consistency) evaluated by patients and the IBS Quality of Life scores. Results A total of 285 patients (female: 83%; 36.5±8.9 y old) received at least 1 dose of PB+S (n=140) or placebo (n=145). No difference was observed in overall symptom improvement between the groups (P=0.13). However, PB+S was superior in abdominal pain (effect size: 31%, P=0.038) and bloating (33%, P=0.019). Patients with IBS-C and IBS-M showed the best improvement in the frequency of stool types with PB+S. No differences were observed in IBS Quality of Life scores and adverse events. Conclusions PB+S was superior to placebo in improving abdominal pain and bloating in patients with active IBS. The effect on the frequency of stool consistency was particularly significant in IBS-C and IBS-M.

Background/Aims To evaluate the effectiveness of pantoprazole magnesium (pantoprazole-Mg) 40 mg in the relief of esophageal and extra- esophageal symptoms of gastroesophageal reflux disease (GERD), particularly night-time symptoms. Methods Patients (aged 18-50 years) with 3-month history of heartburn and/or acid regurgitation plus at least one other symptom in the last week were enrolled in a nationwide, prospective and observational study in Mexico. Patients received pantoprazole-Mg 40 mg once daily during 4 weeks. Symptoms were assessed through a physician-administered structured interview and the patient- completed ReQuest in PracticeTM questionnaire. Night-time GERD was defined as arousal from sleep during the night due to GERD-associated symptoms. Results Out of 4,343 patients included at basal visit, 3,665 were considered for the effectiveness per protocol analysis. At baseline, patients had a median of 8 GERD related symptoms. Patients with night-time GERD symptoms (42.7%) were more likely to have extra-esophageal symptoms (P ＜ 0.001) than other GERD patients. Pantoprazole-Mg 40 mg once daily for 4 weeks improved a broad range of GERD-associated symptoms from baseline (80% reduction on physicians assessments; 68-77% reduction on ReQuest in PracticeTM dimensions), including both day- and night-time GERD symptoms; improvements were the greatest for extra-esophageal symptoms in patients with night-time symptoms. Pantoprazole-Mg was well tolerated. Conclusions Pantoprazole-Mg 40 mg significantly improved a broad range of esophageal and extra-esophageal GERD related symptoms including sleep disturbances, as well as well-being, in patients with daytime or night-time GERD, making it a good option for patients with GERD, especially when extra-esophageal and night-time symptoms are present. (J Neurogastroenterol Motil 2014;20:64-73)

Background: Irritable Bowel Syndrome (IBS) is a disorder characterized by abdominal pain or discomfort associated with changes in bowel habit. Currently there are no objective outcome measures for evaluating the effectiveness of treatments for this disorder. Aims: To determine the usefulness of a method of analysis that employs polar vectors to evaluate the effectiveness of IBS treatments. Methods: Data from a Phase IV clinical study with 1677 active IBS-Rome III patients who received 100 mg of pinaverium bromide + 300 mg of simethicone (PB + S) po bid for a period of four weeks were used for the analysis. Using the Bristol Stool Scale as a reference, the consistency and frequency of each type of bowel movement were recorded weekly in a Bristol Matrix (BM) and the data were expressed as polar vectors. Results: The analysis showed a differential response to the PB + S treatment among the IBS subtypes: in reference to the IBS with constipation subtype, the magnitude of the vector increased from 10.2 to 12.5, reaching maximum improvement at two weeks of treatment (p

We have tested the hypothesis that selenium (Se)-containing antioxidative enzymes protect thyroid epithelial cells from oxidative damage associated with enzymatic production of hydrogen peroxide required for thyroid hormone biosynthesis. Thyroid epithelial cells therefore express antioxidative enzymes, including catalase, peroxiredoxins, thioredoxin reductases, and glutathione peroxidases (GPxs). The latter two enzyme families contain highly active peroxide-degrading enzymes that carry selenocysteine (Sec) in their active centers. Since low Se status has been associated with thyroid disorders, selenoproteins are considered essential for thyroid integrity and function. We have conditionally inactivated selenoprotein biosynthesis in thyrocytes by targeting Sec tRNA.Constitutive and inducible Cre/loxP-mediated recombination of tRNA([Ser]Sec) drastically reduced activities of selenoenzymes GPx and type I-deiodinase in thyroid extracts. Immunohistochemical staining revealed increased 4-hydroxynonenal and 3-nitro-tyrosine levels consistent with increased oxidative stress. However, gross thyroid morphology remained intact for at least 6 months after recombination. Circulating thyroid hormone levels remained normal in mutant mice, while thyrotropin (TSH) levels were moderately elevated. Challenging mutant mice with low iodine diet increased TSH, but did not lead to destruction of selenoprotein-deficient thyroids.This is the first report probing the assumed physiological roles of selenoproteins in the thyroid using a genetic loss-of-function approach.We conclude that selenoproteins protect thyrocytes from oxidative damage and modulate thyroid hormone biosynthesis, but are not essential for thyrocyte survival.

Objectives:(1) Effectiveness of intranasal ciclesonide 200 mcg qd (CIC). (2) Time-of-day predominance (TDP) of nasal and nonnasal AR symptoms. TDP is the main focus of this report.Methods:Phase IV, open-label, noninterventional study. Patients aged 12 years with at least a 2-year history of AR were eligible; 1526 patients with active AR were enrolled and received CIC during 4 weeks. TDP was recorded by patients and classified as: Morning, noon, afternoon, night or none. TDP was evaluated at T0 (basal), once daily during the first treatment-week, and once a week during the rest of the study (weeks 2 to 4). Relative frequencies of AR symptoms were calculated with corresponding 95% confidence intervals. Differences between basal TDP-relative frequency and at treatment-days 7 and 28, were calculated using z test.Results:All symptoms were of morning predominance at baseline, for example, runny nose 51%, nasal congestion 51%, sneezing 49%. Morning predominance remained the highest for all evaluated symptoms dur...

ContextThyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 (MCT8). Mutations in MCT8 (or SLC16A2) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma triiodothyronine (T3) and low/normal thyroxine (T4). MCT8 contributes to hormone release from the thyroid gland.ObjectiveTo characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice.DesignThyroid morphology in a patient carrying the A224V mutation was followed by ultrasound imaging for over 10 years. After thyroidectomy, a histopathological analysis was carried out. The findings were compared with histological analyses of mouse thyroids from the Mct8−/y model.ResultsWe show that an inactivating mutation in MCT8 leads to a unique, progressive thyroid follicular pathology in a patient. After thyroidectomy, histological analysis revealed gross morphological changes, including several hyperplastic nodules, microfollicular areas with stromal fibrosis and a small focus of microfollicular structures with nuclear features reminiscent of papillary thyroid carcinoma (PTC). These findings are supported by an Mct8-null mouse model in which we found massive papillary hyperplasia in 6- to 12-month-old mice and nuclear features consistent with PTC in almost 2-year-old animals. After complete thyroidectomy and substitution with levothyroxine (l-T4), the preoperative, inadequately low T4 and free T4 remained, while increasing the l-T4 dosage led to T3 serum concentrations above the normal range.ConclusionsOur results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients. Other MCT8-deficient patients should be closely monitored for potential thyroid abnormalities.

Distribution of selenium (Se) within the mammalian body is mediated by SePP (selenoprotein P), an Se-rich glycoprotein secreted by hepatocytes. Genetic and biochemical evidence indicate that the endocytic receptors ApoER2 (apolipoprotein E receptor 2) and megalin mediate tissue-specific SePP uptake. In the present study megalin-mutant mice were fed on diets containing adequate (0.15 p.p.m.) or low (0.08 p.p.m.) Se content and were analysed for tissue and plasma Se levels, cellular GPx (glutathione peroxidase) activities and protein expression patterns. Megalin-mutant mice displayed increased urinary Se loss, which correlated with SePP excretion in their urine. Accordingly, serum Se and SePP levels were significantly reduced in megalin-mutant mice, reaching marginal levels on the low-Se diet. Moreover, kidney Se content and expression of renal selenoproteins were accordingly reduced, as was SePP internalization along the proximal tubule epithelium. Although GPx4 expression was not altered in testis, Se and GPx activity in liver and brain were significantly reduced. When fed on a low-Se diet, megalin-mutant mice developed impaired movement co-ordination, but no astrogliosis. These findings suggest that megalin prevents urinary SePP loss and participates in brain Se/SePP uptake.

Background: IBS is a functional gastrointestinal disorder with a high placebo response; however, Pinaveriumbromide 100mg + Symeticone 300mg bid (PB+S) has shown to improve the severity of abdominal pain and bloating.1-2 Recently, increased IL-8 concentrations have been found in intestinal segments of IBD compared with non-inflamed IBS mucosa,3 and according to our findings, lower IL-8 concentrations are present in unstimulated-cultured PBMCs in IBS vs. controls.4 Additionally, IBS has been associated with the IL-8 intronic variant GG at +396 (rs2227307).5 These results suggest that this cytokine may be related with an inflammatory variant of IBS. Aim: To analyze the association between improvement of abdominal pain in IBS patients treated with PB+S and IL-8 variant rs2227307. Methods: Two-hundred and seventy nine patients with active IBS were randomly allocated to PB+S (n=104) or placebo (n=109), in a 3-month double-blind clinical trial. A 10-cm VAS was used to evaluate the severity of abdominal pain. The rs2227307 was analyzed by QPCR. MANOVA analysis for repeated measurements adjusted by gender, age, BMI and IBS subtype, was performed. A priori multiplicative interaction was considered significant if p,0.20 and for main effects if p,0.05. Results: Mean (+/-SD) age of the population was 36 (+/-9) years and mean BMI 26.5 (+/-5.3). Allele frequencies were T=0.63, G=0.37 and genotypes TT= 38.7%, TG= 48.4% and GG=12.9%. The sample was in HW equilibrium (X2= 0.38, p= 0.54). Abdominal pain improved in patients with the three genotypes with a size effect of 34% (favoring PB+S p=0.004). The larger size effect was in those with GG (70.5%, interaction with treatment p=0.18). Conclusions: This study shows that patients with the rs2227307 do not have the same magnitude of response to placebo compared to those with the other genotypes. We hypothesized that an underlying inflammatory-variant of IBS may be more responsive to PB+S. An effect on mucosal immunological mediators and/or epithelial permeability needs to be elucidated. This study was supported by Takeda-Mexico. References: 1.Schmulson M, et al. Gastroenterology 2011;140(Suppl.1):M1327. 2.Remes-Troche JM. Gastroenterology 2011;140(Suppl.1):M1332. 3.Nielsen OH, et al. Gastroenterol. 1997;32:1028-34. 4.Rodriguez-Fandino O et al. Submitted to DDW 2013. 5. RomeroValdovinos M et al. Mol Biol Rep. 2012 Sep;39(9):8837-43.