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As of October 2022, the COVID-19 pandemic continues to pose a major public health conundrum, with increased rates of symptomatic infections in vaccinated individuals. An ideal vaccine candidate for the prevention of outbreaks should be rapidly scalable, easy to administer, and able to elicit a potent mucosal immunity. Towards this aim, we proposed an engineered Escherichia coli (E. coli) Nissle 1917 (EcN) strain with SARS-CoV-2 spike protein (SP)-coding plasmid, which was able to expose SP on its cellular surface by a hybridization with the adhesin involved in diffuse adherence 1 (AIDA1). In this study, we presented the effectiveness of a 16-week intragastrically administered, engineered EcN in producing specific systemic and mucosal immunoglobulins against SARS-CoV-2 SP in mice. We observed a time-dependent increase in anti-SARS-CoV-2 SP IgG antibodies in the sera at week 4, with a titre that more than doubled by week 12 and a stable circulating titre by week 16 (+309% and +325% vs. control; both p < 0.001). A parallel rise in mucosal IgA antibody titre in stools, measured via intestinal and bronchoalveolar lavage fluids of the treated mice, reached a plateau by week 12 and until the end of the immunization protocol (+300, +47, and +150%, at week 16; all p < 0.001 vs. controls). If confirmed in animal models of infection, our data indicated that the engineered EcN may be a potential candidate as an oral vaccine against COVID-19. It is safe, inexpensive, and, most importantly, able to stimulate the production of both systemic and mucosal anti-SARS-CoV-2 spike-protein antibodies. [ABSTRACT FROM AUTHOR]

While current anti-Spike protein (SP) vaccines have been pivotal in managing the pandemic, their limitations in delivery, storage, and the inability to provide mucosal immunization (preventing infections) highlight the ongoing necessity for research and innovation. To tackle these constraints, our research group developed a bacterial-based vaccine using a non-pathogenic E. coli Nissle 1917 (EcN) strain genetically modified to express the SARS-CoV-2 spike protein on its surface (EcN-pAIDA1-SP). We intranasally delivered the EcN-pAIDA1-SP in two doses and checked specific IgG/IgA production as well as the key immune mediators involved in the process. Moreover, following the initial and booster vaccine doses, we exposed both immunized and non-immunized mice to intranasal delivery of SARS-CoV-2 SP to assess the effectiveness of EcN-pAIDA1-SP in protecting lung tissue from the inflammation damage. We observed detectable levels of anti-SARS-CoV-2 spike IgG in serum samples and IgA in bronchoalveolar lavage fluid two weeks after the initial treatment, with peak concentrations in the respective samples on the 35th day. Moreover, immunoglobulins displayed a progressively enhanced avidity index, suggesting a selective binding to the spike protein. Finally, the pre-immunized group displayed a decrease in proinflammatory markers (TLR4, NLRP3, ILs) following SP challenge, compared to the non-immunized groups, along with better preservation of tissue morphology. Our probiotic-based technology provides an effective immunobiotic tool to protect individuals against disease and control infection spread. [Display omitted] • E. coli Nissle was genetically engineered to express the SARS-CoV-2 spike protein on its surface. • E. coli Nissle (EcN)-pAIDA1-SP is intranasally administrable in mice. • EcN-pAIDA1-SP increased anti-SARS-CoV-2 spike IgG/IgA after immunization. • EcN-pAIDA1-SP immunization mitigated Spike protein- induced lung injury in mice. [ABSTRACT FROM AUTHOR]

Background and Aim: Angiogenesis is emerging as a pivotal process in chronic inflammatory pathologies, promoting immune infiltration and prompting carcinogenesis. Ulcerative Colitis (UC) and Crohn’s Disease (CD) represent paradigmatic examples of intestinal chronic inflammatory conditions in which the process of neovascularization correlates with the severity and progression of the diseases. Molecules able to target the angiogenesis have thus the potential to synergistically affect the disease course. Beyond its anti-inflammatory effect, palmitoylethanolamide (PEA) is able to reduce angiogenesis in several chronic inflammatory conditions, but no data about its anti-angiogenic activity in colitis have been produced, yet. Methods: The effects of PEA on inflammation-associated angiogenesis in mice with dextran sulphate sodium (DSS)-induced colitis and in patients with UC were assessed. The release of Vascular Endothelial Growth Factor (VEGF), the hemoglobin tissue content, the expression of CD31 and of phosphatidylinositol 3-kinase/Akt/mammalian-target-of-rapamycin (mTOR) signaling axis were all evaluated in the presence of different concentrations of PEA and concomitant administration of PPAR-α and -γ antagonists. Results: Our results demonstrated that PEA, in a selective peroxisome proliferator activated receptor (PPAR)-α dependent mechanism, inhibits colitis-associated angiogenesis, decreasing VEGF release and new vessels formation. Furthermore, we demonstrated that the mTOR/Akt axis regulates, at least partly, the angiogenic process in IBD and that PEA directly affects this pathway. Conclusions: Our results suggest that PEA may improve inflammation-driven angiogenesis in colonic mucosa, thus reducing the mucosal damage and potentially affecting disease progression and the shift towards the carcinogenesis. [ABSTRACT FROM AUTHOR]

Achalasia is a major esophageal motor disorder featured by the altered relaxation of the esophagogastric junction in the absence of effective peristaltic activity. As a consequence of the esophageal outflow obstruction, achalasia patients present with clinical symptoms of dysphagia, chest pain, weight loss, and regurgitation of indigested food. Other less specific symptoms can also present including heartburn, chronic cough, and aspiration pneumonia. The delay in diagnosis, particularly when the presenting symptoms mimic those of gastroesophageal reflux disease, may be as long as several years. The widespread use of high-resolution manometry has permitted earlier detection and uncovered achalasia phenotypes which can have prognostic and therapeutic implications. Other tools have also emerged to help define achalasia severity and which can be used as objective measures of response to therapy including the timed barium esophagogram and the functional lumen imaging probe. Such diagnostic innovations, along with the increased awareness by clinicians and patients due to the availability of alternative therapeutic approaches (laparoscopic and robotic Heller myotomy, and peroral endoscopic myotomy) have radically changed the natural history of the disorder. Herein, we report the most recent advances in the diagnosis, classification, and management of esophageal achalasia and underline the still-grey areas that needs to be addressed by future research to reach the goal of personalizing treatment. [ABSTRACT FROM AUTHOR]

Background/Aims Bitter taste receptors are expressed throughout the digestive tract. Data on animals have suggested these receptors are involved in the gut hormone release, but no data are available in humans. Our aim is to assess whether bitter agonists influence food intake and gut hormone release in healthy subjects. Methods Twenty healthy volunteers were enrolled in a double-blind cross-over study. On 2 different days, each subject randomly received an acid-resistant capsule containing either placebo or 18 mg of hydrochloride (HCl) quinine. After 60 minutes, all subjects were allowed to eat an ad libitum meal until satiated. Plasma samples were obtained during the experiment in order to evaluate cholecystokinin (CCK) and ghrelin levels. Each subject was screened to determine phenylthiocarbamide (PTC) tasting status. Results Calorie intake was significantly lower when subjects received HCl quinine than placebo (514 ± 248 vs 596 ± 286 kcal; P = 0.007). Significantly higher CCK ΔT90 vs T0 and ΔT90 vs T60 were found when subjects received HCl quinine than placebo (0.70 ± 0.69 vs 0.10 ± 0.86 ng/mL, P = 0.026; 0.92 ± 0.75 vs 0.50 ± 0.55 ng/mL, P = 0.033, respectively). PTC tasters ingested a significantly lower amount of calories when they received HCl quinine compared to placebo (526 ± 275 vs 659 ± 320 kcal; P = 0.005), whereas no significant differences were found for PTC non-tasters (499 ± 227 vs 519 ± 231 kcal; P = 0.525). Conclusions This study showed that intra-duodenal release of a bitter compound is able to significantly affect calorie intake and CCK release after a standardized meal. Our results suggest that bitter taste receptor signaling may have a crucial role in the control of food intake. [ABSTRACT FROM AUTHOR]

In line with a growing body of evidence, if some Th2-driven pathophysiological mechanisms are shared across multiple atopic/allergic disorders, it is possible to hypothesize that, by treating a single clinical condition in an individual with multiple Th2 diseases, a simultaneous improvement can be obtained. Patients with atopic/allergic disorders, including atopic dermatitis (AD), allergic rhino-conjunctivitis (AR), chronic rhinosinusitis with/without nasal polyps (CRSwNP/CRSsNP), bronchial asthma, food allergy, and eosinophilic esophagitis (EoE), often share a common genetic background, a type Th2 polarized immune response, and several environmental factors [[1]]. However, although the positive clinical response to biologics confirms the association between Th2-driven diseases, no biomarker with high specificity can anticipate the therapeutic response in either single or multiple Th2 conditions. The presence of several allergic disorders in the same individuals suggests that some subgroups of allergic diseases share the same subtype of health condition, namely the "endotype" variety, especially the Th2-driven endotype. [Extracted from the article]

Objective Enteric glial cells (EGC) have been suggested to participate in host-bacteria cross-talk, playing a protective role within the gut. The way EGC interact with microorganisms is still poorly understood. We aimed to evaluate whether: EGC participate in host-bacteria interaction; S100B and Toll-like receptor (TLR) signalling converge in a common pathway leading to nitric oxide (NO) production. Design Primary cultures of human EGC were exposed to pathogenic (enteroinvasive Escherichia coli; EIEC) and probiotic (Lactobacillus paracasei F19) bacteria. Cell activation was assessed by evaluating the expression of cFos and major histocompatibility complex (MHC) class II molecules. TLR expression in EGC was evaluated at both baseline and after exposure to bacteria by real-time PCR, fluorescence microscopy and western blot analysis. S100B expression and NO release from EGC, following exposure to bacteria, were measured in the presence or absence of specific TLR and S100B pathway inhibitors. Results EIEC activated EGC by inducing the expression of cFos and MHC II. EGC expressed TLR at baseline. Pathogens and probiotics differentially modulated TLR expression in EGC. Pathogens, but not probiotics, significantly induced S100B protein overexpression and NO release from EGC. Pretreatment with specific inhibitors of TLR and S100B pathways abolished bacterial-induced NO release from EGC. Conclusions Human EGC interact with bacteria and discriminate between pathogens and probiotics via a different TLR expression and NO production. In EGC, NO release is impaired in the presence of specific inhibitors of the TLR and S100B pathways, suggesting the presence of a novel common pathway involving both TLR stimulation and S100B protein upregulation. [ABSTRACT FROM AUTHOR]

A wealth of evidence supports the concept that achalasia represents an autoimmune disorder in which a triggering factor (probably a virus) is the starter of an uncontrolled myenteric ganglionitis leading to neurodegeneration. The reasons whereby this process occurs only in some individuals and at the oesophageal level are unknown, but it is reasonable to assume that some genetic influence may affect the achalasia phenotype, making some individuals more or less susceptible to the disease. Association studies between achalasia and polymorphisms of genes involved in the regulation of immune responses may help to explain the complexity of achalasia pathogenesis and progression. [ABSTRACT FROM AUTHOR]

Introduction: Patients with constipation often report dyspeptic symptoms, but whether constipation is associated with specific dyspeptic symptoms and altered gastrointestinal (GI) motility, remains to be established. Our aim was to study symptoms association and GI motility parameters in patients with constipation and functional dyspepsia. Patients and Method: 42 patients with different symptoms and severity of constipation and dyspepsia were enrolled. Scintigraphic gastric emptying, colonic transit time and gallbladder contraction were studied in all subjects. Results: No significant association was observed between individual symptoms of constipation and dyspepsia. Patients with more severe constipation did not have higher dyspepsia severity scores. Colonic transit time, gastric half emptying and gallbladder contraction were not significantly correlated. Although patients with severe nausea had faster colonic transit than those with absent/mild symptom (19 ± 2 vs. 48 ± 7 h; p < 0.05), the multivariate analysis only revealed a significant association between severe postprandial fullness, delayed t½ (OR 1.05, CI 1-1.1) and impaired gallbladder contraction (OR 0.94, CI 0.89-0.99). Conclusions: Constipation was not associated with severity, or any particular dyspeptic symptom. Although motor abnormalities of both colon and proximal GI tract regions existed in the subset of constipated dyspeptic patients, they did not seem associated with the genesis of different dyspeptic symptoms. [ABSTRACT FROM AUTHOR]

After a meal, the proximal stomach relaxes probably through the activation of nitrergic neurons in the gastric wall. Nitric oxide-induced smooth muscle relaxation involves activation of soluble guanylate cyclase, with cGMP production, which is then degradated by phosphodiesterase-5 (PDE-5). The aim of this study was to investigate the effect of sildenafil, a selective PDE-5 inhibitor, on fasting and postprandial proximal gastric volume and on gastric emptying rates in humans. A gastric barostat was used to study gastric compliance and perception to isobaric distension in healthy subjects before and after placebo (n = 13) or sildenafil, 50 mg (n = 15). In 10 healthy subjects, two gastric barostat studies were performed in randomized order to study the effect of placebo or sildenafil on postprandial gastric relaxation. Similarly, solid and liquid gastric emptying rates were studied in 12 healthy subjects. Sildenafil significantly increased fasting intragastric volume (141 ± 15 vs. 163 ± 15 ml, P < 0.05) and volumes of first perception. Sildenafil induced a higher and prolonged gastric relaxation either at 30 min (357 ± 38 vs. 253 ± 42 ml, P < 0.05) or 60 min (348 ± 49 vs. 247 ± 38 ml, P < 0.05) after the meal. Sildenafil did not alter solid half-emptying time but significantly delayed liquid emptying (43 ± 4 vs. 56 ± 4 min, P < 0.01). In conclusion, sildenafil significantly increases postprandial gastric volume and slows liquid emptying rate, confirming that meal-induced accommodation in humans involves the activation of a nitrergic pathway. The effect of sildenafil on gastric fundus suggests a therapeutic potential for phosphodiesterase inhibitors in patients with impaired gastric accommodation. [ABSTRACT FROM AUTHOR]

Galanin modulates gastrointestinal motility by inhibiting the release of ACh from enteric neurons. It is, however, not known whether galanin also inhibits neuronal cholinergic transmission postsynaptically and whether galanin also reduces the action of other excitatory neurotransmitters. The aim of the present study was thus to investigate the effect of galanin on the evoked intracellular Ca2+ concentration ([Ca2+]i) responses in myenteric neurons. Cultured myenteric neurons from small intestine of adult guinea pigs were loaded with the Ca2+ indicator fluo-3 AM, and the [Ca2+]i responses following the application of different stimuli were quantified by confocal microscopy and expressed as a percentage of the response to high-K+ solution (75 mM). Trains of electrical pulses (2 s, 10 Hz) were applied to stimulate the neuronal fibers before and after a 30-s superfusion with galanin (10-6 M). Substance P (SP), 5-HT, 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP), and carbachol were used as direct postsynaptic stimuli (10-5 M, 30 s) and were applied alone or after galanin perfusion. Galanin significantly reduced the responses induced by electrical fiber stimulation (43 ± 2 to 35 ± 3%, P = 0.01), SP (15.4 ± 1 to 8.0 ± 0.3%, P < 0.01), and 5-HT (26 ± 2 to 21.4 ± 1.5%, P < 0.05). On the contrary, galanin did not affect the responses induced by local application of DMPP and carbachol. We conclude that in cultured myenteric neurons, galanin inhibits the excitatory responses induced by electrical stimulation, SP, and 5-HT. Finally, the inhibitory effect of galanin on electrical stimulation, but not on DMPP- and carbachol-induced responses, suggests that, at least for the cholinergic component, galanin acts at the presynaptic level. [ABSTRACT FROM AUTHOR]

: ObjectivesThe relationship between functional dyspepsia and delayed gastric emptying of solids or liquids is still unclear. The aim of the present study was to investigate in dyspeptic patients the prevalence of delayed gastric emptying for solids or for liquids and to investigate the relationship to the dyspepsia symptom pattern.: MethodsIn 392 and 330 patients with functional dyspepsia, the solid and liquid gastric emptying, respectively, was measured using breath tests, and the severity of eight dyspeptic symptoms was scored.: ResultsGastric emptying of solids and liquids were delayed in 23% and 35% of the patients. Multivariate analysis showed that the presence of vomiting and postprandial fullness was associated with delayed solid emptying (OR 2.65, 95% CI = 1.62–4.35 and OR 3.08, 95% CI = 1.28–9.16, respectively). Postprandial fullness was also associated with the risk of delayed liquid emptying when symptom was present (OR 3.5, 95% CI = 1.57–8.68), relevant or severe (OR 2.504, 95% CI = 1.41–4.65), and severe (OR 2.214, 95% CI = 1.34–3.67). Severe early satiety was associated with the risk of delayed liquid emptying (OR 1.902, 95% CI = 1.90–3.30).: ConclusionsA subset of dyspeptic patients has delayed gastric emptying of solids or of liquids. Delayed gastric emptying of solids was constantly associated with postprandial fullness and with vomiting. Delayed emptying for liquids was also associated with postprandial fullness and with severe early satiety. [Copyright &y& Elsevier]

Background/Objectives: Although long-term COVID-19 symptoms are common, little is known about the management of post-COVID-19 condition. The aim of the current report is to evaluate the effects of a combination of lactoferrin, lysozyme, lactobacillus, resveratrol, vitamins, and oligoelements (PIRV-F20®) on the exercise capacity of post-COVID-19 patients. Methods: A retrospective analysis of consecutive patients referred to a specific outpatient clinic dedicated to post-COVID-19 condition from April 2022 to April 2023 was conducted. Subjects of both sexes, aged ≥18 years, with previous COVID-19 in the preceding 12 months, persistent symptoms consistent with post-COVID syndrome, and initial exercise impairment were included. Exclusion criteria were as follows: active cancer, end-stage conditions, severe musculoskeletal conditions, or patients with a history of limited functional capacity, pregnancy, or breastfeeding. Patients who reported having taken PIRV-F20® for at least 6 weeks were compared to patients who refused this treatment. Six-minute walking distance was the primary endpoint. Results: Forty-four patients (56.8% women, aged 49.1 ± 18.1 years) were included in the study. The group of patients who reported having taken PIRV-F20® exhibited a significant improvement of 6MWD (median: +40 m; IQR: 10–65 m, p vs. baseline: 0.02), which was significantly superior (p: 0.01) when compared to the controls (median: +10 m; IQR: −5–30 m). No differences were found with regard to muscular strength, echocardiographic parameters, and perception of symptoms. Conclusions: Post-COVID-19 individuals who reported having taken PIRV-F20® for at least six weeks showed a significant improvement in exercise capacity. This finding should be confirmed in larger, prospective, randomized controlled trials. [ABSTRACT FROM AUTHOR]

Background: Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity.Methods: Diarrhea was induced by intracolonic administration of HIV-1 Tat protein in rats at day 1. PEA alone or in the presence of peroxisome proliferator-activated receptor (PPAR) antagonists was given intraperitoneally from day 2 to day 7. S100B, iNOS, NF-kappaB, TLR4 and GFAP expression were evaluated in submucosal plexi, while S100B and NO levels were measured in EGC submucosal plexi lysates, respectively. To verify whether PEA effects were PPARα-mediated, PPARα-/- mice were also used. After 7 days from diarrhea induction, endogenous PEA levels were measured in submucosal plexi homogenates deriving from rats and PPARα-/- mice.Results: HIV-1 Tat protein induced rapid onset diarrhea alongside with a significant activation of EGCs. Tat administration significantly increased all hallmarks of neuroinflammation by triggering TLR4 and NF-kappaB activation and S100B and iNOS expression. Endogenous PEA levels were increased following HIV-1 Tat exposure in both wildtype and knockout animals. In PPARα-/- mice, PEA displayed no effects. In wildtype rats, PEA, via PPARα-dependent mechanism, resulted in a significant antidiarrheal activity in parallel with marked reduction of EGC-sustained neuroinflammation.Conclusions: EGCs mediate HIV-1 Tat-induced diarrhea by sustaining the intestinal neuroinflammatory response. These effects are regulated by PEA through a selective PPARα-dependent mechanism. PEA might be considered as an adjuvant therapy in HIV-1-induced diarrhea. [ABSTRACT FROM AUTHOR]

Achalasia is a rare esophageal motility disorder of unknown etiology. With the ageing of the general population, treatment in elderly patients has become increasingly common; however, the gold standard treatment in this population remains unclear. The aim of this study was to evaluate the outcomes of laparoscopic Heller-Dor myotomy (LHM) in geriatric patients. In this study, consecutive achalasia patients undergoing LHM at the University Hospital 'Federico II' of Naples from November 2018 to November 2022 were prospectively enrolled. Patients were divided into two groups based on their age at intervention: elderly (≥70 years) and younger (<70 years). The two study groups were compared by minimizing the different distribution of covariates through a propensity score matching analysis (PSM). In both populations, there was a significant improvement in terms of manometric parameters and symptoms after surgery. After applying one-on-one PSM, we obtained a total population of 48 achalasia patients divided into two groups (24 patients each). No significant differences were found in terms of demographic characteristics as well as preoperative and intraoperative variables between two groups. At 12 months from surgery, integrated relaxation pressure (IRP) was significantly lower in patients ≥ 70 years (p = 0.032), while younger patients scored significantly less at the post-operative Eckardt score (p = 0.047). Laparoscopic Heller-Dor myotomy is a safe and effective treatment even in elderly patients with rapid post-operative recovery, improvement of symptoms and manometric parameters. [ABSTRACT FROM AUTHOR]

Improving clinical outcomes and delaying disease recrudescence in Ulcerative Colitis (UC) patients is crucial for clinicians. In addition to traditional and new pharmacological therapies that utilize biological drugs, the development of medical devices that can ameliorate UC and facilitate the remission phase should not be overlooked. Drug-based therapy requires time to be personalized and to evaluate the benefit/risk ratio. However, the increasing number of diagnosed UC cases worldwide necessitates the exploration of new strategies to enhance clinical outcomes. By incorporating medical devices alongside pharmacological treatments, clinicians can provide additional support to UC patients, potentially improving their condition and slowing down the recurrence of symptoms. Chemically identified as an azelaic acid derivative and palmitoylethanolamide (PEA) analog, adelmidrol is a potent anti-inflammatory and antioxidant compound. In this study, we aimed to evaluate the effect of an intrarectal administration of 2% adelmidrol (Ade) and 0.1% hyaluronic acid (HA) gel formulation in both the acute and resolution phase of a mouse model of colitis induced via DNBS enema. We also investigated its activity in cultured human colon biopsies isolated from UC patients in the remission phase at follow-up when exposed in vitro to a cytomix challenge. Simultaneously, with its capacity to effectively alleviate chronic painful inflammatory cystitis when administered intravesically to urological patients such as Vessilen, the intrarectal administration of Ade/HA gel has shown remarkable potential in improving the course of colitis. This treatment approach has demonstrated a reduction in the histological damage score and an increase in the expression of ZO-1 and occludin tight junctions in both in vivo studies and human specimens. By acting independently on endogenous PEA levels and without any noticeable systemic absorption, the effectiveness of Ade/HA gel is reliant on a local antioxidant mechanism that functions as a "barrier effect" in the inflamed gut. Building on the findings of this preliminary study, we are confident that the Ade/HA gel medical device holds promise as a valuable adjunct in supporting traditional anti-UC therapies. [ABSTRACT FROM AUTHOR]

Highlights • The use of Cannabis as a complementary and alternative medicine in inflammatory bowel disease has increased due to the evolving policies regarding its legalization. • Endocannabinoids in IBD represent both an appealing therapeutic strategy and a captivating scientific dilemma. • Results from clinical trials must be carefully interpreted owing to possible reporting-biases related to cannabinoids psychotropic effects. Also, discriminating between symptomatic improvement and the real gain on the underlying inflammatory process is often challenging. • Despite these limitations in the current use of these drugs in clinical practice, several novel therapeutic strategies are under consideration to overcome these flaws. The evolving policies regarding the use of therapeutic Cannabis have steadily increased the public interest in its use as a complementary and alternative medicine in several disorders, including inflammatory bowel disease. Endocannabinoids represent both an appealing therapeutic strategy and a captivating scientific dilemma. Results from clinical trials have to be carefully interpreted owing to possible reporting-biases related to cannabinoids psychotropic effects. Moreover, discriminating between symptomatic improvement and the real gain on the underlying inflammatory process is often challenging. This review summarizes the advances and latest discovery in this ever-changing field of investigation, highlighting the main limitations in the current use of these drugs in clinical practice and the possible future perspectives to overcome these flaws. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a short-lived gas molecule which has been studied for its role as a signaling molecule in the vasculature and later, in a broader view, as a cellular messenger in many other biological processes such as immunity and inflammation, cell survival, apoptosis, and aging. Fractional exhaled nitric oxide (FeNO) is a convenient, easy-to-obtain, and non-invasive method for assessing active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid the diagnosis and monitoring of several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory and/or immunological conditions, including allergic rhinitis, chronic rhinosinusitis with/without nasal polyps, atopic dermatitis, eosinophilic esophagitis, and food allergy. In this review, we aim to provide an extensive overview of the current state of knowledge about FeNO as a biomarker in type 2 inflammation, outlining past and recent data on the application of its measurement in patients affected by a broad variety of atopic/allergic disorders. [ABSTRACT FROM AUTHOR]

The functional disease of the esophago-gastric junction (EGJ) is one of the most common health problems. It often happens that patients suffering from GERD need surgical management. The laparoscopic fundoplication has been considered the gold standard surgical treatment for functional diseases of the EGJ. The aim of our meta-analysis is to investigate functional outcomes after robotic fundoplication compared with conventional laparoscopic fundoplication. A prospective search of online databases was performed by two independent reviewers using the search string "robotic and laparoscopic fundoplication", including all the articles from 1996 to December 2021. The risk of bias within each study was assessed with the Cochrane ROBINS-I and RoB 2.0 tools. Statistical analysis was performed using Review Manager version 5.4. In addition, sixteen studies were included in the final analysis, involving only four RCTs. The primary endpoints were functional outcomes after laparoscopic (LF) and robotic fundoplication (RF). No significant differences between the two groups were found in 30-day readmission rates (p = 0.73), persistence of symptomatology at follow-up (p = 0.60), recurrence (p = 0.36), and reoperation (p = 0.81). The laparoscopic fundoplication represents the gold standard treatment for the functional disease of the EGJ. According to our results, the robotic approach seems to be safe and feasible as well. Further randomized controlled studies are required to better evaluate the advantages of robotic fundoplication. [ABSTRACT FROM AUTHOR]

Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy. [ABSTRACT FROM AUTHOR]

Background: The sense of taste is involved in food behavior and may drive food choices, likely contributing to obesity. Differences in taste preferences have been reported in normal-weight as compared to obese subjects. Changes in taste perception with an increased sweet-induced sensitivity have been reported in surgically treated obese patients, but data regarding the perception of basic tastes yielded conflicting results. We aimed to evaluate basic taste identification, induced perception, and pleasantness in normal-weight controls and obese subjects before and after bariatric surgery. Methods: Severe obese and matched normal weight subjects underwent a standardized spit test to evaluate sweet, bitter, salty, umami, and sour taste identification, induced perception, and pleasantness. A subset of obese subjects were also studied before and 12 months after sleeve gastrectomy. Results: No significant differences in basic taste-induced perceptions were observed, although a higher number of controls correctly identified umami than did obese subjects. Sleeve-gastrectomy-induced weight loss did not affect the overall ability to correctly identify basic tastes but was associated with a significant increase in taste intensities, with higher scores for sour and bitter, and a significantly reduced bitter-induced pleasantness. Conclusions: The perception of basic tastes is similar in normal-weight and severely obese subjects. Sleeve-gastrectomy-induced weight loss significantly increases basic taste-induced intensity, and selectively reduces bitter-related pleasantness without affecting the ability to identify the tastes. Our findings reveal that taste perception is influenced by body mass index changes, likely supporting the hypothesis that centrally mediated mechanisms modulate taste perception in severe obesity. [ABSTRACT FROM AUTHOR]

To evaluate the potential differences in the propensity of β-casein A1 (β-CNA1) and A2 (β-CNA2) from bovine milk to release health-relevant β-casomorphins (BCMs), food-derived peptides were monitored over time in the blood of eight human volunteers who consumed milk containing both protein variants. Liquid chromatography coupled with high resolution tandem mass spectrometry revealed interindividual variability of milk peptidomic profiles in human blood. BCMs were not detected, whereas BCM precursors originating from both β-CNA1 and β-CNA2 were ascertained, with β-CNA2-derived peptides showing a slightly greater susceptibility to proteolysis. Ten synthetic peptides mimicking circulating BCM precursors from β-CNA1 and β-CNA2, which were incubated ex vivo with the blood of two volunteers, showed comparable potential to generate BCMs. The formation of BCMs seemed to depend mainly on the size of the BCM precursors and less on the presence of His67 or Pro67. These findings challenge the belief that BCMs are released exclusively from β-CNA1 and support the nutritional safety of conventional milk, informing health policies regarding milk consumption. [Display omitted] • β-Casomorphins (BCMs) do not occur in the blood of volunteers after milk ingestion. • BCM precursors from β-CNA1 and A2 were detected in the blood of volunteers fed milk. • Ex vivo incubation of synthetic BCM precursors with human blood can generate BCMs. • The harmful effects associated with ingestion of β-CNA1-containing milk are doubted. [ABSTRACT FROM AUTHOR]

Engineered probiotics represent a cutting-edge therapy in intestinal inflammatory disease (IBD). Genetically modified bacteria have provided a new strategy to release therapeutically operative molecules in the intestine and have grown into promising new therapies for IBD. Current IBD treatments, such as corticosteroids and immunosuppressants, are associated with relevant side effects and a significant proportion of patients are dependent on these therapies, thus exposing them to the risk of relevant long-term side effects. Discovering new and effective therapeutic strategies is a worldwide goal in this research field and engineered probiotics could potentially provide a viable solution. This review aims at describing the proceeding of bacterial engineering and how genetically modified probiotics may represent a promising new biotechnological approach in IBD treatment. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2012; 42 (10): 1068-1078 Abstract Background In many countries, the introduction of generic proton pump inhibitors (PPIs) onto the pharmaceutical market increased the phenomenon of therapeutic substitution in acid-related disorders (ARDs). Aim To investigate the treatment of ARDs in an Italian primary care setting from 2005 to 2008 by verifying: (i) dynamics of PPI prescribing; (ii) predictors of PPI switching; and (iii) healthcare resource consumption costs. Methods This was a retrospective cohort study of 102 general practitioners (GPs) who managed an average of 150 000 inhabitants in Naples. Multilevel logistic regression was used to assess the potential predictors of both PPI switching and termination. Primary care costs were expressed as the cost of ARD management per PPI user year. Results The percentage of PPI users with ARD increased from 5·5% (2005) to 7·0% (2008) ( P < 0·0001), especially for dyspepsia (from 9·5% to 13·7%; P < 0·0001) and chronic treatments (from 23·4% to 29·4%; P < 0·0001). PPI switching rose from 13·0% to 16·7% during the period observed ( P < 0·0001). Calendar years, long-term treatments and gastroesophageal reflux disease were positive predictors of PPI switching. Primary care costs relating to PPI switchers increased by 61·14€ compared with nonswitchers ( P < 0·0001). Conclusions The introduction of generic PPIs onto the Italian market was associated with an increasing amount of PPI prescribing related to chronic treatments, unlicensed indications (e.g. dyspespsia) and therapeutic substitutions. Growing overall costs linked to the phenomenon of PPI switching was also found. Our data support the need to assess the effects of the introduction of generic drugs on both clinical outcomes and the cost management of ARDs. [ABSTRACT FROM AUTHOR]

Background: Intestinal inflammation is partly driven by enteroglial-derived S100B protein. The antiprotozoal drug pentamidine directly blocks S100B activity. We aimed to investigate the effect of pentamidine on intestinal inflammation using an animal model of dextran sodium sulphate (DSS)-induced acute colitis. Methods: Mice were divided into: control group, colitis group (4% DSS for four days) and two pentamidine-treated colitis groups (0.8 mg/kg and 4 mg/kg). Anti-inflammatory effect of pentamidine was assessed in colonic tissue by evaluating the disease activity index and the severity of histological changes. Colonic tissue were also used to evaluate cyclooxigenase-2, inducible nitric oxide synthase, S100B, glial fibrillary acidic protein, phosphorylated-p38 MAPkinase, p50, p65 protein expression, malondyaldheyde production, mieloperoxidase activity, and macrophage infiltration. Nitric oxide, prostaglandin E2, interleukin-1 beta, tumor necrosis factor alpha, and S100B levels were detected in plasma samples. Parallel measurements were performed in vitro on dissected mucosa and longitudinal muscle myenteric plexus (LMMP) preparations after challenge with LPS + DSS or exogenous S100B protein in the presence or absence of pentamidine. Results: Pentamidine treatment significantly ameliorated the severity of acute colitis in mice, as showed by macroscopic evaluation and histological/biochemical assays in colonic tissues and in plasma. Pentamidine effect on inflammatory mediators was almost completely abrogated in dissected mucosa but not in LMMP. Conclusions: Pentamidine exerts a marked anti-inflammatory effect in a mice model of acute colitis, likely targeting S100B activity. Pentamidine might be an innovative molecule to broaden pharmacological tools against colitis. [ABSTRACT FROM AUTHOR]

Backgorund: Parents after Neonatal Intensive Care Unit (NICU) hospitalization of preterm infant may develop psychopathological symptoms. The aim of the study was to determine how parental stress and psychophysical wellbeing affect posttraumatic symptoms (PTTS) in parents during the first year after NICU discharge. Moreover, this study aimed to explore any gender-specific difference in psychological distress among mothers and fathers. Methods: Prospective study design from September 2018 to September 2019. 20 pairs of parents of preterm infants admitted to a tertiary-level NICU were enrolled. Primary outcome was evaluation of PTTS in parents of preterm infants at one year after NICU discharge through Impact of Event Scale- Revised. Secondary outcomes were: impact of parental stress, psychophysical wellbeing, anxiety and depression respectively through Parental Stressor Scale: NICU, Short Form Health Survey-36(SF-36), Self-rating Anxiety Scale and Self-rating Depression Scale. Results: Mothers experienced higher rates of PTTS than fathers across the first year after NICU discharge (55% vs 20%). Maternal avoidance symptoms were associated with perception of their own infant look. Emotional aspects linked to maternal role predicted 36,8% of their hyperarousal symptoms. Maternal PTTS severity was predicted by their social functioning. Paternal mental health was associated both with maternal and paternal intrusive symptoms.. Maternal stress was associated with paternal avoidance symptoms. Paternal mental health predicted their hyperarousal symptoms (40%) and PTSD severity (52%). Conclusions: Parents who experienced NICU hospitalization of their own infant are at heightened risk to develop psychopathological symptoms. According to our initial hypothesis, investigating parental psychophysical wellbeing, through SF-36, originally provides a valuable support to detect parents at higher risk to develop posttraumatic outcomes across the first year after NICU discharge. In addition, paternal depression deserves to be taken into account since hospitalization as it could impact paternal PTSD development. Finally, these findings provide an initial evidence of gender-related patterns in PTSD development and psychological distress among mothers and fathers across the first year of their infant. [ABSTRACT FROM AUTHOR]

Background: Recent reports have demonstrated that de novo reflux and worsening of pre-existing symptoms occur after SG; concerns are still expressed about the risk of symptomatic biliary reflux gastritis and oesophagitis. The aim of our study was to investigate and compare the rate of postoperative acid and non-acid reflux following Mini-/One anastomosis gastric bypass (MGB/OAGB) and laparoscopic sleeve gastrectomy (LSG). Study design: A prospective randomized open-label, controlled trial registered on clinicaltrial.gov (NCT number: NCT02987673) has been carried out to evaluate esophagogastric junction exposure to reflux in the first year after MGB/OAGB and LSG using high impedance manometry, endoscopy, and a validated questionnaire. Results: A total of 58 individuals were eventually enrolled in this trial and represented the per-protocol population (n = 28 MGB/OAGB, n = 30 LSG). No difference was found between the two groups in terms of demographic characteristics, PAGI-SYM score, acid exposure time percent of the esophagus (AET%), esophagitis, and other HRiM and MII-pH data at baseline. Comparing MII-pH outcomes of the two groups, AET% resulted significantly higher after LSG at 12 months. Endoscopic findings showed a significant increase of esophagitis ≥ B in the LSG group after 1 year; postoperative esophagitis ≥ B resulted also significantly worsened after LSG when compared to MGB/OAGB. Conclusion: Since AET% and rate of esophagitis are significantly higher after LSG when compared to MGB/OAGB, this procedure should be preferred in case of preoperative subclinical reflux or low grade (A) esophagitis. [ABSTRACT FROM AUTHOR]

Background: Mood and metabolic disorders are interrelated and may share common pathological processes. Autonomic neurons link the brain with the gastrointestinal tract and constitute a likely pathway for peripheral metabolic challenges to affect behaviors controlled by the brain. The activities of neurons along these pathways are regulated by glia, which exhibit phenotypic shifts in response to changes in their microenvironment. How glial changes might contribute to the behavioral effects of consuming a high-fat diet (HFD) is uncertain. Here, we tested the hypothesis that anxiogenic and depressive-like behaviors driven by consuming a HFD involve compromised duodenal barrier integrity and subsequent phenotypic changes to glia and neurons along the gut-brain axis.Methods: C57Bl/6 male mice were exposed to a standard diet or HFD for 20 weeks. Bodyweight was monitored weekly and correlated with mucosa histological damage and duodenal expression of tight junction proteins ZO-1 and occludin at 0, 6, and 20 weeks. The expression of GFAP, TLR-4, BDNF, and DCX were investigated in duodenal myenteric plexus, nodose ganglia, and dentate gyrus of the hippocampus at the same time points. Dendritic spine number was measured in cultured neurons isolated from duodenal myenteric plexuses and hippocampi at weeks 0, 6, and 20. Depressive and anxiety behaviors were also assessed by tail suspension, forced swimming, and open field tests.Results: HFD mice exhibited duodenal mucosa damage with marked infiltration of immune cells and decreased expression of ZO-1 and occludin that coincided with increasing body weight. Glial expression of GFAP and TLR4 increased in parallel in the duodenal myenteric plexuses, nodose ganglia, and hippocampus in a time-dependent manner. Glial changes were associated with a progressive decrease in BDNF, and DCX expression, fewer neuronal dendritic spines, and anxiogenic/depressive symptoms in HFD-treated mice. Fluorocitrate (FC), a glial metabolic poison, abolished these effects both in the enteric and central nervous systems and prevented behavioral alterations at week 20.Conclusions: HFD impairs duodenal barrier integrity and produces behavioral changes consistent with depressive and anxiety phenotypes. HFD-driven changes in both peripheral and central nervous systems are glial-dependent, suggesting a potential glial role in the alteration of the gut-brain signaling that occurs during metabolic disorders and psychiatric co-morbidity. [ABSTRACT FROM AUTHOR]

A modified caudal-to-cranial approach to perform laparoscopic left colectomy for benign diseases has been recently designed to facilitate the low-tie mesenteric dissection. A chart review has been performed including all consecutive patients with uncomplicated diverticulitis who have been treated by segmental left colectomy with a caudal-to-cranial approach. A total of 34 patients were included in the study. 21 patients were male, mean age was 54.1 ± 11.3 , and mean BMI was 26 ± 5.5. Patients with ASA Score I were 7, with ASA II were 9, and with ASA Score III were 5. Incontinence Score (IS) resulted in an average of 5 ± 2 , 2 grade of incontinence and the CS score showed an average of 10 ± 3 , 2 grade of constipation. Health status, evaluated by Short Form-36 questionnaire, was demonstrated in these patients' great physical function, role, general health, and social function. The anorectal manometry performed 6 months after surgery showed a normal value in terms of the anal resting pressure (47 ± 13 mmHg) and an increased volume to stimulate desire to defecate (197 ± 25 ml). The length of the anal sphincter was normal compared to the reference value (37 ± 5.4 mm). Although further studies are required to obtain definitive conclusions, our results are encouraging to propose low-tie segmental colectomy as the standard procedure for the treatment of uncomplicated diverticulitis, and our modified surgical approach could be considered useful to facilitate the surgical approach. [ABSTRACT FROM AUTHOR]

Identifying drugs effective in the new coronavirus disease 2019 (COVID‐19) is crucial, pending a vaccine against SARS‐CoV2. We suggest the hypothesis that cannabidiol (CBD), a non‐psychotropic phytocannabinoid, has the potential to limit the severity and progression of the disease for several reasons:‐ (a) High‐cannabidiol Cannabis sativa extracts are able to down‐regulate the expression of the two key receptors for SARS‐CoV2 in several models of human epithelia, (b) cannabidiol exerts a wide range of immunomodulatory and anti‐inflammatory effects and it can mitigate the uncontrolled cytokine production responsible for acute lung injury, (c) being a PPARγ agonist, it can display a direct antiviral activity and (d) PPARγ agonists are regulators of fibroblast/myofibroblast activation and can inhibit the development of pulmonary fibrosis, thus ameliorating lung function in recovered patients. We hope our hypothesis, corroborated by preclinical evidence, will inspire further targeted studies to test cannabidiol as a support drug against the COVID‐19 pandemic. Linked Articles: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc [ABSTRACT FROM AUTHOR]

Summary: Background: Patients with chronic constipation (CC) or with irritable bowel syndrome with constipation are often dissatisfied about their medical therapy, but their condition remains poorly defined. Aim: To evaluate the patients' satisfaction rates and which factors predict favourable outcomes through the aggregate analysis of N‐of‐1 trials. Methods: Eighty‐one outpatients with CC or with irritable bowel syndrome with constipation underwent N‐of‐1 trials with at least a one‐month cycle of effective treatment. Three primary endpoints (satisfaction with therapy, improvement after treatment and an extended satisfaction criterion including both endpoints) were adopted to define satisfaction with therapy. Dyssynergia, resting anal pressure, colonic transit time and somatisation were assessed. The Patient Assessment of Constipation‐Symptoms (PAC‐SYM) questionnaire and its Modified version (M‐PAC‐SYM) measured constipation severity. Straining at defecation, stool frequency and form were daily recorded. K statistics for agreement and logistic regression were used at statistical analysis. Results: Satisfaction with therapy was not achieved by 43% of patients, who had a significantly lower Body Mass Index (BMI) and more severe constipation at baseline. Only the change in constipation severity according to M‐PAC‐SYM remained significantly associated with satisfaction with therapy (OR = 4.3; P < 0.001) at multivariate analysis. Conclusions: Satisfaction with therapy is often an unmet need for patients with CC or with irritable bowel syndrome with constipation. Lower BMI and more severe constipation are associated with worse outcome. Changes in M‐PAC‐SYM reflect satisfaction with therapy. ClinicalTrials.gov no. NCT02813616. [ABSTRACT FROM AUTHOR]

Background: TME has revolutionized the surgical management of rectal cancer, and since the introduction of robotic TME (RTME), many reports have shown the feasibility and the safety of this approach. However, concerns persist regarding the advantages of robotic in surgery for the completeness of TME. The aim of this review is to compare robotic versus laparoscopic total mesorectal excision (TME) in rectal cancer, focusing on the completeness of TME. Methods: A systematic search was performed in the electronic databases for all available studies comparing RTME versus conventional laparoscopic LTME with declared grade of mesorectum excision. Data regarding sample size, clinical and demographic characteristics, number of complete, nearly complete, and incomplete TME were extracted. Primary outcome was the number of complete TME in robotic and laparoscopic procedures. Secondary outcomes were the numbers of nearly complete and incomplete TME in robotic and laparoscopic rectal resections. Results: Twelve articles were included in the final analysis. Complete TME was reported by all authors, involving 1510 procedures, showing a significant difference in favor of robotic surgery (OR = 1.83, 95% CI 1.08–3.10, p = 0.03). Nearly complete and incomplete TME showed no significant difference between the procedures. Meta-regression analysis showed that none of patients' and tumors' characteristics significantly impacted on complete TME. Conclusions: Our results underline that the robotic approach to rectal resection is the better way to obtain a complete TME. However, it is mandatory that randomized clinical trials should be performed to assess definitively if robotic minimally invasive surgery is better than a laparoscopic resection. [ABSTRACT FROM AUTHOR]

Background: Europeans consume large quantities of bakery products, although these are known as one of the food categories that potentially leads to postprandial symptoms (such as fullness and bloating).Objective: The aim of this study was to evaluate the effects of sourdough baked goods on gastric emptying and gastrointestinal fermentation and symptoms in healthy people.Methods: In a double-blind, randomized crossover study, 2 sourdough croissants (SCs) or 2 brewer's yeast croissants (BCs) were served as single meals to 17 healthy adults [9 women; age range: 18-40 y; body mass index range (in kg/m2): 18-24]. Gastric volume (GV) was evaluated by magnetic resonance to calculate gastric-emptying rate in the 3-h interval after croissant ingestion. A hydrogen breath test was performed to measure hydrogen production after SC and BC ingestion. Palatability and postprandial gastrointestinal symptoms (discomfort, nausea, fullness, and bloating) over a 4-h period after the meal were evaluated. The area under the curve (AUC) was used to evaluate the overall effects on all variables tested.Results: The total GV AUC was reduced by 11% during the 3 h after the consumption of SCs compared with BCs (P = 0.02). Hydrogen production during the 4-h interval after ingestion of SCs was 30% lower than after BCs (P = 0.03). SCs were rated as being >2 times as palatable as BCs (P < 0.001). The overall severity of postprandial symptoms was 36% lower during the 4 h after intake of SCs compared with BCs (P = 0.05).Conclusion: Sourdough bakery products could promote better postprandial gastrointestinal function in healthy adults and be more acceptable than those prepared with brewer's yeast. This trial was registered at www.clinicaltrials.gov as NCT03207516. [ABSTRACT FROM AUTHOR]

Background: Right insular cortex is involved in taste discrimination, but its functional organization is still poorly known. In general, sensory cortices represent the spatial prevalence of relevant features for each sensory modality (visual, auditory, somatosensory) in an ordered way across the cortical space. Following this analogy, we hypothesized that primary taste cortex is organized in similar ordered way in response to six tastes with known receptorial mechanisms (sweet, bitter, sour, salt, umami, CO2). Design: Ten normal subjects were enrolled in a pilot study. We used functional magnetic resonance imaging (fMRI), a high resolution cortical registration method, and specialized procedures of feature prevalence localization, to map fMRI responses within the right insular cortex, to water solutions of quinine hydrochloride (bitter), Acesulfamate K (sweet), sodium chloride (salt), mono potassium glutamate + inosine 5' mono phosphate (Umami), citric acid (sour) and carbonated water (CO2). During an fMRI scan delivery of the solutions was applied in pseudo-random order interleaved with cleaning water. Results: Two subjects were discarded due to excessive head movements. In the remaining subjects, statistically significant activations were detected in the fMRI responses to all tastes in the right insular cortex (p<0.05, family-wise corrected for multiple comparisons). Cortical representation of taste prevalence highlighted two spatially segregated clusters, processing two and three tastes coupled together (sweet-bitter and salt-umami-sour), with CO2 in between. Conclusions: Cortical representation of taste prevalence within the right primary taste cortex appears to follow the ecological purpose of enhancing the discrimination between safe nutrients and harmful substances. [ABSTRACT FROM AUTHOR]

Aim: Targeted molecular probes have been used to detect sporadic colonic dysplasia during confocal laser endomicroscopy (CLE) with promising results. This is a feasibility pilot study aiming to assess the potential role of CLE combined with a fluorescent-labeled peptide to stain and detect dysplasia associated with Ulcerative Colitis. Method: A phage-derived heptapeptide with predicted high binding affinity for dysplastic tissue, was synthesized and labeled with fluorescein. Eleven lesions with suspected dysplasia at endoscopy were excised from nine patients with long-standing ulcerative colitis. Specimens were sprayed with the peptide and examined by CLE. The CLE images were then compared to the corresponding histological sections. Results: At definitive histology, 4 lesions were diagnosed as inflammatory polyps, 6 as dysplastic lesions and one as invasive cancer. In inflammatory polyps, the fluorescence signal came from peri-cryptal spaces and crypt lumen due to passive accumulation of the peptide in these areas. Dysplasia was associated with active binding of the peptide to dysplastic colonocytes. Conclusion: Ex vivo staining of ulcerative colitis-associated dysplasia using a fluorescent labeled molecular probe and CLE is feasible. In vivo studies on larger populations are required to evaluate the safety and the effective contribution of molecular probes in cancer surveillance of ulcerative colitis. [ABSTRACT FROM AUTHOR]

Sitagliptin and saxagliptin are oral hypoglycemic agents inhibitors of DPP-4, indicated in the treatment of type 2 diabetes mellitus in combination with metformin, in patients who have not achieved adequate glycemic control. In our study we enrolled 128 decompensated type 2 diabetes patients while on metformin maximum dosage. At time 0' we have detected, body mass index (BMI), total cholesterol, high- and low-density lipoproteins (HDL and LDL), triglycerides, transaminases and pancreatic amylase; patients were randomized to receive sitagliptin or saxagliptin; follow-up was performed after 4 months with the revaluation of the same variables and adverse events. In both sitagliptin and saxagliptin groups we observed a significant reduction in fasting glucose, glycated hemoglobin, weighing, BMI, triglycerides, while the reduction in total cholesterol, LDL cholesterol did not reach statistical significance. There was no suspension of therapy, adverse events appeared minor and temporary. In conclusion, our observations highlight the almost identical efficacy of sitagliptin and saxagliptin. These data reinforce even more the idea that we should think about this class of drugs as the next step in patients failing therapy with metformin. [ABSTRACT FROM AUTHOR]

S100 calcium-binding protein B (S100B) is highly expressed in glioma cells and promotes cancer cell survival via inhibition of the p53 protein. In melanoma cells, this S100B-p53 interaction is known to be inhibited by pentamidine isethionate, an antiprotozoal agent. Thus, the aim of the present study was to evaluate the effect of pentamidine on rat C6 glioma cell proliferation, migration and apoptosis in vitro. The change in C6 cell proliferation following treatment with pentamidine was determined by performing a 3-[4,5-dimethylthiazol-2-yl] -2,5 diphenyltetrazolium bromide-formazan assay. Significant dose-dependent decreases in proliferation were observed at pentamidine concentrations of 0.05 μM (58.5±5%; P<0.05), 0.5 μM (40.6±7%; P<0.01) and 5 μM (13±4%; P<0.001) compared with the control (100% viability). Furthermore, treatment with 0.05, 0.5 and 5 μM pentamidine was associated with a significant increase in apoptosis versus the untreated cells, as determined by DNA fragmentation assays, immunofluorescence analysis of C6 chromatin using Hoechst staining, and immunoblot analysis of B-cell lymphoma-2 (Bcl-2)-associated X protein (100%, P<0.05; 453%, P<0.01; and 1000%, P<0.001, respectively) and Bcl-2 (-60%, P<0.001; -80.13%, P<0.001; -95%, P<0.001, respectively). In addition, the administration of 0.05, 0.5 and 5 μM pentamidine significantly upregulated the protein expression levels of p53 (681±87.5%, P<0.05; 1244±94.3%, P<0.01; and 2244±111%, P<0.001, respectively), and significantly downregulated the expression levels of matrix metalloproteinase-2 (42±2.3%, P<0.05; 71±2.5%, P<0.01; and 95.8±3.3%, P<0.001, respectively) and aquaporin 4 (38±2.5%, P<0.05; 69±2.6%, P<0.01; and 88±3.0%, P<0.001, respectively), compared with the untreated cells. The wound healing assay demonstrated that cell migration was significantly impaired by treatment with 0.05, 0.5 and 5 μM pentamidine compared with untreated cells (88±4.2%, P<0.05; 64±2%, P<0.01; and 42±3.1%, P<0.001, respectively). Although additional in vivo studies are required to clarify the current in vitro data, the present study indicates that pentamidine and S100B-p53 inhibitors may represent a novel approach for the treatment of glioma. [ABSTRACT FROM AUTHOR]

Background/Aims: Partially hydrolyzed guar gum (PHGG) relieves symptoms in constipation‑predominant irritable bowel syndrome (IBS) and may have prebiotic properties. However, the correlation between the effectiveness of PHGG and patient characteristics has not been examined. We aimed to investigate the effect of PHGG in symptom relief on constipation‑predominant IBS according to gender, age, and body mass index (BMI). Patients and Methods: Sixty‑eight patients with IBS entered a 2‑week run‑in period, followed by a 4‑week study period with PHGG. Patients completed a daily questionnaire to assess the presence of abdominal pain/discomfort, swelling, and the sensation of incomplete evacuation. The number of evacuations/day, the daily need for laxatives/enemas and stool consistency‑form were also evaluated. All patients also underwent a colonic transit time (CTT) evaluation. Results: PHGG administration was associated with a significant improvement in symptom scores, use of laxatives/enemas, stool form/consistency and CTT. At the end of the study period and compared with baseline, the number of evacuations improved in women, patients aged ≥ 45 years and those with BMI ≥ 25 (P < 0.05 for all comparisons); abdominal bloating improved in males (P < 0.05), patients < 45 years (P < 0.01) and those with BMI < 25 (P < 0.05). A decrease in the number of perceived incomplete evacuations/day was reported in patients with a BMI ≥ 25 (P < 0.05). Reductions in laxative/enema use were recorded in females (P < 0.05), patients < 45 years (P < 0.01), and patients with BMI < 25 (P < 0.05). Conclusions: Gender, age, and BMI seem to influence the effect of PHGG supplementation in constipated IBS patients. Further studies are needed to clarify the interaction of such parameters with a fiber‑enriched diet. [ABSTRACT FROM AUTHOR]

Objective Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice. Design Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARa or PPAR? antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs. Results PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARa, but not PPAR?, abolished PEA effects, in mice and in humans. Conclusions Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARa action, PEA might be an innovative molecule to broaden pharmacological strategies against UC. [ABSTRACT FROM AUTHOR]

Background Diverticular disease ( DD) and irritable bowel syndrome ( IBS) share a similar symptom pattern. However, comparative studies are flawed by different age at onset of symptoms. We aimed to verify whether clinical features distinguish DD from IBS. Materials and methods Patients with DD or IBS, matched for age and gender (1/1) were consecutively recruited. Data on demographic parameters, voluptuary habits, inheritance of disease and symptoms were collected. Moreover, the association between pain > 24 h, and clinical parameters were evaluated. Results Ninety patients with DD and 90 patients with IBS ( DD: F/ M: 46/44; age: 50.9 years; IBS: 46/44; 50.4) were selected from an overall population of 1275 patients. Only nine patients with DD (10%) fulfilled the criteria for IBS diagnosis. Abdominal pain > 24 h was more prevalent in SDD than in patients with IBS (20 vs. 6 patients; P < 0·01). Furthermore, compared with IBS, patients with DD showed more episodes of pain > 24 h requiring medical attention (80% vs. 33%; P < 0·01). Conclusions Abdominal pain lasting for more than 24 h discriminates patients with DD compared with those with IBS. Identifying this symptom could be an appropriate strategy to define the diagnosis and management. [ABSTRACT FROM AUTHOR]

Background: There is conflicting data on the effects of carbon dioxide contained in beverages on stomach functions. We aimed to verify the effect of a pre-meal administration of a 300 ml non-caloric carbonated beverage (B+CO2) compared to water or a beverage without CO2 (B-CO2), during a solid (SM) and a liquid meal (LM) on: a) gastric volume, b) caloric intake, c) ghrelin and cholecystokinin (CCK) release in healthy subjects.Methods: After drinking the beverages (Water, B-CO2, B+CO2), ten healthy subjects (4 women, aged 22-30 years; BMI 23 ± 1) were asked to consume either an SM or an LM, at a constant rate (110 kcal/5 min). Total gastric volumes (TGV) were evaluated by Magnetic Resonance Imaging after drinking the beverage and at maximum satiety (MS). Total kcal intake at MS was evaluated. Ghrelin and CCK were measured by enzyme immunoassay until 120 min after the meal. Statistical calculations were carried out by paired T-test and analysis of variance (ANOVA). The data is expressed as mean ± SEM.Results: TGV after B+CO2 consumption was significantly higher than after B-CO2 or water (p < 0.05), but at MS, it was no different either during the SM or the LM. Total kcal intake did not differ at MS after any of the beverages tested, with either the SM (Water: 783 ± 77 kcals; B-CO2: 837 ± 66; B+CO2: 774 ± 66) or the LM (630 ± 111; 585 ± 88; 588 ± 95). Area under curve of ghrelin was significantly (p < 0.05) lower (13.8 ± 3.3 ng/ml/min) during SM following B-CO2 compared to B+CO2 and water (26.2 ± 4.5; 27.1 ± 5.1). No significant differences were found for ghrelin during LM, and for CCK during both SM and LM after all beverages.Conclusions: The increase in gastric volume following a 300 ml pre-meal carbonated beverage did not affect food intake whether a solid or liquid meal was given. The consistency of the meal and the carbonated beverage seemed to influence ghrelin release, but were unable, under our experimental conditions, to modify food intake in terms of quantity. Further studies are needed to verify if other food and beverage combinations are able to modify satiation. [ABSTRACT FROM AUTHOR]

Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine. Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects. Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation. CBD markedly counteracted reactive enteric gliosis in LPS-mice trough the massive reduction of astroglial signalling neurotrophin S100B. Histological, biochemical and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment. Moreover the treatment of LPS-mice with CBD reduced TNF-α expression and the presence of cleaved caspase-3. Similar results were obtained in ex vivo cultured human derived colonic biopsies. In biopsies of UC patients, both during active inflammation and in remission stimulated with LPS+INF-γ, an increased glial cell activation and intestinal damage were evidenced. CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect in septic mice. The activity of CBD is, at least partly, mediated via the selective PPAR-gamma receptor pathway. CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients. These actions lead to a reduction of intestinal damage mediated by PPARgamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

Background Gastroesophageal reflux disease (GERD), including erosive reflux disease and non-erosive reflux disease (NERD), is a chronic disease with a significant negative effect on quality of life. State-of-the-art treatment involves proton pump inhibitors (PPIs). However, relapse of symptoms occurs in the majority of the patients who require recurrent or continuous therapy. Although PPIs are well tolerated, little information is available about gastrointestinal side effects. Aim To evaluate the effects of long-term PPI treatment on development of bowel symptoms and/or small intestinal bacterial overgrowth (SIBO). Methods Patients with NERD not complaining of bowel symptoms were selected by upper endoscopy, 24-h pH-metry and a structured questionnaire concerning severity and frequency of bloating, flatulence, abdominal pain, diarrhoea and constipation. Patients were treated with esomeprazole 20 mg bid for 6 months. Prior to and after 8 weeks and 6 months of therapy, patients received the structured questionnaire and underwent evaluation of SIBO by glucose hydrogen breath test (GHBT). Results Forty-two patients with NERD were selected out of 554 eligible patients. After 8 weeks of PPI treatment, patients complained of bloating, flatulence, abdominal pain and diarrhoea in 43%, 17%, 7% and 2%, respectively. After 6 months, the incidence of bowel symptoms further increased and GHBT was found positive in 11/42 (26%) patients. By a post hoc analysis, a significant (P < 0.05) percentage of patients (8/42) met Rome III criteria for irritable bowel syndrome. Conclusions Prolonged PPI treatment may produce bowel symptoms and SIBO; therefore, the strategy of step-down or on-demand PPI therapy should be encouraged in GERD. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Basilisco et al and Ballou and Lembo papers. To view these articles, visit https://doi.org/10.1111/apt.15657 and https://doi.org/10.1111/apt.15683. [ABSTRACT FROM AUTHOR]

Abstract: S100β is an astroglial-derived Ca2+-binding protein having neurotrophic role on neurons and glial cells. An aberrant S100β production has been observed in neurodegenerative disease, as Alzheimer''s disease and Down syndrome. S100β is responsible to start up a gliotic reaction by the release of pro-inflammatory mediators, including nitric oxide (NO) and cytokines from microglia and astrocytes, which are, in turn, deleterious for neurons. Interestingly, pro-inflammatory effect of S100β seems not be restricted into the brain. Macrophages play a pivotal role in inflammatory diseases, occurring both in the brain and in the periphery. In this study, we tested the hypothesis that S100β may affect macrophage functions, amplifying thus the inflammatory process. Our results demonstrate that S100β stimulates both NO production and iNOS protein transcription and expression in J774 and rat peritoneal macrophages. NO production was concentration and time-dependently inhibited by two iNOS inhibitors, l-NAME and SMT. We also demonstrated that S100β induced oxidative stress by increasing H2O2 production and lipid peroxidation of cell membrane in both macrophage types. The pro-oxidant potential of S100β activates p38 MAP kinase (MAPK), which has been described to directly activate NF-κB. In our study, SB203580, a p38 MAPK inhibitor, and two NF-κB inhibitors, TLCK and BAY 11-7082, decreased both NO production and iNOS protein transcription and expression in S100β-stimulated J774 and peritoneal rat macrophages. Moreover, additional studies demonstrated that S100β affected also TNF-α protein expression in J774 macrophages. In conclusion, our results highlight the potential role of S100β during an inflammatory scenario identifying macrophages as a novel S100β-responsive cell-type. [Copyright &y& Elsevier]

Patients with chronic renal failure (CRF) often have dyspeptic symptoms and may develop peptic disease or digestive disorders leading to severe gastrointestinal complications. The primary aim of this study was to evaluate the prevalence of peptic lesions andHelicobacter pyloriinfection, and the severity of dyspeptic symptoms, in dyspeptic patients with and without CRF. Our secondary aim was to investigate whether uremic status may affect the diagnostic efficiency of the[13]C-urea breath test ([13]C-UBT).We consecutively enrolled in the study 50 dyspeptic patients with chronic kidney failure (mean age 52 ± 5 years), of whom 11 were on hemodialysis treatment (HD), and 93 subjects (mean age 54 ± 7 years) with chronic dyspepsia and normal renal function (NRF). All patients completed an oriented and validated questionnaire scoring the severity of nine dyspeptic symptoms (i.e. epigastric pain, epigastric burning, postprandial fullness, early satiety, bloating, belching, nausea and vomiting) and underwent upper endoscopy with multiple bioptic sampling for rapid urease test and histological examination,[13]C-UBT and HpSA test.The prevalences of peptic lesions andH. pyloriinfection and mean symptom score were 74%, 52% and 3.5 ± 3, respectively, in dyspeptic patients with CRF and 18%, 36% and 8 ± 5, respectively, in dyspeptic patients with NRF. The diagnostic accuracy of[13]C-UBT with respect to histological diagnosis was 94% and 97% for dyspeptic patients with and without renal failure, respectively.1, A high frequency of peptic lesions and low symptom scores were observed in uremic patients in spite ofH. pyloriinfection; 2, uremic status did not affect the diagnostic accuracy of[13]C-UBT. [ABSTRACT FROM AUTHOR]

Clinical Development Phases I ‐ III Regulatory, Quality, ManufacturingPostmarketing Phase IV Thalassemic trait (Thal) is associated with rheumatic disease, particularly a mild form of seronegative polyarthritis resembling rheumatoid arthritis (RA), but not with other rheumatic diseases. The aim of this study was to estimate the frequency of Thal in patients with psoriatic arthritis (PsA) and to evaluate the efficacy of anti ‐ tumor necrosis factor alpha (TNF ‐ α) therapy in patients with PsA and Thal. We performed a retrospective study in 321 patients with PsA who started therapy with TNF ‐ α blockers. For all patients included in the study, at baseline and every 3 months for the 1 year of follow up, data concerning PsA activity and ferritin levels were registered. In our group of PsA patients, a total of 27 (8%) with concomitant Thal were identified and included in the study. In patients without Thal, all variables improved significantly after 6 months of therapy, while in patients with Thal, the same variables showed a significant decrease after 12 months.: Our study shows that PsA is significantly associated with Thal, but further studies are needed to address this issue. The presence of Thal could be a negative predictor of achieving remission during treatment with TNF ‐ α ‐ blockers. [ABSTRACT FROM AUTHOR]