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BMC Nephrology Jun 2024Sarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with...
BACKGROUND
Sarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with sarcoidosis is rare and membranous nephropathy (MN) is cited as the most common. The association between the two diseases remained unclear. This article reported a case of co-occurrence of sarcoidosis and anti-PLA2R-associated MN, to provide a possible relationship between these two entities.
CASE PRESENTATION
A 61-year-old Chinese Han woman with a history of sarcoidosis was admitted to our hospital for nephrotic syndrome. Her sarcoidosis was diagnosed according to the adenopathy observed on the computed tomography scan and the biopsy of lymph nodes. The MN presented with nephrotic syndrome with a PLA2R antibody titer of 357RU/ml, and the final diagnosis was based on a renal biopsy. The patient's sarcoidosis was remitted after treatment with prednisone. One year later MN was diagnosed, and she was treated with prednisone combined with calcineurin inhibitors, based on a full dose of renin-angiotensin system (RAS) inhibitor. The patient's sarcoidosis had been in remission while the MN was recurrent, and her renal function deteriorated to end-stage renal disease 6 years later due to discontinuation of immunosuppression. A genetic test led to the identification of the HLA-DRB1*0301 and HLA-DRB1*150 genes associated with both sarcoidosis and MN, which provides a new possible explanation of the co-occurrence of these two diseases.
CONCLUSION
This case suggested for the first time a potential genetic connection between idiopathic MN and sarcoidosis which needs further studies in the future.
Topics: Humans; Glomerulonephritis, Membranous; Female; Middle Aged; Receptors, Phospholipase A2; Sarcoidosis; Genetic Predisposition to Disease; Autoantibodies
PubMed: 38937663
DOI: 10.1186/s12882-024-03649-0 -
Environmental Health Perspectives Jun 2024Changes in land use and climate change have been reported to reduce biodiversity of both the environment and human microbiota. These reductions in biodiversity may lead... (Review)
Review
BACKGROUND
Changes in land use and climate change have been reported to reduce biodiversity of both the environment and human microbiota. These reductions in biodiversity may lead to inadequate and unbalanced stimulation of immunoregulatory circuits and, ultimately, to clinical diseases, such as asthma and allergies.
OBJECTIVE
We summarized available empirical evidence on the role of inner (gut, skin, and airways) and outer (air, soil, natural waters, plants, and animals) layers of biodiversity in the development of asthma, wheezing, and allergic sensitization.
METHODS
We conducted a systematic search in SciVerse Scopus, PubMed MEDLINE, and Web of Science up to 5 March 2024 to identify relevant human studies assessing the relationships between inner and outer layers of biodiversity and the risk of asthma, wheezing, or allergic sensitization. The protocol was registered in PROSPERO (CRD42022381725).
RESULTS
A total of 2,419 studies were screened and, after exclusions and a full-text review of 447 studies, 82 studies were included in the comprehensive, final review. Twenty-nine studies reported a protective effect of outer layer biodiversity in the development of asthma, wheezing, or allergic sensitization. There were also 16 studies suggesting an effect of outer layer biodiversity on increasing asthma, wheezing, or allergic sensitization. However, there was no clear evidence on the role of inner layer biodiversity in the development of asthma, wheezing, and allergic sensitization (13 studies reported a protective effect and 15 reported evidence of an increased risk).
CONCLUSIONS
Based on the reviewed literature, a future systematic review could focus more specifically on outer layer biodiversity and asthma. It is unlikely that association with inner layer biodiversity would have enough evidence for systematic review. Based on this comprehensive review, there is a need for population-based longitudinal studies to identify critical periods of exposure in the life course into adulthood and to better understand mechanisms linking environmental exposures and changes in microbiome composition, diversity, and/or function to development of asthma and allergic sensitization. https://doi.org/10.1289/EHP13948.
Topics: Animals; Humans; Asthma; Biodiversity; Environmental Exposure; Hypersensitivity; Microbiota
PubMed: 38935403
DOI: 10.1289/EHP13948 -
Polish Archives of Internal Medicine Jun 2024Medications are a common cause of acute kidney injury (AKI). There are various mechanisms that medications can induce AKI, and a better understanding of this...
Medications are a common cause of acute kidney injury (AKI). There are various mechanisms that medications can induce AKI, and a better understanding of this pathophysiology can aid in clinician recognition, treatment and prevention. Hemodynamic-mediated AKI is often associated with drugs that alter renal perfusion and its autoregulation. Acute tubular injury is the result of direct renal tubular cell toxicity. Acute interstitial nephritis is a T-cell mediated immune hypersensitivity reaction to drugs leading to tubule-interstitial inflammation and AKI. Crystalline nephropathy can be caused by medications themselves that crystalize or from the altered urinary chemistries caused by medications. Some medications can cause AKI through uncommon mechanisms such as glomerulonephritis and thrombotic microangiopathy. Notably, some medications may cause a phenomenon called "pseudo-AKI" where serum creatinine is elevated without a true reduction in kidney function. Commonly used medications in clinical practice are reviewed with the focus on mechanisms of injury, diagnosis, treatment, and prevention. Recognizing the common medications that are associated with AKI is an important first step in reducing the risk of AKI. For each medication, understanding general and specific risk factors for AKI allows for early identification and timely discontinuation of offending agents. These measures will help mitigate the risk of AKI and promote renal recovery.
PubMed: 38934852
DOI: 10.20452/pamw.16780 -
Immunity, Inflammation and Disease Jun 2024Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as...
BACKGROUND
Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown.
METHODS
C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF).
RESULTS
The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF.
CONCLUSION
These results highlight OAW's robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.
Topics: Animals; Asthma; Mast Cells; Mice; Disease Models, Animal; Administration, Oral; Mice, Inbred C57BL; beta-Glucans; Cytokines; Inflammation; Ovalbumin; Respiratory Hypersensitivity; Bronchoalveolar Lavage Fluid; Lung
PubMed: 38934407
DOI: 10.1002/iid3.1333 -
Immunity, Inflammation and Disease Jun 2024Asthma, a chronic inflammatory disease with diverse pathomechanisms, presents challenges in developing personalized diagnostic and therapeutic approaches. This review... (Review)
Review
OBJECTIVE
Asthma, a chronic inflammatory disease with diverse pathomechanisms, presents challenges in developing personalized diagnostic and therapeutic approaches. This review aims to provide a comprehensive overview of the role of exosomes, small extracellular vesicles, in asthma pathophysiology and explores their potential as diagnostic biomarkers and therapeutic tools.
METHODS
A literature search was conducted to identify recent studies investigating the involvement of exosomes in asthma. The retrieved articles were analyzed to extract relevant information on the role of exosomes in maintaining lung microenvironment homeostasis, regulating inflammatory responses, and their diagnostic and therapeutic potential for asthma.
RESULTS
Exosomes secreted by various cell types, have emerged as crucial mediators of intercellular communication in healthy and diseased conditions. Evidence suggest that exosomes play a significant role in maintaining lung microenvironment homeostasis and contribute to asthma pathogenesis by regulating inflammatory responses. Differential exosomal content between healthy individuals and asthmatics holds promise for the development of novel asthma biomarkers. Furthermore, exosomes secreted by immune and nonimmune cells, as well as those detected in biofluids, demonstrate potential in promoting or regulating immune responses, making them attractive candidates for designing new treatment strategies for inflammatory conditions such as asthma.
CONCLUSION
Exosomes, with their ability to modulate immune responses and deliver therapeutic cargo, offer potential as targeted therapeutic tools in asthma management. Further research and clinical trials are required to fully understand the mechanisms underlying exosome-mediated effects and translate these findings into effective diagnostic and therapeutic strategies for asthma patients.
Topics: Exosomes; Humans; Asthma; Biomarkers; Animals; Lung; Cell Communication
PubMed: 38934401
DOI: 10.1002/iid3.1325 -
Neural Regeneration Research Jun 2024Successful polyethylene glycol fusion (PEG-fusion) of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to: (1) rapidly restore...
Successful polyethylene glycol fusion (PEG-fusion) of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to: (1) rapidly restore electrophysiological continuity; (2) prevent distal Wallerian Degeneration and maintain their myelin sheaths; (3) promote primarily motor, voluntary behavioral recoveries as assessed by the Sciatic Functional Index; and, (4) rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex (e.g., toe twitch) or voluntary behaviors. The preceding companion paper describes sensory terminal field reorganization following PEG-fusion repair of sciatic nerve transections or ablations; however, sensory behavioral recovery has not been explicitly explored following PEG-fusion repair. In the current study, we confirmed the success of PEG-fusion surgeries according to criteria (1-3) above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis rats. Mechanical nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the hindpaws. Dorsal von Frey filament test was a more reliable method than plantar von Frey filament test to assess mechanical nociceptive sensitivity following sciatic nerve transections. Baseline withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not sex. Withdrawal thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated rats. Following sciatic transection, all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the injury. However, PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative Control rats. Furthermore, PEG-fused rats with significantly improved Sciatic Functional Index scores at or after 4 weeks postoperatively exhibited yet-earlier von Frey filament recovery compared with those without Sciatic Functional Index recovery, suggesting a correlation between successful pPEG-fusion and both motor-dominant and sensory-dominant behavioral recoveries. This correlation was independent of the sex or strain of the rat. Furthermore, our data showed that the acceleration of von Frey filament sensory recovery to baseline was solely due to the PEG-fused sciatic nerve and not saphenous nerve collateral outgrowths. No chronic hypersensitivity developed in any rat up to 12 weeks. All these data suggest that PEG-fusion repair of transection peripheral nerve injuries could have important clinical benefits.
PubMed: 38934383
DOI: 10.4103/NRR.NRR-D-23-01846 -
Tidsskrift For Den Norske Laegeforening... Jun 2024Alpha-gal allergy or red meat allergy is a rare yet potentially severe allergy. Sensitisation usually occurs when alpha-gal present in the tick's saliva is transferred...
BACKGROUND
Alpha-gal allergy or red meat allergy is a rare yet potentially severe allergy. Sensitisation usually occurs when alpha-gal present in the tick's saliva is transferred to humans during a tick bite, prompting the production of IgE antibodies to alpha-gal. Subsequent exposure to mammalian meat or other products containing alpha-gal can lead to allergic reactions.
CASE PRESENTATION
A previously healthy man in his sixties was admitted with acute anaphylaxis. A history of multiple tick bites and recent consumption of mammalian meat raised suspicion of anaphylaxis caused by alpha-gal syndrome.
INTERPRETATION
A diagnosis of alpha-gal syndrome was given based on elevated alpha-gal IgE antibodies, and further supported by medical history and clinical assessment. He was discharged with dietary instructions to eliminate food and products containing alpha-gal, and to manage allergy symptoms and anaphylaxis according to local guidelines.
Topics: Humans; Anaphylaxis; Food Hypersensitivity; Male; Immunoglobulin E; Tick Bites; Middle Aged; Red Meat
PubMed: 38934309
DOI: 10.4045/tidsskr.24.0122 -
Vaccine: X Aug 2024Comirnaty, Pfizer-BioNTech's polyethylene-glycol (PEG)-containing Covid-19 vaccine, can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis...
BACKGROUND
Comirnaty, Pfizer-BioNTech's polyethylene-glycol (PEG)-containing Covid-19 vaccine, can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis in a small fraction of immunized people. A causal role of anti-PEG antibodies (Abs) has been proposed, but causality has not yet proven in an animal model. The aim of this study was to provide such evidence using pigs immunized against PEG, which displayed very high levels of anti-PEG antibodies (Abs). We also aimed to find evidence for a role of complement activation and thromboxane A2 release in blood to explore the mechanism of anaphylaxis.
METHODS
Pigs (n = 6) were immunized with 0.1 mg/kg PEGylated liposome (Doxebo) i.v., and the rise of anti-PEG IgG and IgM were measured in serial blood samples with ELISA. After ∼2-3 weeks the animals were injected i.v. with 1/3 human dose of the PEGylated mRNA vaccine, Comirnaty, and the hemodynamic (PAP, SAP) cardiopulmonary (HR, EtCO2,), hematological (WBC, granulocyte, lymphocyte and platelet counts) parameters and blood immune mediators (anti-PEG IgM and IgG antibodies, thromboxane B2, C3a) were measured as endpoints of HSRs (anaphylaxis).
RESULTS
The level of anti-PEG IgM and IgG rose 5-10-thousand-fold in all of 6 pigs immunized with Doxebo by day 6, after which time all animals developed anaphylactic shock to i.v. injection of 1/3 human dose of Comirnaty. The reaction, starting within 1 min involved maximal pulmonary hypertension and decreased systemic pulse pressure amplitude, tachycardia, granulo- and thrombocytopenia, and skin reactions (flushing or rash). These physiological changes or their absence were paralleled by C3a and TXB2 rises in blood.
CONCLUSIONS
Consistent with previous studies, these data show a causal role of anti-PEG Abs in the anaphylaxis to Comirnaty, which involves complement activation, and, hence, it represents C activation-related pseudo-anaphylaxis. The setup provides the first large-animal model for mRNA-vaccine-induced anaphylaxis in humans.
PubMed: 38933697
DOI: 10.1016/j.jvacx.2024.100497 -
Frontiers in Pharmacology 2024Fexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists...
Establishment of a human nasal epithelium model of histamine-induced inflammation to assess the activity of fexofenadine as an inverse agonist and its link to clinical benefit.
BACKGROUND
Fexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists may be more potent than neutral antagonists, as they bind the same receptor as the agonist (HIS) but stabilize the inactive form and induce an opposite pharmacological response, suppressing the basal activity of H1R and preventing HIS from binding. This study aims to establish and validate a model of HIS-induced inflammation based on fully reconstituted human nasal epithelial tissue to assess the activity of FEX as an inverse agonist in this model and explore its link to clinical benefit.
METHODS
The model was developed using nasal MucilAir™ (Epithelix) epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS + FEX with or without FEX pre-treatment (one-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression, and inflammatory cytokines were assessed.
RESULTS
HIS at 100 µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin (IL)-8 and IL-6, respectively ( < 0.0001), as well as rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced ( < 0.0001). FEX alone decreased H1R expression at all doses tested. With one-hour FEX pre-treatment, there was significantly higher downregulation of IL-8 ( < 0.05) and further downregulation of H1R expression and IL-6 without FEX pre-treatment; the effects of FEX were improved from 22% to 40%.
CONCLUSION
A model of HIS-induced airway inflammation was established based on IL-8, IL-6 and H1R gene expression and was validated with FEX. FEX works as an inverse agonist, with a higher effect when used before+during only during the HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene expression, providing stronger protection against the worsening of symptoms upon allergen exposure.
PubMed: 38933682
DOI: 10.3389/fphar.2024.1393702 -
Frontiers in Pharmacology 2024Cystic fibrosis transmembrane conductance regulator modulators are the only available treatment for cystic fibrosis. Although elexacaftor/tezacaftor/ivacaftor...
Cystic fibrosis transmembrane conductance regulator modulators are the only available treatment for cystic fibrosis. Although elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is well-tolerated, rash has been reported as very frequent. In severe rashes, ELX/TEZ/IVA withdrawal is necessary, leading to clinical deterioration. The objective of the study is to increment the experience of ELX/TEZ/IVA desensitization. Adult patients who developed a delayed hypersensitivity rash to ELX/TEZ/IVA between December 2021 and February 2023 and required withdrawal due to ineffective rescue medication were included. Skins test for ELX/TEZ/IVA and IVA were conducted to establish hypersensitivity mechanism. Balijepally ELX/TEZ/IVA desensitization protocol was selected. In cases where desensitization had to be discontinued due to rash, an extended desensitization was proposed. Clinical and health-related quality of life parameters were collected before ELX/TEZ/IVA and after desensitization. 162 patients (81 women, 31.2 [23.8-42.5] years) started ELX/TEZ/IVA, developing rash 12 of them (7.4%, six women). Six patients (five women) required stopping ELX/TEZ/IVA and were selected for desensitization. Skin tests indicated delayed type-IV hypersensitivity in one patient. Two patients presented adequate tolerance to desensitization; while, four patients developed rash. Three of these patients, successfully concluded extended desensitization (one patient declined participation). No significant clinical deterioration or quality of life worsening was observed during desensitization; in fact, there was an improvement in practically all mesured parameters. All five patients who resumed ELX/TEZ/IVA are currently receiving therapy with good tolerance. Desensitization to ELX/TEZ/IVA could be a successful and safe strategy for reintroducing this essential treatment in cases of a delayed hypersensitivity rash.
PubMed: 38933680
DOI: 10.3389/fphar.2024.1392986