Extracellular Vesicles as Delivery Vehicles for Non-Coding RNAs: Potential Biomarkers for Chronic Liver Diseases.

In recent years, EVs have emerged as promising vehicles for coding and non-coding RNAs (ncRNAs), which have demonstrated remarkable potential as biomarkers for various diseases, including chronic liver diseases (CLDs). EVs are small, membrane-bound particles released by cells, carrying an arsenal of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and other ncRNA species, such as piRNAs, circRNAs, and tsRNAs. These ncRNAs act as key regulators of gene expression, splicing, and translation, providing a comprehensive molecular snapshot of the cells of origin. The non-invasive nature of EV sampling, typically via blood or serum collection, makes them highly attractive candidates for clinical biomarker applications. Moreover, EV-encapsulated ncRNAs offer unique advantages over traditional cell-free ncRNAs due to their enhanced stability within the EVs, hence allowing for their detection in circulation for extended periods and enabling more sensitive and reliable biomarker measurements. Numerous studies have investigated the potential of EV-enclosed ncRNAs as biomarkers for CLD. MiRNAs, in particular, have gained significant attention due to their ability to rapidly respond to changes in cellular stress and inflammation, hallmarks of CLD pathogenesis. Elevated levels of specific miRNAs have been consistently associated with various CLD subtypes, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and chronic hepatitis B and C. LncRNAs have also emerged as promising biomarkers for CLD. These transcripts are involved in a wide range of cellular processes, including liver regeneration, fibrosis, and cancer progression. Studies have shown that lncRNA expression profiles can distinguish between different CLD subtypes, providing valuable insights into disease progression and therapeutic response. Promising EV-enclosed ncRNA biomarkers for CLD included miR-122 (elevated levels of miR-122 are associated with MASLD progression and liver fibrosis), miR-21 (increased expression of miR-21 is linked to liver inflammation and fibrosis in CLD patients), miR-192 (elevated levels of miR-192 are associated with more advanced stages of CLD, including cirrhosis and HCC), LncRNA HOTAIR (increased HOTAIR expression is associated with MASLD progression and MASH development), and LncRNA H19 (dysregulation of H19 expression is linked to liver fibrosis and HCC progression). In the present review, we focus on the EV-enclosed ncRNAs as promising tools for the diagnosis and monitoring of CLD of various etiologies.

Ultrasound-Guided Needle Biopsy as an Alternative to Chamberlain's Mediastinotomy and Video-Assisted Thoracoscopic Surgery (VATS) in the Diagnosis of Anterior Mediastinal Neoformations: A Retrospective Analysis.

(1) Background: The prompt diagnosis of anterior mediastinal lesions is a challenge due to their often being categorized as malignant tumours. Ultrasound-guided Transthoracic Core Needle Biopsy (US-TCNB) is an innovative technique that is arousing increasing interest in clinical practice. However, studies in this area are still scarce. This study aims to compare the diagnostic accuracy and complication rate of US-TCNB with those of traditional surgical methods-Anterior Mediastinotomy and Video Assisted Thoracoscopic Surgery (VATS)-in patients with anterior mediastinal lesions. (2) Methods: This retrospective study involved patients evaluated between January 2011 and December 2021 who had undergone US-TCNB at the Interdepartmental Unit of Internal and Interventional Ultrasound, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy. Personal data, diagnostic questions, and technical information concerning the bioptic procedure, periprocedural complications and histological reports were collected. (3) Results: Eighty-three patients were included in the analysis. Histological examination was performed in 78 cases, with an overall diagnostic accuracy of 94.0% (sensitivity 94%; specificity 100%). Only in 5 patients was a diagnosis not achieved. Complications occurred in 2 patients who were quickly identified and properly treated without need of hospitalization. The accuracy of US-TCNB was comparable to the performance of the main traditional diagnostic alternatives (95.3% for anterior mediastinotomy, and 98.4% for VATS), with a much lower complication rate (2.4% vs. 3-16%). The outpatient setting offered the additional advantage of saving resources. (4) Conclusions: a US-guided needle biopsy can be considered effective and safe, and in the near future it may become the procedure of choice for diagnosing anterior mediastinal lesions in selected patients.

Autoimmune Hepatitis and Fibrosis.

Autoimmune hepatitis (AIH) is a chronic immune-inflammatory disease of the liver, generally considered a rare condition. The clinical manifestation is extremely varied and can range from paucisymptomatic forms to severe hepatitis. Chronic liver damage causes activation of hepatic and inflammatory cells leading to inflammation and oxidative stress through the production of mediators. This results in increased collagen production and extracellular matrix deposition leading to fibrosis and even cirrhosis. The gold standard for the diagnosis of fibrosis is liver biopsy; however, there are serum biomarkers, scoring systems, and radiological methods useful for diagnosis and staging. The goal of AIH treatment is to suppress fibrotic and inflammatory activities in the liver to prevent disease progression and achieve complete remission. Therapy involves the use of classic steroidal anti-inflammatory drugs and immunosuppressants, but in recent years scientific research has focused on several new alternative drugs for AIH that will be discussed in the review.

Gut microbiota, behavior, and nutrition after type 1 diabetes diagnosis: A longitudinal study for supporting data in the metabolic control.

Introduction: Type 1 diabetes (T1D) risk involves genetic susceptibility but also epigenetics, environment, and behaviors. Appropriate metabolic control, especially quickly after the diagnosis, is crucial for the patient quality of life. Methods: This study aimed to produce a quantitative comparison of the behavior, nutrition habits, and gut microbiota composition between the onset and the 1-year follow-up in 35 children with T1D. Results and discussion: At follow-up, with the metabolic control, many parameters improved significantly, with respect to the onset, such as glycated hemoglobin (-19%), body mass index (BMI), and also nutritional behaviors, such as normal calorie intake (+6%), carbohydrate intake (-12%), extra portion request (-4%), and meals distribution during the day. Moreover, glycated hemoglobin decrement correlated with both total and rapid absorption carbohydrate intake (Spearman's rho = 0.288, 95% CI 0.066-0.510, p = 0.013), showing as the nutritional behavior supported the insulin therapy efficiency. The next-generation sequencing (NGS) analysis of microbiota revealed abundance differences for Ruminococcus bromii and Prevotella copri (higher at onset, p < 0.001) and the genera Succinivibrio and Faecalibacterium (lower at onset, p < 0.001), as a consequence of nutritional behavior, but it was not the only changing driver. The qRT-PCR analysis showed significant variations, in particular for Bacteroidetes and Bifidobacterium spp. (+1.56 log gene copies/g stool at follow-up, p < 0.001). During the year, in 11% of the patients, severe clinical episodes occurred (hypoglycemic or ketoacidosis). The likelihood of a severe hypoglycemic episode was modulated when the Methanobrevibacter smithii amount increased (odds ratio 3.7, 95% CI 1.2-11.4, p = 0.026). Integrated evaluation, including nutritional behavior and microbiota composition, could be considered predictive of the metabolic control management for children cohort with a recent diagnosis of T1D.

Association of serum MicroRNA-145-5p levels with microvascular complications of type 1 Diabetes: The EURODIAB prospective complications study.

AIMS: To investigate whether serum miR-145-5p levels were associated with micro-macrovascular chronic complications in patients with type 1 diabetes (DM1). METHODS: A nested case-control study from the EURODIAB Prospective Complications Study was performed. Cases (n = 289) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. We measured miR-145-5p levels by qPCR and investigated the association with diabetes complications. RESULTS: Mean miR-145-5p levels were significantly lower in cases with microangiopathy [2.12 (0.86-4.94)] compared to controls [3.15 (1.21-7.36), P < 0.05] even after adjustment for age, gender, and diabetes duration. In logistic regression analysis, miR-145-5p levels in the lowest tertile were associated with an over three-fold increased odds ratio (OR) of albuminuria [3.22 (1.17-8.81)], independently of both demographic and diabetes-related factors. In addition, mir145-5p levels in the lowest tertile were independently and inversely associated with arterial hypertension [1.96 (1.08-3.56)] and hypertension was the mediator of the relationship between miR-145-5p and albuminuria. CONCLUSIONS: In this large cohort of DM1 patients, we found an inverse association between miR-145-5p and albuminuria that was mediated by systemic hypertension.

Trends in the Comprehension and Management of Gastrointestinal Tract Disorders.

During the last decade, relevant advances have been made in the knowledge of the pathogenetic mechanisms of gastrointestinal (GI) tract disorders [...].

Novel Insight into the Mechanisms of the Bidirectional Relationship between Diabetes and Periodontitis.

Periodontitis and diabetes are two major global health problems despite their prevalence being significantly underreported and underestimated. Both epidemiological and intervention studies show a bidirectional relationship between periodontitis and diabetes. The hypothesis of a potential causal link between the two diseases is corroborated by recent studies in experimental animals that identified mechanisms whereby periodontitis and diabetes can adversely affect each other. Herein, we will review clinical data on the existence of a two-way relationship between periodontitis and diabetes and discuss possible mechanistic interactions in both directions, focusing in particular on new data highlighting the importance of the host response. Moreover, we will address the hypothesis that trained immunity may represent the unifying mechanism explaining the intertwined association between diabetes and periodontitis. Achieving a better mechanistic insight on clustering of infectious, inflammatory, and metabolic diseases may provide new therapeutic options to reduce the risk of diabetes and diabetes-associated comorbidities.

Extra-Intestinal Manifestations of Celiac Disease: What Should We Know in 2022?

Celiac disease (CD) is a chronic, small-intestinal, immune-mediated enteropathy due to gluten exposition in genetically predisposed individuals. It occurs in about 1% of the population and often remains an underdiagnosed condition. This could be due to the fact that the adult population often lacks the classical signs and symptoms of CD, manifesting only atypical symptoms. In this review we analyzed the main extra-intestinal manifestations of CD which include cutaneous and endocrinological disorders, abnormal liver function tests, and neuropsychiatric features. When CD is not diagnosed and therefore is not treated with a gluten-free diet (GFD), it can predispose to severe complications, not only gastrointestinal. Thus, it is important for clinicians to quickly recognize the atypical manifestations of CD, considering that an early diagnosis can significantly impact on a patient's prognosis.

MicroRNA 146a is associated with diabetic complications in type 1 diabetic patients from the EURODIAB PCS.

BACKGROUND: MicroRNA-146a-5p (miR-146a-5p) is a key regulator of inflammatory processes. Expression of miR-146a-5p is altered in target organs of diabetic complications and deficiency of miR-146a-5p has been implicated in their pathogenesis. We investigated if serum miR-146a-5p levels were independently associated with micro/macrovascular complications of type 1 diabetes (DM1). METHODS: A nested case-control study from the EURODIAB PCS of 447 DM1 patients was performed. Cases (n = 294) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. Total RNA was isolated from all subjects and miR-146a-5p levels measured by qPCR. Both the endogenous controls U6 snRNA and the spike (Cel-miR-39) were used to normalize the results. Logistic regression analysis was carried out to investigate the association of miR-146a-5p with diabetes complications. RESULTS: MiR-146a-5p levels were significantly lower in cases [1.15 (0.32-3.34)] compared to controls [1.74 (0.44-6.74) P = 0.039]. Logistic regression analysis showed that levels of miR-146a-5p in the upper quartile were inversely associated with reduced odds ratio (OR) of all complications (OR 0.34 [95% CI 0.14-0.76]) and particularly with cardiovascular diseases (CVD) (OR 0.31 [95% CI 0.11-0.84]) and diabetic retinopathy (OR 0.40 [95% CI 0.16-0.99]), independently of age, sex, diabetes duration, A1c, hypertension, AER, eGFR, NT-proBNP, and TNF-α. CONCLUSIONS: In this large cohort of DM1 patients, we reported an inverse and independent association of miR-146a-5p with diabetes chronic complications and in particular with CVD and retinopathy, suggesting that miR-146a-5p may be a novel candidate biomarker of DM1 complications.

Helicobacter pylori and Respiratory Diseases: 2021 Update.

Helicobacter pylori (H. pylori) is a Gram-negative bacterium involved in the development of gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue. Unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency have also been related to H. pylori infection, whereas for other extra-gastric diseases, the debate is still open. In this review, we evaluate and discuss the potential involvement of H. pylori infection in the pathogenesis of several respiratory diseases. A MEDLINE search of all studies published in English from 1965 to 2021 was carried out. Controversial findings have been reported in patients with bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, tuberculosis, cystic fibrosis, and sarcoidosis. Most of the available literature is concerned with case-control studies based on seroprevalence, with a small sample size and low consideration of confounders, which represents a potential issue. So far, there is no clear evidence of a causal association between H. pylori infection and respiratory diseases, and larger studies with appropriate epidemiological design are required.

Hepatitis delta virus: From infection to new therapeutic strategies.

The hepatitis delta virus (HDV) is a small RNA virus that encodes a single protein and which requires the hepatitis B virus (HBV)-encoded hepatitis B surface antigen (HBsAg) for its assembly and transmission. HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations, specifically intravenous drug users, practitioners of high-risk sexual behaviours, and patients with cirrhosis and hepatocellular carcinoma. The chronic form of HDV-related hepatitis is usually severe and rapidly progressive. Patterns of the viral infection itself, including the status of co-infection or super-infection, virus genotypes (both for HBV and HDV), and persistence of the virus' replication, influence the outcome of the accompanying and manifested liver disease. Unfortunately, disease severity is burdened by the lack of an effective cure for either virus type. For decades, the main treatment option has been interferon, administered as mono-therapy or in combination with nucleos(t)ide analogues. While its efficacy has been reported for different doses, durations and courses, only a minority of patients achieve a sustained response, which is the foundation of eventual improvement in related liver fibrosis. The need for an efficient therapeutic alternative remains. Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle; the most promising among these are myrcludex B, which inhibits virus entry into hepatocytes, lonafarnib, which inhibits farnesylation of the viral-encoded L-HDAg large hepatitis D antigen, and REP-2139, which interferes with HBsAg release and assembly.

Helicobacter pylori eradication with a clarithromycin-based triple therapy in elderly patients.

BACKGROUND: Helicobacter pylori (H. pylori), main agents of several gastroduodenal diseases, represents a therapeutic challenge. Since the influence of age on the success of bacterial treatment remains uncertain, in this case-control study we assessed the efficacy of a standard H. pylori eradication therapy among elderly patients. METHODS: In this retrospective study, a total of 361 naïve patients (194 males, mean age 79.8±3.4 years) aged more than 65 years and treated with a triple therapy regimen comprising a standard dose of omeprazole twice daily, amoxicillin 1g twice daily and clarithromycin 500 mg twice daily, for 7, 10 or 14 days, were included. They were compared with naïve patients, younger than 65 years (mean age 43±2.7 years). Since in the year 2017, we began to use the three-in-one single capsule bismuth-containing quadruple therapy, the search was ended on 31 December 2016. RESULTS: Overall, H. pylori eradication rate in the intention-to-treat (ITT) analysis, was 70.9% (256/361) among elderly patients versus 70.9% (256/361) among young patients. Dividing by treatment duration, among elderly patients, eradication was obtained in 78.1% (50/64), 69.1% (139/201) and 69.7% (67/96) elderly patients within 7-day, 10-day and 14-day regimens, respectively, without statistical difference. Out of 361 elderly patients, 11 were excluded from the per protocol (PP) analysis because of discontinuations (7 for adverse events). One subject discontinued treatment among young patients. Also, the PP analysis showed no statistical difference, with an eradication rate of 73.1% (256/350) among elderly patients versus 71.1% (256/360) among young patients. CONCLUSIONS: In conclusion, elderly does not affect efficacy or safety of a clarithromycin-based triple therapy for H. pylori eradication.

Treatment with eltrombopag of severe immune thrombocytopenia and hemolytic anemia associated with COVID-19 pneumonia: a case report.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Whether SARS-CoV-2 can trigger an autoimmune reaction against platelets and red blood cells remains unclear. Herein, we report a case of COVID-19 pneumonia associated with severe immune thrombocytopenia and hemolytic anemia. An 83-year-old woman was admitted to the hospital because of both dyspnea and diffuse mucocutaneous bleeding. Exams revealed hemolytic anemia (HA), severe immune thrombocytopenia (ITP), and bilateral pneumonia. Molecular testing confirmed a diagnosis of COVID-19 pneumonia. Thrombocytopenia did not respond to first-line treatment with immunoglobulin, corticosteroids, and platelet transfusions. Addition to therapy of the thrombopoietin receptor agonist, eltrombopag, resulted in full recovery. COVID-19 can be associated with ITP and HA. There are neither guidelines nor clinical experience on the treatment of COVID-19-associated ITP and our case, showing complete response to eltrombopag, may help clinicians in their practice during the COVID-19 pandemic. PLAIN LANGUAGE SUMMARY: The case of an 83-year-old woman with COVID-19 pneumonia associated with two severe blood diseases that cause platelet and red cell destruction Coronavirus disease 2019 (COVID-19) is caused by a virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We do not know exactly whether this virus can stimulate our immune system to react against platelets and red blood cells. Herein, we report a case of COVID-19 pneumonia associated with two severe blood diseases, immune thrombocytopenia, which causes platelet destruction, and hemolytic anemia, which causes red cell destruction. An 83-year-old woman was admitted to the hospital because of both difficulty in breathing and diffuse bleeding in mucosae and skin. Exams revealed hemolytic anemia, severe immune thrombocytopenia, and pneumonia in both lungs. Molecular testing confirmed a diagnosis of COVID-19 pneumonia. The first treatment with immunoglobulin, corticosteroids, and platelet transfusions was not enough to cure thrombocytopenia; the addition of eltrombopag which acts on the thrombopoietin receptor agonist resulted in full recovery. COVID-19 can be present together with immune thrombocytopenia and hemolytic anemia. As there are no guidelines on the treatment of immune thrombocytopenia in patients with COVID-19 and the clinical experience is limited, the complete response achieved with eltrombopag may help clinicians in their practice during the COVID-19 pandemic.