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WIREs Mechanisms of Disease 2023Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal... (Review)
Review
Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi-species bacterial communities, called "infection microbiomes," that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi-scale modeling framework, known as template-and-anchor modeling, that allows the gradual integration of refined sub-models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases. This article is categorized under: Congenital Diseases > Computational Models.
Topics: Humans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Lung; Disease Progression; Models, Theoretical
PubMed: 37544654
DOI: 10.1002/wsbm.1625 -
Cell & Bioscience Aug 2023Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained β cell-reactive immune... (Review)
Review
Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained β cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory β cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy.
PubMed: 37641145
DOI: 10.1186/s13578-023-01110-7 -
Science Advances Mar 2024Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and...
Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8 T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by effector/memory T cells that expressed exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with β cell antigen GAD. Infected β cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Our in vitro and ex vivo data highlight limited CD8 T cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8 T cells recognizing structural and nonstructural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.
Topics: Humans; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Insulin-Secreting Cells; Antibodies; Coxsackievirus Infections; Epitopes; Peptides; Antiviral Agents
PubMed: 38446892
DOI: 10.1126/sciadv.adl1122 -
Archives of Physiology and Biochemistry Dec 2023The novel 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly transmissible and pathogenic... (Review)
Review
The novel 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly transmissible and pathogenic coronavirus. Because of the novelty of the COVID-19 pandemic, few data are available on the impact of the SARS-CoV-2 on the different endocrine glands. Previous studies of severe acute respiratory syndrome (SARS) have shown a harmful effect on endocrine function. Notably, the angiotensin-converting enzyme-2 receptor, which is the entry route of coronaviruses to the host cell, is widely expressed in the endocrine organs including testis, endocrine pancreas, thyroid, and adrenal, and pituitary glands. Clinical and biochemical manifestations have been recorded in COVID-19 patients resulting in changes in endocrine activities, which were also recorded during the SARS outbreak in 2003. This review aims to explore the impact of SARS-CoV-2 infection on the function of endocrine glands, based on the latest research in the field.
Topics: Male; Humans; COVID-19; SARS-CoV-2; Pandemics; Peptidyl-Dipeptidase A; Endocrine System
PubMed: 33653188
DOI: 10.1080/13813455.2021.1890131 -
Cureus Sep 2023This research presents a systematic review focusing on rituximab's therapeutic applications in immunoglobulin G4 (IgG4)-related disease (IgG4-RD), a rare condition... (Review)
Review
This research presents a systematic review focusing on rituximab's therapeutic applications in immunoglobulin G4 (IgG4)-related disease (IgG4-RD), a rare condition characterized by immune-mediated systemic inflammation and tissue fibrosis, as well as the clinical features of IgG4-RD. While the disease commonly affects organs such as the bile ducts, lymph nodes, retroperitoneum, pancreas, and salivary glands, it can potentially involve other organs. This intricacy often leads to diagnostic challenges due to clinical overlaps with cancer, infections, and other autoimmune disorders. The diagnosis of IgG4-RD necessitates a comprehensive approach involving laboratory tests, imaging studies, and clinical assessments. Symptoms can vary, ranging from lymphadenopathy to jaundice, affecting multiple organs. Although elevated blood IgG4 levels and findings of tissue involvement and fibrosis on imaging can be suggestive, they lack the specificity for a definitive diagnosis. Early diagnosis is crucial for initiating corticosteroids and immunosuppressive to prevent further damage from IgG4-RD. This study highlights the therapeutic role of rituximab in managing this condition. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, the research identifies and evaluates relevant literature across various electronic databases, including PubMed, ScienceDirect, and Google Scholar. This review includes 14 selected publications, comprising three systematic reviews, three observational studies, four narrative reviews, and four case reports. The study design ensures a comprehensive evaluation of rituximab's potential efficacy in treating IgG4-RD and its associated clinical characteristics. Based on this study, it can be concluded that IgG4-RD can potentially be treated with rituximab, particularly in cases of relapse and maintaining remission.
PubMed: 37701160
DOI: 10.7759/cureus.45044 -
Annals of Surgery Nov 2023We aimed to determine the current incidence rate and risk factors for surgical site infection (SSI) after abdominal surgery in China and to further demonstrate the...
OBJECTIVES
We aimed to determine the current incidence rate and risk factors for surgical site infection (SSI) after abdominal surgery in China and to further demonstrate the clinical features of patients with SSI.
BACKGROUND
Contemporary epidemiology and clinical features of SSI after abdominal surgery remain poorly characterized.
METHODS
A prospective multicenter cohort study was conducted from March 2021 to February 2022; the study included patients who underwent abdominal surgery at 42 hospitals in China. Multivariable logistic regression analysis was performed to identify risk factors for SSI. Latent class analysis (LCA) was used to explore the population characteristics of SSI.
RESULTS
In total, 23,982 patients were included in the study, of whom 1.8% developed SSI. There was a higher SSI incidence in open surgery (5.0%) than in laparoscopic or robotic surgeries (0.9%). Multivariable logistic regression indicated that the independent risk factors for SSI after abdominal surgery were older age, chronic liver disease, mechanical bowel preparation, oral antibiotic bowel preparation, colon or pancreas surgery, contaminated or dirty wounds, open surgery, and colostomy/ileostomy. LCA revealed 4 subphenotypes in patients undergoing abdominal surgery. Types α and β were mild subclasses with a lower SSI incidence; whereas types γ and δ were the critical subgroups with a higher SSI incidence, but their clinical features were different.
CONCLUSIONS
LCA identified 4 subphenotypes in patients who underwent abdominal surgery. Types γ and δ were critical subgroups with a higher SSI incidence. This phenotype classification can be used to predict SSI after abdominal surgery.
Topics: Humans; Surgical Wound Infection; Prospective Studies; Cohort Studies; Laparoscopy; Risk Factors; Incidence
PubMed: 37309899
DOI: 10.1097/SLA.0000000000005939 -
Journal of Molecular Medicine (Berlin,... Aug 2023Altered circulating hormone and metabolite levels have been reported during and post-COVID-19. Yet, studies of gene expression at the tissue level capable of identifying...
Altered circulating hormone and metabolite levels have been reported during and post-COVID-19. Yet, studies of gene expression at the tissue level capable of identifying the causes of endocrine dysfunctions are lacking. Transcript levels of endocrine-specific genes were analyzed in five endocrine organs of lethal COVID-19 cases. Overall, 116 autoptic specimens from 77 individuals (50 COVID-19 cases and 27 uninfected controls) were included. Samples were tested for the SARS-CoV-2 genome. The adrenals, pancreas, ovary, thyroid, and white adipose tissue (WAT) were investigated. Transcript levels of 42 endocrine-specific and 3 interferon-stimulated genes (ISGs) were measured and compared between COVID-19 cases (virus-positive and virus-negative in each tissue) and uninfected controls. ISG transcript levels were enhanced in SARS-CoV-2-positive tissues. Endocrine-specific genes (e.g., HSD3B2, INS, IAPP, TSHR, FOXE1, LEP, and CRYGD) were deregulated in COVID-19 cases in an organ-specific manner. Transcription of organ-specific genes was suppressed in virus-positive specimens of the ovary, pancreas, and thyroid but enhanced in the adrenals. In WAT of COVID-19 cases, transcription of ISGs and leptin was enhanced independently of virus detection in tissue. Though vaccination and prior infection have a protective role against acute and long-term effects of COVID-19, clinicians must be aware that endocrine manifestations can derive from virus-induced and/or stress-induced transcriptional changes of individual endocrine genes. KEY MESSAGES: • SARS-CoV-2 can infect adipose tissue, adrenals, ovary, pancreas and thyroid. • Infection of endocrine organs induces interferon response. • Interferon response is observed in adipose tissue independently of virus presence. • Endocrine-specific genes are deregulated in an organ-specific manner in COVID-19. • Transcription of crucial genes such as INS, TSHR and LEP is altered in COVID-19.
Topics: Female; Humans; COVID-19; SARS-CoV-2; Interferons; Pancreas
PubMed: 37246981
DOI: 10.1007/s00109-023-02334-3 -
Digestive and Liver Disease : Official... Nov 2023Splanchnic vein thrombosis (SVT) is a well-recognised though little-studied complication in acute pancreatitis (AP). SVT risk factors, its clinical consequences and the...
BACKGROUND
Splanchnic vein thrombosis (SVT) is a well-recognised though little-studied complication in acute pancreatitis (AP). SVT risk factors, its clinical consequences and the role of anticoagulation (AC) therapy is scarce.
AIMS
To evaluate the incidence and natural history of SVT in AP.
METHODS
Post hoc analysis of a prospective multicentre cohort study involving 23 hospitals in Spain. AP complications were identified by computer tomography, and patients with SVT were re-evaluated after two years.
RESULTS
A total of 1655 patients with AP were included. The overall incidence of SVT was 3.6%. SVT was significantly associated with male gender, younger age and alcoholic aetiology. Every local complication increased SVT incidence, and this risk rose gradually with larger extension and infection of necrosis. These patients had a longer hospital stay and underwent a greater number of invasive treatments, regardless of AP severity. Forty-six patients with SVT were followed up. SVT resolution rate was 54.5% in the AC group and 30.8% in the non-AC group with lower thrombotic complications in the SVT resolution group (83.3% vs 22.7%; p<0.001). No AC-related adverse events occurred.
CONCLUSION
This study identifies the risk factors and negative clinical impact of SVT in AP. Our results justify future trials to demonstrate the role of AC in this clinical scenario.
Topics: Humans; Male; Pancreatitis; Cohort Studies; Prospective Studies; Acute Disease; Venous Thrombosis; Thrombosis; Anticoagulants
PubMed: 37210302
DOI: 10.1016/j.dld.2023.04.026 -
Simultaneous Pancreas and Kidney Transplantation from Donors after Circulatory Death in Switzerland.Journal of Clinical Medicine Jun 2024Simultaneous pancreas and kidney transplantation (SPK) remains the only curative treatment for type I diabetics with end-stage kidney disease. SPK using donors after...
Simultaneous pancreas and kidney transplantation (SPK) remains the only curative treatment for type I diabetics with end-stage kidney disease. SPK using donors after circulatory death (DCD) is one important measure to expand the organ pool for pancreas transplantation (PT). After initial doubts due to higher complications, DCD SPK is now considered safe and equivalent to donation after brain death in terms of survival and graft function. We assessed pancreas and kidney graft function, as well as complications of the first three patients who underwent a DCD SPK in Switzerland. Two transplantations were after rapid procurement, one following normothermic regional perfusion (NRP). Intra- and postoperative courses were uneventful and without major complications in all patients. In the two SPK after rapid procurement, pancreas graft function was excellent, with 100% insulin-free survival, and hemoglobin A1C dropped from 7.9 and 7.5 before SPK and to 5.1 and 4.3 after three years, respectively. Kidney graft function was excellent in the first year, followed by a gradual decline due to recurrent infections. The patient, after NRP SPK, experienced short-term delayed pancreatic graft function requiring low-dose insulin treatment for 5 days post-transplant, most likely due to increased peripheral insulin resistance in obesity. During follow-up, there was persistent euglycemia and excellent kidney function. We report on the first series of DCD SPK ever performed in Switzerland. Results were promising, with low complication rates and sustained graft survival. With almost half of all donors in Switzerland currently being DCD, we see great potential for the expansion of DCD PT.
PubMed: 38930054
DOI: 10.3390/jcm13123525 -
Journal of Digestive Diseases 2023Autoimmune pancreatitis (AIP) is a rare and enigmatic immune-mediated inflammatory disease. We aimed to investigate the prevalence, characteristics, and associated...
OBJECTIVES
Autoimmune pancreatitis (AIP) is a rare and enigmatic immune-mediated inflammatory disease. We aimed to investigate the prevalence, characteristics, and associated factors of AIP-inflammatory bowel disease (IBD) in China.
METHODS
A retrospective bidirectional case-control study was performed. The diagnoses of IBD and AIP were made based on the European Crohn's and Colitis Organization guidelines and the International Consensus Diagnostic Criteria. IBD controls were matched by age, sex, and IBD type at a ratio of 1:4, while AIP controls were matched by AIP types.
RESULTS
The age-standardized prevalence of AIP-IBD patients in the IBD and AIP population were 292.0 and 8151.93 per 100 000 population, respectively. IBD patients had a higher risk of AIP compared to non-IBD patients (odds ratio 8.4, 95% confidence interval 4.7-14.9, P < 0.0001), and AIP patients had a higher risk of developing IBD compared to the general population in China. The mean age at diagnosis of IBD and AIP was 34.83 years and 40.42 years. IBD was diagnosed before AIP in seven cases. The median total IBD and AIP duration was 43.5 months and 13.5 months. Use of mesalamine and tuberculosis were associated with AIP in IBD patients (P = 0.031). And fecal occult blood test was associated with IBD in AIP patients (P = 0.008).
CONCLUSIONS
Most AIP-IBD patients had ulcerative colitis and type 2 AIP. IBD patients are more likely to develop AIP compared to the general population, and vice versa. Use of mesalamine and tuberculosis infection were associated with AIP, and fecal occult blood test was associated with IBD.
Topics: Humans; Case-Control Studies; Retrospective Studies; Autoimmune Pancreatitis; Mesalamine; Autoimmune Diseases; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; China; Tuberculosis
PubMed: 37503771
DOI: 10.1111/1751-2980.13209