Ly6C
hi
monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the ...immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6C
hi
monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6C
hi
monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6C
hi
monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6C
hi
monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6C
hi
monocytes. In consistence with these results, COMMD10-deficiency in Ly6C
hi
monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6C
hi
monocytes and their corresponding human CD14
hi
monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6C
hi
monocyte inflammasome activity during systemic inflammation and IBD.
: Background: The upper normal limit (ULN) of serum alanine‐aminotrasferase (ALT) normal range was recently challenged, because patients diagnosed with liver diseases may have ‘normal’ or ...near‐‘normal’ ALT levels, and because possible modulators are often ignored in determining normal range.
Aim: To estimate the ULN for serum ALT and to identify factors modulating it.
Subjects and methods: We reviewed medical records of subjects aged 15–90, who underwent standard panels of laboratory tests, including serum ALT, over 6 months at a central laboratory. Three groups were defined: Group 1, comprised total study population (N=272 273). Group 2 (N=87 020) comprised total study population, excluding those receiving potentially hepatotoxic drugs, or diagnosed with liver disease, or had any abnormal laboratory test results other than for triglycerides, cholesterol, glucose, or HbA1c. Group 3 (N=17 496) the ‘healthy’ population, from whose ALT values we established the new ULN, comprised Group 2 subjects with normal triglycerides, cholesterol, glucose, and HbA1c levels.
Results: The 95th percentile ALT values, corresponding to the ULN, in groups 1, 2, and 3 were 50.1, 40, and 37.5 U/l, respectively. 6.2% (16 943/273 273) of subjects whose ALT was below ULN listed by the test manufacturer (52 U/l), had ALT level above our new ULN. Linear and logistic‐regression analyses showed that ALT levels were significantly modified by gender, age, glucose, cholesterol, triglycerides, and overweight/obesity diagnosis. Significant interaction was found between gender, glucose and cholesterol levels.
Conclusions: In this first large‐scale study of ‘healthy’ population, serum ALT ULN was far lower than currently accepted value. Age and gender may be considered when determining the ULN for ALT.
To compare the effect of oral erythromycin vs no preparation with prokinetics on the transit time and the image quality of capsule endoscopy (CE) in evaluating small bowel (SB) pathology.
We ...conducted a retrospective, blinded (to the type of preparation) review of 100 CE studies, 50 with no preparation with prokinetics from one medical center (Group A) and 50 from another center with administration of a single dose of 200 mg oral erythromycin 1 h prior to CE (Group B). Gastric, SB and total transit times were calculated, the presence of bile in the duodenum was scored, as was cleanliness within the proximal, middle and distal intestine.
The erythromycin group had a slightly shorter gastric transit time (21 min vs 28 min, with no statistical significance). SB transit time was similar for both groups (all P > 0.05). Total transit time was almost identical in both groups. The rate of incomplete examination was 16% for Group A and 10% for Group B (P = 0.37). Bile and cleanliness scores in different parts of the intestine were similar for the two groups (P > 0.05).
Preparation for capsule endoscopy with erythromycin does not affect SB or total transit time. It tends to reduce gastric transit time, but it does not increase the cecum-reaching rate. Erythromycin does not adversely affect image quality. We consider the routine use of oral erythromycin preparation as being unjustified, although it might be considered in patients with known prolonged gastric emptying time.
Gastroesophageal reflux disease (GERD) is a common condition, managed mostly in primary care practice. Heartburn and acid regurgitation are considered primary symptoms, and are usually highly ...specific. However, the symptom spectrum is much wider and in many cases it is difficult to determine whether the patient has GERD or dyspepsia from another origin. The aim of this study is to develop a symptom score and rule for the diagnosis of GERD, using data mining techniques, to provide a clinical diagnostic tool for primary care practitioners in the evaluation and management of upper gastrointestinal symptoms. A diagnostic symptom questionnaire consisting of 15 items and based on the current literature was designed to measure the presence and severity of reflux and dyspepsia symptoms using a 5-point Likert-type scale. A total of 132 subjects with uninvestigated upper abdominal symptoms were prospectively recruited for symptom evaluation. All patients were interviewed and examined, underwent upper gastrointestinal endoscopy, and completed the questionnaire. Based on endoscopic findings as well as the medical interview, the subjects were classified as having reflux disease (GERD) or non-reflux disease (non-GERD). Data mining models and algorithms (neural networks, decision trees, and logistic regression) were used to build a short and simple new discriminative questionnaire. The most relevant variables discriminating GERD from non-GERD patients were heartburn, regurgitation, clinical response to antacids, sour taste, and aggravation of symptoms after a heavy meal. The sensitivity and specificity of the new symptom score were 70%-75% and 63%-78%, respectively. The area under the ROC curve for logistic regression and neural networks were 0.783 and 0.787, respectively. We present a new validated discriminative GERD questionnaire using data mining techniques. The questionnaire is useful, friendly, and short, and therefore can be easily applied in clinical practice for choosing the appropriate diagnostic workup for patients with upper gastrointestinal complaints.
The present study examined whether the perinephric and epididymal visceral fat (PEVF) depot under short‐term excess nutrient protected the liver by trapping nutrient‐derived nonesterified free fatty ...acids (NEFAs) or had deleterious effects on hepatic triglycerides (TGs) accumulation and insulin resistance due to adipokine secretion. Young rats pre‐emptively underwent surgical PEVF removal or sham operations and were fed with either high‐fat diet (HFD) (PEVF‐HFD) or regular chow (RC) (PEVF‐RC) for 3 days. Insulin sensitivity was measured by hyperinsulinemic‐euglycemic clamp. Liver TG, serum NEFA, and fat‐derived adipokines were assessed. Insulin and lipogenesis signaling were assessed by western blots. Pre‐emptive PEVF removal significantly decreases insulin‐induced suppression of hepatic glucose production (HGP) both in RC and in HFD‐fed rats. In accordance with the clamp results, hepatic TG accumulation is also significantly reduced by PEVF excision both in RC and HFD‐fed rats. These results are further validated by insulin signaling results, which show that pre‐emptive PEVF removal increases phosphorylation of hepatic Akt, irrespective of diet. Notably, high levels of serum leptin induced by HFD are significantly reduced by pre‐emptive PEVF excision. Additionally, expression of lipogenic enzyme p‐acetyl‐CoA‐carboxylase, denoting reduced lipogenesis, is increased in the PEVF‐HFD rats. In conclusion, PEVF has a deleterious effect on the liver as a source of insulin resistance‐inducing adipokines irrespective of diet, and does not serve as a buffer for excess nutrients.
Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains ...sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.
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•The murine & human gut mucosal microbiome only partially correlates with stool•Mice feature an indigenous-microbiome driven colonization resistance to probiotics•Humans feature a person-specific gut mucosal colonization resistance to probiotics•Probiotic colonization is predictable by pre-treatment microbiome & host features
Probiotics transiently colonize the human gut mucosa in highly individualized patterns, thereby differentially impacting the indigenous microbiome and host gene-expression profile, a trait which is predictable by baseline host and microbiome features, but not by stool shedding.
Background and study aims:
The Aer-O-Scope™ Colonoscope System (AOS) combines panoramic 360° view with standard forward view. We assessed the AOS’s ability to identify lesions implanted in live ...swine, compared to conventional colonoscopy (CC).
Patients and methods:
Twelve swine colons were surgically ligated and beads sewn within. Five procedures (3 AOS and 2 CC) were performed on each swine and findings reported. Physicians were blinded to number, size, and color of beads. The sequence of procedures and physicians was randomized. Pigs, physicians, and colonoscopes were randomly alternated between examination rooms, maintaining physician blindness. Two independent blinded physicians interpreted procedure videos offline.
Results:
A total of 259 /273 (94.9 %) of lesions were visualized by AOS compared to 158 /182 with CC (86.8 %) (
P
= 0.002). Miss rates of lesions ≥ 6 mm were 2.6 % and 10.5 %, respectively (
P
= 0.022), and 6.9 % and 15.1 %, respectively, for lesions < 6 mm (
P
= 0.031). Mean agreement between AOS and CC for lesion detection was 88.3 %. The benefit of AOS was maintained in offline video review.
Conclusions:
AOS, featuring panoramic 360° view, demonstrated high detection rates for simulated colonic lesions in a live swine model.
Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy ...individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds.
Current strategies for follow up of murine models of liver disease are flawed by inability to continuously monitor disease progression in the tissue level, and necessitate sacrifice of animals for ...tissue sampling.
In this study we aimed at developing a safe repetitive tool for sampling livers in vivo, by utilization of a miniaturized endoscopy system for laparoscopic liver biopsies and for injection of tumor cells into livers.
We report the development of a protocol for murine laparoscopy that allows repeated visualization of murine intra-abdominal organs. The system enables safe and repeated liver biopsies in mice and rats, yielding adequate tissue for histological staining and RNA extraction. In addition, injection of tumor cells into livers facilitates under-vision implantation of hepatic tumors in liver, followed by visualization of tumor growth.
Murine laparoscopy may be employed as a novel imaging modality for continuous assessment and manipulation of chronic liver disease models.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims Glucagon-like peptide-1 (GLP-1), a gut-derived peptide degraded by dipeptidyl peptidase-4 (DPP4), stimulates insulin secretion in response to nutrients, yet its direct effect on the ...liver is controversial. We investigated the effects of GLP-1 on hepatic fat and glucose metabolism and elucidated its mechanism of action. Methods Hepatic fat metabolism, including lipogenic enzymes and signal transduction regulators, was assessed in livers of DPP4-deficient rats (DPP4-) with chronically elevated GLP-1 and in GLP-1-treated primary hepatocytes. The effect of chronic elevated GLP-1 on insulin sensitivity was measured using the hyperinsulinemic–euglycemic clamp. Results Normal and high fat diet fed DPP4-rats displayed reduced hepatic triglycerides, accompanied by down-regulation of lipogenesis enzymes and parallel up-regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid β-oxidation. In vitro studies demonstrated that these effects were directly induced by GLP-1. Mechanistically, GLP-1 increased cAMP in hepatocytes, resulting in the phosphorylation of cAMP-activated protein kinase (AMPK), a suppressor of lipogenesis. Indeed, hepatocytes expressing a dominant negative Ad-DN-AMPK displayed attenuated GLP-1 effects on AMPK phosphorylation and its downstream lipogenic targets. Importantly, normoglycemic DPP4-rats did not display improved hepatic insulin sensitivity in vivo , suggesting a direct effect of GLP-1 on fat metabolism. Finally, DPP4-rats expressed lower levels of hepatic proinflammatory and profibrotic cytokines in response to nutrient stimuli. Conclusions GLP-1 suppresses hepatic lipogenesis via activation of the AMPK pathway. GLP-1 inhibitory effects on hepatic fat accumulation and nutrient-induced hepatic proinflammatory response suggest GLP-1 analogs as novel therapies for non-alcoholic fatty liver diseases.
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