Advancing Diabetes Research: A Novel Islet Isolation Method from Living Donors.

Pancreatic islet isolation is critical for type 2 diabetes research. Although -omics approaches have shed light on islet molecular profiles, inconsistencies persist; on the other hand, functional studies are essential, but they require reliable and standardized isolation methods. Here, we propose a simplified protocol applied to very small-sized samples collected from partially pancreatectomized living donors. Islet isolation was performed by digesting tissue specimens collected during surgery within a collagenase P solution, followed by a Lympholyte density gradient separation; finally, functional assays and staining with dithizone were carried out. Isolated pancreatic islets exhibited functional responses to glucose and arginine stimulation mirroring donors' metabolic profiles, with insulin secretion significantly decreasing in diabetic islets compared to non-diabetic islets; conversely, proinsulin secretion showed an increasing trend from non-diabetic to diabetic islets. This novel islet isolation method from living patients undergoing partial pancreatectomy offers a valuable opportunity for targeted study of islet physiology, with the primary advantage of being time-effective and successfully preserving islet viability and functionality. It enables the generation of islet preparations that closely reflect donors' clinical profiles, simplifying the isolation process and eliminating the need for a Ricordi chamber. Thus, this method holds promises for advancing our understanding of diabetes and for new personalized pharmacological approaches.

Diagnostic and Prognostic Role of Extracellular Vesicles in Pancreatic Cancer: Current Evidence and Future Perspectives.

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer.

Autoimmune Pancreatitis: From Pathogenesis to Treatment.

Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The standard therapy for AIP is oral administration of corticosteroids. Rituximab (RTX) has also been proposed for induction of remission and maintenance therapy in relapsing AIP-1. In selected patients, immunomodulators such as azathioprine are used to maintain remission. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis. In addition, the review also considers various therapeutic options, including biologic drugs, such as anti-tumor necrosis factor (TNF) therapy, a well-tolerated and effective second-line therapy for AIP type 2 relapses or steroid dependence. Other biologic therapies are also being explored that could provide a useful therapeutic alternative to corticosteroids and immunosuppressants, which are poorly tolerated due to significant side effects.

Neuropancreatology: The Nervous System and Pain Management in Pancreatic Diseases.

The intricate network of the pancreatic nervous system plays a fundamental role in physiologic functions of the endocrine and exocrine pancreas. Several pancreatic diseases affect the normal functionality of the pancreatic nervous system. This chronic derangement leads to anatomical alterations, such as neural hypertrophy and increased nerve density. Perineural invasion is a prominent feature of pancreatic cancer, contributing to cancer progression and metastasis. Despite the fact that these pathogenic mechanisms are still incompletely studied and understood, the constant occurrence of these alterations highlights their importance in the pathophysiology of the pancreatic diseases. The occurrence of anatomical changes is strictly linked to the appearance of pain. Pancreatic pain has peculiar features, and its management is complex in clinical practice. In the present review, the evidence on lifestyle, pharmacological and interventional approaches for the management of pancreatic pain is presented. Analgesic therapy is the cornerstone of pain treatment. However, it is important to identify the individual characteristic of the patients and personalize the approach to pain management. Nevertheless, the incomplete efficacy of these strategies makes this field an area of unmet needs. The study of neuroplasticity is crucial to understand the mechanisms that regulate the pathophysiology of pancreatic diseases. Several trials testing new drugs with specific neuromodulatory effects are ongoing. However, further studies are needed to investigate crucial targets to develop novel therapies for the modulation of the nervous system and the prevention of complications of pancreatic diseases. This comprehensive review summarizes the importance of the nervous system in pancreatic diseases with a special focus on its anatomy and physiology, its pathophysiological features and clinical relevance in pancreatic disease, the treatment of pancreatic pain, and the identification of future trends of research.

Beta-cell function and glucose metabolism in patients with chronic pancreatitis.

AIMS: Chronic pancreatitis (CP) is - along with acute pancreatitis - the most frequent cause of diabetes of the exocrine pancreas (DEP). Although insulin deficiency is widely accepted as the major feature of DEP, it is still unclear whether diabetes associated with CP is characterized by additional or different functional defects of the insulin secretory machinery. To identify possible functional defects specifically induced by CP, we performed a cross-sectional study in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM) comparing patients with and without CP (CP vs. NCP). METHODS: We administered an oral glucose tolerance test (OGTT) to all participants and, according to their glucose tolerance, classified them as NGT, IGT and DM. Insulin sensitivity and beta-cell functional parameters were derived from OGTT, hyperglycemic clamp and hyperinsulinemic euglycemic clamp. RESULTS: Studying 146 subjects, we found that beta-cell function and insulin secretion were significantly lower in CP compared to NCP patients. However, when we classified the subjects according to OGTT-derived glucose tolerance, we found no differences in beta-cell function or in insulin sensitivity between CP and NCP with the same glucose tolerance status. Of note, we found that arginine-stimulated insulin secretion is reduced only in subjects with CP and DM compared to NCP subjects with DM. CONCLUSIONS: Patients with CP had no specific alterations in insulin secretion and beta-cell function. However, in patients diagnosed with diabetes, we found a lower arginine-stimulated insulin secretion, a marker of reduced functional mass.

Antibiotic Utilization in Acute Pancreatitis: A Narrative Review.

Acute pancreatitis is a complex inflammatory disease with significant morbidity and mortality. Despite advances in its management, the role of antibiotics in the prophylaxis and treatment of acute pancreatitis remains controversial. The aim of this comprehensive review is to analyze current evidence on the use of antibiotics in acute pancreatitis, focusing on prophylactic and therapeutic strategies. Prophylactic use aims to prevent local and systemic infections. However, recent studies have questioned the routine use of antibiotics for prophylaxis and highlighted the potential risks of antibiotic resistance and adverse effects. In selected high-risk cases, such as infected necrotizing pancreatitis, prophylactic antibiotic therapy may still be beneficial. As for therapeutic use, antibiotics are usually used to treat infected pancreatic necrosis and extrapancreatic infections. When selecting an antibiotic, the microbiologic profile and local resistance patterns should be considered. Combination therapy with broad-spectrum antibiotics is often recommended to cover both Gram-positive and Gram-negative pathogens. Recent research has highlighted the importance of individualized approaches to antibiotic use in acute pancreatitis and underscored the need for a tailored approach based on patient-specific factors. This review also highlights the potential role of new antimicrobial agents and alternative strategies, such as probiotics, in the management of acute pancreatitis.

Pancreatic Cancer Resistance to Treatment: The Role of Microbiota.

Pancreatic cancer (PC) is an aggressive malignancy and the fourth leading cause of cancer death in the United States and Europe. It is estimated that PC will be the second leading cause of cancer death by 2030. In addition to late diagnosis, treatment resistance is a major cause of shortened survival in pancreatic cancer. In this context, there is growing evidence that microbes play a regulatory role, particularly in therapy resistance and in creating a microenvironment in the tumor, that favors cancer progression. The presence of certain bacteria belonging to the gamma-proteobacteria or mycoplasmas appears to be associated with both pharmacokinetic and pharmacodynamic changes. Recent evidence suggests that the microbiota may also play a role in resistance mechanisms to immunotherapy and radiotherapy. However, the interactions between microbiota and therapy are bilateral and modulate therapy tolerance. Future perspectives are increasingly focused on elucidating the role of the microbiota in tumorigenesis and processes of therapy resistance, and a better understanding of these mechanisms may provide important opportunities to improve survival in these patients.

State-of-the-Art and Upcoming Innovations in Pancreatic Cancer Care: A Step Forward to Precision Medicine.

Pancreatic cancer remains a social and medical burden despite the tremendous advances that medicine has made in the last two decades. The incidence of pancreatic cancer is increasing, and it continues to be associated with high mortality and morbidity rates. The difficulty of early diagnosis (the lack of specific symptoms and biomarkers at early stages), the aggressiveness of the disease, and its resistance to systemic therapies are the main factors for the poor prognosis of pancreatic cancer. The only curative treatment for pancreatic cancer is surgery, but the vast majority of patients with pancreatic cancer have advanced disease at the time of diagnosis. Pancreatic surgery is among the most challenging surgical procedures, but recent improvements in surgical techniques, careful patient selection, and the availability of minimally invasive techniques (e.g., robotic surgery) have dramatically reduced the morbidity and mortality associated with pancreatic surgery. Patients who are not candidates for surgery may benefit from locoregional and systemic therapy. In some cases (e.g., patients for whom marginal resection is feasible), systemic therapy may be considered a bridge to surgery to allow downstaging of the cancer; in other cases (e.g., metastatic disease), systemic therapy is considered the standard approach with the goal of prolonging patient survival. The complexity of patients with pancreatic cancer requires a personalized and multidisciplinary approach to choose the best treatment for each clinical situation. The aim of this article is to provide a literature review of the available treatments for the different stages of pancreatic cancer.

Nutrition in Acute Pancreatitis: From the Old Paradigm to the New Evidence.

The nutritional management of acute pancreatitis (AP) patients has widely changed over time. The "pancreatic rest" was the cornerstone of the old paradigm, and nutritional support was not even included in AP management. Traditional management of AP was based on intestinal rest, with or without complete parenteral feeding. Recently, evidence-based data underlined the superiority of early oral or enteral feeding with significantly decreased multiple-organ failure, systemic infections, surgery need, and mortality rate. Despite the current recommendations, experts still debate the best route for enteral nutritional support and the best enteral formula. The aim of this work is to collect and analyze evidence over the nutritional aspects of AP management to investigate its impact. Moreover, the role of immunonutrition and probiotics in modulating inflammatory response and gut dysbiosis during AP was extensively studied. However, we have no significant data for their use in clinical practice. This is the first work to move beyond the mere opposition between the old and the new paradigm, including an analysis of several topics still under debate in order to provide a comprehensive overview of nutritional management of AP.

Drug-Induced Acute Pancreatitis in Adults: Focus on Antimicrobial and Antiviral Drugs, a Narrative Review.

Acute pancreatitis (AP) is an acute inflammation of the pancreas caused by the activation of digestive enzymes in the pancreatic tissue. The main causes of AP are cholelithiasis and alcohol abuse; less commonly, it can be caused by drugs, with a prevalence of up to 5%. Causal associations between drugs and pancreatitis are largely based on case reports or case series with limited evidence. We reviewed the available data on drug-induced AP, focusing on antimicrobial drugs and antivirals, and discussed the current evidence in relation to the classification systems available in the literature. We found 51 suspected associations between antimicrobial and antiviral drugs and AP. The drugs with the most evidence of correlation are didanosine, protease inhibitors, and metronidazole. In addition, other drugs have been described in case reports demonstrating positive rechallenge. However, there are major differences between the various classifications available, where the same drug being assigned to different probability classes. It is likely that the presence in multiple case reports of an association between acute pancreatitis and a drug should serve as a basis for conducting prospective randomized controlled trials to improve the quality of the evidence.

Physical Activity and Type 2 Diabetes: In Search of a Personalized Approach to Improving ß-Cell Function.

Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases worldwide. Lifestyle interventions, including diet and physical activity (PA), are fundamental non-pharmacological components of T2DM therapy. Exercise interventions are strongly recommended for people with or at risk of developing or already with overt diabetes, but adherence to PA guidelines in this population is still challenging. Furthermore, the heterogeneity of T2DM patients, driven by differing residual ß-cell functionality, as well as the possibility of practicing different types and intensities of PA, has led to the need to develop tailored exercise and training plans. Investigations on blood glucose variation in response to exercise could help to clarify why individuals do not respond in the same way to PA, and to guide the prescription of personalized treatments. The aim of this review is to offer an updated overview of the current evidence on the effects of different regimens and modalities of PA regarding glucose sensing and ß-cell secretory dynamics in individuals with prediabetes or T2DM, with a special focus on ß-cell function.

Clinical Implications of Helicobacter pylori Antibiotic Resistance in Italy: A Review of the Literature.

Helicobacter pylori (H. pylori) resistance to antibiotics has increased worldwide in recent decades, especially to clarithromycin. As a result, the World Health Organization (WHO) identified clarithromycin-resistant H. pylori as a "high priority" pathogen in 2017. As international guidelines recommend empirical therapy as first-line treatment, it is crucial to know local resistance rates and history of antibiotic use to determine the most appropriate first-line antibiotic treatment. Italy is one of the European countries with the highest prevalence of H. pylori infection and the highest percentage of antibiotic-resistant H. pylori. The aim of this review is to summarize all data on H. pylori antibiotic resistance in Italy in order to quantify the current rate and determine the most effective therapeutic approach. The study confirms an elevated level of resistance to clarithromycin, metronidazole, and levofloxacin in Italy. In addition, our results show a satisfactory eradication rate for a bismuth-based regimen when used as first- or second-line treatment. Naive patients are also successfully treated with clarithromycin-based quadruple therapies. Considering the good results of bismuth-based therapy as recovery therapy, this argues for the potential use of clarithromycin quadruple therapy as a first-line treatment.

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features.

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

Effect of influenza vaccine on COVID-19 mortality: a retrospective study.

It has been proposed that vaccines may exert an unspecific protective effect against infectious agents, different than expected. Coronavirus disease 2019 (COVID-19) is a pandemic infection with high mortality in older patients due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The high number of vaccinations may be one of the reasons why children show a lower susceptibility to SARS-CoV-2 infection and milder severity when compared to adults. We have designed a study aimed at investigating whether the influenza vaccine may reduce the susceptibility and severity of SARS-CoV-2 infection. We retrospectively enrolled 635 patients who accessed our Emergency Department from March 1st to June 30th, 2020, and were diagnosed with COVID-19 infection confirmed by an RT-PCR on an oropharyngeal swab. Clinical data, outcomes, and influenza vaccination status were collected from the electronic medical records of our Hospital. We also used data from the Italian Health Ministry to compare the prevalence of flu vaccination among the general population of the Lazio Region and our enrolled patients. We then compared clinical outcomes between vaccinated and non-vaccinated patients, by univariate and multivariate analysis. COVID-19-positive patients older than 65 years reported a lower prevalence of flu vaccination when compared to the general population residing in the Lazio (p = 0.004). After correction for gender, age, and comorbidities, we found a lower risk of death at 60 days in patients with flu vaccination than in not vaccinated patients (p = 0.001). Our study shows that flu vaccination could reduce the mortality of COVID-19. Prospective studies are needed to confirm this result.

Clinical Management of Infectious Diarrhea.

BACKGROUND: Infectious diarrhea is the most common cause of diarrhea worldwide and is responsible for more deaths than other gastrointestinal tract diseases such as gastrointestinal cancers, peptic ulcer disease or inflammatory bowel disease. Diarrheal disease still represents the 8th leading cause of death worldwide, with more than 1,6 million attributed fatalities in 2016 alone. The majority of cases can be divided into three principal clinical presentations: acute watery diarrhea lasting 5-10 days and normally self-limiting, bloody diarrhea (dysentery), and persistent diarrhea with or without intestinal malabsorption. METHODS: We performed an electronic search on PUBMED of the scientific literature concerning infectious diarrhea and its clinical management. AIM: In this review article, we analyze the most important causes of infectious diarrhea and their constellation of signs and symptoms, providing an update on the diagnostic tools available in today's practice and on the different treatment options. CONCLUSION: Even though the majority of intestinal infections are self-limiting in immunocompetent individuals, specific diagnosis and identification of the causative agent remain crucial from public health and epidemiological perspectives. Specific diagnostic investigation can be reserved for patients with severe dehydration, more severe illness, persistent fever, bloody stools, immunosuppression, and for cases of suspected nosocomial infection or outbreak and it includes complete blood count, creatinine and electrolytes evaluation, determination of leukocytes and lactoferrin presence in the stools, stool culture, together with C. difficile testing, PCR, ova and parasites' search, endoscopy and abdominal imaging. Since acute diarrhea is most often self-limited and caused by viruses, routine antibiotic use is not recommended for most adults with mild, watery diarrhea. However, when used appropriately, antibiotics are effective against shigellosis, campylobacteriosis, C. difficile colitis, traveler's diarrhea, and protozoal infections. Furthermore, antibiotics use should be considered in patients who are older than 65 years, immunocompromised, severely ill, or septic.

Regression of lactose malabsorption in coeliac patients after receiving a gluten-free diet.

OBJECTIVE: In a recent study by our group, it was shown that a large proportion of patients with lactose malabsorption and with no bacterial overgrowth are affected by silent coeliac disease (CD). Our aim was to evaluate the effect of a gluten-free diet on lactose malabsorption assessed using the hydrogen lactose breath test (LBT) and also the relationship with normalization of duodenal biopsies in coeliac patients. MATERIAL AND METHODS: Fifteen patients (11 F, 4 M; mean age 35.8+/-6) affected by CD with a positive LBT and negative glucose breath test were enrolled. All were started on a gluten-free diet and were re-evaluated after 6 months by LBT and after 12 months by both LBT and upper gastrointestinal endoscopy with biopsies. RESULTS: LBT normalization was observed in 1 out of 15 patients (6.7%) after 6 months and in 9 of the remaining 14 (64.2%) after 12 months. Duodenal biopsies showed normal villi in 8 patients, partial villous atrophy in 5 and total atrophy in 2. CONCLUSIONS: The present study shows that a large proportion of CD patients experience a regression of lactose malabsorption after receiving a gluten-free diet. This may be related to normalization of the brush border with an improvement of lactase enzyme activity. LBT should be performed after 12 months in CD patients on a gluten-free diet in order to assess the persistence/disappearance of lactose malabsorption, thus avoiding an unnecessary lactose-free diet.

Rifaximin-based regimens for eradication of Helicobacter pylori: a pilot study.

BACKGROUND: Triple therapy is the treatment of choice for Helicobacter pylori-infected patients with an eradication rate ranging from 70 to 85%. Poor compliance and antibiotic resistance are the main causes of treatment failure. The aim of the present study was to assess the efficacy of rifaximin, a poorly absorbed antibiotic, for H. pylori eradication. METHODS: We enrolled 48 consecutive H. pylori-positive patients affected. They were randomized to receive two 7-day rifaximin-based triple therapies: rifaximin tablets 400 mg t.i.d., esomeprazole 40 mg o.d. and clarithromycin 500 mg b.i.d. (CRE) or levofloxacin 500 mg o.d. (LRE). H. pylori eradication was assessed using a (13)C-urea breath test 4 weeks after the end of therapy. Treatment compliance and the incidence of side effects were also evaluated. RESULTS: No dropouts were observed. The eradication rate both on intention-to-treat and per-protocol analysis did not show significant differences between groups: 58% (14/24 patients) in group 1 and 42% (10/24 patients) in group 2 (p = 0.24, OR 1.96, 95% CI 0.62-6.18). No significant differences in patients' compliance and incidence of side effects were found between groups. CONCLUSIONS: Rifaximin-based therapy showed optimal compliance but a limited eradication rate compared to standard first-line treatment. Further investigations are needed to evaluate different dosages and combinations.

High prevalence of celiac disease in patients with lactose intolerance.

BACKGROUND/AIMS: Acquired lactase deficiency is a common cause of gastrointestinal symptoms but its etiology remains unclear. Celiac disease could lead to lactase deficiency and is much more common than previously suspected. Several studies have highlighted the prevalence of lactose intolerance in celiac disease, but studies assessing the prevalence of celiac disease in lactose intolerance are lacking. We evaluated the prevalence of celiac disease in patients with a positive H2-lactose breath test compared to a control group. METHODS: This retrospective study included 54 patients (15 males/39 females; mean age 37.8 +/- 7 years) from southern Italy, referred to the Gastroenterology Unit for bloating and diarrhea after the introduction of milk or dietary lactose. They had a positive H2-lactose breath test and a negative H2-glucose breath test. 50 blood donors were drawn from a similar population, matched for sex and age, and enrolled as a control group. All patients were screened for possible celiac disease by measuring the serum level of IgA antibodies to endomysium, anti-transglutaminase and total IgA. Patients positive for at least one of these markers were submitted to upper gastrointestinal endoscopy. RESULTS: None of the patients had a IgA deficiency. 24% of the patients showed positivity of celiac disease antibodies compared to 2% in the control group (p < 0.001). Histologic samples of these patients showed villous atrophy (53.8% Marsh type IIIa, 38.4% Marsh IIIb, and 7.6% with Marsh type IIIc) confirming the celiac disease, while in the control subjects duodenal biopsies were normal. CONCLUSIONS: A high prevalence of celiac disease was observed in patients with a positive H2-lactose breath test compared to healthy controls. In these subjects lactase deficiency seems to be the only manifestation of celiac disease. We suggest serologic screening for celiac disease in all patients with a positive H2-lactose breath test before beginning a milk-exclusion diet.