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Cureus Mar 2024This case presents an instance of an extremely delayed diagnosis of hereditary angioedema (HAE) type I in an elderly female with no significant past medical history. The...
This case presents an instance of an extremely delayed diagnosis of hereditary angioedema (HAE) type I in an elderly female with no significant past medical history. The patient had a prolonged history of recurrent lip swelling and itchiness dating back to her teenage years, leading to multiple visits to the emergency room (ER). These recurrent episodes were characterized by random onset and accompanied by generalized pruritus and urticaria. During these ER visits, the patient would be inappropriately treated for presumed hypersensitivity reaction due to her confounding environmental allergies presenting with urticaria, complicating and significantly delaying her diagnosis. The patient was adopted, and the family history was unknown. There was no history of medication use suggestive of acquired angioedema. At the time of the visit, she had signs of chronic lip changes and atopy. After an extensive workup, it showed severely low levels of C1 esterase inhibitor and borderline low to normal C4 and C1q, consistent with the diagnosis of HAE type I. Initial treatment with an on-demand C1 esterase inhibitor reduced the recurrence of lip swelling and transitioned to long-term prophylaxis use. Overall, the treatment outcome was generally successful, with less recurrence of lip swelling and ER visits.
PubMed: 38690445
DOI: 10.7759/cureus.57303 -
Journal of Inflammation (London,... Apr 2024The DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing...
BACKGROUND
The DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing double-stranded DNA breaks (DSBs) is established, but its role in inflammation, as a complex or individual subunits, remains elusive. While only ~ 1% of PRKDC is necessary for DNA repair, we reported that partial inhibition blocks asthma in mice without causing SCID.
METHODS
We investigated the central role of PRKDC in inflammation and its potential association with DNA repair. We also elucidated the relationship between inflammatory cytokines (e.g., TNF-α) and PRKDC by analyzing its connections to inflammatory kinases. Human cell lines, primary human endothelial cells, and mouse fibroblasts were used to conduct the in vitro studies. For animal studies, LPS- and oxazolone-induced mouse models of acute lung injury (ALI) and delayed-type hypersensitivity (DHT) were used. Wild-type, PRKDC, or Ku70 mice used in this study.
RESULTS
A ~ 50% reduction in PRKDC markedly blocked TNF-α-induced expression of inflammatory factors (e.g., ICAM-1/VCAM-1). PRKDC regulates Th1-mediated inflammation, such as DHT and ALI, and its role is highly sensitive to inhibition achieved by gene heterozygosity or pharmacologically. In endothelial or epithelial cells, TNF-α promoted rapid PRKDC phosphorylation in a fashion resembling that induced by, but independent of, DSBs. Ku70 heterozygosity exerted little to no effect on ALI in mice, and whatever effect it had was associated with a specific increase in MCP-1 in the lungs and systemically. While Ku70 knockout blocked VP-16-induced PRKDC phosphorylation, it did not prevent TNF-α - induced phosphorylation of the kinase, suggesting Ku70 dispensability. Immunoprecipitation studies revealed that PRKDC transiently interacts with p38MAPK. Inhibition of p38MAPK blocked TNF-α-induced PRKDC phosphorylation. Direct phosphorylation of PRKDC by p38MAPK was demonstrated using a cell-free system.
CONCLUSIONS
This study presents compelling evidence that PRKDC functions independently of the DNA-PK complex, emphasizing its central role in Th1-mediated inflammation. The distinct functionality of PRKDC as an individual enzyme, its remarkable sensitivity to inhibition, and its phosphorylation by p38MAPK offer promising therapeutic opportunities to mitigate inflammation while sparing DNA repair processes. These findings expand our understanding of PRKDC biology and open new avenues for targeted anti-inflammatory interventions.
PubMed: 38689261
DOI: 10.1186/s12950-024-00386-x -
Frontiers in Immunology 2024Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement....
Sulfasalazine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) coinfected with COVID-19 complicated by hemophagocytic lymphohistiocytosis: a case report.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement. Conversely, hemophagocytic lymphohistiocytosis (HLH) is an infrequent yet critical condition presenting with fever, hepatosplenomegaly, cytopenias, coagulation abnormalities, and elevated inflammatory markers. The overlapping clinical and laboratory features between DRESS and HLH poses a significant diagnostic challenge. Secondary HLH (sHLH) typically occurs in adults triggered by viral infections, malignancies, rheumatologic diseases, or immune deficiencies. Recently, COVID-19 has also been identified as one of the triggers for sHLH. Herein, we present a case of Sulfasalazine-induced DRESS coinfected with COVID-19 that subsequently progressed into HLH. Our patient exhibited common hepatorenal and splenic involvement along with rare cholecystitis and appendicitis. However, a significant improvement was observed upon the addition of etoposide and azathioprine. We hypothesize that excessive activation of the immune system and cytokine storm due to DRESS combined with COVID-19 infection led to more extensive systemic damage resulting in HLH development. This highlights the potential for severe consequences when DRESS coincides with HLH during a COVID-19 infection.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; COVID-19; Drug Hypersensitivity Syndrome; Sulfasalazine; SARS-CoV-2; Coinfection; Male; Middle Aged; Female
PubMed: 38686382
DOI: 10.3389/fimmu.2024.1371490 -
The Pan African Medical Journal 2024
Topics: Humans; Anticonvulsants; Carbamazepine; Disease Progression; Stevens-Johnson Syndrome
PubMed: 38681105
DOI: 10.11604/pamj.2024.47.44.42577 -
Vaccines Mar 2024Cancer vaccines present a promising avenue for treating immune checkpoint blockers (ICBs)-refractory patients, fostering immune responses to modulate the tumor...
Cancer vaccines present a promising avenue for treating immune checkpoint blockers (ICBs)-refractory patients, fostering immune responses to modulate the tumor microenvironment. We revisit a phase I/II trial using Tumor Antigen-Presenting Cells (TAPCells) (NCT06152367), an autologous antigen-presenting cell vaccine loaded with heat-shocked allogeneic melanoma cell lysates. Initial findings showcased TAPCells inducing lysate-specific delayed-type hypersensitivity (DTH) reactions, correlating with prolonged survival. Here, we extend our analysis over 15 years, categorizing patients into short-term (<36 months) and long-term (≥36 months) survivors, exploring novel associations between clinical outcomes and demographic, genetic, and immunologic parameters. Notably, DTH patients exhibit a 53.1% three-year survival compared to 16.1% in DTH patients. Extended remissions are observed in long-term survivors, particularly DTH/M1c patients. Younger age, stage III disease, and moderate immune events also benefit short-term survivors. Immunomarkers like increased C-type lectin domain family 2 member D on CD4 T cells and elevated interleukin-17A were detected in long-term survivors. In contrast, toll-like receptor-4 D229G polymorphism and reduced CD32 on B cells are associated with reduced survival. TAPCells achieved stable long remissions in 35.2% of patients, especially M1c/DTH cases. Conclusions: Our study underscores the potential of vaccine-induced immune responses in melanoma, emphasizing the identification of emerging biological markers and clinical parameters for predicting long-term remission.
PubMed: 38675738
DOI: 10.3390/vaccines12040357 -
International Journal of Molecular... Apr 2024Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K...
Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 () gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: = 23), those with hypercalcemia without nephrolithiasis (Group II: = 38), and those without nephrolithiasis or hypercalcemia (Group III: = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no polymorphisms (OR = 7.73; 95% CI 1.79-33.4; = 0.001). The presence of a C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings.
Topics: Humans; Female; Vitamin K Epoxide Reductases; Male; Sarcoidosis; Middle Aged; Nephrolithiasis; Risk Factors; Adult; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Retrospective Studies; Aged; Alleles
PubMed: 38674033
DOI: 10.3390/ijms25084448 -
BMC Ophthalmology Apr 2024Although choroidal thickening was reported as a sign of active inflammation in ocular sarcoidosis, there has been no research on the choroidal changes in non-ocular...
BACKGROUND
Although choroidal thickening was reported as a sign of active inflammation in ocular sarcoidosis, there has been no research on the choroidal changes in non-ocular sarcoidosis (defined as systemic sarcoidosis without overt clinical signs of ocular involvement). Therefore, this study aimed to investigate choroidal structural changes in patients with non-ocular sarcoidosis.
METHODS
This retrospective case-control study was conducted at Asan Medical Center, a tertiary referral center. We evaluated 30 eyes with non-ocular sarcoidosis and their age- and spherical equivalent-matched healthy control eyes. The subfoveal choroidal thickness, area ratio (Sattler layer-choriocapillaris complex [SLCC] area to Haller layer [HL] area), and choroidal vascularity index (CVI, luminal area to choroidal area) were analyzed using enhanced depth imaging in optical coherence tomography. Systemic and ocular factors associated with the choroidal thickness were investigated.
RESULTS
Compared with the healthy control group, the non-ocular sarcoidosis group had significantly thicker subfoveal choroid (total and all sublayers [SLCC and HL]) and lower area ratio. There were no significant differences in the CVIs at all sublayers between groups. In the non-ocular sarcoidosis group, eyes under oral steroid treatment had thinner choroid than eyes under observation. In the control group, eyes with older age and more myopic spherical equivalent had thinner choroidal thickness.
CONCLUSION
Total and all sublayers of the subfoveal choroid were significantly thicker without significant vascularity changes in non-ocular sarcoidosis eyes than in healthy control eyes. The degree of choroidal thickening was disproportionally greater at HL than at SLCC. These characteristic choroidal changes may be the subclinical manifestations in non-ocular sarcoidosis.
Topics: Humans; Tomography, Optical Coherence; Retrospective Studies; Male; Female; Sarcoidosis; Middle Aged; Choroid; Case-Control Studies; Choroid Diseases; Adult; Aged; Visual Acuity
PubMed: 38671442
DOI: 10.1186/s12886-024-03463-0 -
BMJ Case Reports Apr 2024We describe a patient who had failed renal transplant after 13 years, eventually requiring a graft nephrectomy and discontinuation of immunosuppressive therapy,...
We describe a patient who had failed renal transplant after 13 years, eventually requiring a graft nephrectomy and discontinuation of immunosuppressive therapy, including antithymocyte globulin, tacrolimus and mycophenolate while on steroid avoidance protocol. Within a few months of complete discontinuation of the immunosuppressive medications, she developed lower back pain associated with numbness in her right anterolateral thigh. The radiological imaging demonstrated multiple bony lesions throughout her axial and appendicular skeleton with normal pulmonary findings. A computerised tomography-guided bone biopsy from the left iliac crest revealed fragments of bone with granulomatous inflammation, thus making the diagnosis of extrapulmonary sarcoidosis. Initiating treatment with prednisone resulted in near-complete resolution of symptoms. Long-term immunosuppressive therapy is administered to all renal transplant recipients to help prevent acute rejection and loss of renal allograft. This case highlights that immunosuppressants can conceal the presence of underlying conditions in transplant patients.
Topics: Humans; Female; Sarcoidosis; Immunosuppressive Agents; Kidney Transplantation; Bone Diseases; Tomography, X-Ray Computed; Middle Aged; Prednisone
PubMed: 38670568
DOI: 10.1136/bcr-2023-255611 -
Pathogens (Basel, Switzerland) Apr 2024Currently, the responsible use of antimicrobials in pigs has allowed the continuous development of alternatives to these antimicrobials. In this study, we describe the...
Currently, the responsible use of antimicrobials in pigs has allowed the continuous development of alternatives to these antimicrobials. In this study, we describe the impact of treatments with two probiotics, one based on live () and another based on fragmented (beta-glucans), that were administered to piglets at birth and at prechallenge with . Thirty-two pigs were divided into four groups of eight animals each. The animals had free access to water and food. The groups were as follows: Group A, untreated negative control; Group B, inoculated by nebulization with positive control; Group C, first treated with disintegrated (disintegrated ) and inoculated by nebulization with ; and Group D, treated with live yeast (live ) and inoculated by nebulization with . In a previous study, we found that on Days 1 and 21 of blood sampling, nine proinflammatory cytokines were secreted, and an increase in their secretion occurred for only five of them: TNF-α, INF-α, INF-γ, IL-10, and IL-12 p40. The results of the clinical evolution, the degree of pneumonic lesions, and the productive parameters of treated Groups C and D suggest that has an immunomodulatory effect in chronic proliferative pneumonia characterized by delayed hypersensitivity, which depends on the alteration or modulation of the respiratory immune response. The data presented in this study showed that contributed to the innate resistance of infected pigs.
PubMed: 38668277
DOI: 10.3390/pathogens13040322 -
Cureus Mar 2024Glutaraldehyde (GA), a potent disinfectant and sterilizing agent extensively used in healthcare settings, has garnered attention for its association with contact...
Glutaraldehyde (GA), a potent disinfectant and sterilizing agent extensively used in healthcare settings, has garnered attention for its association with contact dermatitis. This occupational skin condition, often induced by repeated exposure to GA, poses significant challenges to the well-being of healthcare professionals and patients alike. Understanding the causes, symptoms, and preventive measures against GA-induced contact dermatitis is essential for promoting a safe and healthy working environment in healthcare facilities. A 28-year-old female presented with a severe burning sensation and dark brown patches in the lower chin region, one day following root canal treatment. Based on the characteristic appearance of patches and the typical burning sensation associated with an allergic reaction, a diagnosis of acute contact dermatitis was made. Patch testing by an expert dermatologist confirmed that the patient was allergic to GA. GA, a popular commercial germicidal product, is widely used as a cold sterilizing agent for operative dental instruments. The patient developed a reaction as the endodontic files used during the root canal procedure were cold sterilized with 2% GA. The lesion experienced significant improvement and ultimately healed following the administration of corticosteroids and antihistamines. This report concerns a case of GA-induced contact dermatitis. As GA is being used more widely, particularly in dental clinics, this case was of interest and is reported in the safety interest of patients and clinicians.
PubMed: 38665736
DOI: 10.7759/cureus.56954