Ebselen impairs cellular oxidative state and induces endoplasmic reticulum stress and activation of crucial mitogen-activated protein kinases in pancreatic tumour AR42J cells.

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is an organoselenium radical scavenger compound, which has strong antioxidant and anti-inflammatory effects. However, evidence suggests that this compound could exert deleterious actions on cell physiology. In this study, we have analyzed the effect of ebselen on rat pancreatic AR42J cells. Cytosolic free-Ca2+ concentration ([Ca2+ ]c ), cellular oxidative status, setting of endoplasmic reticulum stress, and phosphorylation of major mitogen-activated protein kinases were analyzed. Our results show that ebselen evoked a concentration-dependent increase in [Ca2+ ]c . The compound induced an increase in the generation of reactive oxygen species in the mitochondria. We also observed an increase in global cysteine oxidation in the presence of ebselen. In the presence of ebselen an impairment of cholecystokinin-evoked amylase release was noted. Moreover, involvement of the unfolded protein response markers, ER chaperone and signaling regulator GRP78/BiP, eukaryotic translation initiation factor 2α and X-box binding protein 1 was detected. Finally, increases in the phosphorylation of SAPK/JNK, p38 MAPK, and p44/42 MAPK in the presence of ebselen were also observed. Our results provide evidences for an impairment of cellular oxidative state and enzyme secretion, the induction of endoplasmic reticulum stress and the activation of crucial mitogen-activated protein kinases in the presence of ebselen. As a consequence ebselen exerts a potential toxic effect on AR42J cells.

Intermittent boluses versus pump continuous infusion for endoscopist-directed propofol administration in colonoscopy.

BACKGROUND: non-anesthesiologist administration of propofol (NAAP) using continuous infusion systems may achieve a more sustained sedative action. AIM: to compare intermittent boluses (IB) with pump continuous infusion (PCI) for NAAP, targeted to moderate sedation, for colonoscopy. METHODS: 192 consecutive outpatients were randomized to receive IB (20 mg propofol boluses on demand) or PCI (3 mg/kg/h plus 20 mg boluses on demand). Sedation could be stopped at cecal intubation at the discretion of the endoscopist. Satisfaction rates of the patient, nurses and endoscopist, propofol doses, depth of sedation (at the beginning, at cecal intubation and at the end), recovery times, complications and were collected. RESULTS: there were no differences between groups regarding patient, nurse or endoscopist satisfaction rates with procedural sedation. Propofol doses (mg) were significantly higher during the induction phase -86 (30-172) vs. 78 [30-160], p 0.03- and overall -185 (72-400) vs. 157 (60-460), p = 0.003- for PCI group. 81 % of assessments of the depth of sedation were moderate. The level of sedation (O/AAS scale) was borderline significantly deeper at cecal intubation (2.38 vs. 2.72; p = 0.056) and at the end of the procedure (4.13 vs. 4.45; p = 0.05) for PCI group, prolonging thus early recovery time (6.3 vs. 5.1 minutes, p = 0.008), but not discharge time. Complications, all of them in minors, were non-significantly more frequent in the PCI group (9 vs. 7 %, p = 0.07). CONCLUSIONS: NAAP for colonoscopy was safely administered with comparable satisfaction and complication rates with either IB or PCI.

[Split-dose sodium picosulphate/magnesium citrate for morning colonoscopies performed 2 to 6 hours after fluid intake]. / Preparación con picosulfato sódico/citrato de magnesio en dosis fraccionadas para colonoscopias en turno de mañana realizadas entre las 2 y 6 horas posteriores a la ingesta de líquidos.

BACKGROUND: Split dosage of bowel preparations has been shown to substantially improve bowel cleansing. AIM: To compare the split dose (SD) sodium picosulphate/magnesium oxide/anhydrous citric acid (Citrafleet(®)) regimen for morning colonoscopies with standard cleansing the day before. METHODS: Consecutive outpatients were randomized to receive Citrafleet(®) the day before colonoscopy or SD, in whom the second half was administered on an individual basis from 2 to 6 hours before the procedure. No bisacodyl was administered. All procedures were performed with non-anesthesiologist administered propofol sedation. The Boston scale was used to assess the quality of bowel preparation (adequate cleansing if score ≥ 6, with no score of 0/1 in any segment). RESULTS: A total of 193 patients were included. Overall bowel cleansing was significantly better in the SD group (7 vs. 5.2, p<0.001), as well as in the cecum (2.4 vs. 1.4, p < 0.001), ascending colon (2.5 vs. 1.6, p<0.001) and transverse colon (2.4 vs. 2, p=0.004). A significant proportion of SD patients had adequate bowel cleansing (71% vs. 30%, p<0.001). Patients in the SD group drank a greater amount of liquid (4.9 vs. 4 liters, p=0.006) and more frequently perceived the cleansing process to be easy or very easy to complete (89 vs. 68%, p=0.04), although they slept significantly fewer hours (6.5 vs. 7.9, p<0.001). No bronchoaspiration pneumonia was reported. CONCLUSIONS: SD Citrafleet(®) 2 to 6 hours before colonoscopy increased the rate of procedures with adequate bowel cleansing by 40%, especially in the proximal colon, allowed more liquids to be drunk and increased the perception of ease in completing the preparation, with no sedation-related complications.

Nonbismuth quadruple (concomitant) therapy: empirical and tailored efficacy versus standard triple therapy for clarithromycin-susceptible Helicobacter pylori and versus sequential therapy for clarithromycin-resistant strains.

BACKGROUND: Using quadruple clarithromycin-containing regimens for Helicobacter pylori eradication is controversial with high rates of macrolide resistance. AIM: To evaluate antibiotic resistance rates and the efficacy of empirical and tailored nonbismuth quadruple (concomitant) therapy in a setting with cure rates <80% for triple and sequential therapies. METHODS: 209 consecutive naive H. pylori-positive patients without susceptibility testing were empirically treated with 10-day concomitant therapy (proton pump inhibitors (PPI), amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg; all drugs b.i.d.). Simultaneously, 89 patients with positive H. pylori culture were randomized to receive triple versus concomitant therapy for clarithromycin-susceptible H. pylori, and sequential versus concomitant therapy for clarithromycin-resistant strains. Eradication was confirmed with ¹³C-urea breath test or histology 8 weeks after completion of treatment. RESULTS: Per-protocol (PP) and intention-to-treat eradication rates after empirical concomitant therapy without susceptibility testing were 89% (95%CI:84-93%) and 87% (83-92%). Antibiotic resistance rates were: clarithromycin, 20%; metronidazole, 34%; and both clarithromycin and metronidazole, 10%. Regarding clarithromycin-susceptible H. pylori, concomitant therapy was significantly better than triple therapy by per protocol [92% (82-100%) vs 74% (58-91%), p = 0.05] and by intention to treat [92% (82-100%) vs 70% (57-90%), p = 0.02]. As for antibiotic-resistant strains, eradication rates for concomitant and sequential therapies were 100% (5/5) vs 75% (3/4), for clarithromycin-resistant/metronidazole-susceptible strains and 75% (3/4) vs 60% (3/5) for dual-resistant strains. CONCLUSIONS: Empirical 10-day concomitant therapy achieves good eradication rates, close to 90%, in settings with multiresistant H. pylori strains. Tailored concomitant therapy is significantly superior to triple therapy for clarithromycin-susceptible H. pylori and at least as effective as sequential therapy for resistant strains.

Nonanesthesiologist-administered propofol versus midazolam and propofol, titrated to moderate sedation, for colonoscopy: a randomized controlled trial.

BACKGROUND: Nonanesthesiologist-administered propofol (NAAP) is controversial due to deep sedation concerns. AIM: The purpose of this study was to evaluate the feasibility of moderate sedation with two different NAAP regimens for colonoscopy. METHODS: This was a double-blinded, randomised, placebo-controlled trial allocating 135 consecutive outpatients to placebo (group P) or midazolam 2 mg (group M+P) before NAAP targeted to moderate sedation. Depth of sedation every 2 min throughout the procedure, propofol doses, recovery times, complications and patient and endoscopist satisfaction were measured. RESULTS: A total of 84 % of assessments of the depth of sedation were moderate. Mean induction (76 [40-150] vs. 53 [30-90]) and total propofol doses (mg) (136 [60-270] vs. 104 [50-190]) were significantly higher for group P (p < 0.001). However, deep sedation was significantly more prevalent in group M+P in minutes 4 (16 vs. 1 %, p = 0.05), 6 (20 vs. 3.5 %, p = 0.046) and 8 (17 vs. 1.8 %, p = 0.06) of the procedure, coinciding with midazolam peak action. From minute 8 on, moderate sedation was significantly deeper for M+P (p = 0.002). Early recovery time (6.8 min vs. 5.2, p = 0.007), but not discharge time (10.4 min vs. 9.8, p = 0.5), was longer for M+P. Pain perception (P 1.03 vs. M+P 0.3, p = 0.009) and patient satisfaction scores (P 9.4 vs. M+P 9.8, p = 0.047) were better for M+P. No major complications occurred. CONCLUSIONS: Moderate sedation was feasible with both NAAP regimens. Drug synergy in the midazolam plus propofol sedation regimen promotes a deeper and longer moderate sedation, improving patient satisfaction rates but prolonging early recovery time (Clinical Trials gov NCT01428882).

Endoscopic-assisted colopexy and push percutaneous colostomy in the transverse colon for refractory chronic intestinal pseudo-obstruction.

Percutaneous endoscopic colostomy (PEC), using the classic pull-through technique in the ascending or the descending colon, has been proven useful to treat chronic intestinal pseudo-obstruction. We report the case of a high-surgical risk 70-year-old male with refractory chronic intestinal pseudo-obstruction, in whom the ascending colon could not be reached due to tortuous left dolichocolon. Endoscopic-assisted colopexy and push colostomy in the proximal transverse colon was decided accordingly. Colopexy was performed under direct endoscopic vision in the proximal transverse colon using 3 preloaded T-fasteners surrounding the intended stoma site. The stoma tract was created with an introducer needle, allowing the advance of the 24 Fr 4-sleeve dilator over a guidewire. Afterwards, the dilator was removed and the peel-away sheath was left in place. Over the guidewire, a 20-Fr gastrostomy tube was advanced into the colon lumen through the covering, which was finally removed. The patient recovered uneventfully, despite postprocedure pneumoperitoneum, which was related to the technique. He died a month later due to unrelated comorbidities, without further abdominal complaints after discharge. This is the first report of PEC both using a push technique, and the first report in a different location than the ascending or the descending colon. We believe this novel push technique may be feasible for PEC, avoiding the need of reinsertion in patients with difficult colonoscopy.

Intermittent boluses versus pump continuous infusion for endoscopist-directed propofol administration in colonoscopy / Administración de propofol mediante bolus intermitente frente a infusión continua con bomba controlada por el endoscopista en la colonoscopia

Background: non-anesthesiologist administration of propofol (NAAP) using continuous infusion systems may achieve a more sustained sedative action. Aim: to compare intermittent boluses (IB) with pump continuous infusion (PCI) for NAAP, targeted to moderate sedation, for colonoscopy. Methods: 192 consecutive outpatients were randomized to receive IB (20 mg propofol boluses on demand) or PCI (3 mg/ kg/h plus 20 mg boluses on demand). Sedation could be stopped at cecal intubation at the discretion of the endoscopist. Satisfaction rates of the patient, nurses and endoscopist, propofol doses, depth of sedation (at the beginning, at cecal intubation and at the end), recovery times, complications and were collected. Results: there were no differences between groups regarding patient, nurse or endoscopist satisfaction rates with procedural sedation. Propofol doses (mg) were significantly higher during the induction phase (86 [30-172] vs. 78 [30-160], p 0.03) and overall (185 [72-400] vs. 157 [60-460], p = 0.003) for PCI group. 81 % of assessments of the depth of sedation were moderate. The level of sedation (O/AAS scale) was borderline significantly deeper at cecal intubation (2.38 vs. 2.72; p = 0.056) and at the end of the procedure (4.13 vs. 4.45; p = 0.05) for PCI group, prolonging thus early recovery time (6.3 vs. 5.1 minutes, p = 0.008), but not discharge time. Complications, all of them in minors, were non-significantly more frequent in the PCI group (9 vs. 7 %, p = 0.07). Conclusions: NAAP for colonoscopy was safely administered with comparable satisfaction and complication rates with either IB or PCI (AU)

Preparación con picosulfato sódico/citrato de magnesio en dosis fraccionadas para colonoscopias en turno de mañana realizadas entre las 2 y 6 horas posteriores a la ingesta de líquidos / Split-dose sodium picosulphate/magnesium citrate for morning colonoscopies performed 2 to 6hours after fluid intake

Introducción La preparación de la colonoscopia en dosis fraccionadas (DF) mejora la calidad de la limpieza. Objetivo Comparar la preparación para colonoscopias de mañana con picosulfato sódico/citrato de magnesio (Citrafleet®) en DF con su administración el día previo. Material y métodos Pacientes consecutivos fueron aleatorizados a Citrafleet® el día anterior o en DF administrándose la segunda mitad individualizadamente con un intervalo de 2 a 6 h antes del procedimiento, sin bisacodilo. La sedación fue realizada con propofol, definiéndose una limpieza adecuada si ≥ 6 (escala de Boston), sin ninguna puntuación 0/1.ResultadosSe incluyeron 193 pacientes. La calidad de la limpieza fue significativamente mejor en el grupo DF de manera global (7 vs. 5,2, p<0,001), en ciego (2,4 vs. 1,4, p<0,001), colon ascendente (2,5 vs.1,6, p = 0,001) y colon transverso (2,4 vs. 2, p = 0,004). La limpieza adecuada del colon se detectó en un porcentaje significativamente superior de pacientes con DF (71 vs. 30%, p<0,001). Los pacientes del grupo DF bebieron un volumen de líquido superior (4,9 vs. 4 l, p = 0,006) y percibieron con mayor frecuencia el proceso como fácil o muy fácil de completar (89 vs. 68%, p = 0,04), aunque durmieron menor número de horas (6,5 vs.7,9, p<0,001). No se registró ninguna bronconeumonía aspirativa. Conclusiones La preparación en DF con Citrafleet® incrementó en un 40% las exploraciones con una limpieza adecuada, especialmente en colon proximal, aumentó el volumen de ingesta líquida y mejoró la percepción de facilidad para su cumplimiento, sin complicaciones derivadas de la sedación (AU)

Background Split dosage of bowel preparations has been shown to substantially improve bowel cleansing. Aim To compare the split dose (SD) sodium picosulphate/magnesium oxide/anhydrous citric acid (Citrafleet®) regimen for morning colonoscopies with standard cleansing the day before. Methods Consecutive outpatients were randomized to receive Citrafleet® the day before colonoscopy or SD, in whom the second half was administered on an individual basis from 2 to 6hours before the procedure. No bisacodyl was administered. All procedures were performed with non-anesthesiologist administered propofol sedation. The Boston scale was used to assess the quality of bowel preparation (adequate cleansing if score ≥ 6, with no score of 0/1 in any segment).Results A total of 193 patients were included. Overall bowel cleansing was significantly better in the SD group (7 vs. 5.2, p<0.001), as well as in the cecum (2.4 vs. 1.4, p < 0.001), ascending colon (2.5vs. 1.6, p<0.001) and transverse colon (2.4 vs. 2, p = 0.004). A significant proportion of SD patients had adequate bowel cleansing (71% vs. 30%, p<0.001). Patients in the SD group drank a greater amount of liquid (4.9 vs. 4 liters, p = 0.006) and more frequently perceived the cleansing process to be easy or very easy to complete (89 vs. 68%, p = 0.04), although they slept significantly fewer hours (6.5 vs. 7.9, p<0.001). No bronchoaspiration pneumonia was reported. Conclusions SD Citrafleet® 2 to 6hours before colonoscopy increased the rate of procedures with adequate bowel cleansing by 40%, especially in the proximal colon, allowed more liquids to be drunk and increased the perception of ease in completing the preparation, with no sedation-related complications (AU)