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Current Opinion in Pharmacology Dec 2018The development of islet autoimmunity and type 1 diabetes has long been linked with enteroviral infection but a causal relationship has proven hard to establish. This is... (Review)
Review
The development of islet autoimmunity and type 1 diabetes has long been linked with enteroviral infection but a causal relationship has proven hard to establish. This is partly because much of the epidemiological evidence derives from studies of neutralising antibody generation in blood samples while less attention has been paid to the pancreatic beta cell as a site of infection. Nevertheless, recent studies have revealed that beta cells express specific enteroviral receptors and that they can sustain a productive enteroviral infection. Importantly, they can also mount antiviral responses which attenuate viral replication and may favour the establishment of a persistent enteroviral infection. Together, these responses combine to create the Trojan horse by which enteroviruses might precipitate islet autoimmunity.
Topics: Animals; Antiviral Agents; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Drug Design; Enterovirus; Enterovirus Infections; Host-Pathogen Interactions; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Risk Factors
PubMed: 30064099
DOI: 10.1016/j.coph.2018.07.006 -
Biochimica Et Biophysica Acta Jun 2016In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by...
In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-, Src- and small-GTPase-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2's role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini, PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin (CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3β pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell-necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs-inhibitor and infection with a PAK2-dominant negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK's effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells.
Topics: Acinar Cells; Animals; Cell Death; Enzyme Activation; Male; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Signal Transduction; p21-Activated Kinases
PubMed: 26912410
DOI: 10.1016/j.bbadis.2016.02.008 -
BMJ Case Reports Jul 2023Pancreatic tuberculosis is the rarest form of abdominal and extrapulmonary tuberculosis. We present a patient in his 40s who presented with pain abdomen and a fever. On...
Pancreatic tuberculosis is the rarest form of abdominal and extrapulmonary tuberculosis. We present a patient in his 40s who presented with pain abdomen and a fever. On examination, the patient had mild jaundice and right hypochondriac tenderness. Blood investigation was suggestive of obstructive jaundice. Imaging studies were representative of pancreatic head lesion, causing mild intrahepatic biliary radical dilatation. Endoscopic ultrasound-guided fine-needle aspiration done from the pancreatic head lesion was diagnostic of tuberculosis. The patient was started on antitubercular medications and responded well.
Topics: Humans; Pancreatic Neoplasms; Pancreas; Tuberculosis; Antitubercular Agents; Endoscopic Ultrasound-Guided Fine Needle Aspiration
PubMed: 37402588
DOI: 10.1136/bcr-2022-254250 -
Journal of Medical Ultrasonics (2001) Apr 2024Advancements in diagnostic radiology have amplified the incorporation of these techniques into routine clinical practice. Concurrently, the frequency of incidentally... (Review)
Review
Advancements in diagnostic radiology have amplified the incorporation of these techniques into routine clinical practice. Concurrently, the frequency of incidentally identifying pancreatic cystic lesions (PCLs) has surged. PCLs encompass diverse categories contingent upon their origin. Among them, branch duct-intraductal papillary mucinous neoplasms (BD-IPMN) and mucinous cystic neoplasms (MCN) are categorized as mucinous cystic lesions that have malignant potential. Even solid neoplasms occasionally show cystic degeneration. Therefore, precise differential PCL diagnosis is crucial to optimize clinical management strategies and detect malignant transformations. Endoscopic ultrasound (EUS) affords comprehensive visualization of the pancreas with high-resolution ultrasound, complemented by fine-needle aspiration (FNA) under real-time EUS guidance, which is a minimally invasive procedure for obtaining pathological samples. This synergy has established EUS and EUS-FNA as vital procedures in the management of PCLs, enabling differentiation of PCLs. Cyst fluid analysis has played a pivotal role in deciding the optimal management strategy. The efficacy of cytological analysis is limited by scant cytologic material. The "string sign" test evaluates fluid viscosity, and its simplicity warrants initial consideration. Amylase and tumor markers, such as CEA, have been studied, but they yield varied sensitivity and specificity. Glucose and genetic mutations (KRAS, GNAS) exhibit promise, while comprehensive genomic profiling underscores genetic insights. Through-the-needle biopsy and needle-based confocal laser endomicroscopy also show high diagnostic yield. EUS-FNA, however, entails risks like infection and needle tract seeding, emphasizing the need for proper utilization. Pancreatic cyst fluid analysis augments diagnostic accuracy and informs clinical decisions, making it a valuable adjunct to imaging.
Topics: Humans; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Pancreatic Cyst; Pancreas; Pancreatic Neoplasms; Diagnosis, Differential
PubMed: 38051460
DOI: 10.1007/s10396-023-01389-6 -
Journal of Laparoendoscopic & Advanced... Apr 2019This systematic review and meta-analysis were performed to summarize available evidence comparing totally minimally invasive pancreaticoduodenectomy (TMIPD) versus open... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This systematic review and meta-analysis were performed to summarize available evidence comparing totally minimally invasive pancreaticoduodenectomy (TMIPD) versus open pancreaticoduodenectomy (OPD) Materials and Methods: We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for comparative cohort studies published from January 1990 through April 2018 comparing TMIPD versus OPD. Outcomes evaluated were postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postoperative hemorrhage, wound infection, estimated blood loss, transfusion rate, retrieved lymph nodes (RLNs), R0 rate, reoperation rate, length of hospital stay, and mortality. Statistical analysis was performed with Review Manager, version 5.3 (Cochrane Collaboration).
RESULTS
Sixteen comparative studies were included. Meta-analysis showed no significant difference between TMIPD and OPD in rates of POPF (risk ratio [RR] = 0.80; 95% confidence interval [CI]: 0.58-1.11; P = .18), DGE (RR = 0.80; 95% CI: 0.63-1.01; P = .06), postoperative hemorrhage (RR = 1.32; 95% CI: 0.87-2.00; P = .19), or reoperation (RR = 0.68; 95% CI: 0.45-1.05; P = .08). TMIPD resulted in fewer wound infections (RR = 0.49; 95% CI: 0.33-0.74; P = .0006), less blood loss (mean difference [MD] = 371.65 mL; 95% CI: -473.77 to -269.53; P < .00001), and lower transfusion rate (RR = 0.59; 95% CI: 0.48-0.72; P < .00001) than OPD. No significant differences were found in the rate of R0 resection (P = .32), RLNs (P = .09), hospital stay (P = .73), or mortality (P = .67). However, TMIPD had much longer operative times than OPD (MD = 80.78 minutes; 95% CI: 29.25-132.31; P = .002).
CONCLUSION
TMIPD appears to be as safe and effective as OPD for periampullary disease. These findings need confirmation with large volume well-designed randomized controlled trials.
Topics: Cohort Studies; Humans; Operative Time; Pancreas; Pancreatic Diseases; Pancreaticoduodenectomy; Postoperative Complications
PubMed: 30256164
DOI: 10.1089/lap.2018.0460 -
Frontiers in Immunology 2023Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that... (Review)
Review
Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of anti-viral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-and-run scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies.
Topics: Humans; Diabetes Mellitus, Type 1; Pancreas; Enterovirus Infections; Virus Diseases; Coronavirus Infections; COVID-19
PubMed: 38239343
DOI: 10.3389/fimmu.2023.1326711 -
Clinical Journal of Gastroenterology Dec 2019Acute pancreatitis (AP) is a common disease associated with a substantial medical and financial burden, and with an incidence across Europe ranging from 4.6 to 100 per... (Review)
Review
Acute pancreatitis (AP) is a common disease associated with a substantial medical and financial burden, and with an incidence across Europe ranging from 4.6 to 100 per 100,000 population. Although most cases of AP are caused by gallstones or alcohol abuse, several other causes may be responsible for acute inflammation of the pancreatic gland. Correctly diagnosing AP etiology is a crucial step in the diagnostic and therapeutic work-up of patients to prescribe the most appropriate therapy and to prevent recurrent attacks leading to the development of chronic pancreatitis. Despite the improvement of diagnostic technologies, and the availability of endoscopic ultrasound and sophisticated radiological imaging techniques, the etiology of AP remains unclear in ~ 10-30% of patients and is defined as idiopathic AP (IAP). The present review aims to describe all the conditions underlying an initially diagnosed IAP and the investigations to consider during diagnostic work-up in patients with non-alcoholic non-biliary pancreatitis.
Topics: Acute Disease; Autoimmune Diseases; Biliary Tract Neoplasms; Early Diagnosis; Gallstones; Genetic Diseases, Inborn; Humans; Infections; Metabolic Diseases; Mitochondrial Diseases; Mutation; Pancreas; Pancreatic Neoplasms; Pancreatitis; Rheumatic Diseases; Sphincter of Oddi Dysfunction; Substance-Related Disorders; Vasculitis; Wounds and Injuries
PubMed: 31041651
DOI: 10.1007/s12328-019-00987-7 -
Digestive Diseases (Basel, Switzerland) 2016The management of acute necrotizing pancreatitis (ANP) has undergone a change of paradigms during the last 2 decades with a decreasing impact of surgical interventions....
The management of acute necrotizing pancreatitis (ANP) has undergone a change of paradigms during the last 2 decades with a decreasing impact of surgical interventions. Modern ANP management is done conservatively as long as possible and therapeutic approaches aim at volume resuscitation, pain management and early enteral nutrition. The diagnostic gold standard of contrast-enhanced CT scan helps to evaluate the extent of necrosis of the pancreas, which correlates with the risk of tissue infection. The crucial point for decision making is the proven existence of infected pancreatic necrosis. This can be achieved by diagnostic needle aspiration of the necrotic material and staining to prove bacterial and/or fungal infection. In case of infected necrosis - besides calculated antimicrobial treatment - an interventional or surgical approach is required to prevent systemic septic progression of the disease. As the first step, percutaneous interventional drainage and spilling of the necrosis are preferable. In case of insufficient clearing of the infectious focus, a step-up approach must be considered, which implies a retroperitoneoscopic or transabdominal minimally invasive necrosectomy and drain placement. Postoperatively, a continuous lavage should be performed using these drains. In case of further deterioration of the patient or development of associated intra-abdominal complications (e.g. bowel perforation or uncontrolled bleeding), an open surgical intervention must always be regarded as a salvage therapy and this offers the possibility to control complications and perform a further necrosectomy and extensive lavage for focus control. However, associated morbidity (e.g. pancreatic fistula, fluid collections, pseudocysts) is about 50-60% and mortality up to 20%. In summary, ANP is managed primarily by a conservative therapy. In case of infected necrosis, interventional and minimally invasive approaches are the therapy of choice. Open surgery should be considered for patients deteriorating despite other measures and should be postponed as long as possible.
Topics: Anti-Bacterial Agents; Biopsy, Needle; Cholangiopancreatography, Endoscopic Retrograde; Decision Making; Disease Management; Drainage; Enteral Nutrition; Humans; Male; Pancreas; Pancreatitis, Acute Necrotizing; Tomography, X-Ray Computed
PubMed: 27332898
DOI: 10.1159/000445232 -
Journal of Gastroenterology and... Aug 2023Over last few years, there has been a paradigm shift in the management of infected pancreatic necrosis with endoscopic and minimally invasive "step-up" management... (Review)
Review
Over last few years, there has been a paradigm shift in the management of infected pancreatic necrosis with endoscopic and minimally invasive "step-up" management approach replacing open surgical necrosectomy. Because of being associated with reduced occurrence of new onset multi-organ failure, external pancreatic fistulae, shorter hospital stay, lower costs, and better quality of life compared with minimally invasive surgical approach, endoscopic "step-up" management approach is the preferred intervention for endoscopically accessible pancreatic necrotic collections at expert centers with endoscopic expertise. Development of lumen apposing metal stents and improvised accessories for interventional endoscopic ultrasound has revolutionized the endoscopic management of pancreatic necrosis making it more effective and safer. Despite these promising developments, endoscopic transluminal necrosectomy (ETN) remains the Achilles heel. Lack of dedicated endoscopic accessories, poor endoscopic visualization within the necrotic cavity, limited diameter of the instrument channel of the endoscope that is a significant impediment to remove large amount of necrotic material, and uncertain ability to avoid vessels and vital structures in the necrotic cavity are important limitations during endoscopic necrosectomy. Recent devices and solutions including use of cap assisted necrosectomy, over the scope grasper and powered endoscopic debridement device are welcome steps in our pursuit for an ideal, safer, and efficacious ETN device. This review will discuss recent advances as well as challenges in the endoscopic management of pancreatic necrosis.
Topics: Humans; Pancreatitis, Acute Necrotizing; Quality of Life; Endoscopy; Pancreas; Stents; Drainage; Necrosis; Treatment Outcome
PubMed: 37309053
DOI: 10.1111/jgh.16262 -
Frontiers in Endocrinology 2022Although type 1 diabetes (T1D) is primarily a disease of the pancreatic beta-cells, understanding of the disease-associated alterations in the whole pancreas could be...
Although type 1 diabetes (T1D) is primarily a disease of the pancreatic beta-cells, understanding of the disease-associated alterations in the whole pancreas could be important for the improved treatment or the prevention of the disease. We have characterized the whole-pancreas gene expression of patients with recently diagnosed T1D from the Diabetes Virus Detection (DiViD) study and non-diabetic controls. Furthermore, another parallel dataset of the whole pancreas and an additional dataset from the laser-captured pancreatic islets of the DiViD patients and non-diabetic organ donors were analyzed together with the original dataset to confirm the results and to get further insights into the potential disease-associated differences between the exocrine and the endocrine pancreas. First, higher expression of the core acinar cell genes, encoding for digestive enzymes, was detected in the whole pancreas of the DiViD patients when compared to non-diabetic controls. Second, In the pancreatic islets, upregulation of immune and inflammation related genes was observed in the DiViD patients when compared to non-diabetic controls, in line with earlier publications, while an opposite trend was observed for several immune and inflammation related genes at the whole pancreas tissue level. Third, strong downregulation of the regenerating gene family () genes, linked to pancreatic islet growth and regeneration, was observed in the exocrine acinar cell dominated whole-pancreas data of the DiViD patients when compared with the non-diabetic controls. Fourth, analysis of unique features in the transcriptomes of each DiViD patient compared with the other DiViD patients, revealed elevated expression of central antiviral immune response genes in the whole-pancreas samples, but not in the pancreatic islets, of one DiViD patient. This difference in the extent of antiviral gene expression suggests different statuses of infection in the pancreas at the time of sampling between the DiViD patients, who were all enterovirus + in the islets by immunohistochemistry based on earlier studies. The observed features, indicating differences in the function, status and interplay between the exocrine and the endocrine pancreas of recent onset T1D patients, highlight the importance of studying both compartments for better understanding of the molecular mechanisms of T1D.
Topics: Antiviral Agents; Diabetes Mellitus, Type 1; Humans; Inflammation; Pancreas; Pancreas, Exocrine; Transcriptome
PubMed: 35498413
DOI: 10.3389/fendo.2022.861985