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- Grüttner, Jana, et al.
(författare)
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Trophozoite fitness dictates the intestinal epithelial cell response to Giardia intestinalis infection
- 2023
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 19:5
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Tidskriftsartikel (refereegranskat)abstract
- Giardia intestinalis is a non-invasive, protozoan parasite infecting the upper small intestine of most mammals. Symptomatic infections cause the diarrhoeal disease giardiasis in humans and animals, but at least half of the infections are asymptomatic. However, the molecular underpinnings of these different outcomes of the infection are still poorly defined. Here, we studied the early transcriptional response to G. intestinalis trophozoites, the disease-causing life-cycle stage, in human enteroid-derived, 2-dimensional intestinal epithelial cell (IEC) monolayers. Trophozoites preconditioned in media that maximise parasite fitness triggered only neglectable inflammatory transcription in the IECs during the first hours of co-incubation. By sharp contrast, “non-fit” or lysed trophozoites induced a vigorous IEC transcriptional response, including high up-regulation of many inflammatory cytokines and chemokines. Furthermore, “fit” trophozoites could even suppress the stimulatory effect of lysed trophozoites in mixed infections, suggesting active G. intestinalis suppression of the IEC response. By dual-species RNA-sequencing, we defined the IEC and G. intestinalis gene expression programs associated with these differential outcomes of the infection. Taken together, our results inform on how G. intestinalis infection can lead to such highly variable effects on the host, and pinpoints trophozoite fitness as a key determinant of the IEC response to this common parasite.Author summaryDiarrhoeal infectious diseases are still a major problem worldwide, each year killing nearly 800,000 children. These infections are caused by a variety of pathogenic bacteria, viruses, fungi and protozoa. The protozoan parasite Giardia intestinalis is the most common eukaryotic intestinal pathogen found in humans. In contrast to most bacteria and viruses that cause diarrhoea, Giardia parasites elicit a highly variable clinical picture and often do not cause pronounced inflammation in the intestine of infected patients. Here we show, by using human intestinal epithelial cells derived from adult intestinal stem cells, that “fit” Giardia parasites can actively suppress epithelial inflammatory signalling, while their “non-fit” counterparts instead induce inflammatory responses. These two faces of the parasite are associated with specific gene expression programs and may explain the earlier observed high variability in outcome of a Giardia infection, and its modulatory effect on infection by other intestinal pathogens.
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- Halim, M. Abdul, et al.
(författare)
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Nitric oxide regulation of migrating motor complex : randomized trial of N-G-monomethyl-L-arginine effects in relation to muscarinic and serotonergic receptor blockade
- 2015
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 215:2, s. 105-118
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using N-G-monomethyl-L-arginine (L-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron. Methods: Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor L-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using L-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. Results: L-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. L-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by L-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Conclusion: Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.
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- Sjoblom, A., et al.
(författare)
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The influence of humic substances on the speciation and bioavailability of dissolved mercury and methylmercury, measured as uptake by Chaoborus larvae and loss by volatilization
- 2000
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Ingår i: Science of the Total Environment. - 0048-9697 .- 1879-1026. ; 261:1-3, s. 115-124
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Tidskriftsartikel (refereegranskat)abstract
- The influence of dissolved humic substances (HS) on the bioavailability of dissolved inorganic and methyl mercury (Hg) was quantified by measuring the direct uptake of 203Hg in Chaoborus larvae using laboratory microcosms containing artificial freshwater. The animals were exposed individually in triplicate aquaria at 10 different concentrations of HS covering the whole range found in natural freshwaters (0-110 mg C l-1). Mercury-203 concentrations were monitored repeatedly in the same individuals and in their ambient water during up to 10 days. Near-steady state Hg concentrations in Chaoborus were usually reached within 5 days. The bioconcentration factor (BCF, direct uptake only) for the larvae in the absence of HS was 0.55 ± 0.09 (S.E.) ml individual-1 for inorganic Hg and 5.3 ± 0.7 ml individual-1 for methyl Hg, thus showing a 10-fold difference. Normalizing to the organic carbon content of the larvae yields a BCF(OC) in the absence of HS of 2.8 ± 0.4 x 103 ml (gC)-1 for inorganic Hg and 2.7 ± 0.3 x 104 ml (gC)-1 for methyl Hg. The uptake of both inorganic and methyl Hg decreased markedly with increasing concentration of HS. For inorganic Hg, the decrease in uptake was most pronounced at HS concentrations below 0.2 mg C l-1. For methyl Hg, the relationship between uptake and log([HS]) was sigmoid, showing a reduction by >90% when increasing HS concentrations from 1 to 50 mg C l-1. Similar patterns were observed for losses of Hg from the water phase, mainly through volatilization. These results have implications for both the biouptake and the abiotic cycling of Hg in natural ecosystems and suggest that most dissolved inorganic Hg is bound to dissolved organic matter in most natural freshwaters, whereas dissolved methyl Hg is bound only in humic waters. Assuming that only free aqueous Hg is taken up by the organisms, the rather simple methodology employed here can be used for estimating distribution coefficients (K(OC)) for Hg between HS and water. In this study, the K(OC) values were 2.5 ± 0.7 (S.E.) x 107 ml (gC)-1 for inorganic Hg and 1.5 ± 0.6 x 105 ml (gC)-1 for methyl Hg. Values of similar magnitude were derived from observed losses of Hg from the water phase, supporting the assumption of an immobilization of both inorganic and methyl Hg by HS. The strong negative influence of dissolved HS on the bioavailability of both inorganic and methyl Hg in freshwater suggests that the high Hg levels often found in fish from humic lakes in the boreal forest zone cannot be explained alone by direct uptake of methyl Hg from the water phase into biota at low trophic levels. (C) 2000 Elsevier Science B.V.
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| 17. |
- Sundbom, M., et al.
(författare)
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Reduction in serum pepsinogen I after Roux-en-Y gastric bypass
- 2003
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Ingår i: Journal of Gastrointestinal Surgery. - 1091-255X .- 1873-4626. ; 7:4, s. 529-535
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Tidskriftsartikel (refereegranskat)abstract
- The excluded stomach after Roux-en-Y gastric bypass (RYGBP) cannot be readily examined by endoscopy for obvious anatomic reasons. Thus it is difficult to monitor possible changes in the gastric mucosa. However, the type and severity of gastritis can now be assessed by a combination of serologic tests: pepsinogen I and antibodies to Helicobacter pylori and H,K-ATPase. Morbidly obese patients were examined before and 1 to 4 years after surgery. A group of 34 patients (mean age 39 years, BMI 44 kg/m2) underwent RYGBP, another group of 30 patients (mean age 42 years, BMI 44 kg/m2) had simple gastric restriction and served as control subjects. All patients, except one in the control group, had normal titers of pepsinogen I before surgery. One year after RYGBP, pepsinogen I levels were significantly reduced, as compared to the control group (P<0.0001), and remained low throughout the study. The control group had stable pepsinogen I levels. In both groups, few patients had increased titers of H. pylori or H,K-ATPase antibodies, but these abnormalities remained unchanged. Low pepsinogen I levels, similar to those we observed in our RYGBP patients, have been linked to chronic atrophic gastritis. However, the absence of food stimulation in the excluded stomach could also be a reason for the low pepsinogen I levels. © 2003 The Society for Surgery of the Alimentary Tract, Inc.
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| 18. |
- Thanikkal, Edvin J., et al.
(författare)
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The Yersinia pseudotuberculosis Cpx envelope stress system contributes to transcriptional activation of rovM
- 2019
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Ingår i: Virulence. - : Taylor & Francis Group. - 2150-5594 .- 2150-5608. ; 10:1, s. 37-57
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Tidskriftsartikel (refereegranskat)abstract
- The Gram-negative enteropathogen Yersinia pseudotuberculosis possesses a number of regulatory systems that detect cell envelope damage caused by noxious extracytoplasmic stresses. The CpxA sensor kinase and CpxR response regulator two-component regulatory system is one such pathway. Active Cpx signalling upregulates various factors designed to repair and restore cell envelope integrity. Concomitantly, this pathway also down-regulates key determinants of virulence. In Yersinia, cpxA deletion accumulates high levels of phosphorylated CpxR (CpxR~P). Accumulated CpxR~P directly repressed rovA expression and this limited expression of virulence-associated processes. A second transcriptional regulator, RovM, also negatively regulates rovA expression in response to nutrient stress. Hence, this study aimed to determine if CpxR~P can influence rovA expression through control of RovM levels. We determined that the active CpxR~P isoform bound to the promoter of rovM and directly induced its expression, which naturally associated with a concurrent reduction in rovA expression. Site-directed mutagenesis of the CpxR~P binding sequence in the rovM promoter region desensitised rovM expression to CpxR~P. These data suggest that accumulated CpxR~P inversely manipulates the levels of two global transcriptional regulators, RovA and RovM, and this would be expected to have considerable influence on Yersinia pathophysiology and metabolism.
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| 19. |
- van Rijn, Jorik M., et al.
(författare)
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High-Definition DIC Imaging Uncovers Transient Stages of Pathogen Infection Cycles on the Surface of Human Adult Stem Cell-Derived Intestinal Epithelium
- 2022
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Ingår i: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between individual pathogenic microbes and host tissues involve fast and dynamic processes that ultimately impact the outcome of infection. Using live-cell microscopy, these dynamics can be visualized to study, e.g., microbe motility, binding and invasion of host cells, and intrahost-cell survival. Such methodology typically employs confocal imaging of fluorescent tags in tumor-derived cell line infections on glass. This allows high-definition imaging but poorly reflects the host tissue’s physiological architecture and may result in artifacts. We developed a method for live-cell imaging of microbial infection dynamics on human adult stem cell-derived intestinal epithelial cell (IEC) layers. These IEC layers are grown in apical imaging chambers, optimized for physiological cell arrangement and fast, but gentle, differential interference contrast (DIC) imaging. This allows subsecond visualization of both microbial and epithelial surface ultrastructure at high resolution without using fluorescent reporters. We employed this technology to probe the behavior of two model pathogens, Salmonella enterica serovar Typhimurium and Giardia intestinalis, at the intestinal epithelial surface. Our results reveal pathogen-specific swimming patterns on the epithelium and show that Salmonella lingers on the IEC surface for prolonged periods before host cell invasion, while Giardia uses circular swimming with intermittent attachments to scout for stable adhesion sites. The method even permits tracking of individual Giardia flagella, demonstrating that active flagellar beating and attachment to the IEC surface are not mutually exclusive. This work describes a generalizable and relatively inexpensive approach to resolving dynamic pathogen-IEC layer interactions, applicable even to genetically nontractable microorganisms.
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| 22. |
- Elias, Khalid, et al.
(författare)
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Gastrointestinal Physiology Before and After Duodenal Switch with Comparisons to Unoperated Lean Controls : Novel Use of the SmartPill Wireless Motility Capsule
- 2021
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Ingår i: Obesity Surgery. - : Springer. - 0960-8923 .- 1708-0428. ; 31:8, s. 3483-3489
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Bariatric surgery alters gastrointestinal anatomy. In this exploratory study, the SmartPill® wireless motility capsule (WMC) was used to study changes in gastrointestinal physiology following biliopancreatic diversion with duodenal switch (BPD/DS).MATERIAL AND METHODS: Twenty-eight BPD/DS patients (35 ± 11 years, 50% females, body mass index [BMI] 56 ± 5) were to be examined preoperatively and postoperatively. In addition to transit time, appetite control and gastrointestinal symptoms were studied by patient-scored questionnaires (visual analogue scale and Gastrointestinal Symptom Rating Scale (GSRS)). Data was compared to 41 lean unoperated controls.RESULTS: About 1.8 years postoperatively, 18 patients (BMI 35.8 ± 8.3) returned for a second WMC test. As expected, small bowel transit time was reduced, from 3.9 ± 1.6 h to 2.8 ± 2.0, p = 0.02, and at both these time points, it was shorter than in lean controls (5.4 ± 1.9 h, p = 0.001). Postoperatively, a trend towards reduced colon and whole gut transit times was seen in BPD/DS-patients, thus approaching those of lean controls. Surprisingly, BPD/DS patients scored higher satiety than controls preoperatively as well as increased hunger and desire to eat postoperatively. Compared to lean, BPD/DS patients reported a higher total GSRS score at both time points (1.2 ± 0.2 vs 1.7 ± 0.6 and 2.3 ± 0.5, p < 0.001). Postoperatively, the scores for diarrhea and indigestion increased.CONCLUSIONS: The novel use of the SmartPill system in BPD/DS patients gave the expected readouts. Although small bowel transit time was further shortened after BPD/DS, whole gut transit time did not differ from controls. Typical gastrointestinal symptoms were reported postoperatively.
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| 23. |
- Elias, Khalid, 1975-, et al.
(författare)
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Impact of biliopancreatic diversion with duodenal switch on glucose homeostasis and gut hormones and their correlations with appetite
- 2022
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Ingår i: Surgery for Obesity and Related Diseases. - : Elsevier. - 1550-7289 .- 1878-7533. ; 18:12, s. 1392-1398
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundBiliopancreatic diversion with duodenal switch (BPD/DS) results in lifelong changes in gastrointestinal physiology with unclear associations with appetite perception.ObjectiveTo explore mixed meal–induced changes in glucose homeostasis and gut hormones and their correlations with appetite perception.SettingUniversity hospital.MethodsOf 28 patients studied preoperatively (age: 38.4 ± 11.3 years; body mass index [BMI]: 56.5 ± 5.1 kg/m2; 14 women), 19 (68%) returned for postoperative follow-up. Plasma was sampled for 180 minutes during a 260-kcal standardized mixed meal. Concentrations of leptin, glucose, insulin, triglycerides, active acyl-ghrelin, motilin, total glucose-dependent insulinotropic polypeptide (GIP), active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) were measured. Subjective appetite sensations were scored.ResultsBPD/DS resulted in 66.1% ± 23.3% excess BMI loss. Leptin was halved. Glucose and insulin levels were reduced, blunting a preoperative peak at 30 minutes, giving a lower homeostasis model assessment for insulin resistance (HOMA-IR; 13.9 versus 4.8). In contrast, reduced ghrelin and motilin concentrations were accompanied by pronounced peaks 20–30 minutes prior to meal responses. GIP was reduced, whereas GLP-1 and PYY responses were markedly increased, with an early postprandial peak (P < .05, for all). HOMA-IR correlated with insulin (r = .72) and GIP (r = .57). Postoperatively, satiety correlated with GLP-1 (r = .56), whereas the gastric motility index correlated with the desire to eat (r = .60), percentage excess BMI loss (r = –.55), and percentage total weight loss (r = –.49). Delta insulin, GLP-1, and leptin correlated positively with percentage total weight loss (r = .51, r = .48, and r = .58, respectively).ConclusionsBPD/DS reduces leptin, HOMA-IR, and GIP while markedly increasing GLP-1 and PYY. This study marks the magnitude change in GLP-1 with additional effects of PYY as important factors for weight loss.
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| 26. |
- Geiser, Petra, et al.
(författare)
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Salmonella enterica Serovar Typhimurium Exploits Cycling through Epithelial Cells To Colonize Human and Murine Enteroids
- 2021
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Ingår i: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Enterobacterial pathogens infect the gut by a multistep process, resulting in colonization of both the lumen and the mucosal epithelium. Due to experimental constraints, it remains challenging to address how luminal and epithelium-lodged pathogen populations cross-feed each other in vivo. Enteroids are cultured three-dimensional miniature intestinal organs with a single layer of primary intestinal epithelial cells (IECs) surrounding a central lumen. They offer new opportunities to study enterobacterial infection under near-physiological conditions, at a temporal and spatial resolution not attainable in animal models, but remain poorly explored in this context. We employed microinjection, time-lapse microscopy, bacterial genetics, and barcoded consortium infections to describe the complete infection cycle of Salmonella enterica serovar Typhimurium in both human and murine enteroids. Flagellar motility and type III secretion system 1 (TTSS-1) promoted Salmonella Typhimurium targeting of the intraepithelial compartment and breaching of the epithelial barrier. Strikingly, however, TTSS-1 also potently boosted colonization of the enteroid lumen. By tracing the infection over time, we identified a cycle(s) of TTSS-1-driven IEC invasion, intraepithelial replication, and reemergence through infected IEC expulsion as a key mechanism for Salmonella Typhimurium luminal colonization. These findings suggest a positive feed-forward loop, through which IEC invasion by planktonic bacteria fuels further luminal population expansion, thereby ensuring efficient colonization of both the intraepithelial and luminal niches.IMPORTANCE Pathogenic gut bacteria are common causes of intestinal disease. Enteroids—cultured three-dimensional replicas of the mammalian gut—offer an emerging model system to study disease mechanisms under conditions that recapitulate key features of the intestinal tract. In this study, we describe the full life cycle of the prototype gut pathogen Salmonella enterica serovar Typhimurium within human and mouse enteroids. We map the consecutive steps and define the bacterial virulence factors that drive colonization of luminal and epithelial compartments, as well as breaching of the epithelial barrier. Strikingly, our work reveals how bacterial colonization of the epithelium potently fuels expansion also in the luminal compartment, through a mechanism involving the death and expulsion of bacterium-infected epithelial cells. These findings have repercussions for our understanding of the Salmonella infection cycle. Moreover, our work provides a comprehensive foundation for the use of microinjected enteroids to model gut bacterial diseases.
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| 27. |
- Halim, Abdul, 1983-, et al.
(författare)
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Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans
- 2018
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:2, s. 575-585
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Tidskriftsartikel (refereegranskat)abstract
- Context: Glucagon-like peptide-1 (GLP-1) secretion from L-cells and postprandial inhibition of gastrointestinal motility.Objective: Investigate whether physiological plasma concentrations of GLP-1 can inhibit human postprandial gastrointestinal motility; determine target mechanism of GLP-1 and analogue ROSE-010 action.Design: Single-blind parallel study.Setting: University research laboratory.Participants: Healthy volunteers investigated with antroduodenojejunal manometry. Human gastric, intestinal and colonic muscle strips.Interventions: Motility indices (MI) obtained before and during infusion of saline or GLP-1 were compared. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips, pre-contracted with bethanechol/electric field stimulation (EFS), investigated for GLP-1- or ROSE-010-induced relaxation. GLP-1, GLP-2 and their receptors localized by immunohistochemistry. Action mechanisms studied employing exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2´,5´-dideoxyadenosine (DDA), tetrodotoxin (TTX).Main outcome measures: Hypothesize postprandial gastric relaxation induced by GLP-1, the mechanism of which intrinsic neuronally-mediated.Results: Food intake increased MI to 6.4±0.3 (antrum), 5.7±0.4 (duodenum) and 5.9±0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg·min significantly suppressed MI to 4.6±0.2, 4.7±0.4 and 5.0±0.2, respectively, while 1.2 pmol/kg·min suppressed corresponding MI to 5.4±0.2, 4.4±0.3 and 5.4±0.3 (p<0.0001-0.005). GLP-1 and ROSE-010 prevented bethanechol- or EFS-induced muscle contractions (p <0.005-0.05). Inhibitory responses to GLP-1 and ROSE-10 were blocked by exendin(9-39)amide, L-NMMA, DDA or TTX (all p <0.005-0.05). GLP-1 and GLP-2 were localized to epithelial cells; GLP-1 also in myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle, GLP-1R also in epithelial cells.Conclusions: GLP-1 inhibits postprandial motility through GLP-1R at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.
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| 28. |
- Halim, Md. Abdul, 1983-, et al.
(författare)
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GLP-1 Inhibits Prandial Antro-Duodeno-Jejunal Motility in Humans: Native GLP-1 Compared With Analogue ROSE-010 In Vitro
- 2016
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Ingår i: Gastroenterology. - 0016-5085 .- 1528-0012. ; 150:4, suppl. 1, s. S97-S98
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glucagon-like peptide-1 (GLP-1) is secreted from L-cells after nutrient ingestion, inhibiting motility. Aims: To clarify whether infused GLP-1 inhibits in vivo prandial motility response and determine the likeliest target cell type and mechanism of action of GLP-1 and its analogue ROSE-010 using in vitro human gut muscle strips. Methods: Sixteen healthy volunteers underwent antroduodenojejunal manometry. Recordings of 1 hour infusion of saline or GLP-1 (0.7 or 1.2 pmol/kg/min) were compared. Plasma GLP-1 and GLP-2 were measured by RIA. Gastrointestinal muscle strips from surgical re-sections, pre-contracted with bethanechol or electric field stimulation (EFS), were investigated for GLP-1 or ROSE-010 induced relaxation. GLP-1, GLP-2 and receptors for GLP-1 and GLP-2 (GLP-1R, GLP-2R) were visualized by immunohistochemistry. Mechanisms were studied employing exendin(9-39) amide, Lw-nitro-monomethyl arginine (L-NMMA), 2´5´-dideoxyadenosine (DDA) and tetrodotoxin (TTX). Results: Food-intake increased motility index from 4.0±0.5 to 6.4±0.3 (antrum), 4.2±0.4 to 5.7±0.4 (duodenum) and 4.6±0.3 to 5.9±0.2 (jejunum) ln(Σ(mmHg·s·min-1)). GLP-1 at 0.7 pmol/kg/minwas sufficient to suppress these indexes from 6.2±0.4 to 3.8±0.7, 5.6±0.6 to 3.9±0.6 and 5.8±0.1 to 4.6±0.4 ln(Σ(mmHg·s·min-1)). Both GLP-1 doses raised plasma GLP-1, but not GLP-2. GLP-1 (EC50 40 nM) and ROSE-010 (EC50 50 nM) relaxed bethanechol-induced contractions in muscle strips. Inhibitory responses were blocked by exendin(9-39) amide, L-NMMA, DDA or TTX pre-treatment. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit motility through GLP-1R at myenteric neurons, which also possess GLP-2 receptors. GLP-1 increases more than GLP-2 with meals and does not increase plasma GLP-2. GLP-1 and ROSE-010 relaxations are cAMP and NO dependent.
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| 29. |
- Halim, Md Abdul, 1983-, et al.
(författare)
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Nitric oxide regulation of migrating motor complex : randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade
- 2015
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 215:2, s. 105-118
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Tidskriftsartikel (refereegranskat)abstract
- AimThe migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.MethodsTwenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.Resultsl-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.ConclusionNitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.
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| 30. |
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| 31. |
- Hellgren, R, et al.
(författare)
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The association between breast cancer risk factors and background parenchymal enhancement at dynamic contrast-enhanced breast MRI
- 2020
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Ingår i: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 61:12, s. 1600-1607
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Tidskriftsartikel (refereegranskat)abstract
- Background parenchymal enhancement (BPE) of normal tissue at breast magnetic resonance imaging is suggested to be an independent risk factor for breast cancer. Its association with established risk factors for breast cancer is not fully investigated. Purpose To study the association between BPE and risk factors for breast cancer in a healthy, non-high-risk screening population. Material and Methods We measured BPE and mammographic density and used data from self-reported questionnaires in 214 healthy women aged 43–74 years. We estimated odds ratios for the univariable association between BPE and risk factors. We then fitted an adjusted model using logistic regression to evaluate associations between BPE (high vs. low) and risk factors, including mammographic breast density. Results The majority of women had low BPE (84%). In a multivariable model, we found statistically significant associations between BPE and age ( P = 0.002) and BMI ( P = 0.03). We did find a significant association between systemic progesterone medication and BPE, but due to small numbers, the results should be interpreted with caution. The adjusted odds ratio for high BPE was 3.1 among women with density D (compared to B) and 2.1 for density C (compared to B). However, the association between high BPE and density was not statistically significant. We did not find statistically significant associations with any other risk factors. Conclusion Our study confirmed the known association of BPE with age and BMI. Although our results show a higher likelihood for high BPE with increasing levels of mammographic density, the association was not statistically significant.
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| 32. |
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| 33. |
- Kierkegaard, Amelie, et al.
(författare)
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Bioconcentration of Several Series of Cationic Surfactants in Rainbow Trout
- 2021
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 55:13, s. 8888-8897
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Tidskriftsartikel (refereegranskat)abstract
- Cationic surfactants have a strong affinity to sorb to phospholipid membranes and thus possess an inherent potential to bioaccumulate, but there are few measurements of bioconcentration in fish. We measured the bioconcentration of 10 alkylamines plus two quaternary ammonium compounds in juvenile rainbow trout at pH 7.6, and repeated the measurements at pH 6.2 for 6 of these surfactants. The BCF of the amines with chain lengths <= C-14 was positively correlated with chain length, increasing similar to 0.5 log units per carbon. Their BCF was also pH dependent and approximately proportional to the neutral fraction of the amine in the water. The BCFs of the quaternary ammonium compounds showed no pH dependence and were >2 orders of magnitude less than for amines of the same chain length at pH 7.6. This indicates that systemic uptake of permanently charged cationic surfactants is limited. The behavior of the quaternary ammonium compounds and the two C-16 amines studied was consistent with previous observations that these surfactants accumulate primarily to the gills and external surfaces of the fish. At pH 7.6 the BCF exceeded 2000 L kg(-1) for 4 amines with chains >= C-13, showing that bioconcentration can be considerable for some longer chained cationic surfactants.
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| 34. |
- Lundquist, Patrik, et al.
(författare)
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Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat
- 2022
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 16:9, s. 14210-14229
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Tidskriftsartikel (refereegranskat)abstract
- Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. In situ studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Pess, Gary M., et al.
(författare)
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A post hoc analysis of Dupuytren contracture treated with collagenase Clostridium histolyticum across disease stages
- 2018
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - 2000-656X. ; 52:5, s. 301-306
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Tidskriftsartikel (refereegranskat)abstract
- This post hoc analysis from a multicenter study (NCT01674634) was designed to evaluate the efficacy of collagenase Clostridium histolyticum (CCH) treatment in patients with different stages of Dupuytren contracture. Previously untreated patients who received two concurrent injections of CCH in two affected joints in the same finger were assessed by disease severity (Tubiana stage). The mean (SD) improvement in total fixed flexion contraction (FFC) 31 days post-CCH treatment in 181 patients was: 71.1 (36.5)% for Tubiana I, 77.0 (21.0)% for Tubiana II, 72.0 (20.4)% for Tubiana III and 66.4 (22.2)% for Tubiana IV. Treatment of metacarpophalangeal and proximal interphalangeal joints in the same finger resulted in a mean (SD) improvement of 82.5 (24.8)% and 66.4 (27.9)%, respectively. In conclusion, CCH is an effective treatment alternative for all stages of Dupuytren contracture and it provides a less invasive treatment alternative to surgery with similar short-term efficacy in patients with more severe disease.
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| 39. |
- Petrus, P, et al.
(författare)
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Depot-specific differences in fatty acid composition and distinct associations with lipogenic gene expression in abdominal adipose tissue of obese women
- 2017
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 41:8, s. 1295-1298
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Tidskriftsartikel (refereegranskat)abstract
- Cardiometabolic diseases are primarily linked to enlarged visceral adipose tissue (VAT). However, some data suggest heterogeneity within the subcutaneous adipose tissue (SAT) depot with potential metabolic differences between the superficial SAT (sSAT) and deep SAT (dSAT) compartments. We aimed to investigate the heterogeneity of these three depots with regard to fatty acid (FA) composition and gene expression. Adipose tissue biopsies were collected from 75 obese women undergoing laparoscopic gastric bypass surgery. FA composition and gene expression were determined with gas chromatography and quantitative real-time-PCR, respectively. Stearoyl CoA desaturase-1 (SCD-1) activity was estimated by product-to-precursor FA ratios. All polyunsaturated FAs (PUFA) with 20 carbons were consistently lower in VAT than either SAT depots, whereas essential PUFA (linoleic acid, 18:2n-6 and α-linolenic acid, 18:3n-3) were similar between all three depots. Lauric and palmitic acid were higher and lower in VAT, respectively. The SCD-1 product palmitoleic acid as well as estimated SCD-1 activity was higher in VAT than SAT. Overall, there was a distinct association pattern between lipid metabolizing genes and individual FAs in VAT. In conclusion, SAT and VAT are two distinct depots with regard to FA composition and expression of key lipogenic genes. However, the small differences between sSAT and dSAT suggest that FA metabolism of SAT is rather homogenous.
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| 40. |
- Poelemeijer, Youri Q. M., et al.
(författare)
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Gastric Bypass Versus Sleeve Gastrectomy Patient Selection and Short-term Outcome of 47,101 Primary Operations From the Swedish, Norwegian, and Dutch National Quality Registries
- 2020
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Ingår i: Annals of Surgery. - : LIPPINCOTT WILLIAMS & WILKINS. - 0003-4932 .- 1528-1140. ; 272:2, s. 326-333
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to compare the use and short-term outcome of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) in Sweden, Norway, and the Netherlands. Background: Although bariatric surgery is performed in high volumes worldwide, no consensus exists regarding the choice of bariatric procedure for specific groups of patients. Methods: Data from 3 national registries for bariatric surgery were used. Patient selection, perioperative data (severe complications, mortality, and rate of readmissions within 30 days), and 1-year results (follow-up rate and weight loss) were studied. Results: A total of 47,101 primary operations were registered, 33,029 (70.1%) RYGB and 14,072 (29.9%) SG. Patients receiving RYGB met international guidelines for having bariatric surgery more often than those receiving SG (91.9% vs 83,0%,P< 0.001). The 2 procedures did not differ in the rate of severe complications (2.6% vs 2.4%,P= 0.382), nor 30-day mortality (0.04% vs 0.03%,P= 0.821). Readmission rates were higher after RYGB (4.3% vs 3.4%,P< 0.001). One-year post surgery, less RYGB-patients were lost-to follow-up (12.1% vs 16.5%,P< 0.001) and RYGB resulted in a higher rate of patients with total weight loss of more than 20% (95.8% vs 84.6%,P< 0.001). While the weight-loss after RYGB was similar between hospitals, there was a great variation in weight loss after SG. Conclusion: This study reflects the pragmatic use and short-term outcome of RYGB and SG in 3 countries in North-Western Europe. Both procedures were safe, with RYGB having higher weight loss and follow-up rates at the cost of a slightly higher 30-day readmission rate.
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| 41. |
- Poelemeijer, Youri Q. M., et al.
(författare)
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Perioperative Outcomes of Primary Bariatric Surgery in North-Western Europe : a Pooled Multinational Registry Analysis
- 2018
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Ingår i: Obesity Surgery. - : SPRINGER. - 0960-8923 .- 1708-0428. ; 28:12, s. 3916-3922
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The global prevalence of obesity has increased in recent decades, and bariatric surgery has become a part of the treatment algorithm of obesity. National high-quality registries enable large-scale evaluations of the use and outcome of bariatric surgery and may allow for improved knowledge. The main objective was to evaluate the rate and type of complications after primary bariatric surgery in three North-Western European countries using nationwide registries.Materials and Methods: Data from three registries for bariatric surgery were used (January 2015-December 2016). All registries have nationwide coverage with data on patient characteristics, obesity-related diseases, surgical technique, complications, grading of complications, reinterventions, readmissions, and mortality. Eligibility criteria for bariatric surgery were similar and included body mass index of 40.0 or 35.0kg/m(2), with one or more obesity-associated diseases.Results: A total of 35,858 procedures (32,177 primary) were registered. The most common procedure was gastric bypass in the Netherlands (78.9%) and Sweden (67.0%), and sleeve gastrectomy in Norway (58.2%). A total of 904 (2.8%) patients developed major complications after primary surgery and 12 patients (0.04%) died within 30days. Total number of complications between the registries were comparable (p=0.939). However, significant differences were seen for Clavien-Dindo Classification grades IIIb and IV (p<0.001). Pooled readmission rates were 4.3% (n=1386).Discussion: Bariatric surgery is safely performed in the three evaluated countries. Standardization of registries and consensus of variables are essential for international comparison and may contribute to improved quality of treatment across nations.
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| 42. |
- Samperio Ventayol, Pilar, et al.
(författare)
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Bacterial detection by NAIP/NLRC4 elicits prompt contractions of intestinal epithelial cell layers
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:16
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Tidskriftsartikel (refereegranskat)abstract
- The gut epithelium serves to maximize the surface for nutrient and fluid uptake, but at the same time must provide a tight barrier to pathogens and remove damaged intestinal epithelial cells (IECs) without jeopardizing barrier integrity. How the epithelium coordinates these tasks remains a question of significant interest. We used imaging and an optical flow analysis pipeline to study the dynamicity of untransformed murine and human intestinal epithelia, cultured atop flexible hydrogel supports. Infection with the pathogen Salmonella Typhimurium (S.Tm) within minutes elicited focal contractions with inward movements of up to similar to 1,000 IECs. Genetics approaches and chimeric epithelial monolayers revealed contractions to be triggered by the NAIP/NLRC4 inflammasome, which sensed type-III secretion system and flagellar ligands upon bacterial invasion, converting the local tissue into a contraction epicenter. Execution of the response required swift sublytic Gasdermin D pore formation, ion fluxes, and the propagation of a myosin contraction pulse across the tissue. Importantly, focal contractions preceded, and could be uncoupled from, the death and expulsion of infected IECs. In both two-dimensional monolayers and three-dimensional enteroids, multiple infection-elicited contractions coalesced to produce shrinkage of the epithelium as a whole. Monolayers deficient for Caspase-1(-11) or Gasdermin D failed to elicit focal contractions but were still capable of infected IEC death and expulsion. Strikingly, these monolayers lost their integrity to a markedly higher extent than wild-type counterparts. We propose that prompt NAIP/NLRC4/Caspase-1/Gasdermin D/myosin-dependent contractions allow the epithelium to densify its cell packing in infected regions, thereby preventing tissue disintegration due to the subsequent IEC death and expulsion process.
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| 43. |
- Semb, Olof, 1968-, et al.
(författare)
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Shame and Shame-Proneness in Relation to PTSD and Post-Victimization Reactions
- 2012
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Ingår i: Beyond Boundaries: Innovations to Expand Services andTailor Traumatic Stress Treatments.
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Konferensbidrag (refereegranskat)abstract
- Focusing mainly on the effects of fear and helplessness in PTSD, shame has been described as being anunderestimated possible factor for post trauma reactions. Shame and shame proneness have independently been shown to predict maladjustment after traumatizing events like criminal victimization, while guilt typically is described as unrelated to symptomatology. In a cross-sectional study, victims of interpersonal violence were investigated. Measures of shame and guilt proneness as well as self-rated experienced shame and guilt in association with the crime were related to symptomatology (PTSD-specific as well as general psychiatric symptoms). The shame measures were independently related to symptomatology but also to each other, while the guilt measures were unrelated to symptomatology and to each other. Further, event-related shame appeared as mediator between shame-proneness and post-victimization symptoms. A better understanding of the relationship between event-related emotions like shame and guilt and the propensity to react with shame or guiltmay have important clinical implications. Some suggestions as to how we move on from here will bepresented.
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| 44. |
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| 45. |
- Siilin, H., et al.
(författare)
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The proximal gastric pouch invariably contains acid-producing parietal cells in Roux-en-Y gastric bypass
- 2005
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Ingår i: Obes Surg. ; 15:6, s. 771-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Roux-en-Y gastric bypass (RYGBP) is well tolerated and effective in ameliorating diseases common to morbidly obese patients. A potential drawback, however, is the risk for stomal ulcers, probably due to acid and peptic digestion of the mucosa in the proximal Roux limb. METHODS: In 23 RYGBP patients (mean BMI 45 kg/m(2), age 39 years), the gastro-jejunostomy was performed by circular stapler and the gastric suture ring retrieved for histological examination. 13 consecutive patients received our standard totally transected 4 x 3 cm proximal gastric pouch. The anvil was passed transgastricly and reference biopsies were taken from the gastrotomy in the corpus of the stomach. In the last 10 patients, the pouch size was reduced to 2 x 3 cm by a modified surgical technique. RESULTS: All suture rings from the standard pouches consisted of corpus-fundus mucosa with a large amount of parietal cells, histologically identical to the reference biopsies from the gastrotomy. Also, the 10 suture rings from the modified small pouches contained corpus-fundus mucosa. In 5 of these samples, cardiac mucosa was found, but only in a small segment (6 mm). In addition, 3 patients had esophageal epithelium in the suture ring. CONCLUSION: The proximal pouch invariably contains acid-producing parietal cells. In order to reduce acid production and, hence, the risk of stomal ulcers, the pouch has to be made as small as possible.
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| 46. |
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| 47. |
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| 48. |
- Sima, Eduardo, Ph.D. 1975-, et al.
(författare)
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Non-responders After Gastric Bypass Surgery for Morbid Obesity : Peptide Hormones and Glucose Homeostasis
- 2019
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Ingår i: Obesity Surgery. - : Springer Science and Business Media LLC. - 0960-8923 .- 1708-0428. ; 29:12, s. 4008-4017
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: About 20% of patients operated with Roux-en-Y gastric bypass (RYGBP) experience poor long-term weight result. This study compared levels of leptin and gut hormones in long-term weight responders with non-responders after RYGBP. In a subgroup analysis, hormone levels were assessed in T2DM (type 2 diabetes mellitus) and normoglycemic participants.METHODS: Insulin, glucose, leptin, acyl-ghrelin, total PYY, active GLP-1, and GIP were measured during an oral glucose tolerance test (OGTT) in post-RYGBP subjects: 22 non-responders (BMI 40.6 ± 6.0 kg/m2 after an excess BMI loss [EBMIL] of 26.0 ± 15.9%) and 18 responders (BMI 29.5 ± 3.5 kg/m2 after an EBMIL of 74.9 ± 18.2%). Subjects were matched for preoperative age, BMI, and years of follow-up. Measures of glucose homeostasis were calculated, and body composition was measured.RESULTS: Fat mass-adjusted fasting leptin correlated negatively with %EBMIL (r = - 0.57, p < 0.01). Non-responders presented higher levels of leptin during the OGTT. Leptin decreased and ghrelin returned to baseline levels earlier in non-responders. Despite having higher insulin resistance than responders, non-responders demonstrated similar OGTT responses of GLP-1, GIP, and PYY. T2DM participants demonstrated lower GLP-1 levels than normoglycemic participants of similar weight.CONCLUSION: Fasting leptin is associated with weight result after RYGBP, and hormonal responses to a glucose oral load might work towards promoting obesity in long-term non-responders after RYGBP. Poor long-term weight result and glycemic status after RYGBP are each associated with differences in peptide hormone levels.
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