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Veterinary Immunology and... May 2024Nitric oxide (NO) is gaseous bioactive molecule that is synthesized by NO synthase (NOS). Inducible NOS (iNOS) expression occurs in response to pathogenic challenges,...
Nitric oxide (NO) is gaseous bioactive molecule that is synthesized by NO synthase (NOS). Inducible NOS (iNOS) expression occurs in response to pathogenic challenges, resulting in the production of large amounts of NO. However, there is a lack of knowledge regarding neuronal NOS (nNOS) and endothelial NOS (eNOS) in birds during pathogenic challenge. Therefore, the present study was conducted to determine the influence of intraperitoneal (IP) injection of zymosan (cell wall component of yeast) and lipopolysaccharide (LPS, a cell wall component of gram-negative bacteria) on NOS expression in chicks (Gallus gallus). Furthermore, the effect of NOS inhibitors on the corresponding behavioral and physiological parameters was investigated. Zymosan and LPS injections induced iNOS mRNA expression in several organs. Zymosan had no effect on eNOS mRNA expression in the organs investigated, whereas LPS increased its expression in the pancreas. Zymosan and LPS decreased nNOS mRNA expression in the lung, heart, kidney, and pancreas. The decreased nNOS mRNA expression in pancreas was probably associated with the NO from iNOS provided that such effect was reproduced by IP injection of sodium nitroprusside, which is a NO donor. Furthermore, pancreatic nNOS mRNA expression decreased following subcutaneous injection of corticosterone. Furthermore, IP injections of a nonspecific NOS inhibitor, NG-nitro-L-arginine methyl ester, and an nNOS-specific inhibitor, 7-nitroindazole, resulted in the significant decreases in food intake, cloacal temperature, and feed passage via the digestive tract in chicks. Collectively, the current findings imply the decreased nNOS expression because of fungal and bacterial infections, which affects food intake, body temperature, and the digestive function in birds.
Topics: Animals; Zymosan; Lipopolysaccharides; Chickens; Nitric Oxide Synthase Type I; Male; Indazoles; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III
PubMed: 38579442
DOI: 10.1016/j.vetimm.2024.110752 -
The Journal of Molecular Diagnostics :... Jun 2024Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset...
Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset diabetes of the young, caused by pathogenic variants in the HNF1B gene, is important for optimal disease management and prognosis, and it has implications for genetic counseling and follow-up of at-risk family members. We hypothesized that the functional characterization could provide valuable information to assist the interpretation of pathogenicity of HNF1B variants. Using different in vitro functional assays, variants identified among 313 individuals, suspected to have monogenic diabetes with or without kidney disease, were characterized. The data from the functional assays were subsequently conjugated with obtained clinical, biochemical, and in silico data. Two variants (p.A167P, p.H336Pfs∗22) showed severe loss of function due to impaired transactivation, reduced DNA binding (p.A167P), and mRNA instability (p.A167P). Although both these variant carriers were diagnosed with diabetes, the p.H336Pfs∗22 carrier also had congenital absence of a kidney, which is a characteristic trait for HNF1B maturity-onset diabetes of the young. Functional analysis of the p.A167P variant revealed damaging effects on HNF-1B protein function, which may warrant imaging of the kidneys and/or pancreas. In addition, the current study has generated important data, including evidence supporting the benign functional impact of five variants (p.D82N, p.T88A, p.N394D, p.V458G, and p.T544A), and piloting new approaches that will prove critical for the growth of HNF1B-diabetes diagnosis.
Topics: Humans; Hepatocyte Nuclear Factor 1-beta; Diabetes Mellitus, Type 2; Female; Male; Adult; Precision Medicine; Mutation; Adolescent; Middle Aged; Young Adult
PubMed: 38575066
DOI: 10.1016/j.jmoldx.2024.03.006 -
Cureus Mar 2024Acute pancreatitis, marked by sudden inflammation of the pancreas, presents a complex spectrum of causative factors including gallstone obstruction, alcohol abuse, and... (Review)
Review
Acute pancreatitis, marked by sudden inflammation of the pancreas, presents a complex spectrum of causative factors including gallstone obstruction, alcohol abuse, and viral infections. Recent studies have illuminated the emergence of vaccine-induced acute pancreatitis, notably associated with COVID-19 vaccinations, presenting diverse mechanisms ranging from direct viral-mediated injury to autoimmune reactions. Understanding this link is pivotal for public health, yet challenges persist in identifying and managing cases post-vaccination. Comprehensive literature reviews employing the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement outline the potential pathways and mechanisms leading to vaccine-induced pancreatitis, emphasizing the need for deeper investigations into underlying health conditions and modifications to vaccine components. Notably, the rare occurrences of vaccine-induced pancreatitis extend beyond COVID-19 vaccines, with reports also documenting associations with measles, mumps, and rubella (MMR), human papillomavirus (HPV), and other viral vaccinations. Mechanistically, hypotheses such as molecular mimicry and immunologic injury have been proposed, necessitating ongoing vigilance and exploration. Regulatory agencies play a crucial role in monitoring and communicating vaccine safety concerns, emphasizing transparency to address potential risks and maintain public trust. Understanding and communicating these rare adverse events with transparency remain integral for informed vaccination policies and to allay concerns surrounding vaccine safety.
PubMed: 38571842
DOI: 10.7759/cureus.55426 -
Diabetes & Metabolic Syndrome Mar 2024The impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women, especially those with gestational diabetes mellitus (GDM), has yet to be fully... (Review)
Review
BACKGROUND AND AIMS
The impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women, especially those with gestational diabetes mellitus (GDM), has yet to be fully understood. This review aims to examine the interaction between GDM and COVID-19 and to elucidate the pathophysiological mechanisms underlying the comorbidity of these two conditions.
METHODS
We performed a systematic literature search using the databases of PubMed, Embase, and Web of Science with appropriate keywords and MeSH terms. Our analysis included studies published up to January 26, 2023.
RESULTS
Despite distinct clinical manifestations, GDM and COVID-19 share common pathophysiological characteristics, which involve complex interactions across multiple organs and systems. On the one hand, infection with severe acute respiratory syndrome coronavirus 2 may target the pancreas and placenta, resulting in β-cell dysfunction and insulin resistance in pregnant women. On the other hand, the hormonal and inflammatory changes that occur during pregnancy could also increase the risk of severe COVID-19 in mothers with GDM. Personalized management and close monitoring are crucial for treating pregnant women with both GDM and COVID-19.
CONCLUSIONS
A comprehensive understanding of the interactive mechanisms of GDM and COVID-19 would facilitate the initiation of more targeted preventive and therapeutic strategies. There is an urgent need to develop novel biomarkers and functional indicators for early identification and intervention of these conditions.
Topics: Humans; COVID-19; Pregnancy; Diabetes, Gestational; Female; SARS-CoV-2; Pregnancy Complications, Infectious; Pandemics; Coronavirus Infections; Pneumonia, Viral; Betacoronavirus
PubMed: 38569447
DOI: 10.1016/j.dsx.2024.102991 -
Australian Veterinary Journal Jun 2024Although cryptococcosis is the most common systemic fungal disease of cats, abdominal involvement is rarely reported. The pathogenesis of cryptococcosis usually involves...
A case of disseminated cryptococcosis with abdominal involvement due to Cryptococcus neoformans species complex in a Ragdoll cat and false-negative cryptococcal antigen lateral flow tests due to the postzone phenomenon.
Although cryptococcosis is the most common systemic fungal disease of cats, abdominal involvement is rarely reported. The pathogenesis of cryptococcosis usually involves sinonasal colonisation, followed by tissue invasion and sinonasal infection, with possible subsequent spread to the lungs and/or direct extension into the central nervous system (CNS), for example, via the cribriform plate. Further haematogenous spread can occur to any tissue, including skin and the CNS. This report describes a case of disseminated cryptococcosis due to Cryptococcus neoformans species complex in a 13-year-old cat, the fourth documented Australian feline case with abdominal involvement. The cat presented with a chronic history of upper respiratory disease that progressed to severe lethargy and anorexia. An autopsy revealed striking peritonitis with multifocal abdominal involvement affecting the liver, spleen, adrenal glands, kidneys, pancreas and mesentery. Cryptococcal organisms were also observed in organs within the thoracic cavity, sinonasal tissues and the CNS. Testing of abdominal fluid and serum for cryptococcal antigen using a commercially available lateral flow assay using neat fluid specimen initially tested false-negative. However, after dilution of the sample to 1:64, a positive result was obtained, confirming a postzone phenomenon. Taken together, the collective findings were indicative of widely disseminated cryptococcosis due to Cryptococcus neoformans with atypical involvement of the abdominal cavity.
Topics: Animals; Cryptococcosis; Cryptococcus neoformans; Cats; Cat Diseases; Male; Antigens, Fungal; Fatal Outcome; False Negative Reactions
PubMed: 38567673
DOI: 10.1111/avj.13329 -
Surgical Case Reports Apr 2024Pancreatic adenosquamous cell carcinoma (PASC) is a relatively rare histological type of pancreatic malignancy, and preoperative diagnosis is difficult because of its...
BACKGROUND
Pancreatic adenosquamous cell carcinoma (PASC) is a relatively rare histological type of pancreatic malignancy, and preoperative diagnosis is difficult because of its rarity. PASC accounts for 1-4% of all pancreatic cancers, and even after curative surgery, its prognosis is poorer than that of ordinary pancreatic adenocarcinoma. Pathologically, it shows glandular and squamous differentiation of cells. Complete resection is the only method to achieve a good long-term prognosis, and an increasing doubling time of PASC is considered to indicate early recurrence after surgery. Here, we report a rare case of PASC with an infected pancreatic cyst that was difficult to treat, along with a review of the literature.
CASE PRESENTATION
A woman in her 80s with a history of breast cancer presented with pericardial pain. Computed tomography revealed a 20-mm hypovascular tumor in the body of the pancreas and a 27-mm pseudocyst. Endoscopic retrograde cholangiopancreatography showed a severe main pancreatic duct stenosis in the body of the pancreas that made cannulation impossible, and contrast media extravasation was due to pancreatic duct disruption in the pancreatic tail. Endoscopic fine-needle aspiration revealed that the tumor was a PASC. Because the patient had an infected pancreatic cyst, central intravenous nutrition and antibiotics were administered, which stabilized her general condition. She was diagnosed with resectable PASC and underwent distal pancreatectomy with lymphadenectomy. The postoperative course was uneventful. Immunohistochemical analysis of the resected specimen confirmed T2N0M0 stage IB. Systemic adjuvant chemotherapy with S-1 is ongoing.
CONCLUSION
Appropriate preoperative management and preoperative accurate staging (T2N0M0 stage IB) of PASC with curative surgery can ensure predictable outcomes.
PubMed: 38557796
DOI: 10.1186/s40792-024-01868-z -
The Journal of Clinical Investigation Apr 2024Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at...
Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca2+ directly released from acidic Ca2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a) as an organellar Ca2+ regulator protein integral to the membrane of secretory granules that controlled Ca2+ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca2+ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca2+ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.
Topics: Mice; Animals; Calcium Channels; Calcium; Pancreas; Exocytosis; Secretory Vesicles
PubMed: 38557489
DOI: 10.1172/JCI169428 -
Gut Jun 2024Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in (encoding trypsin inhibitor) are common in patients with CP and are...
OBJECTIVE
Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human () for pancreatitis therapy in mice.
DESIGN
A capsid-optimised AAV8-mediated expression vector (AAV8-) to target the pancreas was constructed. Mice were treated with AAV8- by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8- were dynamically evaluated in infected mice. The effectiveness of AAV8- on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and c.194+2T>C mouse models).
RESULTS
The constructed AAV8- vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×10 vg/animal). The expression and efficacy of peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process.
CONCLUSION
One-time injection of AAV8 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.
Topics: Animals; Mice; Genetic Therapy; Dependovirus; Genetic Vectors; Disease Models, Animal; Trypsin Inhibitor, Kazal Pancreatic; Pancreas; Humans; Pancreatitis, Chronic; Male; Pancreatitis
PubMed: 38553043
DOI: 10.1136/gutjnl-2023-330788 -
Journal of Clinical Gastroenterology Mar 2024Cystic fibrosis (CF) is a multisystem disorder that leads to abnormal transport of chloride and sodium across secretory epithelia resulting in thickened, viscous...
BACKGROUND
Cystic fibrosis (CF) is a multisystem disorder that leads to abnormal transport of chloride and sodium across secretory epithelia resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestine, and the reproductive system. Defects in the biliary tract can predispose to stone formation requiring endoscopic retrograde cholangiopancreatography (ERCP). However, there is a paucity of data assessing ERCP outcomes in patients with CF.
METHODS
We identified patients from the Healthcare Cost and Utilization Project (HCUP)-National Inpatient Sample (NIS) between the years 2016 and 2020. Our study group included patients with CF of all ages who underwent an inpatient ERCP. We used ICD10 diagnostic and procedural codes to identify patients, procedures, and complications of the procedure.
RESULTS
From 2016 to 2020, a total of 860,679 inpatient ERCPs were identified. Of these procedures, 535 (0.06%) were performed in patients with CF. The mean age of patients with CF undergoing ERCP was 60.62 years, of which 48% were males and 52% were females. Patients in the CF group had a higher incidence of post-ERCP pneumothorax (0.93%) than the patients in the non-CF group (0.15%). The occurrence of other ERCP-related adverse events was similar in both groups (P>0.05). On multivariate regression analysis, patients with CF were 1.75 times more likely to develop post-ERCP infections [odds ratio (OR): 1.75; 95% CI: 1.03-2.94; P=0.035) and 7.64 times more likely to develop post-ERCP pneumothorax (OR: 7.64; 95% CI: 1.03-56.5; P=0.046) compared to patients without CF after adjusting for confounders. The groups had no significant difference in mortality, post-ERCP pancreatitis, bleeding, perforation, pneumoperitoneum, and gas embolism. There was also no significant difference in the length of stay between the study and control groups.
CONCLUSIONS
ERCP is a safe procedure in patients with CF with a comparable risk of postprocedural complications and mortality to those who do not have cystic fibrosis. However, patients with CF may experience a higher risk of post-ERCP infections and post-ERCP pneumothorax. Further studies are needed to prospectively evaluate outcomes of ERCP in patients with CF and to determine methods of mitigating adverse events.
PubMed: 38546483
DOI: 10.1097/MCG.0000000000001993 -
Clinical Transplantation Apr 2024Data on long-term outcomes following A2/A2B to B kidney transplants since the 2014 kidney allocation system (KAS) changes are few. The primary aim of this study is to...
INTRODUCTION
Data on long-term outcomes following A2/A2B to B kidney transplants since the 2014 kidney allocation system (KAS) changes are few. The primary aim of this study is to report our 7-year experience with A2/A2B to B kidney transplants and to compare post-transplant outcomes of A2/A2B to a concurrent group of B to B kidney transplants. Additionally, the study evaluates the impact of pre-transplant anti-A1 titers on survival outcomes in A2/A2B transplants.
METHODS
This retrospective, single-center analysis included all adults who received A2/A2B to B deceased donor kidney transplants from December 2014 to June 2021 compared to B to B recipients. The effects of pre-transplant IgM/IgG titers, stratified as ≤1:8 and ≥1:16, on death-censored, rejection-free, and overall graft survival were tested.
RESULTS
Fifty-three A2/A2B and 114 B to B adults were included with a median follow-up time of 32 months. Overall graft survival, patient survival, and rejection-free graft survival did not differ between the two groups. There were no differences between the groups' overall kidney function values (p > .80) or their temporal trajectories (time by group interaction p > .11). Unadjusted death-censored graft survival was lower in A2/A2B to B compared to B recipients (p = .03), but the effect was not significant (p = .195) after adjusting for any readmissions (p = .96), rejection episodes (p < .001) or BK infection (p = .76). We did not detect an effect of pre-transplant titer group on death-censored (p = .59), rejection-free (p = .61), or overall graft survival (p = .26) CONCLUSIONS: A2/A2B to B kidney transplants have comparable overall patient and graft survival, rejection-free graft survival, and longitudinal renal function compared to B to B transplants at our center. Allograft survival outcomes were not significantly different between patients with low and high pre-transplant anti-A1 IgM/IgG titers.
Topics: Adult; Humans; Kidney Transplantation; Retrospective Studies; Blood Group Incompatibility; Graft Rejection; Isoantibodies; Immunoglobulin G; Immunoglobulin M; Graft Survival; ABO Blood-Group System
PubMed: 38545909
DOI: 10.1111/ctr.15295