ResearchPad - stomach https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Structure and functional analysis of the <i>Legionella pneumophila</i> chitinase ChiA reveals a novel mechanism of metal-dependent mucin degradation]]> https://www.researchpad.co/article/elastic_article_14652 A broad range of organisms produce chitinase enzymes that digest chitin, the second most abundant carbohydrate on earth. Chitinases have also been identified that are important factors in major bacterial diseases but it is unclear how. Legionella pneumophila causes Legionnaires’ disease, a severe form of pneumonia, and its chitinase ChiA is essential for the survival of L. pneumophila during infection of the lung. Using structural biology and microbiology methods we have determined that ChiA can associate with the L. pneumophila surface and along with other outer membrane proteins can also bind mammalian mucins. We also identified a new and unique enzyme mechanism where L. pneumophila ChiA can hydrolyse the peptide bonds of mucin-like proteins. Mucins are major components of the mucous that lines the surface of the respiratory, digestive, and urogenital tracts and acts as a first line of defence during infection. This is the first mechanistic understanding of how a chitinase can promote disease through additional peptidase activity and suggests that L. pneumophila ChiA can modulate host immune responses and disperse host mucosa during infection.

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<![CDATA[Risk of stomach cancer incidence in a cohort of Mayak PA workers occupationally exposed to ionizing radiation]]> https://www.researchpad.co/article/Nb5246167-3f67-43a4-8a84-93c6a22ed7ff

Stomach cancer is a widespread health condition associated with environmental and genetic factors. Contribution of ionizing radiation to stomach cancer etiology is not sufficiently studied. This study was aimed to assess an association of the stomach cancer incidence risk with doses from occupational radiation exposure in a cohort of workers hired at main Mayak production association facilities in 1948–1982 taking into account non-radiation factors including digestive disorders. The study cohort comprised 22,377 individuals and by 31.12.2013 343 stomach cancer diagnoses had been reported among the cohort members. Occupational stomach absorbed doses were provided by the Mayak Worker Dosimetry System– 2008 (MWDS–2008) for external gamma ray exposure and by the Mayak Worker Dosimetry System– 2013 (MWDS–2013) for internal exposure to plutonium. Excess relative risks (ERR) per Gy for stomach cancer were estimated using the Poisson’s regression. Analyses were run using the AMFIT module of the EPICURE software. The stomach cancer incidence risk in the study cohort was found to be significantly associated with the stomach absorbed dose of gamma rays: ERR/Gy = 0.19 (95% CI: 0.01, 0.44) with a 0 year lag, and ERR/Gy = 0.20 (95% CI: 0.01, 0.45) with a 5 year lag. To estimate the baseline risk, sex, attained age, smoking status and alcohol consumption, chronic diseases (peptic ulcer, gastritis and duodenitis) were taken into account. No modifications of the radiogenic risk by non-radiation factors were found in the study worker cohort. No association of the stomach cancer incidence risk with internal exposure to incorporated plutonium was observed.

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<![CDATA[Hiatal Hernia Presenting with Recurrent Non‐ST Elevation Myocardial Infarction and Cardiac Tamponade]]> https://www.researchpad.co/article/N6dc9a4e5-abde-40fd-bcbd-702fad724130

ABSTRACT

Hiatal hernia is a common pathology, particularly among the elderly or obese populations. Occasionally, markedly dilated hernias can impinge on surrounding structures, notably the heart or lung. In such cases, morbidity can be considerable. We present a case of an enlarging hiatal hernia that compressed the heart, leading to recurrent non-ST elevation myocardial infarction with cardiac tamponade. The patient was successfully managed with nasogastric decompression and surgical repair. We recommend that extrapericardial pathology be considered in tamponade patients with concurrent hiatal hernia and that surgery should be considered the definitive treatment modality.

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<![CDATA[Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response]]> https://www.researchpad.co/article/Nbf2cda20-5e7d-4bb3-a68f-de1ada5bca91

Objective

Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets.

Design

We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs.

Results

We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of ‘clock-like’ mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: ‘mesenchymal-like’ and ‘epithelial-like’ with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive ‘mesenchymal-like’ subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets.

Conclusions

We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.

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<![CDATA[Regeneration of esophagus using a scaffold-free biomimetic structure created with bio-three-dimensional printing]]> https://www.researchpad.co/article/5c8c1978d5eed0c484b4d71e

Various strategies have been attempted to replace esophageal defects with natural or artificial substitutes using tissue engineering. However, these methods have not yet reached clinical application because of the high risks related to their immunogenicity or insufficient biocompatibility. In this study, we developed a scaffold-free structure with a mixture of cell types using bio-three-dimensional (3D) printing technology and assessed its characteristics in vitro and in vivo after transplantation into rats. Normal human dermal fibroblasts, human esophageal smooth muscle cells, human bone marrow-derived mesenchymal stem cells, and human umbilical vein endothelial cells were purchased and used as a cell source. After the preparation of multicellular spheroids, esophageal-like tube structures were prepared by bio-3D printing. The structures were matured in a bioreactor and transplanted into 10-12-week-old F344 male rats as esophageal grafts under general anesthesia. Mechanical and histochemical assessment of the structures were performed. Among 4 types of structures evaluated, those with the larger proportion of mesenchymal stem cells tended to show greater strength and expansion on mechanical testing and highly expressed α-smooth muscle actin and vascular endothelial growth factor on immunohistochemistry. Therefore, the structure with the larger proportion of mesenchymal stem cells was selected for transplantation. The scaffold-free structures had sufficient strength for transplantation between the esophagus and stomach using silicon stents. The structures were maintained in vivo for 30 days after transplantation. Smooth muscle cells were maintained, and flat epithelium extended and covered the inner surface of the lumen. Food had also passed through the structure. These results suggested that the esophagus-like scaffold-free tubular structures created using bio-3D printing could hold promise as a substitute for the repair of esophageal defects.

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<![CDATA[Risk of Upper Gastrointestinal Bleeding and Gastroduodenal Ulcers in Persons With Schizophrenia: A Danish Cohort Study]]> https://www.researchpad.co/article/5c973c55d5eed0c484968513

INTRODUCTION:

There is little evidence about gastrointestinal (GI) disorders in patients with schizophrenia. We examined association of schizophrenia with upper GI bleeding (UGIB) and nonbleeding ulcers and associated risk factors and mortality.

METHODS:

We used the data linked from population-based registries in Denmark. Among patients with incident schizophrenia in 1980–2011, we computed cumulative incidences and standardized incidence ratios of UGIB, bleeding ulcers, and nonbleeding ulcers compared with the general population; evaluated risk factors for the 3 GI endpoints, including somatic and psychiatric comorbidity; and examined subsequent all-cause mortality.

RESULTS:

Among 39,998 patients with schizophrenia, the standardized incidence ratios were 2.92 (95% confidence interval (CI), 2.76–3.08) for UGIB, 2.36 (95% CI, 2.15–2.58) for bleeding ulcers, and 2.00 (95% CI, 1.87–2.15) for nonbleeding ulcers. Risk factors for UGIB and nonbleeding ulcers included age, somatic comorbidity, and medication use. UGIB and nonbleeding ulcers were associated with the subsequent increase in mortality.

CONCLUSIONS:

Schizophrenia is associated with an increased risk of UGIB and nonbleeding ulcers, whose risk factors in patients with schizophrenia are similar to those in the general population.

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<![CDATA[Whole Genome Messenger RNA Profiling Identifies a Novel Signature to Predict Gastric Cancer Survival]]> https://www.researchpad.co/article/5c8bf7d9d5eed0c484b1e889

OBJECTIVES:

Molecular prognostic biomarkers for gastric cancer (GC) are still limited. We aimed to identify potential messenger RNAs (mRNAs) associated with GC prognosis and further establish an mRNA signature to predict the survival of GC based on the publicly accessible databases.

METHODS:

Discovery of potential mRNAs associated with GC survival was undertaken for 441 patients with GC based on the Cancer Genome Atlas (TCGA), with information on clinical characteristics and vital status. Gene ontology functional enrichment analysis and pathway enrichment analysis were conducted to interrogate the possible biological functions. We narrowed down the list of mRNAs for validation study based on a significance level of 1.00 × 10−4, also integrating the information from the methylation analysis and constructing the protein–protein interaction network for elucidating biological processes. A total of 54 mRNAs were further studied in the validation stage, using the Gene Expression Omnibus (GEO) database (GSE84437, n = 433). The validated mRNAs were used to construct a risk score model predicting the prognosis of GC.

RESULTS:

A total of 13 mRNAs were significantly associated with survival of GC, after the validation stage, including DCLK1, FLRT2, MCC, PRICKLE1, RIMS1, SLC25A15, SLCO2A1, CDO1, GHR, CD109, SELP, UPK1B, and CD36. Except CD36, DCLK1, and SLCO2A1, other mRNAs are newly reported to be associated with GC survival. The 13 mRNA-based risk score had good performance on distinguishing GC prognosis, with a higher score indicating worse survival in both TCGA and GEO datasets.

CONCLUSIONS:

We established a 13-mRNA signature to potentially predict the prognosis of patients with GC, which might be useful in clinical practice for informing patient stratification.

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<![CDATA[Emphysematous Gastritis in a Patient with Untreated Cyclic Vomiting Syndrome]]> https://www.researchpad.co/article/5c79b623d5eed0c4841ecc6b

Emphysematous gastritis (EG) is an uncommon and potentially fatal disease characterized by gastric pneumatosis in the setting of infection. While this disease has been described in the literature, it has not previously been identified as a potential complication of cyclic vomiting syndrome. We describe a patient with a history of cyclic vomiting syndrome who presented acutely ill and was found to have radiographic, endoscopic, and histologic evidence of EG. This case illustrates how an untreated functional bowel disorder can lead to severe and potentially fatal complications.

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<![CDATA[Stomach contents of long-finned pilot whales, Globicephala melas mass-stranded in Tasmania]]> https://www.researchpad.co/article/5c466578d5eed0c48451953b

New data are reported from analyses of stomach contents from 114 long-finned pilot whales mass-stranded at four locations around Tasmania, Australia from 1992–2006. Identifiable prey remains were recovered from 84 (74%) individuals, with 30 (26%) individuals (17 females and 13 males) having empty stomachs. Prey remains comprised 966 identifiable lower beaks and 1244 upper beaks, belonging to 17 families (26 species) of cephalopods. Ommastrephidae spp. were the most important cephalopod prey accounting for 16.9% by number and 45.6% by reconstructed mass. Lycoteuthis lorigera was the next most important, followed by Ancistrocheirus lesueurii. Multivariate statistics identified significant differences in diet among the four stranding locations. Long-finned pilot whales foraging off Southern Australia appear to be targeting a diverse assemblage of prey (≥10 species dominated by cephalopods). This is compared to other similar studies from New Zealand and some locations in the Northern Hemisphere, where the diet has been reported to be primarily restricted to ≤3 species dominated by cephalopods. This study emphasises the importance of cephalopods as primary prey for Southern long-finned pilot whales and other marine vertebrates, and has increased our understanding of long-finned pilot whale diet in Southern Ocean waters.

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<![CDATA[Use of Lactobacillus crispatus to produce a probiotic cheese as potential gender food for preventing gynaecological infections]]> https://www.researchpad.co/article/5c3fa5c7d5eed0c484ca86ed

This research is aimed to evaluate the suitability of Squacquerone cheese to support the viability of Lactobacillus crispatus BC4, a vaginal strain endowed with a strong antimicrobial activity against urogenital pathogens and foodborne microorganisms, in order to recommend a gender food for woman wellbeing. The viability of L. crispatus BC4, used as adjunct culture, was evaluated during the refrigerated storage of Squacquerone cheese, as well as when the cheese was subjected to simulated stomach-duodenum passage tested by the patented Simulator of the Human Intestinal Microbial Ecosystem (SHIME). Moreover, the effects of L. crispatus BC4 addition were evaluated on product hydrolytic patterns, in terms of proteolysis, lipolysis and volatile molecule profiles. The data showed that L. crispatus BC4 maintained high viability, also in presence of physiological stress conditions, until the end of the refrigerated storage. Moreover, the inclusion of L. crispatus BC4 gave rise to cheese product with higher score of overall acceptability when compared to control cheese. In addition, the survival of L. crispatus BC4, carried in test cheese, in gastro intestinal conditions was confirmed by SHIME. The results showed that the vaginal Lactobacillus strain was more affected by the low pH of the stomach, simulated by the SHIME reactor, rather than to bile salts and pancreatic juices. Although only in vivo trials will be able to confirm the functionality of the cheese in the vaginal environment, these data represent a first step towards the employment of the Squacquerone cheese as probiotic food able to promote the woman’s health by preventing gynaecological infections.

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<![CDATA[Stomach contents of the archaeocete Basilosaurus isis: Apex predator in oceans of the late Eocene]]> https://www.researchpad.co/article/5c3fa556d5eed0c484ca331a

Apex predators live at the top of an ecological pyramid, preying on animals in the pyramid below and normally immune from predation themselves. Apex predators are often, but not always, the largest animals of their kind. The living killer whale Orcinus orca is an apex predator in modern world oceans. Here we focus on an earlier apex predator, the late Eocene archaeocete Basilosaurus isis from Wadi Al Hitan in Egypt, and show from stomach contents that it fed on smaller whales (juvenile Dorudon atrox) and large fishes (Pycnodus mokattamensis). Our observations, the first direct evidence of diet in Basilosaurus isis, confirm a predator-prey relationship of the two most frequently found fossil whales in Wadi Al-Hitan, B. isis and D. atrox. This extends our understanding of their paleoecology. Late Eocene Basilosaurus isis, late Miocene Livyatan melvillei, and modern Orcinus orca are three marine apex predators known from relatively short intervals of time. Little is known about whales as apex predators through much of the Cenozoic era, and whales as apex predators deserve more attention than they have received.

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<![CDATA[Feeding responses of the golden jackal after reduction of anthropogenic food subsidies]]> https://www.researchpad.co/article/5c141eced5eed0c484d28582

Little is known of the resources that limit or promote the rapidly expanding golden jackal (Canis aureus) population in Europe. We hypothesised that in an area of intensive big game hunting, a reduction of the main food resource (human subsidised big game viscera) would result in dietary switching. We used multivariate analyses to test whether the dietary composition of 200 jackal stomachs varied between two 2-yearly survey occasions, the first without big game viscera removal (availability of 68 kg viscera/year/km2) followed by a period with viscera removal (minimum of 50 kg of viscera/year/km2 removed). The proportion of empty stomachs and the stomach wet content weight did not differ between the two periods. Even after the reduction of food subsidies, the primary food of jackals was viscera and carrion from wild ungulates (frequency of occurrence: 45% vs. 30%; wet weight: 55% vs. 29%, respectively), and scavenging was not affected by season or sex. Log-linear analysis of frequency data revealed no significant differences between survey occasions in consumption of either food type. MANCOVA of wet weight data revealed that in the first period with food subsidies jackals consumed a higher proportion of adult wild boar (11.6% vs. 1.3%; from predation or scavenging), while juvenile wild boar (0 vs. 11.8%; from predation or scavenging), domestic animals (0.8% vs. 6.2%; mostly from scavenging) and invertebrates (2.6% vs. 4.1%) increased in the second period. The stomachs in the second survey occasion contained more varied food items, but the trophic niche was not significantly wider. The feeding responses of this mesopredator to the reduction of food subsidies were less pronounced than expected. Because in high big game density areas, wild ungulate carrion from different mortality causes are available in high quantities throughout the year, predator populations can be maintained despite the high amount of viscera removal.

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<![CDATA[A new microendemic species of the deep-water catshark genus Bythaelurus (Carcharhiniformes, Pentanchidae) from the northwestern Indian Ocean, with investigations of its feeding ecology, generic review and identification key]]> https://www.researchpad.co/article/5c1ab81cd5eed0c484026c1e

A new deep-water catshark, Bythaelurus stewarti, is described based on 121 examined specimens caught on the Error Seamount (Mount Error Guyot) in the northwestern Indian Ocean. The new species differs from all congeners in the restricted distribution, a higher spiral valve turn count and in the morphology of the dermal denticles. It is distinguished from its morphologically and geographically closest congener, B. hispidus (Alcock), by the larger size (maximum size 44 vs. 39 cm TL, maturity size of males 35–39 vs. 21–28 cm TL), darker fresh coloration and dark grayish-brown mottling of the ventral head (vs. ventral head typically uniformly yellowish or whitish). Furthermore, it has a strongly different morphology of dermal denticles, in particular smaller and less elongate branchial, trunk and lateral caudal denticles that are set much less densely and have a surface that is very strongly and fully structured by reticulations (vs. structured by reticulations only in basal fourth). In addition, the new species differs from B. hispidus in having more slender claspers that are gradually narrowing to the bluntly pointed tip without knob-like apex (vs. claspers broader and with distinct knob-like apex), more spiral valve turns (11–12 vs. 8–10) and numerous statistical differences in morphometrics. A review of and a key to the species of Bythaelurus are given.

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<![CDATA[Guide to managing persistent upper gastrointestinal symptoms during and after treatment for cancer]]> https://www.researchpad.co/article/5c0e0ed1d5eed0c484dd28e1

Background

Guidance: the practical management of the gastrointestinal symptoms of pelvic radiation disease was published in 2014 for a multidisciplinary audience. Following this, a companion guide to managing upper gastrointestinal (GI) consequences was developed.

Aims

The development and peer review of an algorithm which could be accessible to all types of clinicians working with patients experiencing upper GI symptoms following cancer treatment.

Methods

Experts who manage patients with upper GI symptoms were asked to review the guide, rating each section for agreement with the recommended measures and suggesting amendments if necessary. Specific comments were discussed and incorporated as appropriate, and this process was repeated for a second round of review.

Results

21 gastroenterologists, 11 upper GI surgeons, 9 specialist dietitians, 8 clinical nurse specialists, 5 clinical oncologists, 3 medical oncologists and 4 others participated in the review. Consensus (defined prospectively as 60% or more panellists selecting ‘strongly agree’ or ‘agree’) was reached for all of the original 31 sections in the guide, with a median of 90%. 85% of panellists agreed that the guide was acceptable for publication or acceptable with minor revisions. 56 of the original 61 panellists participated in round 2. 93% agreed it was acceptable for publication after the first revision. Further minor amendments were made in response to round 2.

Conclusions

Feedback from the panel of experts developed the guide with improvement of occasional algorithmic steps, a more user-friendly layout, clearer time frames for referral to other teams and addition of procedures to the appendix.

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<![CDATA[The role of acid inhibition in Helicobacter pylori eradication]]> https://www.researchpad.co/article/5b5bf228463d7e275b8fb2e6

Infection of the stomach by the gastric pathogen Helicobacter pylori results in chronic active gastritis and leads to the development of gastric and duodenal ulcer disease and gastric adenocarcinoma. Eradication of H. pylori infection improves or resolves the associated pathology. Current treatments of H. pylori infection rely on acid suppression in combination with at least two antibiotics. The role of acid suppression in eradication therapy has been variously attributed to antibacterial activity of proton pump inhibitors directly or through inhibition of urease activity or increased stability and activity of antibiotics. Here we discuss the effect of acid suppression on enhanced replicative capacity of H. pylori to permit the bactericidal activity of growth-dependent antibiotics. The future of eradication therapy will rely on improvement of acid inhibition along with current antibiotics or the development of novel compounds targeting the organism’s ability to survive in acid.

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<![CDATA[Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam®-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging]]> https://www.researchpad.co/article/5989d9d4ab0ee8fa60b65631

Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam® histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam® grew into tumor-like structures with G0/G1 cancer cells in the center and S/G2 cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam® histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam®. In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN-45 cells in tumors on Gelfoam® to cycle from G0/G1 phase to S/G2 phase and reduced their viability. CDDP- or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam®. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam® histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

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<![CDATA[Selective Serotonin Reuptake Inhibitors and Gastrointestinal Bleeding: A Case-Control Study]]> https://www.researchpad.co/article/5989db21ab0ee8fa60bcf41e

Background

Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal (GI) bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding.

Methods

We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months) and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day).

Results

581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57–1.96) or for whichever other grouping of antidepressants.

Conclusions

The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2.

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<![CDATA[Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake]]> https://www.researchpad.co/article/5989db44ab0ee8fa60bd7e64

GLP-1 receptors are ideal targets for preoperative imaging of benign insulinoma and for quantifying the beta cell mass. The existing clinical tracers targeting GLP-1R are all agonists with low specific activity and very high kidney uptake. In order to solve those issues we evaluated GLP-1R agonist Ex-4 and antagonist Ex(9–39) radioiodinated at Tyr40 side by side with [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 (68Ga-Ex-4) used in the clinic. The Kd, Bmax, internalization and binding kinetics of [Nle14,125I-Tyr40-NH2]Ex-4 and [Nle14,125I-Tyr40-NH2]Ex(9–39) were studied in vitro using Ins-1E cells. Biodistribution and imaging studies were performed in nude mice bearing Ins-1E xenografts. In vitro evaluation demonstrated high affinity binding of the [Nle14,125I-Tyr40-NH2]Ex-4 agonist to the Ins-1E cells with fast internalization kinetics reaching a plateau after 30 min. The antagonist [Nle14,125I-Tyr40-NH2]Ex(9–39) did not internalize and had a 4–fold higher Kd value compared to the agonist. In contrast to [Nle14,125I-Tyr40-NH2]Ex(9–39), which showed low and transient tumor uptake, [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated excellent in vivo binding properties with tumor uptake identical to that of 68Ga-Ex-4, but substantially lower kidney uptake resulting in a tumor-to-kidney ratio of 9.7 at 1 h compared to 0.3 with 68Ga-Ex-4. Accumulation of activity in thyroid and stomach for both peptides, which was effectively blocked by irenat, confirms that in vivo deiodination is the mechanism behind the low kidney retention of iodinated peptides. The 124I congener of [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated a similar favourable biodistribution profile in the PET imaging studies in contrast to the typical biodistribution pattern of [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4. Our results demonstrate that iodinated Ex-4 is a very promising tracer for imaging of benign insulinomas. It solves the problem of high kidney uptake of the radiometal-labelled tracers by improving the tumor-to-kidney ratio measured for [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 by 32 fold.

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<![CDATA[Serum Acylated Ghrelin Concentrations in Response to Short-Term Overfeeding in Normal Weight, Overweight, and Obese Men]]> https://www.researchpad.co/article/5989da08ab0ee8fa60b76a68

Background

Ghrelin, an orexigenic gut hormone secreted primarily from the stomach, is involved in energy homeostasis. However, little data is available regarding its response to energy surplus and the development of human obesity.

Objective

The present study investigated the response of circulating acylated ghrelin to a 7-day positive energy challenge.

Design

A total of 68 healthy young men were overfed 70% more calories than required, for 1-week. Subjects were classified based on percent body fat (measured by dual-energy X-ray absorptiometry) as normal weight, overweight, and obese. Serum acylated ghrelin concentration was measured before and after the positive energy challenge. Additionally, the relationship between acylated ghrelin and obesity-related phenotypes including weight, body mass index, percent body fat, cholesterol, HDL-c, LDL-c, glucose, insulin and homeostasis model assessment of insulin resistance and β-cell function at baseline and change due to overfeeding, were assessed.

Results

Contrary to our expectations, serum acylated ghrelin was significantly increased in response to overfeeding and the increase was independent of obesity status. There was no significant difference in fasting acylated ghrelin between normal weight, overweight, and obese men at baseline. Acylated ghrelin was negatively correlated with weight and BMI for normal weight and with BMI in overweight men. Also ghrelin was correlated with change in weight and BMI in overweight (negative relationship) and obese (positive relationship) groups.

Conclusion

Our results showed that circulating acylated ghrelin was increased after a 7-day positive energy challenge regardless of adiposity status. However, acylated ghrelin was correlated with change in weight and BMI in opposing directions, in overweight and obese subjects respectively, thus dependent on obesity status.

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<![CDATA[Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy]]> https://www.researchpad.co/article/5989db5cab0ee8fa60be03d6

Innate lymphocyte cells (ILCs), a novel family of innate immune cells are considered to function as key orchestrators of immune defences at mucosal surfaces and to be crucial for maintaining an intact intestinal barrier. Accordingly, first data suggest depletion of ILCs to be involved in human immunodeficiency virus (HIV)-associated damage of the intestinal mucosa and subsequent microbial translocation. However, although ILCs are preferentially localized at mucosal surfaces, only little is known regarding distribution and function of ILCs in the human gastrointestinal tract. Here, we show that in HIV(-) individuals composition and functional capacity of intestinal ILCs is compartment-specific with group 1 ILCs representing the major fraction in the upper gastrointestinal (GI) tract, whereas ILC3 are the predominant population in ileum and colon, respectively. In addition, we present first data indicating that local cytokine concentrations, especially that of IL-7, might modulate composition of gut ILCs. Distribution of intestinal ILCs was significantly altered in HIV patients, who displayed decreased frequency of total ILCs in ileum and colon owing to reduced numbers of both CD127(+)ILC1 and ILC3. Of note, frequency of colonic ILC3 was inversely correlated with serum levels of I-FABP and sCD14, surrogate markers for loss of gut barrier integrity and microbial translocation, respectively. Both expression of the IL-7 receptor CD127 on ILCs as well as mucosal IL-7 mRNA levels were decreased in HIV(+) patients, especially in those parts of the GI tract with reduced ILC frequencies, suggesting that impaired IL-7 responses of ILCs might contribute to incomplete reconstitution of ILCs under effective anti-retroviral therapy. This is the first report comparing distribution and function of ILCs along the intestinal mucosa of the entire human gastrointestinal tract in HIV(+) and HIV(-) individuals.

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