Effect of P-glycoprotein and Cotreatment with Sofosbuvir on the Intestinal Permeation of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate.

PURPOSE: We aimed to compare the effects of P-glycoprotein (ABCB1) on the intestinal uptake of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), and metabolites, tenofovir isoproxil monoester (TEM) and tenofovir (TFV), and to study the molecular mechanism of drug-drug interaction (DDI) between sofosbuvir (SOF) and TDF/TAF. METHODS: Bidirectional transport experiments in Caco-2 cells and accumulation studies in precision-cut intestinal slices prepared from the ileal segment of rodent (rPCIS) and human (hPCIS) intestines were performed. RESULTS: TDF and TAF were extensively metabolised but TAF exhibited greater stability. ABCB1 significantly reduced the intestinal transepithelial transfer and uptake of the TFV(TDF) and TFV(TAF)-equivalents. However, TDF and TAF were absorbed more efficiently than TFV and TEM. SOF did not inhibit intestinal efflux of TDF and TAF or affect intestinal accumulation of TFV(TDF) and TFV(TAF)-equivalents but did significantly increase the proportion of absorbed TDF. CONCLUSIONS: TDF and TAF likely produce comparable concentrations of TFV-equivalents in the portal vein and the extent of permeation is reduced by the activity of ABCB1. DDI on ABCB1 can thus potentially affect TDF and TAF absorption. SOF does not inhibit ABCB1-mediated transport of TDF and TAF but does stabilise TDF, albeit without affecting the quantity of TFV(TDF)-equivalents crossing the intestinal barrier. Our data thus suggest that reported increases in the TFV plasma concentrations in patients treated with SOF and TDF result either from a DDI between SOF and TDF that does not involve ABCB1 or from a DDI involving another drug used in combination therapy.

[Esophagogastric junction and its tumours - comments to definition and classification]. / Ezofagogastrická junkce a její nádory - poznámky k definici a klasifikaci.

In spite of the worldwide decreasing incidence of gastric cancer the number of esophagogastric junction and proximal third of stomach carcinomas has been gradually growing up. The reason of that is an increasing incidence of reflux esophagitis with Barrett´s metaplasia and a successful eradication of Helicobacter pylori infection. The aim of this work is to provide various views on definition of the esophagogastric junction and to give an overview of tumours classification schemes being used.

Asymptomatic Bochdalek's Hernia in an Adult: A Case Report.

Bochdalek's hernia is the most common congenital malformation of the diaphragm with a defect in its posterolateral part. Its clinical manifestation in adulthood is rare. It is often an incidental finding, and its diagnosis may be challenging. A high index of suspicion is necessary, especially in cases presenting with cardiopulmonary or abdominal symptoms and an ambiguous finding on the initial chest X-ray. We present a case of an asymptomatic 50-year-old male patient with a bulky left-sided Bochdalek's hernia. Surgical treatment was indicated, and a direct suture of the defect after reduction of the herniated greater omentum, transverse colon, and tail of the pancreas was performed from the upper midline laparotomy. The postoperative course was uneventful, and the patient was discharged on the fifth postoperative day. The management of adult patients with these kinds of hernias in both acute and chronic settings is discussed, and some recommendations are mentioned to minimize unnecessary pitfalls.

Exogenous surfactant for lung contusion causing ARDS: A systematic review of clinical and experimental reports.

This systematic review aimed to summarize the available data on the treatment of pulmonary contusions with exogenous surfactants, determine whether this treatment benefits patients with severe pulmonary contusions, and evaluate the optimal type of surfactant, method of administration, and drug concentration. Three databases (MEDline, Scopus, and Web of Science) were searched using the following keywords: pulmonary surfactant, surface-active agents, exogenous surfactant, pulmonary contusion, and lung contusion for articles published between 1945 and February 2023, with no language restrictions. Four reviewers independently rated the studies for inclusion, and the other four reviewers resolved conflicts. Of the 100 articles screened, six articles were included in the review. Owing to the limited number of papers on this topic, various types of studies were included (two clinical studies, two experiments, and two case reports). In all the studies, surfactant administration improved the selected ventilation parameters. The most frequently used type of surfactant was Curosurf® in the concentration of 25 mg/kg of ideal body weight. In most studies, the administration of a surfactant by bronchoscopy into the segmental bronchi was the preferable way of administration. In both clinical studies, patients who received surfactants required shorter ventilation times. The administration of exogenous surfactants improved ventilatory parameters and, thus, reduced the need for less aggressive artificial lung ventilation and ventilation days. The animal-derived surfactant Curosurf® seems to be the most suitable substance; however, the ideal concentration remains unclear. The ideal route of administration involves a bronchoscope in the segmental bronchi.

Gene Expression of Antioxidant Enzymes in the Resected Intestine in Crohn's Disease.

INTRODUCTION: The inflammatory process in Crohn's disease (CD) is closely associated with the formation of reactive oxygen species. Antioxidant enzymes can play an important role in the outcome of CD and may influence postoperative recurrence in these patients. The aim of our study was to evaluate gene expression of intracellular antioxidant enzymes in surgically resected intestinal specimens of patients with CD, both in macroscopically normal and in inflamed tissue. METHODS: A total of 28 patients referred for elective bowel resection were enrolled in the study. Full-thickness small intestinal specimens were investigated. Gene expression of antioxidant enzymes - superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GSR) - was evaluated both in macroscopically normal and inflamed samples. RESULTS: There were significantly lower levels of SOD1 mRNA (p = 0.007) and GSR mRNA (p = 0.027) in inflamed tissue compared to macroscopically normal areas. No significant differences were found between affected and non-affected intestinal segments in mRNA for SOD2, SOD3 and GPX. CONCLUSIONS: Our pilot data clearly showed that the gene expression of major antioxidant enzymes is not a uniform mechanism in the pathogenesis of Crohn's disease. Topically decreased gene expression of SOD1 and GSR might facilitate the segmental tissue injury caused by reactive oxygen species.

Percutaneous cholecystostomy in the management of acute cholecystitis - 10 years of experience.

INTRODUCTION: The preferred treatment for acute cholecystitis is cholecystectomy, but for patients with precluded general anesthesia due to critical illness or multiple medical comorbidities it is not suitable. Cholecystostomy could be a minimally invasive therapeutic alternative. AIM: To retrospectively evaluate the indications, technical features, efficacy, complications, patients' development and relationships among monitored parameters of percutaneous computed tomography (CT)-guided cholecystostomies in cases of acute cholecystitis and find the role of this procedure in appropriate treatment selection. MATERIAL AND METHODS: Over the course of 10 years, 75 percutaneous cholecystostomy procedures in 69 patients were performed in cases with diagnosed acute cholecystitis, precluded general anesthesia and contraindicated cholecystectomy by an experienced surgeon and anesthesiologist. These interventions were done using only local anesthesia. The patients were men in 39 cases and women in 33 cases, aged 33 to 91 years. RESULTS: Technical success was achieved in all cases. The indications were sepsis in 34 (45.3%) cases, bridging acute gallbladder inflammatory status in 15 (20%) interventions, serious medical comorbidities in 8 (10.7%) cases, disseminated malignancy and cardiac failure in 6 cases each (both 8%) and neurological affections in 5 (6.5%) cases. Cholecystostomy was frequently the final solution in acalculous cholecystitis (79.3%). The 30-day mortality rate was determined at 10.7% and the overall complication rate was 21.3%, but all of these complications were managed conservatively or using minimally invasive treatment. CONCLUSIONS: Percutaneous CT-guided cholecystostomy is reserved for patients with a serious medical status for various reasons that preclude surgical treatment and general anesthesia. Simultaneously, technical success and efficacy are high and the complication rate is acceptable.

Neopterin, kynurenine and tryptophan as new biomarkers for early detection of rectal anastomotic leakage.

INTRODUCTION: At present, there are no strong predictors, nor a useful scoring system, that clearly identifies patients at risk for anastomotic leakage. AIM: This study aimed to investigate a new method that assesses this risk by monitoring levels of neopterin, tryptophan, and kynurenine, in bodily fluids. MATERIAL AND METHODS: This prospective study included patients who underwent elective rectal resection for carcinoma. The basic condition for inclusion was rectal anastomosis using the double-stapling technique. Preoperative levels of neopterin, tryptophan, kynurenine, and their ratios, were assessed with blood and urine samples. These levels were then monitored for 6 postoperative days in venous blood, urine, and abdominal drainage fluid. RESULTS: A total of 42 patients were enrolled in the study. Thirty-six patients underwent a laparoscopic resection and 6 patients had an open procedure. No differences were found among neopterin, tryptophan, and kynurenine serum levels. However, the groups were observed to have significant differences in the urinary neopterin/creatinine ratio: the preoperative neopterin/creatinine ratio was 139.5 µmol/mol in the group with leakage, vs 114.8 µmol/mol in the group without complications, p = 0.037. The same results were observed during the postoperative period, p = 0.012. Additionally, the group with complications had a higher mean value of neopterin in drainage fluid, p = 0.048. CONCLUSIONS: Our study demonstrated that high preoperative levels of urinary neopterin could be interpreted as a risk for anastomotic leakage. Moreover, pathological levels of neopterin in urine and abdominal drainage fluid could be useful for early identification of anastomotic leakage during the postoperative period prior to its clinical development.

Higher risk of incomplete mesorectal excision and positive circumferential margin in low rectal cancer regardless of surgical technique.

INTRODUCTION: Currently, the predominant question is whether a laparoscopic approach is comparatively radical in comparison with an open access approach, especially in the circumferential resection margin and quality of the completeness of total mesorectal excision. These factors are important in determining the quality of surgical care as well as long-term results of the treatment. AIM: This article focuses on the evaluation of circumferential resection margins and on the quality of mesorectal excision of middle and lower rectum tumors. In addition, laparoscopic and open techniques are compared. MATERIAL AND METHODS: Data were collected prospectively and stored in a rectal cancer registry over a 3-year period. The parameters studied were age, sex, body mass index, localization and topography of the tumor, clinical stage, neoadjuvant chemotherapy and its response, the type of surgery, character of the circumferential and distal margins, quality of the mesorectal excision, pT and pN. RESULTS: One hundred and twenty-five patients were chosen for our study. Laparoscopy was performed in 53 operations and a conventional approach was performed in 72 operations. Complete mesorectal excision was achieved in 54.7% of laparoscopic operations versus 44.4% in the conventional technique; partially complete excision was performed in 20.8 and 12.5%, respectively. Incomplete excisions were described in 24.5 and 43.1% (p = 0.085). Positive circumferential margin occurred during laparoscopic surgery in 11 (20.8%) patients, and in the case of conventional resection in 27 (37.5%) patients (p = 0.044). CONCLUSIONS: Our study showed comparable results between laparoscopic and open access procedures during rectal resection. The results achieved, in particular in the quality of the mesorectal excision and negative circumferential resection margin, show that the laparoscopic approach is comparable to conventional surgical techniques, with an adequate surgical outcome, in the treatment of rectal cancer.