BACKGROUND: Presensitized patients with circulating donor-specific antibodies (DSAs) before transplantation are at risk for antibody-mediated rejection (AMR). Peritransplant desensitization mitigates but does not eliminate the alloimmune response. We examined the possibility that subthreshold AMR activity undetected by histology could be operating in some early biopsies. METHODS: Transcriptome of kidney allograft biopsies performed within the first month in presensitized patients (DSA+) who had received desensitization and did not develop active/probable AMR by histology (R-) was compared with biopsies showing active/probable AMR (R+/DSA+). As negative controls, biopsies without rejection by histology in patients without DSA at transplantation were used (R-/DSA-). RNA sequencing from biopsies selected from the biobank was used in cohort 1 (n = 32) and microarray, including the molecular microscope (Molecular Microscope Diagnostic System [MMDx]) algorithm, in recent cohort 2 (n = 30). RESULTS: The transcriptome of R-/DSA+ was similar to R+/DSA+ as these groups differed in 14 transcripts only. Contrarily, large differences were found between both DSA+ groups and negative controls. Fast gene set enrichment analyses showed upregulation of the immune system in both DSA+ groups (gene ontology terms: adaptive immune response, humoral immune response, antigen receptor-mediated signaling, and B-cell receptor signaling or complement activation) when compared with negative controls. MMDx assessment in cohort 2 classified 50% of R-/DSA+ samples as AMR and found no differences in AMR molecular scores between R+ and R- DSA+ groups. In imlifidase desensitization, MMDx series showed a gradual increase in AMR scores over time. CONCLUSIONS: Presensitized kidney transplant recipients exhibited frequent molecular calls of AMR in biopsy-based transcript diagnostics despite desensitization therapy and negative histology.

• Publication type
• Journal Article MeSH

BACKGROUND: The safety profile of venom immunotherapy (VIT) is a relevant issue, and considerable differences have been reported in the safety and efficacy of this treatment modality. The primary aim of this study was to evaluate the safety of angiotensin-converting enzyme inhibitors and ß-blockers during VIT. In a second analysis, we evaluated data on premedication and venom preparations and their association with systemic adverse events (AEs) during the up-dosing phase and the first year of the maintenance phase, as well as the outcome of field stings and sting challenges. METHODS: Ours was an open, prospective, observational, multicenter study that recruited 1425 patients, of whom 1342 underwent VIT. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during up-dosing and 19.7% of patients during the maintenance phase. Antihistamines had no effect on the frequency of systemic AEs (P=.11), although large local reactions (LLRs) were less frequent (OR, 0.74; 95%CI, 0.58-0.96; P=.02). Aqueous preparations were preferred for up-dosing (73.0%), and depot preparations were used for the maintenance phase (64.5%). The type of venom preparation had no influence on the frequency of systemic AEs or on the effectiveness of VIT (P=.26 and P=.80, respectively), while LLRs were less frequent with depot preparations (P<.001). CONCLUSIONS: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLRs but not systemic AEs. All venom preparations were equally effective and did not differ in terms of the frequency of systemic AEs.

• MeSH
• Allergens immunology   administration & dosage   MeSH
• Histamine Antagonists therapeutic use   MeSH
• Adrenergic beta-Antagonists therapeutic use   MeSH
• Desensitization, Immunologic * methods   adverse effects   MeSH
• Child MeSH
• Adult MeSH
• Angiotensin-Converting Enzyme Inhibitors therapeutic use   adverse effects   MeSH
• Insect Bites and Stings immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Prospective Studies MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Venoms immunology   adverse effects   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

Background: Activation of cannabinoid receptor 1 (CB1R) in the nervous system modulates the processing of acute and chronic pain. CB1R activity is regulated by desensitization and internalization. SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1) inhibits the internalization of CB1R. This causes increased and prolonged association of the desensitized receptor with G protein-coupled receptor kinase 3 (GRK3) and beta-arrestin on the cell membrane and results in decreased activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Genetic deletion of SGIP1 in mice leads to altered CB1R-related functions, such as decreased anxiety-like behaviors, modified cannabinoid tetrad behaviors, reduced acute nociception, and increased sensitivity to analgesics. In this work, we asked if deletion of SGIP1 affects chronic nociception and analgesic effect of Δ9-tetrahydrocannabinol (THC) and WIN 55,212-2 (WIN) in mice. Methods: We measured tactile responses of hind paws to increasing pressure in wild-type and SGIP1 knock-out mice. Inflammation in the paw was induced by local injection of carrageenan. To determine the mechanical sensitivity, the paw withdrawal threshold (PWT) was measured using an electronic von Frey instrument with the progression of the applied force. Results: The responses to mechanical stimuli varied depending on the sex, genotype, and treatment. SGIP1 knock-out male mice exhibited lower PWT than wild-type males. On the contrary, the female mice exhibited comparable PWT. Following THC or WIN treatment in male mice, SGIP1 knock-out males exhibited PWT lower than wild-type males. THC treatment in SGIP1 knock-out females resulted in PWT higher than after THC treatment of wild-type females. However, SGIP1 knock-out and wild-type female mice exhibited similar PWT after WIN treatment. Conclusions: We provide evidence that SGIP1, possibly by interacting with CB1R, is involved in processing the responses to chronic pain. The absence of SGIP1 results in enhanced sensitivity to mechanical stimuli in males, but not females. The antinociceptive effect of THC is superior to that of WIN in SGIP1 knock-out mice in the carrageenan-induced model of chronic pain.

• MeSH
• Benzoxazines * pharmacology   MeSH
• Hyperalgesia * genetics   MeSH
• Morpholines pharmacology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout * MeSH
• Mice MeSH
• Naphthalenes MeSH
• Nociception drug effects   MeSH
• Receptor, Cannabinoid, CB1 * genetics   metabolism   MeSH
• Dronabinol * pharmacology   MeSH
• Inflammation * MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Alergia na jed blanokrídleho hmyzu je častou príčinou anafylaxie a môže viesť k vzniku závažných až fatálnych reakcií. Diagnostika ochorenia a stanovenie príčinného alergénu sú založené na anamnéze, kožných testoch a vyšetrení prítomnosti sIgE. V sporných prípadoch sú odporúčané bunkové testy. Liečba alergie na jed blanokrídleho hmyzu zahŕňa krátkodobé intervencie zamerané na liečbu akútnych reakcií a dlhodobé liečebné stratégie s cieľom minimalizovať riziko nasledujúcich reakcií. Jedinou liečbou účinnou v prevencii systémových reakcií vyvolaných hmyzím bodnutím je alergénová imunoterapia (VIT). VIT prebieha v dvoch fázach, iniciálnej a udržiavacej. Pre navyšovanie dávok alergénu v iniciálnej fáze liečby je k dispozícii viacero protokolov, udržiavacia dávka jedu tak môže byť dosiahnutá v priebehu jedného dňa (ultra-rush režim), za dva až päť dní (rush režim), alebo v priebehu týždňov až mesiacov (cluster a konvenčný režim).

Hymenoptera venom allergy (HVA) is a common cause of anaphylaxis and may be fatal. Diagnosis of the HVA and the identification of the appropriate venom for immunotherapy are based on detailed patient’s medical history, skin tests and detection of sIgE. In unclear cases, the cellular tests are recommended. The management of hymenoptera venom allergy includes short-term interventions to treat acute reactions and long-term strategies to minimize the risk of consecutive reactions. The only treatment to prevent further systemic sting reactions is venom immunotherapy (VIT). There are 2 phases of VIT: the initial build-up phase and the maintenance phase. There are numerous protocols for dose increase during the initial phase of VIT, e. g. the maintenance dose may be reached within one day (ultra-rush), after two to five days (rush) or within weeks or months (cluster, conventional).

• MeSH
• Anaphylaxis diagnosis   therapy   MeSH
• Hypersensitivity, Immediate diagnosis   immunology   therapy   MeSH
• Desensitization, Immunologic methods   adverse effects   MeSH
• Hymenoptera MeSH
• Immunologic Tests MeSH
• Arthropod Venoms immunology   adverse effects   MeSH
• Insect Bites and Stings immunology   prevention & control   therapy   MeSH
• Humans MeSH
• Venom Hypersensitivity * diagnosis   prevention & control   therapy   MeSH
• Cross Reactions MeSH
• Check Tag
• Humans MeSH

Intravenous immunoglobulins (IVIG) are commonly used in peri-transplant desensitization, but evidence supporting their efficacy is limited. We conducted a prospective, randomized single-center, open-label, Phase IIIb non-inferiority clinical pilot trial to compare the efficacy of IVIG (administered at a dose of 3 × 0.5 g/kg) versus no IVIG, in conjunction with rabbit anti-thymocyte globulin (5-7 mg/kg) induction, in pre-sensitized patients with donor-specific antibodies who had negative pre-transplantation Flow- and CDC-crossmatches, between July 2020 and November 2022. The primary endpoint was the rate of efficacy failure, defined as biopsy-proven rejection within 12-month post-transplant. Secondary endpoints included the incidence of rejection at protocol biopsies, evaluated by histology and biopsy-based transcripts diagnostics. Of the screened patients, 53 (72.6%) were excluded due to crossmatch positivity. Ten patients were randomized to the IVIG+, and 7 to the IVIG-arm. The trial was prematurely terminated due to futility at interim analysis. In the IVIG-arm, 3 patients (43%) experienced the primary endpoint compared to none in the IVIG+ arm (p = 0.026). MMDx identified one molecular ABMR in the IVIG+ and 2 in the IVIG-arm in 12-month protocol biopsies. There was one graft loss in the IVIG-arm. The results of this pilot study, although not definitive, do not support the use of IVIG-sparing regimens in HLA-incompatible kidney transplantation (NCT04302805). This study is registered on ClinicalTrials.gov under the identifier NCT04302805.

• MeSH
• Antilymphocyte Serum * administration & dosage   MeSH
• Desensitization, Immunologic * methods   MeSH
• Adult MeSH
• Immunoglobulins, Intravenous * administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pilot Projects MeSH
• Prospective Studies MeSH
• Graft Rejection * prevention & control   immunology   MeSH
• Kidney Transplantation * adverse effects   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

Alergie na pyly břízovitých stromů je narůstajícím problémem průmyslových zemí. Onemocnění se vyvíjí u predisponovaných osob v důsledku inhalace pylových zrn břízy a dalších příbuzných stromů. Klinické projevy alergie na pyl jarních stromů (sezónní alergická rhinokonjunktivitis, sezónní alergické astma bronchiale a sekundární pylově potravinový syndrom) mají signifikantně negativní vliv na kvalitu života pacientů. Tento přehledový článek pojednává o taxonomii stromů, zkřížené reaktivitě mezi nimi a mezi relevantními potravinami, epidemiologii, vlivu klimatických změn a v neposlední řadě o možnostech léčby včetně alergenové imunoterapie.

Tree pollen allergy presents an increasing problem in industrialized countries. This disease develops in sensitised people after inhalation of pollen grains of birch and other related trees. Clinical symptoms of tree pollen allergy (seasonal allergic rhinoconjunctivitis, seasonal asthma bronchiale and secondary pollen food syndrome) have significant negative impact on the quality of life in these patients. The purpose of this review is to touch the taxonomy of the trees, describe cross-reactivity of relevant allergens, prevalence, the influence of climatic changes and to stress the importance of allergen immunotherapy as a disease modifying treatment.

• Keywords
• zkřížená reaktivita, pylově potravinový syndrom,
• MeSH
• Betula adverse effects   MeSH
• Betulaceae adverse effects   MeSH
• Desensitization, Immunologic MeSH
• Humans MeSH
• Rhinitis, Allergic, Seasonal * physiopathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Highly sensitized (HS) patients in need of kidney transplantation (KTx) typically spend a longer time waiting for compatible kidneys, are unlikely to receive an organ offer, and are at increased risk of antibody-mediated rejection (AMR). Desensitization using imlifidase, which is more rapid and removes total body immunoglobulin G (IgG) to a greater extent than other methods, enables transplantation to occur between HLA-incompatible (HLAi) donor-recipient pairs and allows patients to have greater access to KTx. However, when the project was launched there was limited data and clinical experience with desensitization in general and with imlifidase specifically. Hence, this Delphi methodology was used to reach a consensus from a multi-disciplinary team (MDT) of experts from 15 countries on the management of HS patients undergoing imlifidase HLAi from a deceased donor (DD) KTx. This Delphi consensus provides clinical practice guidance on the use of imlifidase in the end-to-end management of HS patients undergoing an HLAi DD KTx and supports centers in the development of guidelines for the utilization and integration of imlifidase into clinical practice.

• MeSH
• Tissue Donors * MeSH
• Delphi Technique * MeSH
• Desensitization, Immunologic * methods   MeSH
• HLA Antigens * immunology   MeSH
• Immunoglobulin G MeSH
• Consensus * MeSH
• Humans MeSH
• Graft Rejection prevention & control   immunology   MeSH
• Kidney Transplantation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.

• MeSH
• Chronic Disease MeSH
• Humans MeSH
• Disease Management MeSH
• Nasal Polyps * therapy   diagnosis   MeSH
• Rhinosinusitis * diagnosis   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

The somatostatin (SST) receptor family controls pituitary hormone secretion, but the distribution and specific roles of these receptors on the excitability and voltage-gated calcium signaling of hormone producing pituitary cells have not been fully characterized. Here we show that the rat pituitary gland expressed Sstr1, Sstr2, Sstr3, and Sstr5 receptor genes in a cell type-specific manner: Sstr1 and Sstr2 in thyrotrophs, Sstr3 in gonadotrophs and lactotrophs, Sstr2, Sstr3, and Sstr5 in somatotrophs, and none in corticotrophs and melanotrophs. Most gonadotrophs and thyrotrophs spontaneously fired high-amplitude single action potentials, which were silenced by SST without affecting intracellular calcium concentrations. In contrast, lactotrophs and somatotrophs spontaneously fired low-amplitude plateau-bursting action potentials in conjunction with calcium transients, both of which were silenced by SST. Moreover, SST inhibited GPCR-induced voltage-gated calcium signaling and hormone secretion in all cell types expressing SST receptors, but the inhibition was more pronounced in somatotrophs. The pattern of inhibition of electrical activity and calcium signaling was consistent with both direct and indirect inhibition of voltage-gated calcium channels, the latter being driven by cell type-specific hyperpolarization. These results indicate that the action of SST in somatotrophs is enhanced by the expression of several types of SST receptors and their slow desensitization, that SST may play a role in the electrical resynchronization of gonadotrophs, thyrotrophs, and lactotrophs, and that the lack of SST receptors in corticotrophs and melanotrophs keeps them excitable and ready to responses to stress.

• MeSH
• Action Potentials drug effects   MeSH
• Gonadotrophs metabolism   drug effects   MeSH
• Pituitary Gland * metabolism   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Receptors, Somatostatin * metabolism   genetics   MeSH
• Somatostatin metabolism   MeSH
• Calcium metabolism   MeSH
• Calcium Signaling * drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Allergens immunology   classification   MeSH
• Hypersensitivity * diagnosis   drug therapy   immunology   physiopathology   MeSH
• Anaphylaxis drug therapy   MeSH
• Leukotriene Antagonists pharmacology   classification   therapeutic use   MeSH
• Histamine Antagonists pharmacology   classification   therapeutic use   MeSH
• Bronchodilator Agents pharmacology   classification   therapeutic use   MeSH
• Desensitization, Immunologic classification   methods   MeSH
• Glucocorticoids pharmacology   classification   therapeutic use   MeSH
• Immunoglobulin E immunology   MeSH
• Mast Cell Stabilizers pharmacology   therapeutic use   MeSH
• Publication type
• Review MeSH