Viable Mycobacterium avium subsp. paratuberculosis Colonizes Peripheral Blood of Inflammatory Bowel Disease Patients.

Pathobionts, particularly Mycobacterium avium subsp. paratuberculosis (MAP) and Escherichia coli isolates with adherence/invasive ability (AIEC) have been associated with inflammatory bowel disease (IBD), particularly Crohn's disease (CD). This study aimed to evaluate the frequency of viable MAP and AIEC in a cohort of IBD patients. As such, MAP and E. coli cultures were established from faecal and blood samples (with a total n = 62 for each) of patients with CD (n = 18), ulcerative colitis (UC, n = 15), or liver cirrhosis (n = 7), as well as from healthy controls (HC, n = 22). Presumptive positive cultures were tested by polymerase chain reaction (PCR), for a positive confirmation of MAP or E. coli identity. E. coli-confirmed isolates were then tested for AIEC identity using adherence and invasion assays in the epithelial cell line of Caco-2 and survival and replication assays in the macrophage cell line of J774. MAP sub-culture and genome sequencing were also performed. MAP was more frequently cultured from the blood and faecal samples of patients with CD and cirrhosis. E. coli presumptive colonies were isolated from the faecal samples of most individuals, in contrast to what was registered for the blood samples. Additionally, from the confirmed E. coli isolates, only three had an AIEC-like phenotype (i.e., one CD patient and two UC patients). This study confirmed the association between MAP and CD; however, it did not find a strong association between the presence of AIEC and CD. It may be hypothesized that the presence of viable MAP in the bloodstream of CD patients contributes to disease reactivation.

Pharmacological Treatment of Functional Dyspepsia: An Old Story Revisited or a New Story to Be Told? A Clinical Review.

Dyspepsia incorporates a set of symptoms originating from the gastroduodenal region, frequently encountered in the adult population in the Western world. Most patients with symptoms compatible with dyspepsia eventually end up, in the absence of a potential organic cause, being diagnosed with functional dyspepsia. Many have been the new insights in the pathophysiology behind functional dyspeptic symptoms, namely, hypersensitivity to acid, duodenal eosinophilia, and altered gastric emptying, among others. Since these discoveries, new therapies have been proposed. Even so, an established mechanism for functional dyspepsia is not yet a reality, which makes its treatment a clinical challenge. In this paper, we review some of the possible approaches to treatment, both well established and some new therapeutic targets. Recommendations about dose and time of use are also made.

A dispepsia engloba um conjunto de sintomas provenientes do trato gastroduodenal, frequentes na população adulta ocidental. A maioria dos doentes com sintomas compatíveis com dispepsia, acaba eventualmente, na ausência de causa orgânica, por ser diagnosticado com dispepsia funcional. Novos conhecimentos sobre a fisiopatologia responsável pelos sintomas de dispepsia têm sido adquiridos, nomeadamente a hipersensibilidade ao ácido, eosinofilia duodenal e as alterações do esvaziamento gástrico, entre outros. Estas novas descobertas vieram proporcionar novos possíveis alvos terapêuticos. Ainda assim, um mecanismo exato ainda não é conhecido, o que torna o tratamento da dispepsia funcional tantas vezes um desafio clínico. Neste trabalho, algumas abordagens das possíveis terapêuticas são revisitadas, tanto aquelas que já são uma prática usual, bem como novos alvos terapêuticos. Recomendações sobre dose e duração do tratamento são também elaboradas.

Original Article: MicroRNA Dysregulation in the Gastric Carcinogenesis Cascade: Can We Anticipate Its Role in Individualized Care?

BACKGROUND: Gastric carcinogenesis progresses from normal mucosa, atrophic/metaplastic gastritis, and dysplasia to adenocarcinoma. MicroRNAs (miRNAs) regulate DNA expression and have been implicated; however, their role is not fully established. AIMS: The aim of this study was to characterize plasma and tissue expression of several miRNAs in gastric carcinogenesis stages. METHODS: Single-center cross-sectional study in 64 patients: 19 controls (normal mucosa); 15 with extensive atrophic/metaplastic gastritis; and 30 with early gastric neoplasia (EGN). Seven miRNAs (miR-21, miR-146a, miR-181b, miR-370, miR-375, miR 181b, and miR-490) were quantified by real time-qPCR in peripheral blood and endoscopic biopsy samples. RESULTS: We found a significant upregulation of miR-181b, miR-490, and miR-21 in the EGN mucosa (overexpression 2-14-times higher than controls). We observed a significant underexpression of miR-146a and miR-370 in atrophic/metaplastic gastritis (86 and 66% decrease, p = 0.008 and p = 0.001) and in EGN (89 and 62% reduction, p = 0.034 and p = 0.032) compared with controls. There were no differences between lesions and nonneoplastic mucosa and no dysregulation of plasma miRNAs. CONCLUSION: We found significant dysregulation of 5 miRNAs in gastric carcinogenesis, suggesting a tumor suppressor role for miR-146a and miR-370 and oncogenic potential for miR-21, miR-181, and miR-490. These changes happen diffusely in the gastric mucosa, suggesting a high-risk field defect, which may influence these patients' surveillance.

Mechanistic perspectives on differential mitochondrial-based neuroprotective effects of several carnitine forms in Alzheimer's disease in vitro model.

Mitochondrial deregulation has emerged as one of the earliest pathological events in Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Improvement of mitochondrial function in AD has been considered a relevant therapeutic approach. L-carnitine (LC), an amino acid derivative involved in the transport of long-chain fatty acids into mitochondria, was previously demonstrated to improve mitochondrial function, having beneficial effects in neurological disorders; moreover, acetyl-L-carnitine (ALC) is currently under phase 4 clinical trial for AD (ClinicalTrials.gov NCT01320527). Thus, in the present study, we investigated the impact of different forms of carnitines, namely LC, ALC and propionyl-L-carnitine (PLC) on mitochondrial toxicity induced by amyloid-beta peptide 1-42 oligomers (AßO; 1 µM) in mature rat hippocampal neurons. Our results indicate that 5 mM LC, ALC and PLC totally rescued the mitochondrial membrane potential and alleviated both the decrease in oxygen consumption rates and the increase in mitochondrial fragmentation induced by AßO. These could contribute to the prevention of neuronal death by apoptosis. Moreover, only ALC ameliorated AßO-evoked changes in mitochondrial movement by reducing the number of stationary mitochondria and promoting reversal mitochondrial movement. Data suggest that carnitines (LC, ALC and PLC) may act differentially to counteract changes in mitochondrial function and movement in neurons subjected to AßO, thus counteracting AD-related pathological phenotypes.

Gastric microbiome profile throughout gastric carcinogenesis: beyond helicobacter.

BACKGROUND: Gastric dysbiosis has been hinted as a potential cause of gastric cancer. However, changes in microbiome throughout the major stages of gastric carcinogenesis remain mostly unknown. OBJECTIVE: To describe gastric microbiome at different stages, analysing for the first time dysbiosis specifically in patients with early gastric cancer (EGC). METHODS: Cross-sectional study including patients (n = 77) with endoscopically and histologically confirmed normal stomachs (controls; n = 25), advanced atrophic gastritis with intestinal metaplasia (IM; n = 18) and EGC (n = 34). Endoscopic biopsies from antrum and corpus (n = 154) were analyzed. Next-generation sequencing was performed characterizing microbial communities down to the species level based on full-length 16SrRNA gene profiling. RESULTS: Significant differences were found in the microbiome profile between the groups. Firmicutes were more frequent (p = .012) and Proteobacteria were less frequent (p = .04) both in the IM and EGC when comparing to controls. Relative frequency of Helicobacter pylori, when present, was much higher in the controls (83%) when comparing to the other groups (IM 1%, EGC 27%; p = .006), being the dominant bacteria only in the controls. Dysbiosis was present already and more significantly at the IM stage, with two bacteria progressively increasing from controls to IM then to cancer: Gemella from 1.48 to 3.9% (p = .014); and Streptococcus from 19.3 to 33.7% (p = .04), being the EGC dominant bacteria. CONCLUSIONS: Our results confirm Helicobacter pylori dominancy in non-atrophic stomachs and progressive dysbiosis throughout gastric carcinogenesis. Gemella but particularly Streptococcus is significantly increased in patients with EGC. Specific modulation of these bacteria may change gastric cancer risk.

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature.

3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, C57BL/6J mice were exposed to a binge MDPV or METH regimen (four intraperitoneal injections every 2 h, 10 mg/kg). Locomotor, exploratory, and emotional behavior, in addition to striatal neurotoxicity and glial signature, were assessed within 18-24 h, a known time-window encompassing classical amphetamine dopaminergic neurotoxicity. MDPV resulted in unchanged locomotor activity (open field test) and emotional behavior (elevated plus maze, splash test, tail suspension test). Additionally, striatal TH (METH neurotoxicity hallmark), Iba-1 (microglia), GFAP (astrocyte), RAGE, and TLR2/4/7 (immune modulators) protein densities remained unchanged after MDPV-exposure. Expectedly, and in sheer contrast with MDPV, METH resulted in decrease general locomotor activity paralleled by a significant striatal TH depletion, astrogliosis, and microglia arborization alterations (Sholl analysis). This comparative study newly highlights that binge MDPV-exposure comes without evident behavioral, neurochemical, and glial changes at a time-point where METH-induced striatal neurotoxicity is clearly evident. Nevertheless, neuropharmacological MDPV signature needs further profiling at different time-points, regimens, and brain regions.

Endoscopic ultrasound-guided sampling of gastrointestinal subepithelial lesions: just wet it.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the main method for acquisition of tissue from gastrointestinal subepithelial lesions (SELs). Despite the development of new needles, diagnostic yield remains low. A new method of aspiration has been described, where the needle is filled with saline [wet-suction technique (WST)], with promising results in pancreatic lesions. This method has not been tested in SELs. AIMS AND METHODS: Prospective single center study to assess the diagnostic yield of EUS-FNA+WST in the diagnosis of SELs, without the use of rapid on-site evaluation. In mesenchymal tumors, the diagnosis was considered positive only when immunohistochemistry could differentiate between gastrointestinal stromal tumor and leiomyoma. RESULTS: Eighty-seven patients with SELs were included (55% male, mean age 66 years). Mean SEL size was 25 mm (min 10 mm, max 120 mm), mean number of passes was 3 (±0.8). A 22G needle was used in 72 patients (83%), 19G in 10 (12%) and 25G in 5 (6%). We obtained a conclusive cytopathological diagnosis in 74 cases (diagnostic yield of 85%) and immunohistochemistry was performed in 70 cases (81%). The most frequent diagnoses were gastrointestinal stromal tumor (n = 34, 37%), leiomyoma (n = 13, 15%) and metastases (n = 10, 11%). CONCLUSION: Wet suction technique allowed an excellent diagnostic yield in the EUS-guided evaluation of SELs. We suggest that, after proper replication of these results, WST may become the first-line method in the management of these lesions.

Cancer-risk by family history and mismatch-repair mutation in Lynch syndrome.

Introduction: Surveillance of Lynch syndrome (LS) is recommended to reduce cancer-risk. There is an increased awareness that cancer-risk may vary with mismatch-repair mutation and family history. However, gene-specific and family-specific surveillance are not recommended. Therefore, we aimed to estimate the cumulative incidence of lesions and to assess the cancer-risk by family history and mismatch-repair mutation (MMR).Methods: Single-centre retrospective cohort of all individuals (n = 241) in a specialized institution was conducted.Results: Forty-eight percent of individuals inherited MSH2 mutations, 32% MLH1, 15% MSH6 and 5% PMS2. The calculated cumulative incidence for any cancer increased with age. By age 70, the cumulative incidence for low-risk, high-risk adenomas and CRC was estimated at 66.6%, 57.7% and 25.7%, respectively. By age 70, the cumulative incidence of endometrial cancer (EC), gastric cancer and urinary tract cancer was estimated at 17.3%, 3.3% and 12.6%, respectively. MLH1 and MSH2 mutation carriers had lower mean age of CRC diagnosis than MSH6 and PMS2 [MLH1:44(CI95% 38-50); MSH2:43(CI95% 40-47); MSH6:52(CI95% 45-59); PMS2:46(CI95% 35-57)]. The risk of EC was higher when family history was present (RR = 2.39, CI95%[1.3;4.6]). MSH6 mutation carriers had higher risk of EC comparative to other MMR mutation carriers (RR = 1.9, p = .09). The risk of urinary tract cancer was higher with MSH2 (RR = 8.4, CI95%[2.7;25.9]) and positive family history (RR = 10.8, CI95%[1.4;82.8]).Conclusion: This cohort demonstrates the effectiveness of LS surveillance and suggests possible tailored surveillance strategies by gene mutation and family history.

Random biopsies in patients harboring a CDH1 mutation: time to change the approach?

INTRODUCTION AND AIM: hereditary diffuse gastric cancer (HDGC) can be caused by a CDH1 mutation. It often presents as multiple foci of signet ring cell carcinoma (SRCC) that is rarely detected by gastroscopy. Prophylactic total gastrectomy is recommended at a young age. The aim of this study was to determine the adequacy of gastroscopy according to the Cambridge protocol in patients with a CDH1 mutation. METHODS: patients with a CDH1 mutation admitted to our department between September 2016 and October 2018 were evaluated. All patients underwent a baseline gastroscopy according to the Cambridge protocol, followed by a recommended total gastrectomy. Endoscopic findings, the number of biopsies and histological evaluation of biopsy samples were registered. Postoperative histopathological assessment was compared with endoscopic findings in patients that underwent a total gastrectomy (n = 13). RESULTS: twenty-five patients were included and 35 gastroscopies performed. On these, 996 gastric biopsies were performed, which included 952 random and 44 targeted. Only three patients had SRCC foci in random biopsies and one also had SRCC lesions in two targeted biopsies. In our cohort, 332 random and 22 targeted biopsies were needed to identify a single SRCC focus. Total gastrectomy was performed in 13 patients and SRCC foci were identified in 12 surgical specimens, the remaining specimen had a precursor lesion of HDGC. DISCUSSION: gastroscopy has a poor sensitivity to detect SRCC. Even with Cambridge protocol, gastroscopy has a very limited role in the surveillance of patients with a CDH1 mutation and prophylactic total gastrectomy is the most advisable option. Nevertheless, endoscopic protocols should be optimized to favor targeted biopsies over a high number of random biopsies

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Clinicopathologic Characteristics of Patients with Gastric Superficial Neoplasia and Risk Factors for Multiple Lesions after Endoscopic Submucosal Dissection in a Western Country.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a treatment for early gastric neoplasms that preserves the stomach. However, the risk of multiple lesions persists. OBJECTIVES: To assess clinicopathologic characteristics of patients with early gastric neoplasms in a Western country and evaluate risk factors for multiple gastric lesions, synchronous, or metachronous. METHODS: A retrospective cohort of 230 consecutive patients who underwent ESD for primary neoplasms from 2012 to 2017 (median follow-up: 33 months) was assessed to determine the clinicopathologic characteristics and risk factors for multiple lesions. RESULTS: The mean age was 68 years, and 53.9% were male. Current/former smoking status was present in 40.4%, and 29.5% had family history of gastric cancer. A third of the patients had only focal gastric atrophy/metaplasia (operative link on gastritis assessment/operative link on gastric intestinal metaplasia assessment [OLGA/OLGIM] I/II; endoscopic grading of gastric intestinal metaplasia [EGGIM] 1-4). Synchronous and me-tachronous lesions occurred in 14.3 and 8.6% of patients, respectively. There was a trend for higher risk of multiple lesions in smokers and patients with extensive metaplasia (EGGIM >4), but only older age was an independent risk factor (OR 3.30; 95% CI 1.05-10.34). Age >60 years (OR 10.10, 95% CI 1.40-88.04), current/former smoking status (OR 3.64, 95% CI 1.07-12.40), and OLGIM III/IV (OR 3.07, 95% CI 1.01-9.36) were independent risk factors for synchronous lesions. No risk factors for metachronous lesions were found. CONCLUSIONS: Surveillance limited to patients with advanced stages of gastritis may miss some primary superficial neoplasms. Although older age increases the risk of multiple lesions, no risk factors were found for metachronous lesions. Therefore, endoscopic surveillance after ESD should be done equally in all patients.

INTRODUÇÃO: A dissecção endoscópica da submucosa (DES) é uma opção terapêutica para neoplasias gástricas em estadios iniciais e que permite preservar o estômago. No entanto, o risco de desenvolver lesões múltiplas mantém-se. OBJETIVOS: Avaliar as características clinicopatológicas dos pacientes com neoplasias gástricas superficiais primárias num país ocidental e avaliar os fatores de risco (FR) para lesões gástricas múltiplas, síncronas ou metácronas. MÉTODOS: Foram estudados, retrospetivamente, 230 doentes submetidos a DES por lesões gástricas primárias entre 2012 e 2017 (tempo de seguimento mediano: 33 meses). As características clínicopatológicas eos FR para lesões múltiplas foram analisados. RESULTADOS: A idade média foi de 68 anos, 53,9% eram homens, 40,4% eram fumadores/ex-fumadores e 29,5% tinham história familiar de cancro gástrico. Um terço dos pacientes apresentava apenas atrofia/metaplasia focal (OLGA/OLGIM l/ll; EGGIM 1­4). Foram detetadas lesões síncronas em 14,3% e metácronas em 8,6% dos doentes. Para lesões gástricas múltiplas, tabagismo e metaplasia extensa (EGGIM<4) mostraram uma associação, mas apenas a idade avançada foi FR independente (Odds Ratio [OR] 3, 30; Intervalo de Confiança a 95% [IC 95%] 1, 05­10, 34). Idade superior a 60 anos (OR 10,10; IC95% 1,40­88,04), tabagismo (OR 3,64; IC95% 1,07­12,40) e OLGIM lll/IV (OR 3,07; IC95% 1,01­9,36) foram FR independentes para lesões síncronas. Não foram encontrados FR para lesões metácronas. CONCLUSÕES: Limitar a vigilância aos pacientes com gastrite em estadios avançados não permite identificar todas as lesões neoplásicas precoces. A idade avançada aumenta o risco de lesões múltiplas, contudo não foi encontrado nenhum FR para lesões metácronas. Assim, a vigilância endoscópica após DES deve ser idêntica em todos os pacientes.

Random biopsies in patients harboring a CDH1 mutation: time to change the approach?

INTRODUCTION AND AIM: hereditary diffuse gastric cancer (HDGC) can be caused by a CDH1 mutation. It often presents as multiple foci of signet ring cell carcinoma (SRCC) that is rarely detected by gastroscopy. Prophylactic total gastrectomy is recommended at a young age. The aim of this study was to determine the adequacy of gastroscopy according to the Cambridge protocol in patients with a CDH1 mutation. METHODS: patients with a CDH1 mutation admitted to our department between September 2016 and October 2018 were evaluated. All patients underwent a baseline gastroscopy according to the Cambridge protocol, followed by a recommended total gastrectomy. Endoscopic findings, the number of biopsies and histological evaluation of biopsy samples were registered. Postoperative histopathological assessment was compared with endoscopic findings in patients that underwent a total gastrectomy (n = 13). RESULTS: twenty-five patients were included and 35 gastroscopies performed. On these, 996 gastric biopsies were performed, which included 952 random and 44 targeted. Only three patients had SRCC foci in random biopsies and one also had SRCC lesions in two targeted biopsies. In our cohort, 332 random and 22 targeted biopsies were needed to identify a single SRCC focus. Total gastrectomy was performed in 13 patients and SRCC foci were identified in 12 surgical specimens, the remaining specimen had a precursor lesion of HDGC. DISCUSSION: gastroscopy has a poor sensitivity to detect SRCC. Even with Cambridge protocol, gastroscopy has a very limited role in the surveillance of patients with a CDH1 mutation and prophylactic total gastrectomy is the most advisable option. Nevertheless, endoscopic protocols should be optimized to favor targeted biopsies over a high number of random biopsies.

Endoscopic grading of gastric intestinal metaplasia on risk assessment for early gastric neoplasia: can we replace histology assessment also in the West?

OBJECTIVES: To assess the value of endoscopic grading of gastric intestinal metaplasia (EGGIM), operative link on gastritis assessment (OLGA) and operative link on gastric intestinal metaplasia (OLGIM) on risk stratification for early gastric neoplasia (EGN) and to investigate other factors possibly associated with its development. DESIGN: Single centre, case-control study including 187 patients with EGN treated endoscopically and 187 age-matched and sex-matched control subjects. Individuals were classified according to EGGIM, OLGA and OLGIM systems. EGN risk according to gastritis stages and other clinical parameters was further evaluated. RESULTS: More patients with EGN had EGGIM of ≥5 than control subjects (68.6% vs 13.3%, p<0.001). OLGA and OLGIM stages III/IV were more prevalent in patients with EGN than in control subjects (68% vs 11%, p<0.001, and 61% vs 3%, p<0.001, respectively). The three systems were the only parameters significantly related to the risk of EGN in multivariate analysis: for EGGIM 1-4 (adjusted OR (AOR) 12.9, 95% CI 1.4 to 118.6) and EGGIM 5-10 (AOR 21.2, 95% CI 5.0 to 90.2); for OLGA I/II (AOR 5.0, 95% CI 0.56 to 44.5) and OLGA III/IV (AOR 11.1, 95% CI 3.7 to 33.1); for OLGIM I/II (AOR 11.5, 95% CI 4.1 to 32.3) and OLGIM III/IV (AOR 16.0, 95% CI 7.6 to 33.4). CONCLUSION: This study confirms the role of histological assessment as an independent risk factor for gastric cancer (GC), but it is the first study to show that an endoscopic classification of gastric intestinal metaplasia is highly associated with that outcome. After further prospective validation, this classification may be appropriate for GC risk stratification and may simplify every day practice by reducing the need for biopsies.

Reliability and accuracy of blue light imaging for staging of intestinal metaplasia in the stomach.

Background and aims: An endoscopic grading system (EGGIM) using narrow-band-imaging (NBI) has shown to accurately identify patients with extensive gastric intestinal metaplasia (GIM). However, description with alternative systems such as blue-light-imaging (BLI) is limited. The aim of this study is to determine the reliability and accuracy of BLI-bright regarding diagnosis and staging of GIM.Methods: Reliability of WLE (white-light-endoscopy) and BLI among 6 observers was assessed using a standard classification based on endoscopic images. Afterward, 37 patients were submitted to gastroscopy using FujifilmEG-760Z and endoscopists had to determine EGGIM score using BLI-bright and to perform gastric biopsies for operative-link-of-gastric-intestinal-metaplasia (OLGIM) calculation. BLI-bright accuracy was determined by comparing results with prior EGGIM scores with NBI and current OLGIM.Results: Compared with WLE, the interobserver reliability between observers was substantially better with BLI (Weighted Kappa: 0.8 vs 0.41). There was an 84% agreement between BLI and NBI assessing EGGIM intervals (EGGIM 0-4vs5-10). The area under the ROC curve was 0.90 (95%CI: 0.79-1.0) using the cut-off of EGGIM > 4 to determine advanced GIM, with a sensitivity of 100% (95%CI: 88-100%).Discussion: BLI-bright is reliable for the diagnosis of gastric intestinal metaplasia and agrees significantly with NBI evaluation. Preliminary data suggests high sensitivity for identifying patients with increased risk of gastric cancer.

Acute Colonic Pseudo-Obstruction as a Manifestation of Lead Intoxication in a Conservator.

We report a case of a 39-year-old art conservator who presented complaining of abdominal pain and constipation. His laboratory results showed normocytic normochromic anemia and abnormal liver tests. Computed tomography revealed distention of the whole colon without obstruction. Evaluation of anemia was compatible with nonimmune hemolysis. A liver biopsy showed accumulation of ferric pigment in Kupffer cells. Given the typical findings in the blood smear and the epidemiological context, a serum lead assay was performed (92 µg/dL). This clinical case illustrates the need for gastroenterologists to recognize digestive manifestations of systemic diseases, including intoxications.