Postprandial splenic stiffness changes on magnetic resonance elastography in a young healthy population.

Magnetic resonance elastography (MRE) is an accurate noninvasive diagnostic tool for assessing the stiffness of parenchymal organs, including the spleen. However, this measurement may be biased due to postprandial changes in splenic stiffness. The aim of the current study was to evaluate postprandial changes in spleen stiffness assessed by MRE in a large sample of healthy volunteers. This was a prospective institutional research ethics board-approved study. Healthy volunteers with no history of liver disease were recruited for an MRE test and blood draw from December 2018 to July 2019. Each participant underwent spleen MRE after at least 4 h of fasting and again 30 min after a 1000 kcal meal. Also, 14 randomly selected volunteers underwent additional MRE examinations at 1.5 and 2.5 h after food intake. The MRE data were acquired at 60 Hz using a 1.5-T MRI scanner. The spleen stiffness was assessed using a weighted mean of stiffness values from regions of interest manually drawn on three to five spleen slices. Spearman's rank correlation, Wilcoxon signed-rank, Friedman, and Mann-Whitney tests were used for statistical analysis. A total of 100 volunteers met the inclusion criteria and were eventually enrolled in this study (age 23 ± 2 years; 65 women). The mean spleen stiffness for the whole group increased by 7.9% (p < 0.001) from the mean ± SD value of 5.09 ± 0.63 (95% CI: 4.96-5.21) kPa in the fasting state to 5.47 ± 0.66 (95% CI 5.34-5.60) kPa 30 min after the meal and then gradually decreased. However, even 2 h 30 min after the meal, the spleen stiffness was higher than in the fasting state. This difference was statistically significant at p less than 0.001. It was concluded that meal intake results in a statistically significant elevation of spleen stiffness that persists for 2.5 h. This finding supports the recommendation for routine fasting for more than 2.5 h prior to assessing MRE-based spleen stiffness.

Evaluation of Spleen Stiffness in Young Healthy Volunteers Using Magnetic Resonance Elastography.

PURPOSE: Magnetic resonance elastography (MRE) has been established as the most accurate noninvasive technique for diagnosing liver fibrosis. Recent publications have suggested that the measurement of splenic stiffness is useful in setting where portal hypertension may be present. The goal of the current study was to compile normative data for MRE-assessed stiffness measurements of the spleen in young adults. MATERIALS AND METHODS: A total of 100 healthy young Caucasian volunteers (65 females and 35 males) in the age range of 20 to 32 years were enrolled in this study. The participants reported no history of chronic spleen and liver disease, normal alcohol consumption, and a normal diet. The MRE data were acquired by using a 1.5 T whole-body scanner and a 2D GRE pulse sequence with 60 Hz excitation. Spleen stiffness was calculated as a weighted mean of stiffness values in the regions of interest manually drawn by the radiologist on three to five spleen slices. RESULTS: Mean spleen stiffness was 5.09 ± 0.65 kPa for the whole group. Male volunteers had slightly higher splenic stiffness compared to females: 5.28 ± 0.78 vs. 4.98 ± 0.51 kPa, however, this difference was not statistically significant (p = 0.12). Spleen stiffness did not correlate with spleen fat content and liver stiffness but a statistically significant correlation with spleen volume was found. CONCLUSIONS: The findings of this study provide normative values for 2D MRE-based measurement of spleen stiffness in young adults, a basis for assessing the value of this biomarker in young patients with portal system pathologies.

Postprandial hepatic stiffness changes on magnetic resonance elastography in healthy volunteers.

Magnetic resonance elastography (MRE) is a reliable noninvasive method for assessment of hepatic stiffness. Liver stiffness is known to be affected by elevated postprandial portal blood flow in patients with chronic liver disease. The goal of this study was to determine whether food intake affects liver stiffness in the absence of known liver disease. We evaluated 100 volunteers (35 men and 65 women) who met inclusion criteria. The subjects had two MRE examinations, first while fasting and then 30 min after a test meal. Fourteen subjects also had two additional MRE exams 1 h 30 min and 2 h 30 min after the meal. Liver stiffness was measured by placing the largest possible polygon ROIs on the four widest liver slices and calculated as a mean of stiffness values from each slice. The correlation of liver stiffness values before and after the meal was assessed using a paired t-test. To evaluate the relationship between the change in postprandial liver stiffness and fasting liver stiffness values, linear regression was performed. The liver stiffness values in the fasting state ranged from 1.84 to 2.82 kPa, with a mean of 2.30 ± 0.23 kPa (95% CI 2.25-2.34). At 30 min after the meal, liver stiffness values ranged from 2.12 to 3.50 kPa, with a mean of 2.70 ± 0.28 kPa (95% CI 2.64-2.75), demonstrating a systematic postprandial increase by 0.40 ± 0.23 kPa (17.7 ± 3.5%). Meal intake significantly increases liver stiffness in healthy individuals, which persists for at least 2 h 30 min. Patients should fast for 3-4 h before MRE examinations to avoid fibrosis overstaging due to postprandial liver stiffness augmentation.

The bile salt content of human bile impacts on simulated intestinal proteolysis of ß-lactoglobulin.

The gastrointestinal hydrolysis of food proteins has been portrayed in scientific literature to predominantly depend on the activity and specificity of proteolytic enzymes. Human bile has not been considered to facilitate proteolysis in the small intestine, but rather to assist in intestinal lipolysis. However, human bile can potentially influence proteins that are largely resistant to gastric digestion, and which are mainly hydrolysed after they have been transferred to the small intestine. We used purified and food-grade bovine milk ß-lactoglobulin (ßLg) to assess the impact of bile salts (BS) on the in vitro gastrointestinal digestion of this protein. Quantitative analysis showed that the proteolysis rate increased significantly with increasing BS concentration. The effect was consistent regardless of whether individual BS or real human bile samples, varying in BS concentrations, were used. The total BS content of bile was more important than its BS composition in facilitating the proteolysis of ßlg. We also show that the impact of human bile observed during the digestion of purified ßLg and ßLg-rich whey protein isolate can be closely replicated by the use of individual BS mixed with phosphatidylcholine. This could validate simple BS/phosphatidylcholine mixtures as human-relevant substitutes of difficult-to-obtain human bile for in vitro proteolysis studies.

Unresectable malignant obstructive jaundice: a 2-year experience of EUS-guided biliary drainage.

OBJECTIVES: Endoscopic biliary drainage is a first-line treatment in patients with unresectable malignant biliary obstruction. In most cases the drainage is conducted using endoscopic retrograde cholangiopancreatography (ERCP). Percutaneous transhepatic biliary drainage or endosonography-guided biliary drainage (EUS-BD) represents therapeutic options after unsuccessful ERCP. Here we report on 2 years experience in the management of patients diagnosed with malignant biliary obstruction using EUS-BD. METHODS: Retrospective data were collected on patients who underwent EUS-BD due to malignant biliary obstruction at our centre between April 2016 and April 2018. Only patients who had two unsuccessful attempts of ERCP prior to EUS-BD were included. We analysed the technical success (ie, creation of anastomosis and successful placement of a stent) and complication rate of EUS-BD, and monitored changes in serum bilirubin and liver function tests after 2 days, and at least 2 weeks, following the procedure. RESULTS: Screening of 1781 ERCP procedures performed in our department during the inclusion period led to the identification of 31 patients (18 women, age range 51-92 years, 58% with pancreatic cancer) who fulfilled the inclusion criteria. Hepaticogastrostomy and choledochoduodenostomy were performed in 12 and 19 patients, respectively. The technical success rate was 97% and the complication rate was 12.9%. EUS-BD resulted in a significant decrease in serum bilirubin (p<0.01). CONCLUSIONS: EUS-BD represents a reasonable therapeutic option after unsuccessful ERCP in patients with malignant biliary obstruction. Possible complications have to be kept in mind and this procedure should be performed at centres experienced in ERCP and EUS.

Colloidal transport of lipid digesta in human and porcine small intestinal mucus.

Small intestinal mucus transport of food-derived particulates has not been extensively studied, despite mucus being a barrier nutrients need to cross before absorption. We used complex dispersions of digesta obtained from simulated, dynamic gastrointestinal digestion of yogurt to examine the penetrability of human and porcine mucus to the particles formed of lipolysis products. Quantitative, time-lapse confocal microscopy revealed a sieve-like behaviour of the pig jejunal and ileal mucus. The digesta diffusivity decreased significantly over the first 30 min of mucus penetration, and then remained constant at ca. 5 × 10-12 m2 s-1 (approx. 70% decrease from initial values). A non-significantly different penetrability was recorded for the ileal mucus of adult humans. The digesta diffusion rates in neonatal, jejunal mucus of 2 week old piglets were 5-8 times higher than in the three different types of adult mucus. This is the first report that validates the mucus of fully-grown pigs as a human-relevant substitute for mucus permeation studies of nutrients/bio-actives and/or complex colloidal dispersions (e.g., post-digestion food particulates, orally-administrated delivery systems).

Comparing the permeability of human and porcine small intestinal mucus for particle transport studies.

The gastrointestinal mucus layer represents the last barrier between ingested food or orally administered pharmaceuticals and the mucosal epithelium. This complex gel structure plays an important role in the process of small intestinal absorption. It provides protection against hazardous particles such as bacteria but allows the passage of nutrients and drug molecules towards the intestinal epithelium. In scientific research, mucus from animal sources is usually used to simulate difficult-to-obtain human small intestinal mucus for investigating the intramucus transport of drug delivery systems or food nanoparticles. However, there is a lack of evidence the human mucus can be reliably substituted by animal counterparts for human-relevant transport models. In this report, a procedure for collecting human mucus has been described. More importantly, the permeability characteristics of human and porcine small intestinal mucus secretions to sub-micron sized particles have been compared under simulated intestinal conditions. Negatively charged, 500 nm latex beads were used in multiple-particle tracking experiments to examine the heterogeneity and penetrability of mucus from different sources. Diffusion of the probe particles in adult human ileal mucus and adult pig jejunal and ileal mucus revealed no significant differences in microstructural organisation or microviscosity between the three mucus types (P > 0.05). In contrast to this interspecies similarity, the intraspecies comparison of particle diffusivity in the mucus obtained from adult pigs vs. 2-week old piglets showed better penetrability of the piglet mucus. The mean Stokes-Einstein viscosity of the piglet jejunal mucus was approx. two times lower than the viscosity of the pig jejunal mucus (P < 0.05). All mucus structures were also visualised by scanning electron microscopy. This work validates the use of porcine small intestinal mucus collected from fully-grown pigs for studying colloidal transport of sub-micron sized particles in mucus under conditions mimicking the adult human small intestinal environment.

Value of liver iron concentration in healthy volunteers assessed by MRI.

Iron overload is a relatively common clinical condition resulting from disorders such as hereditary hemochromatosis, thalassemia, sickle cell disease, and myelodysplasia that can lead to progressive fibrosis and eventually cirrhosis of the liver. Therefore, it is essential to recognize the disease process at the earliest stage. Liver biopsy is the reference test for the assessment of liver fibrosis. It also allows for quantifying liver iron concentration (LIC) in patients. However, this is an invasive method with significant limitations and possible risks. Magnetic resonance imaging (MRI) and evaluation of the R2* relaxation rate can be an alternative to biopsy for assessing LIC. However, it causes a need for accurate R2* data corresponding to standard value for further comparison with examined patients. This study aimed to assess the normative values of liver R2* in healthy individuals. A total of 100 volunteers that met established criteria were enrolled in the study: 36 (36%) men and 64 (64%) women. The mean age was 22.9 years (range 20 to 32 years). R2* was estimated by an MRI exam with a 1.5 T clinical magnetic resonance scanner. Images for measuring the LIC and liver fat concentration were obtained using the IDEAL-IQ technique for liver imaging. The Mean (SD) liver R2* was 28.34 (2.25) s-1 (95% CI, 27.78-28.90, range 23.67-33.00 s-1) in females, 29.57 (3.20) s-1 (95% CI, 28.49-30.66, range 23.93-37.77 s-1) in males, and 28.72 (2.69) s-1 (range 23.67-37.77 s-1) in the whole group. R2* value in this particular population with a high proportion of young women did not exceed 38 s-1. In the absence of fibrosis or steatosis, liver stiffness and fat fraction did not show any relationship with R2*.

Synergistic effects of extracellular vesicle phenotyping and AFP in hepatobiliary cancer differentiation.

BACKGROUND: Biliary cancer, comprising cholangio- and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation. METHODS: Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer patients, as well as from healthy individuals, were isolated by sequential two-step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis. RESULTS: Two directly tumour-related antigen combinations (AnnV+ CD44v6+ and AnnV+ CD44v6+ CD133+ ) and two combinations related to progenitor cells from the tumour microenvironment (AnnV+ CD133+ gp38+ and AnnV+ EpCAM+ CD133+ gp38+ ) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV+ CD44v6+ EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively. CONCLUSIONS: EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies.

How To Make Nitroaromatic Compounds Glow: Next-Generation Large X-Shaped, Centrosymmetric Diketopyrrolopyrroles.

Red-emissive π-expanded diketopyrrolopyrroles (DPPs) with fluorescence reaching λ=750 nm can be easily synthesized by a three-step strategy involving the preparation of diketopyrrolopyrrole followed by N-arylation and subsequent intramolecular palladium-catalyzed direct arylation. Comprehensive spectroscopic assays combined with first-principles calculations corroborated that both N-arylated and fused DPPs reach a locally excited (S1 ) state after excitation, followed by internal conversion to states with solvent and structural relaxation, before eventually undergoing intersystem crossing. Only the structurally relaxed state is fluorescent, with lifetimes in the range of several nanoseconds and tens of picoseconds in nonpolar and polar solvents, respectively. The lifetimes correlate with the fluorescence quantum yields, which range from 6 % to 88 % in nonpolar solvents and from 0.4 % and 3.2 % in polar solvents. A very inefficient (T1 ) population is responsible for fluorescence quantum yields as high as 88 % for the fully fused DPP in polar solvents.

N-Arylation of Diketopyrrolopyrroles with Aryl Triflates.

A new methodology for the double N-arylation of diketopyrrolopyrroles with aryl triflates has been developed. It is now possible to prepare diketopyrrolopyrroles bearing N-substituents derived from naphthalene, anthracene and coumarin in two steps from commercially available phenols. This represents the first time arenes lacking strong electron-withdrawing groups were inserted onto lactamic nitrogen atoms via arylation. The ability to incorporate heretofore unprecedented substituents translates to increased modulation of the resulting photophysical properties such as switching-on/off solvatofluorochromism. TD-DFT calculations have been performed to explore the nature of the relevant excited states. This new synthetic method made it possible to elucidate the influence of such substituents on the absorption and emission properties of tetraaryl substituted diketopyrrolopyrroles.

Oncomir MicroRNA-346 Is Upregulated in Colons of Patients With Primary Sclerosing Cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder that is frequently associated with ulcerative colitis (UC). Patients with PSC and UC (PSC-UC) have a higher risk of colorectal neoplasia compared with patients with UC. The oncogenic properties of microRNA-346 (miR-346) have been recently reported. We investigated the expression of miR-346 and its 2 target genes, the receptor of vitamin D (VDR), and the tumor necrosis factor-α (TNF-α), which are known to modulate carcinogenesis. METHODS: Ascending and sigmoid colon biopsies were obtained from patients with PSC, PSC and UC (PSC-UC), UC, and healthy controls (n = 10 in each group). Expressions of VDR, TNF-α, 18S RNA, p27, miR-346, and reference microRNA, miR-191, were evaluated by real-time PCR using human TaqMan Gene Expression and TaqMan MicroRNA Assays. Functional studies with miR-346 mimic and inhibitor were conducted in HepG2 and Caco-2 cells. The effect of ursodeoxycholic acid on miR-346 expression was examined in Caco-2 cells. RESULTS: An increased expression of miR-346 in the ascending colon of PSC-UC was observed (P < 0.001 vs all groups). In patients with UC, an exceptionally low colonic expression of miRNA-346 was accompanied by the extensive upregulation of VDR and TNF-α genes. A functional in vitro analysis demonstrated that inhibition of miR-346 resulted in the upregulation of VDR and TNF-α, whereas the induction of miR-346 activity suppressed VDR, TNF-α, and p27. DISCUSSION: The upregulation of miRNA-346 in the colon of patients with PSC may be responsible for the disturbance of VDR and TNF-α signaling pathway, which could result in an inadequate suppression of neoplasia.

Preoperative colonoscopy in patients with a supposed primary ovarian cancer.

The final diagnosis of ovarian cancer is based on surgery and pathological verification. Therefore patients who are presented to surgery may be described only as supposed ovarian cancer. According to the literature the diagnosis of ovarian cancer is confirmed only in 2/3 of them. The rest are that which mimic ovarian cancer. One of them is colorectal cancer. Colonoscopy is a gold standard in its diagnostics. On the other hand, ovarian cancer may disturb the bowel patency and makes the bowel resection or stoma necessary.The main aim was to find out the distribution of bowel patency disturbances in ovarian cancer patients during preoperative colonoscopy and to assess their predictive value with respect to the bowel resection or stoma and the additional aim to identify the pathologies which mimic the ovarian cancer.In a prospective study among 104 patients with supposed ovarian cancer, primary ovarian cancer was diagnosed in 68 patients. The rest of them suffered from colorectal cancer found at colonoscopy (N = 6), ovarian benign pathology (N = 8), ovarian borderline tumor (N = 5), and other nonandexal malignant diseases (N = 17). In ovarian cancer group dominated serous carcinoma and fedération international de gynécologie et d'obstétrique stage 3 (N = 33).During preoperative colonoscopy in ovarian cancer patients, the complete obstruction was found in 27.9%, and relative risk of bowel resection or stoma was in them 4.29 and 4.38, respectively. Another colonoscopic finding was limited patency caused by extrinsic compression (29%) which is connected with relative risk of bowel resection or stoma 3.16 and 3.21 accordingly. The last colonoscopy finding was described as moderate limited patency of unknown origin (20.6%) and the relative risk of bowel resection or stoma was 5.14 and 4.17, respectively.Colonoscopy enables the diagnoses of colorectal cancer one of the diseases which mimic ovarian cancer in patients supposed to have this diseases.Bowel patency disturbances found at colonoscopy are a potential risk factor to intestine resection or ostomy.Colonoscopy is not fully noninvasive procedure and its obligatory use in patients supposed to have ovarian cancer should be limited to the cases with specific symptoms, and tumor marker pattern. Preoperative computed tomography, dedicated to bowel examination, candidates as an alternative to colonoscopy, but not completely.

Normative values for magnetic resonance elastography-based liver stiffness in a healthy population.

INTRODUCTION Chronic liver disease resulting in fibrosis, and ultimately cirrhosis, is a significant cause of morbidity and mortality worldwide. None of the conventional imaging techniques are able to detect early fibrosis and compare its grade with the histopathologic scale. Liver biopsy, as the diagnostic standard for liver fibrosis, also has limitations and is not well accepted by patients. Magnetic resonance elastography is a well­established technique for evaluating liver stiffness and may replace invasive procedures. Detection of liver fibrosis in its early stages, however, requires a detailed knowledge of normal liver stiffness. OBJECTIVES This study aimed to determine normal liver stiffness values in healthy volunteers. PATIENTS AND METHODS A total of 102 volunteers (mean age, 21.6 years; range, 20-28 years) with no history of gastrointestinal, hepatobiliary, or cardiovascular disease were enrolled in the study. Liver stiffness was evaluated by magnetic resonance elastography with a 1.5T clinical magnetic resonance scanner. Images of the induced transverse wave propagation were obtained and converted to tissue stiffness maps (elastograms). RESULTS The mean (SD) liver stiffness for the entire group of volunteers was 2.14 (0.28) kPa (range, 1.37-2.66 kPa). For women, the mean (SD) stiffness value was 2.14 (0.30) kPa (range, 1.37-2.66 kPa), and for men, 2.14 (0.25) kPa (range, 1.54-2.54 kPa). CONCLUSIONS Liver stiffness in a healthy adult cohort did not exceed 2.7 kPa and is not influenced by sex, body mass index, or fat content.