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In allergen-specific immunotherapy, adjuvants are explored for modulating allergen-specific Th2 immune responses to re-establish clinical tolerance. One promising class of adjuvants are β-glucans, which are naturally derived sugar structures and components of dietary fibers that activate C-type lectin (CLR)-, "Toll"-like receptors (TLRs), and complement receptors (CRs). We characterized the immune-modulating properties of six commercially available β-glucans, using immunological (receptor activation, cytokine secretion, and T cell modulating potential) as well as metabolic parameters (metabolic state) in mouse bone marrow-derived myeloid dendritic cells (mDCs). All tested β-glucans activated the CLR Dectin-1a, whereas TLR2 was predominantly activated by Zymosan. Further, the tested β-glucans differentially induced mDC-derived cytokine secretion and activation of mDC metabolism. Subsequent analyses focusing on Zymosan, Zymosan depleted, β-1,3 glucan, and β-1,3 1,6 glucan revealed robust mDC activation with the upregulation of the cluster of differentiation 40 (CD40), CD80, CD86, and MHCII to different extents. β-glucan-induced cytokine secretion was shown to be, in part, dependent on the activation of the intracellular Dectin-1 adapter molecule Syk. In co-cultures of mDCs with Th2-biased CD4+ T cells isolated from birch allergen Bet v 1 plus aluminum hydroxide (Alum)-sensitized mice, these four β-glucans suppressed allergen-induced IL-5 secretion, while only Zymosan and β-1,3 glucan significantly suppressed allergen-induced interferon gamma (IFNγ) secretion, suggesting the tested β-glucans to have distinct effects on mDC T cell priming capacity. Our experiments indicate that β-glucans have distinct immune-modulating properties, making them interesting adjuvants for future allergy treatment. [ABSTRACT FROM AUTHOR]

Background. Autoimmune thyroiditis (AIT) affects more than 5 % of the world’s population.The aim. To determine the level of sPD-1, sPD-L1, sCTLA-4 and sB7.2 molecules in individuals suffering from various forms of autoimmune thyroiditis.Methods. The study included 31 individuals aged 18 to 40 years. They were divided into four groups: group I – healthy individuals (n = 10); group II – carriers of antibodies to thyroid peroxidase (n = 11); group III – individuals with AIT accompanied with subclinical form of hypothyroidism (n = 6); group IV – individuals with AIT complicated by compensated hypothyroidism (n = 4). Venous blood was collected to determine the level of antibodies to thyroid peroxidase using enzyme immunoassay, the concentration of thyroid stimulating hormone and free thyroxine – using chemiluminescence immunoassay, and the levels of sPD-1, sPD-1L, sCTLA-4, and sB7.2 – using flow cytofluorometry. Statistical processing was performed using the Kruskal – Wallis one-way analysis of variance.Results. When comparing the level of sPD-1L in groups I (54.1 (28.7; 67.6) pg/ml) and II (4.36 (2.36; 18.0) pg/ml), the decreased in this indicator was 91.94 % (p = 0.001). When comparing the sPD-1 level in the group of healthy individuals (16.6 (13.6; 37.2) pg/ml) and group IV (7.28 (5.18; 11.1) pg/ml), werecorded a decrease of 56.14 % (p = 0.001). The sB7.2 concentration decreased by 65.03 % in group II (16.4 (15.6; 32.7) pg/ml) compared to the control group (46.9 (39.3; 54.4) pg/ml) (p = 0.001). In group III, the sCTLA-4 level was 3.22 (3.06; 3.33) pg/ml and decreased by 88.66% compared to the control group (p = 0.001).Conclusion. The development of autoimmune thyroiditis is accompanied with the decrease in the concentration of sPD-1, sPD-1L, sCTLA-4 and sB7.2.

Background: Allergen immunotherapy (AIT) may have a long‐term disease‐modifying effect. The aim of this study was to demonstrate the long‐term effects of pollen allergoid tyrosine‐adsorbed subcutaneous AIT on allergic rhinitis (AR) and asthma (AA) in clinical practice. Methods: This retrospective study, funded by an AIT manufacturer, analysed the impact of AIT on AR progression and onset of need for AA medication, using a German database covering ~35% of national prescriptions during 2008–2020. Anonymized prescription data of AR patients aged 5–65 years treated with grass or tree pollen AIT between 2009 and 2013 and followed for at least 2 years after AIT cessation were compared with matched control patients with seasonal AR. Results: 181,496 patients received AIT prescriptions. 5959 fulfilled the inclusion criteria. The median AIT treatment duration was 1092 days and the follow‐up duration was 6.4 years. Less patients treated with AIT received prescriptions for symptomatic AR medication in the follow‐up versus controls (AIT: OR: 0.37; 95% Confidence Interval (CI) 0.34, 0.40; p <.001, tyrosine‐adsorbed AIT: OR: 0.27; 95% CI 0.20, 0.35 p <.001). Less asthmatic patients under AIT received prescriptions for AA medications versus controls (AIT: OR: 0.48; 95% CI 0.41, 0.55; p <.001, tyrosine‐adsorbed AIT: OR: 0.48; 95% CI 0.29, 0.79; p =.004). AR and AA medication prescriptions for AIT patients were reduced in the follow‐up versus baseline and controls (AIT: AR: 20.0%; 1.5 vs. 0.2 prescriptions; AA: 29.1%; 2.0 vs. 0.6 prescriptions, p <.001; tyrosine‐adsorbed AIT: AR: 24.2%, 1.4 vs. 0.2 prescriptions; AA: 35.6%, 2.1 vs. 0.6 prescriptions, p <.001). The probability of AA medication onset in non‐asthmatic patients during follow‐up was reduced for AIT patients compared to controls (OR: 0.77, 95% CI 0.66, 0.90; p =.001). All endpoints were significant for children/adolescents and adults in stratified analyses. Conclusions: We found evidence for long‐term effects up to 9.5 years for tyrosine‐adsorbed AIT. [ABSTRACT FROM AUTHOR]

Objective: Amiodarone is an iodine-rich molecule and an effective antiarrhythmic drug. It is a first-line treatment for patients with life-threatening ventricular arrhythmias and for prevention in patients at high risk. The use of amiodarone may cause serious adverse effects such as pharmacotherapy-resistant, life-threatening amiodarone-induced thyrotoxicosis (AIT)leading to rapid deterioration of the patient's condition.According to the European Thyroid Association (ETA) guidelines, emergency thyroidectomy is the first-line treatment option in these cases. ; however, is not always feasible in the clinical setting due to the high anesthetic risk.We aimed to assess the clinical course and results of urgent thyroidectomy and 131-I therapy in patients with severe AIT with worsening of cardiac status. Methods: Retrospective analysis of the clinical course and outcomes of life-threatening AIT refractory to pharmacotherapy in patients hospitalized at a tertiary endocrinology center between 2014 and 2022. Results: An electronic database search identified 75 patients hospitalized for severe AIT. At the time of AIT diagnosis, median Thyroid-stimulating hormone (TSH) concentration was 0.001 mIU/L (range 0.001–0.35), fT4 63.2 pmol/L (range 9.0 - >100), and fT3 10.2 pmol/L (range 3.8–49.3). All patients received optimal conservative treatment. Among them, 20 required urgent radical therapy due to worsening arrhythmias and/or AIT-related heart failure. In this group, 6 patients died before any radical treatment was applied, 6 underwent total thyroidectomy, while 8 patients were successfully treated with 131-I (in 6 cases after rhTSH stimulation). The median dose of 131-I used for the therapy was 784MBq (range 627–860). The decision to treat with 131-I despite low but detectable 131-I uptake (median value 6 %) was made in cases of significant contraindications to anesthesia due to refractory ventricular arrhythmias, exacerbation of severe heart failure unresponsive to cardiac treatment, myocardial infarction during AIT course, massive pulmonary embolism. Conclusion: The decision regarding the optimal time and type of radical treatment of AIT refractory to pharmacotherapy is critical for patients management and should not be delayed. Urgent therapy with 131-I may be an effective therapeutic option in patients who are unsuitable for thyroidectomy due to the high risk of anesthesia.

In allergen-specific immunotherapy, adjuvants are explored for modulating allergen-specific Th2 immune responses to re-establish clinical tolerance. One promising class of adjuvants are β-glucans, which are naturally derived sugar structures and components of dietary fibers that activate C-type lectin (CLR)-, “Toll”-like receptors (TLRs), and complement receptors (CRs). We characterized the immune-modulating properties of six commercially available β-glucans, using immunological (receptor activation, cytokine secretion, and T cell modulating potential) as well as metabolic parameters (metabolic state) in mouse bone marrow-derived myeloid dendritic cells (mDCs). All tested β-glucans activated the CLR Dectin-1a, whereas TLR2 was predominantly activated by Zymosan. Further, the tested β-glucans differentially induced mDC-derived cytokine secretion and activation of mDC metabolism. Subsequent analyses focusing on Zymosan, Zymosan depleted, β-1,3 glucan, and β-1,3 1,6 glucan revealed robust mDC activation with the upregulation of the cluster of differentiation 40 (CD40), CD80, CD86, and MHCII to different extents. β-glucan-induced cytokine secretion was shown to be, in part, dependent on the activation of the intracellular Dectin-1 adapter molecule Syk. In co-cultures of mDCs with Th2-biased CD4+ T cells isolated from birch allergen Bet v 1 plus aluminum hydroxide (Alum)-sensitized mice, these four β-glucans suppressed allergen-induced IL-5 secretion, while only Zymosan and β-1,3 glucan significantly suppressed allergen-induced interferon gamma (IFNγ) secretion, suggesting the tested β-glucans to have distinct effects on mDC T cell priming capacity. Our experiments indicate that β-glucans have distinct immune-modulating properties, making them interesting adjuvants for future allergy treatment.

Introduction: Group 2 innate lymphoid cells (ILC2s) play a crucial role in house dust mite (HDM)-induced allergic inflammation, and allergen immunotherapy (AIT) holds promise for treating the disease by reducing the frequency of ILC2s. Despite significant progress in AIT for allergic diseases, there remains a need to improve the control of allergic symptoms. Methods: We investigated the synergistic effect of the Notch signaling pathway and subcutaneous immunotherapy (SCIT) in treating allergic airway inflammation in mice and their impact on the ratio of ILC2s in lung tissues. This was achieved by establishing the HDM-induced airway allergic disorders (HAAD) model and SCIT model. Additionally, we conducted in vitro investigations into the effect of the Notch signaling pathway on the secretory function of activated ILC2s using fluorescence-activated cell sorting. Furthermore, we explored the coactivation of the Notch signaling pathway with SCIT in vitro by sorting ILC2s from the lung tissues of mice after SCIT modeling. Results: Previously, our group demonstrated that Notch signaling pathway inhibitors can reduce allergic airway inflammation in mice. Notch signaling induces lineage plasticity of mature ILC2s. In this study, we showed that AIT alleviates allergic airway inflammation and suppresses the frequency of ILC2s induced by HDM. Interestingly, AIT combined with a g-secretase inhibitor (GSI), an inhibitor of the Notch signaling pathway, significantly inhibited the frequency of ILC2s, reduced airway inflammation, and suppressed Th2-type responses in a mouse model. Furthermore, lung ILC2s from HDM-challenged mice with or without AIT were treated with GSI in vitro, and we found that GSI dramatically reduced the secretion of type 2 inflammatory factors in ILC2s. Discussion: These findings suggest that Notch signaling pathway inhibitors can be used as adjuvant therapy for AIT and may hold potential treatment value in the cooperative control of allergic airway inflammation during early AIT. [ABSTRACT FROM AUTHOR]

Introduction: Allergen‐specific immunotherapy (AIT) is the only disease‐modifying treatment in allergic airway diseases. Underlying immunological mechanisms and candidate biomarkers, which may be translated into predictive/surrogate measures of clinical efficacy, remain an active area of research. The aim of this study was to evaluate Pollinex Quattro (PQ) Grass AIT induced immunomodulatory mechanisms, based on transcriptome profiling of peripheral blood mononuclear cells. Methods: 119 subjects with grass pollen induced seasonal allergic rhinitis (SAR) were randomized in a 2:2:1:1 ratio to receive a cumulative dose of PQ Grass as a conventional or extended pre‐seasonal regimen, placebo, or placebo with MicroCrystalline Tyrosine. Gene expression analysis was an exploratory endpoint evaluated in a subgroup of 30 subjects randomly selected from the four treatment arms. Samples were collected at three time points: screening (baseline), before the start of the grass pollen season and at the end of the season. This study was funded by the manufacturer of PQ. Results: Transcriptome analysis demonstrated that the most significant changes in gene expression, for both treatment regimens, were at the end of the grass pollen season, with the main Th1 candidate molecules (IL‐12A, IFNγ) upregulated and Th2 signature cytokines downregulated (IL‐4, IL‐13, IL‐9) (p <.05). Canonical pathways analysis demonstrated Th1, Th2, Th17 and IL‐17 as the most significantly enriched pathways based on absolute value of activation z‐score (IzI score ≥ 2, p <.05). Upstream regulator analysis showed pronounced inhibition of pro‐inflammatory allergic molecules IgE, IL‐17A, IL‐17F, IL‐25 (IL‐17E) (IzI score ≥ 2, FDR < 0.05) and activation of pro‐tolerogenic molecules IL‐12A, IL‐27, IL‐35 (EBI3) at the end of the grass pollen season. Conclusion: Peripheral blood mononuclear cells transcriptome profile showed an inhibition of Th2, Th17 pro‐inflammatory allergic responses and immune deviation towards Th1 responses. PQ Grass extended regimen exhibited a superior mechanistic efficacy profile in comparison with PQ conventional regimen. [ABSTRACT FROM AUTHOR]

To date, there has been a steady increase in allergic diseases, which is a heavy burden on the population and the health care system. The high prevalence, chronic course and pronounced impact on the quality of life require specialists to take a rational approach to the treatment of allergic pathology. From the moment of its appearance to the present, antihistamines have been widely used in real clinical practice, without losing their relevance. This article examines the place of antihistamines in modern therapy of the most common allergic and other histamine-dependent diseases.

Abstract Several studies have been carried out to expand the use of Ricinus communis L. castor bean (Ricinus communis L castor bean.). This oilseed finds appropriate conditions for its development in Brazil, with more than 700 applications. The main allergens of this plant are Ric c1 and Ric c3, that cross-react with various aeroallergens and food allergens such as peanuts, soybeans, corn, and wheat. This study aimed to determine the effect of mutations in Ric c3 amino acid residues known to affect IgE binding and allergy challenges. Based on the Ric c3 structure, B-cell epitopes, and amino acid involved in IgE binding, we produce recombinant mutant protein, mrRic c3, secreted from E. coli. Strategic glutamic acid residues in IgE-biding regions were changed by Leucine. The allergenicity of mrRic c3 was evaluated by determination of IgE, IgG1, and total IgG in immunized Balb/c mice and by degranulation assays of mast cells isolated from Wistar rats. The mrRic c3 presented a percentage of mast cell degranulation close to that seen in the negative control, and the immunization of mice with mrRic c3 presented lower levels of IgE and IgG1 than the group treated with the protein without mutations. The mutant mrRic c3 had an altered structure and reduced ability to stimulate pro-inflammatory responses and bind IgE but retained its ability to induce blocking antibodies. Thus, producing a hypoallergenic mutant allergen (mrRic c3) may be essential in developing new AIT strategies.

Background: House dust mite extract–based allergen immunotherapy (AIT) to treat house dust mite allergy is substantially effective but still presents some safety and efficacy concerns that warrant improvement. Several major allergen-based approaches to increase safety and efficacy of AIT have been proposed. One of them is the use of the group 2 allergen, Der p 2. Objective: We sought to investigate the immunomodulatory effects of sialic acid–modified major allergen recombinant Der p 2 (sia-rDer p 2) on PBMCs from healthy volunteers. Methods: We activated PBMCs with anti-CD3/CD28 antibodies and incubated them at 37°C for 6 days in the presence or absence of either native rDer p 2 or α2-3 sialic acid–modified rDer p 2 (sia-rDer p 2). We assessed the changes in CD4+ T-cell activation and proliferation by flow cytometry and changes in T-lymphocyte cytokine production in cell culture supernatant by ELISA. Results: We observed that PBMCs treated with sia-rDer p 2 presented with a markedly decreased expression of CD69 and an increased abundance of LAG-3+ lymphocytes compared with cells treated with rDer p 2. Moreover, PBMCs treated with sia-rDer p 2 showed a reduced production of IL-4, IL-13, and IL-5 and displayed a higher IL-10/IL-5 ratio compared with rDer p 2–treated PBMCs. Conclusions: We demonstrate that sia-rDer p 2 might be a safer option than native rDer p 2 for Der p 2–specific AIT. This is most relevant in the early phase of AIT that is often characterized by heightened TH2 responses, because sia-rDer p 2 does not enhance the production of TH2 cytokines.

Introduction. Primary hypothyroidism is observed in women of reproductive age in 2–3 % of cases. The most common thyroid pathology during pregnancy is subclinical hypothyroidism (SHT), which is caused by newly diagnosed autoimmune thyroiditis (AIT) or severe iodine deficiency. In some regions of the Russian Federation, the population has a mild iodine deficiency, the average concentration of iodine in the urine being found at 78 µg/L (the normal range is 100–200 µg/L). In women with primary hypothyroidism, complications of pregnancy and childbirth include: premature birth, weakness of labor, eclampsia, premature rupture of premature rupture of membranes (PROM), gestational diabetes mellitus (GDM), intrauterine growth retardation syndrome, fetal macrosomia, congenital hypothyroidism in the fetus, etc.Aim: to study the features of pregnancy and childbirth course in women with primary hypothyroidism.Materials and Methods. In a retrospective study, there were analyzed 62 birth histories, of which 37 were for patients with thyroid diseases. Two groups were formed: the main group – 25 patients with primary hypothyroidism, the comparison group – 25 patients without thyroid pathology. During the study, the next parameters were analyzed: age, number of pregnancies, number of births, term of delivery, body mass index, level of thyroid stimulating hormone (TSH), titer of thyroid peroxidase antibodies, newborn body weight, newborn assessment according to Apgar scale.Results. In the main group, the cause of primary hypothyroidism was as follows: newly diagnosed SHT – in 18 (48.6 %), AIT – in 7 (18.9 %) pregnant women. In the first trimester of pregnancy, TSH level in patients with hypothyroidism was 3.06 ± 0.36 mU/L. The following complications of pregnancy and childbirth course were identified: GDM (32.0 %), anemia of the first degree (12.0 %), large fetus (12.0 %), PROM (12.0 %), perineal rupture of the first degree (16.0 %), anomalies of labor activity with ineffective labor stimulation (8.0 %), pelvic-head disproportion (8.0 %).Conclusion. Timely diagnosis and compensation of hypothyroidism with hormone replacement therapy and iodine preparations, prediction of possible complications and correction of identified complications are the main ways to achieve a successful outcome of pregnancy and childbirth for mother and fetus.

Context: Patients with amiodarone-induced thyrotoxicosis (AIT) often receive initial therapy for thyrotoxicosis in several different medical settings before admission to a referral center. Objective: This work aimed to determine whether first-line medical therapy (ie, therapies for thyrotoxicosis at first diagnosis of AIT) affects the outcome of AIT patients. Methods: A single-center historical-prospective cohort study was conducted on 313 AIT patients. Clinical and biochemical data were collected at first diagnosis, at a referral center, and during the course of AIT. Primary outcomes were cardiovascular (CV) events and hospitalizations. First-line therapies were considered appropriate when they included glucocorticoids for type 2 AIT and methimazole for type 1 AIT at the approved dose, either alone (optimal medical therapy, OMT) or in combination (right-dose combination therapy, RCT). Other therapies were considered not appropriate, including no therapy. Duration of exposure to thyrotoxicosis was the time from first diagnosis of AIT to its remission. Results: A total of 34.5% patients received appropriate therapies (28.1% OMT, 6.4% RCT), whereas the remaining (65.5%) received inappropriate therapies. CV events and hospitalizations were more frequent in patients who received inappropriate therapies (33.2% vs 4.5%, and 24.9% vs 6.5%, respectively; P<.0001 for both). Appropriate therapies reduced serum thyroid hormone concentrations (P=.018) from first diagnosis to referral, unlike the inappropriate therapies. The duration of exposure to thyrotoxicosis was longer in patients receiving inappropriate therapies and was a risk factor for arrhythmias (hazard ratio [HR] 1.004; P=.0008), major acute CV events (HR 1.004; P= .020), and hospitalizations (HR 1.006; P<.0001). Conclusion: The first medical therapy of AIT influences the exposure time to thyrotoxicosis and the occurrence of CV events and hospitalizations. [ABSTRACT FROM AUTHOR]

Advanced Integrative Therapy (AIT) is a novel therapy grounded in Energy Psychology combined with cognitive and somatic therapy techniques. As more research is being conducted into the efficacy of AIT and other trauma-based therapies, there is a need to define the modality more clearly for researchers, the clinical community, and potential clients. This article aims to discuss the theory behind AIT and its mechanism of action, compare it with other somatic trauma and Energy Psychology techniques, and explore the gap in the available data and knowledge of AIT. Additionally, a case study will be discussed to report on the potential clinical effectiveness of AIT in treating trauma-related dissociation. [ABSTRACT FROM AUTHOR]

Background: The experimental fusion protein rFlaA:Betv1 was shown to efficiently suppress allergen‐specific sensitization in mice. However, the detailed mechanism of rFlaA:Betv1‐mediated immune modulation is not fully understood. In this study, we investigated the effect of rFlaA:Betv1 on naïve murine B cells. Methods: Immune modulating capacity of rFlaA:Betv1 was screened in IL‐10 reporter mice. B cells were isolated from spleens of naïve C57Bl/6, TLR5−/−, or MyD88−/− mice, stimulated with rFlaA:Betv1 and controls, and monitored for the expression of the regulatory B cell markers CD1d, CD24, CD38, and surface IgM by flow cytometry. Secreted cytokines, antibodies, and reactivity of the induced antibodies were investigated by ELISA and intracellular flow cytometry. Suppressive capacity of rFlaA:Betv1‐stimulated B cells was tested in mDC:CD4+ T cell:B cell triple cultures. Results: Upon in vivo application of rFlaA:Betv1 into IL‐10‐GFP reporter mice, CD19+ B cells were shown to produce anti‐inflammatory IL‐10, suggesting B cells to contribute to the immune‐modulatory properties of rFlaA:Betv1. rFlaA:Betv1‐induced IL‐10 secretion was confirmed in human B cells isolated from buffy coats. In vitro stimulation of naïve murine B cells with rFlaA:Betv1 resulted in an mTOR‐ and MyD88‐dependent production of IL‐10 and rFlaA:Betv1 induced Bet v 1‐reactive IgG production, which was not observed for IgA. rFlaA:Betv1‐stimulated B cells formed a CD19+CD24+CD1d+IgM+CD38+ Breg subpopulation capable of suppressing Bet v 1‐induced TH2 cytokine secretion in vitro. Conclusion: rFlaA:Betv1 can act as a thymus‐independent B cell antigen, stimulating the mTOR‐ and MyD88‐dependent differentiation of B cells displaying a regulatory phenotype, IL‐10 secretion, antigen‐binding antibody production, and a suppressive capacity in vitro. [ABSTRACT FROM AUTHOR]

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Purpose: The success of satellites in orbit depends on the quality of the engineering processes adopted in the development cycle of the mission. The facilities and processes provided by Assembly, Integration and Testing (AIT) laboratories support the verification and validation of satellite’ systems regarding their capacities to operating into space environmental conditions. Choose an ideal AIT organization to a particular satellite project requires knowing their processes and services provided. This paper presents a framework for evaluating the services for satellite AIT provided by an AIT organization. The framework, named PRONT-AIT, allows to assess the organization’s readiness based on both process areas and criteria of adherence to the stakeholder’s requirements. Methodology/approach – Inspired by the CMMI model, the framework was structured in process areas, covering management and technical processes of the AIT organization, that supports 5 levels of readiness. Each readiness level expresses the organization maturity in terms of the processes and practices established to provide the services required by a particular space project. Findings – The framework’s effectiveness is demonstrated through its use to assess the readiness of a particular AIT organization on meeting the specific requirements of two types of satellites: remote sensing and CubeSat satellites. The results reveal that the example organization readiness fully reached level 2 (Manageable Readiness) for remote sensing satellite and partially reached level 2 for CubeSat satellite. Originality/value – The framework has a good value to satellite project managers because it supports them on evaluating an AIT organization prior to contracting its services. Higher readiness level revealed by PRONT-AIT gives to the satellite project manager more confidence on the AIT organization capacities. Thus, an AIT organization is not chosen solely on the basis of the facilities it offers and the cost of the services but also on the level of readiness revealed by this framework.

Background: Idursulfase and laronidase are drugs used to treat Hunter syndrome (mucopolysaccharidosis type 2) and Scheie syndrome (mucopolysaccharidosis type 1 S), respectively. These are rare lysosomal storage disorders, leading to accumulation of glycosaminoglycans within lysosomes. Failure of early recognition of the disease and/or delay in starting the appropriate treatment result in severe clinical impairment and death. For almost 20 years, enzyme replacement therapy with recombinant proteins has represented the first line therapeutic option. However, administration of idursulfase and laronidase is associated with infusion-related hypersensitivity reactions, in approx. 20% of patients. In these patients, rapid desensitization by intravenous administration protocols has been used in order to avoid treatment discontinuation. This approach proved effective and safe. However, long-term tolerance could not be achieved. Thus, we decided to combine rapid desensitization with allergen immunotherapy-like desensitization.Results: Two patients with Hunter syndrome and one patient with Scheie syndrome developed severe allergy to idursulfase and laronidase, respectively, preventing them from continuing the otherwise indispensable therapy. In all three patients, the possible IgE-mediated nature of the reactions suffered was suggested by positive skin tests with the two enzymes, respectively. By devising 12-step, 3-dilution rapid desensitization protocols, we resumed the enzyme replacement therapy. However, the prolonged time required for administration (a not negligible pitfall, since therapy should be given weekly for life) and the persistent occurrence of reactions (mild but still requiring anti-allergic medication at full dosage) led us to combine rapid desensitization with a compact 11-step, 24-day allergen immunotherapy-like desensitization protocol. Thus, idursulfase and laronidase were injected subcutaneously, with a 500-fold increase from step 1 to step 11 for idursulfase and a 222-fold increase for laronidase. This strategy led to restoration of long-term tolerance, allowing weekly intravenous therapy administration under standard conditions, according to the manufacturer instructions, in the absence of side effects and with only precautionary low-dose premedication.Conclusion: Rapid desensitization is a suitable and safe option in the case of idursulfase and laronidase allergy. Combination with subcutaneous allergen immunotherapy-like desensitization afforded restoration of enzyme replacement therapy given by the normal administration schedule, by inducing sustained tolerance. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that both subcutaneous (SCIT) and sublingual specific immunotherapy (SLIT) are effective in treating allergic rhinitis (AR). Further studies have evaluated the efficacy of allergen-specific immunotherapy (AIT) on different ear, nose, and throat (ENT) manifestations, in which allergy might have an etiopathogenetic role, such as local allergic rhinitis (LAR), rhinosinusitis (RS), otitis media (OM), and adenotonsillar (AT) disease. Nevertheless, the management of allergy in ENT diseases is still debated. To the best of our knowledge, this is the first systematic review assessing the efficacy of AIT in ENT diseases aside from AR. Literature data confirmed that AIT might be an effective therapeutic option in LAR, although its effect is restricted to studies with short-term follow-up. Furthermore, previous research demonstrated that AIT may improve symptoms and surgical outcomes of chronic rhinosinusitis when used as an adjunctive treatment. Few studies supported the hypothesis that AIT may exert positive therapeutic effects on recurrent upper airway infections as adenotonsillar disease. Finally, some clinical observations suggested that AIT may add some benefits in the management of otitis media with effusion (OME). The results of this systematic review allow us to conclude that the efficacy of AIT in ENT disorders has been only slightly investigated and additional studies are needed. [ABSTRACT FROM AUTHOR]

• Increased PD-1 expression in CD4 and Th2 cells in Allergen-specific immunotherapy. • Allergen exposure increases PD-1 expression on CD4+T cells. • Allergen exposure did not affect CTLA-4 in CD4+ T and Th2+T cells. • T cell exhaustion plays an important role in Allergen-specific immunotherapy. Recent evidence has shown that T cell exhaustion is implicated in Allergen-specific Immunotherapy (AIT). However, how T cell exhaustion plays a role in AIT is far from clear. Our study aimed to investigate T cell exhaustion associated with allergen exposure during AIT in mice. Ovalbumin (OVA) − sensitized C57BL/6J asthma mouse and AIT mouse models were constructed. Quantitative real-time PCR (qRTPCR) and flow cytometry were used to monitor the occurrence of local and systemic CD4+ T cells and Th2+T cells exhaustion in OVA-sensitized mice. The inhibitory surface marker programmed cell death protein 1 (PD-1) on CD4+ T cells and Th2+T cells was significantly upregulated in AIT mice compared with asthmatic and control mice. The level of PD-1 on the surface of CD4+T cells of asthma mice was significantly higher than that of control mice. The inhibitory surface marker cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on CD4+ T cells and Th2+T cells showed no significant difference between the AIT, asthma and control mice. Collectively, our study indicated that the expression of PD-1 on CD4+ T cells and Th2+T cells was increased in AIT. Allergen exposure promotes the expression of PD-1 on the surface of CD4+ T cells. T cell exhaustion plays an important role in AIT. [ABSTRACT FROM AUTHOR]

House dust mite (HDM) allergens are considered to be one of the most common causes of asthma and allergic rhinitis in the world. Cysteine proteases Der p 1 and Der f 1 (group 1) and also NPC 2 family proteins Der p 2 and Der f 2 (group 2) of D. pteronyssinus and D. farinae respectively are considered the main allergens of HDMs. The difference in the sensitivity of the population to these and other allergy causing components of HDM determines the treatment strategy. Thus, the purpose of this work was to determine the pattern of sensitization of the Ukrainian population to individual allergy causing molecular components of HDM in order to improve treatment strategies for the HDM allergy in various regions of Ukraine. To determine the molecular profile of sensitization to HDM, the data of multiplex allergy test Alex2 have been obtained from 10,651 patients. The sample included 57.86% children under the age of 18 and 42.14% adults. A Python language-based statistical analysis was performed, in order to group patients by sensitization to individual molecules and their combinations, regarding the age and geographical location of the patients. Simultaneous sensitization to Der f 2 and Der p 2 allergens was the most common among the entire group Simultaneous sensitization to 5 molecules—of group 1 (Der p 1 and Der f 1), group 2 (Der f 2 and Der p 2), and Der p 23—was the second most common for entire dataset and for the children group. This pattern differed in adults, where monosensitization to Der p 23 occupied the second position, suggesting that this molecule is an important factor of HDM allergy in Ukraine. Of the 16 analyzed regions, sensitization to Der p 23 prevailed in 2 Western regions of Ukraine. In the rest of the regions combination of Der p 2 and Der f 2 was the most prevalent. The established character of population sensitization to HDM in Ukraine is a good prognostic marker of allergen immunotherapy (AIT) efficacy. [ABSTRACT FROM AUTHOR]

House dust mite (HDM) allergens are considered to be one of the most common causes of asthma and allergic rhinitis in the world. Cysteine proteases Der p 1 and Der f 1 (group 1) and also NPC 2 family proteins Der p 2 and Der f 2 (group 2) of D. pteronyssinus and D. farinae respectively are considered the main allergens of HDMs. The difference in the sensitivity of the population to these and other allergy causing components of HDM determines the treatment strategy. Thus, the purpose of this work was to determine the pattern of sensitization of the Ukrainian population to individual allergy causing molecular components of HDM in order to improve treatment strategies for the HDM allergy in various regions of Ukraine. To determine the molecular profile of sensitization to HDM, the data of multiplex allergy test Alex2 have been obtained from 10,651 patients. The sample included 57.86% children under the age of 18 and 42.14% adults. A Python language-based statistical analysis was performed, in order to group patients by sensitization to individual molecules and their combinations, regarding the age and geographical location of the patients. Simultaneous sensitization to Der f 2 and Der p 2 allergens was the most common among the entire group Simultaneous sensitization to 5 molecules—of group 1 (Der p 1 and Der f 1), group 2 (Der f 2 and Der p 2), and Der p 23—was the second most common for entire dataset and for the children group. This pattern differed in adults, where monosensitization to Der p 23 occupied the second position, suggesting that this molecule is an important factor of HDM allergy in Ukraine. Of the 16 analyzed regions, sensitization to Der p 23 prevailed in 2 Western regions of Ukraine. In the rest of the regions combination of Der p 2 and Der f 2 was the most prevalent. The established character of population sensitization to HDM in Ukraine is a good prognostic marker of allergen immunotherapy (AIT) efficacy.

In the field of severe asthma, the concept of disease control has recently been integrated by the one of clinical remission. With this new concept, we move on to analyze the efficacy of therapy on multiple parameters simultaneously, starting with the mandatory discontinuation of the systemic glucocorticoids, to which is added the effect on exacerbations, respiratory function, and symptoms control. The Italian severe asthma registry SANI (Severe Asthma Network Italy) drafted criteria for the definition of disease remission, allowing patients to be classified into two groups, partial and complete remission. The greater dynamism of the definition, provided by SANI, allows us to hypothesize its practical use, concerning therapy management of severe asthma patients, starting from the level of remission, with the aim to facilitate the clinical decision on replacement, continuation or modulation of patients' therapy.

Objective: Amiodarone is an iodine-rich molecule and an effective antiarrhythmic drug. It is a first-line treatment for patients with life-threatening ventricular arrhythmias and for prevention in patients at high risk. The use of amiodarone may cause serious adverse effects such as pharmacotherapy-resistant, life-threatening amiodarone-induced thyrotoxicosis (AIT)leading to rapid deterioration of the patient's condition.According to the European Thyroid Association (ETA) guidelines, emergency thyroidectomy is the first-line treatment option in these cases. ; however, is not always feasible in the clinical setting due to the high anesthetic risk.We aimed to assess the clinical course and results of urgent thyroidectomy and 131-I therapy in patients with severe AIT with worsening of cardiac status., Methods: Retrospective analysis of the clinical course and outcomes of life-threatening AIT refractory to pharmacotherapy in patients hospitalized at a tertiary endocrinology center between 2014 and 2022., Results: An electronic database search identified 75 patients hospitalized for severe AIT. At the time of AIT diagnosis, median Thyroid-stimulating hormone (TSH) concentration was 0.001 mIU/L (range 0.001-0.35), fT4 63.2 pmol/L (range 9.0 - >100), and fT3 10.2 pmol/L (range 3.8-49.3). All patients received optimal conservative treatment. Among them, 20 required urgent radical therapy due to worsening arrhythmias and/or AIT-related heart failure. In this group, 6 patients died before any radical treatment was applied, 6 underwent total thyroidectomy, while 8 patients were successfully treated with 131-I (in 6 cases after rhTSH stimulation). The median dose of 131-I used for the therapy was 784MBq (range 627-860). The decision to treat with 131-I despite low but detectable 131-I uptake (median value 6 %) was made in cases of significant contraindications to anesthesia due to refractory ventricular arrhythmias, exacerbation of severe heart failure unresponsive to cardiac treatment, myocardial infarction during AIT course, massive pulmonary embolism., Conclusion: The decision regarding the optimal time and type of radical treatment of AIT refractory to pharmacotherapy is critical for patients management and should not be delayed. Urgent therapy with 131-I may be an effective therapeutic option in patients who are unsuitable for thyroidectomy due to the high risk of anesthesia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Jagiellonian Univerity Medical College.)

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Complex posttraumatic stress disorder (C-PTSD) and adverse childhood experiences (ACEs) pose health problems in the United States, and intergenerational relational trauma plays a role in the continuation and transmission of these issues. Advanced Integrative Therapy (AIT), a novel treatment, was used to treat a case of C-PTSD. The client's chief concern was a flare-up of anxiety, relational distress, and fibromyalgia that occurred when they (chosen pronoun) accepted custody of their nephew. Over a span of nine 90-minute sessions, the clinician assessed progress using the PTSD Checklist for DSM-5 (PCL-5; Weathers et al., 2013) to measure PTSD symptoms; the International Trauma Questionnaire (ITQ; Cloitre et al., 2018), which measures C-PTSD symptoms according to the criteria of the World Health Organization (WHO) International Classification of Diseases, 11th revision (ICD-11); the Child-Parent Relationship Scale (CPRS; Pianta, 1992), which measures connection and conflict in the caregiver-child relationship; and the Subjective Units of Distress (SUD) scale (Wolpe, 1969), which rates the client's current level of distress or discomfort. The clinician also used the self-report questionnaire Helpful Aspects of Therapy (HAT; Llewelyn et al., 1988) and the Change Interview (CI) method (Elliott et al., 2001) to measure client experience and perspective. After treatment with AIT, the client no longer met criteria for C-PTSD and showed dramatic improvement in intergenerational relationship satisfaction. In addition, there was a rapid reduction of hard to eradicate C-PTSD symptoms as well as reduction in the quantity and intensity of fibromyalgia induced pain. Use of AIT with caregivers could interrupt the transmission of intergenerational trauma thereby reducing or preventing ACEs by increasing emotional regulation and resilience. [ABSTRACT FROM AUTHOR]

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AIT1) due to Graves' disease (GD). However, the TRAb role and function in AIT have not been clarified. Methods: A retrospective cohort study of 309 AIT patients followed at a single academic center over a 30-year period. AIT TRAb-positive patients (n = 21, 7% of all cases) constituted the study group; control groups consisted of type 2 AIT (AIT2) TRAb-negative patients (n = 233), and 100 non-AIT patients with GD. Clinical and biochemical data at diagnosis and during the course of disease were compared. Histological samples of patients who had total thyroidectomy were reviewed. Stored serum samples were used for a functional assay of TRAb class G immunoglobulins (IgGs) in Chinese hamster ovary (CHO) cells stably transfected with complementary DNA encoding for the TSH receptor. Results: TRAb-positive patients were grouped according to color flow Doppler sonography, radioactive iodine thyroid uptake, and duration of amiodarone therapy before thyrotoxicosis in type 1 (n = 9, 43%; TRAb1) or type 2 (n = 12, 57%; TRAb2) AIT. TRAb1 patients had clinical and biochemical features indistinguishable from GD controls, and were responsive to methimazole. Conversely, TRAb2 patients had clinical features similar to AIT2 controls, and were responsive to glucocorticoids, but not to methimazole. The CHO cell functional assay demonstrated that TRAb1 IgGs had a stimulatory effect on cyclic AMP production, which was absent in TRAb2 IgGs. Pathology in TRAb1 showed hyperplastic thyroid follicles and mild lymphocyte infiltration, reflecting thyroid stimulation. On the contrary, TRAb2 samples revealed follicle destruction, macrophage infiltration, and sometimes fibrosis, consistent with a destructive process. Conclusions: Almost 60% of TRAb-positive AIT patients had a destructive thyroiditis. TRAb-positive tests in AIT patients do thus not necessarily imply a diagnosis of GD and AIT1, and should be evaluated in the clinical and biochemical setting of each AIT patient and confirmed by measuring thyroid-stimulating immunoglobulins. [ABSTRACT FROM AUTHOR]

Background: Studies show that proallergic TH2 cells decrease after successful allergen‐specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T‐cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts. Methods: OVA‐sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH2 cells was analyzed. In patients, the expression of exhaustion‐associated surface markers on TH2 cells was evaluated using flow cytometry in a cross‐sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long‐term AIT cohort. Results: The exhaustion‐associated surface markers CTLA‐4 and PD‐1 were significantly upregulated on TH2 cells upon OVA aerosol exposure in OVA‐allergic compared to non‐allergic mice. CTLA‐4 and PD‐1 decreased after AIT, in particular on the surface of local lung TH2 cells. Similarly, CTLA‐4 and PD‐1 expression was enhanced on TH2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late‐differentiated TH2 population expressing both markers that decreased during up‐dosing but persisted long term during the maintenance phase. Conclusions: This study shows that allergen exposure promotes CTLA‐4 and PD‐1 expression on TH2 cells and that the dynamic change in frequencies of exhausted TH2 cells exhibits a differential pattern during the up‐dosing versus the maintenance phases of AIT. [ABSTRACT FROM AUTHOR]

Abstract Background Observational comparative effectiveness studies in allergen immunotherapy (AIT) represent an important evidence source answering research questions that can be challenging to obtain from randomized controlled trials (RCTs), such as long‐term benefits of AIT, the effects on asthma prevention and the onset of new allergen sensitizations. However, observational studies are prone to several sources of bias, which limit their reliability. The REal Life Evidence AssessmeNt Tool (RELEVANT) was recently developed to assist in quality appraisal of observational comparative research to enable identification of useful nonrandomized studies to be considered within guideline development. Objective To systematically appraise the quality of published observational comparative AIT studies using RELEVANT. Methods Observational studies comparing AIT to pharmacotherapy for respiratory allergies, assessing as outcome measures reduction of symptoms and/or medication use reduction, were retrieved by computerized bibliographic searches. According to RELEVANT, a failure to meet any one of primary items (background, design, measures, analysis, results, discussion/interpretation, and conflict of interest) represents a critical flaw, significantly undermining the validity of the study results. Results The 14 studies identified supported the benefit of AIT in real‐life, which persists after treatment discontinuation. However, none of them met all the 7 primary RELEVANT criteria. The main defects were reported in the design (28.6% of studies), measures and analysis (64.3% of studies), and results (78.6% of studies) items, due to selection bias and lack of methods for adjusting controls. Half of the studies did not report on conflict of interest. Conclusion There is a need for more robust observational research in AIT. RELEVANT appears as an easy‐to‐use and sensitive tool for quality appraisal in AIT studies.

Educational Institutions are often under pressure for cost cutting. Electricity charges, especially in a residential institution, is one of the biggest drain on finances. In this case study, we would like to discuss the grid connected roof top solar project in Army Institute of Technology (AIT), Dighi, Pune. This 350 kW system has been installed without any cost to AIT, on Build-Operate-Transfer (BOT) model, for 25 years at the rate of Rs 6/- per electricity unit. The power generated by the system is approximately 1000 to 1200 electricity units per day as against a requirement of about 1800 to 2000 electricity units per day. Net Metering Policy implemented by Maharashtra Government enables AIT to send excess electricity generated during day time back to the grid. This excess power given to the grid is credited back during night time. A new Net Meter has been installed in AIT that provides daily status of the power import/export. This has resulted in Cost Savings of nearly Rs 1,50,000/- per month which comes close to Rs 18,00,000/- per annum. [ABSTRACT FROM AUTHOR]

In view of at the problem that the traditional STK simulation algorithm for tracking angle of relay antenna cannot he used in real - time testing processing for spacecraft AIT, a real - time tracking algorithm for relay antenna is proposed and implemented in software. In this method, the orbit of spacecraft, antenna beam and coordinate system are applied to establish the equivalent model of the direction angle for relay antenna. Combining the spacecraft flight altitude and real - time telemetry, the tracking angle algorithm, real - time test result verification and closed - loop control strategy for relay antenna are realized. The experimental results show that the proposed method not only achieve real - Lime comparison of relay antenna angle tracking during the AIT test process, but also achieves the real - Lime prediction of TIC coverage under various flight altitude on orbit. The maximum TIC coverage of a single arc is increased by 13.3%. The method described in the study has been already applied to a certain type of spacecraft sub - system test and in orbit flight missions. [ABSTRACT FROM AUTHOR]

Background: Observational comparative effectiveness studies in allergen immunotherapy (AIT) represent an important evidence source answering research questions that can be challenging to obtain from randomized controlled trials (RCTs), such as long‐term benefits of AIT, the effects on asthma prevention and the onset of new allergen sensitizations. However, observational studies are prone to several sources of bias, which limit their reliability. The REal Life Evidence AssessmeNt Tool (RELEVANT) was recently developed to assist in quality appraisal of observational comparative research to enable identification of useful nonrandomized studies to be considered within guideline development. Objective: To systematically appraise the quality of published observational comparative AIT studies using RELEVANT. Methods: Observational studies comparing AIT to pharmacotherapy for respiratory allergies, assessing as outcome measures reduction of symptoms and/or medication use reduction, were retrieved by computerized bibliographic searches. According to RELEVANT, a failure to meet any one of primary items (background, design, measures, analysis, results, discussion/interpretation, and conflict of interest) represents a critical flaw, significantly undermining the validity of the study results. Results: The 14 studies identified supported the benefit of AIT in real‐life, which persists after treatment discontinuation. However, none of them met all the 7 primary RELEVANT criteria. The main defects were reported in the design (28.6% of studies), measures and analysis (64.3% of studies), and results (78.6% of studies) items, due to selection bias and lack of methods for adjusting controls. Half of the studies did not report on conflict of interest. Conclusion: There is a need for more robust observational research in AIT. RELEVANT appears as an easy‐to‐use and sensitive tool for quality appraisal in AIT studies. [ABSTRACT FROM AUTHOR]

Iodine excess (IE) intake leads to lymphocyte dysfunction and contributes to autoimmune thyroiditis (AIT). Abnormal thyroid function is associated with adverse cardiovascular events, endothelial dysfunction is often an early pathophysiological feature in most cardiovascular disease. However, the relationship between iodine and the cardiovascular system is currently unclear. Therefore, the aim of this study was to investigate the effects of IE on endothelial function in mouse model. A total of 24 NOD.H-2h4 mice were randomly divided into different groups. A sodium iodide (NaI) group supplied with 0.05% NaI water for 8 weeks. Serum levels of tumor necrosis factors α (TNFα), interleukin-6 (IL-6) and C-reactive Protein (CRP), as well as endothelin-1 (ET-1), von Willebrand factor (VWF) and thrombomodulin (THBD) were detected by Elisa. In addition, the mRNA and protein expression of these genes were measured by RT-PCR and Western blotting. Here, we found the urinary iodine concentration (UIC) was higher in the NaI group compared to the control group. Serum levels of ET-1, VWF, and THBD were also significantly lower in the NaI group, however, CRP serum levels are significantly increased. In aorta, the mRNA and protein expression of ET-1, VWF, THBD were downregulated, however, the expression of IL-6, CRP and TNFα mRNA and protein were upregulated in the NaI group. A correlation analysis showed negative correlation between UIC with ET-1, VWF, and THBD, similarly, negative correlation between CRP with THBD was observed. In addition, positive correlations between UIC with CRP. Collectively, in the NOD.H-2h4 mice, IE supplementation had a suppressive effect on endothelial function, and this inhibition maybe due to the increase expression of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Abstract Background Autoimmune thyroiditis (AIT) with euthyroid is associated with miscarriage. But the exact mechanism remains unclear. Studies have shown that the programmed cell death-1 (PD-1)/programmed cell death -ligand 1 (PD-L1) pathway is essential for normal pregnancy. However, the expression of PD-L1 in gestational trophoblasts in mice with autoimmune thyroiditis and the mechanisms leading to miscarriage have not been fully investigated. Methods Immunofluorescence and Western blot were used to detect the expression of PD-L1, p-ERK, MMP-2 and MMP-9 in embryonic trophoblast cells of pregnant mice with AIT. The expression of PD-L1 in HTR-8/SVneo cells were silenced, and the expression of PD-L1, MMP-2, MMP-9, ERK and p-ERK1/2 was detected by Western blot analyses and immunofluorescence assays. Invasive assays were performed in PD-L1 silenced HTR-8/SVneo cells using a Transwell chamber. Results Compared with normal pregnancy, the expression of PD-L1, ERK, p-ERK, MMP-2 and MMP-9 in embryonic trophoblast cells was significantly lower in pregnant mice with AIT. Compared with the negative control (NC) group (cells transfected with negative control siRNA), phosphorylation of MMP-2, MMP-9 and P-ERK1/2 proteins was significantly reduced in HTR-8/SVneo cells transfected with PD-L1 siRNA, and the number of cells penetrating the membrane was reduced. Conclusion AIT inhibits ERK/MMP-2 and MMP-9 pathways through PD-L1 reduction, attenuates embryonic trophoblast invasion and ultimalely induces miscarriage ultimately.

In vitro somaclonal variation via callus is considered as one of the most effective tool for improvement of vegetative propagated crops. Different combinations of cytokinine (BA) and auxine (NAA) were used to induce somaclonal variation from leaf explants of the Egyptian geranium cultivar, Pelargonium graveolens L’Herit, Ait. El Qanater El khayria cv.8. Callus induction and regenerated shoots from callus were evaluated; 2.5 mg/L BA and 0.5 mg/L NAA was the optimal for callus induction and number of regenerated shoots. The obtained plantlets were acclimatized under glasshouse conditions with 80% to 90% survival and were transferred to the open field. The evaluation of growth traits and oil analysis were done for the new 13 clones compared with the mother plant in randomized block design for two successive seasons. Characterization of these new clones for morphological traits and essential oil yield and quality demonstrated the induction of variability in negative and positive directions in some characteristics in comparison with the mother plant. Clone no.7 was the superior clone in herb 2264.7 & 2357.3 g/plant and oil yield 2.436 & 3.065 ml/plant in first and second season, respectively, than the mother plant and other new clones with acceptable content of citronellol 25.63% and geraniol 26.52% as a parameter for volatile oil quality. The genetic variation of the new geranium clones were tested using SRAP technique based on PCR, the polymorphism was detected using 16 pairs of SRAP primers in combinations as forward and reverse. The genetic differences between new clones and the mother plant were ascertained with SRAP primer pair (me2 em4); a unique profile for clone no.7 was detected in SRAP analysis. The similarity percentage varied between 66.7% to 100% homologies among the new clones and their mother plant. The presence of genetic variation between new clones and the mother plant proved that the calliclones were somaclonal mutants, and the geranium cultivar, El Qanater El khayria cv.8, was improved for high yield in herb and essential oil.

Background: Immune-mediated cytopenias (AIC) are challenging complications following allogeneic hematopoietic stem cell transplantation (HSCT). While broad-acting immunosuppressive agents like corticosteroids are often standard of care, several novel therapies which target specific immunological pathways have recently been developed and provide hope for patients with steroid-refractory courses and may limit long-term toxicity. The successful off-label use of the plasma cell depleting anti-CD38 antibody daratumumab was published in several case reports, suggesting efficacy, i.e., in patients with antibody-mediated AIC refractory to previous B cell depletion. We want to share our experience with two children, whom we treated with daratumumab, including one fatal course with uncontrolled disease. Given the absence of substantial data from HSCT registries or prospective trials, we furthermore provide a critical review of the literature on daratumumab treatment of AIC. Case presentations: Patient 1 (P1), an 11-year-old girl with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who developed immune-mediated thrombocytopenia (AIT) from day +58 after HSCT, showed a complete response to daratumumab after the fourth of six total daratumumab doses. She remains transfusion independent for over a year of follow-up. Previously, her thrombocytopenia was refractory to corticosteroids, rituximab, intravenous immunoglobulins (IVIG), eltrombopag, cyclosporine A, and sirolimus. Patient 2 (P2), a 6-year-old boy with CD40 ligand (CD40L) deficiency, developed both AIT and hemolytic anemia (AIHA) after HSCT on days +58 and +83, respectively, and was also treated with daratumumab after being previously refractory to prednisolone, rituximab, and IVIG. Yet, he did neither respond to daratumumab nor the concomitantly administered methyprednisolone pulse, plasmapheresis, and eculizumab and succumbed due to refractory disease. Conclusion: Reviewing the literature on the use of daratumumab for refractory AIC post-HSCT, we consider daratumumab a promising agent for this life-threatening disorder: ten of the twelve patients reached transfusion independency in the literature. However, treatment failures are likely to be underreported. Thus, controlled trials are needed to explore the safety and efficacy of daratumumab in this rare post-HSCT complication. [ABSTRACT FROM AUTHOR]

During the ongoing pandemic of Coronavirus Disease 2019 (COVID-19) allergic patients need to continue their constant and proper treatment, including allergen-specific immunotherapy. These patients are expected to be at a higher risk for exacerbation of lung inflammation during viral infection. We investigated the putative interplay existing between allergen-specific immunotherapy and COVID-19 infection in a Hymenoptera venom–allergic population. We evaluated the frequency and severity of COVID-19 infection in a cohort of 211 subjects referring to our center for the regular administration of venom immunotherapy (VIT). Our result showed that the median age of our cohort is similar to the one that in our region has been associated with a high incidence of COVID-19 infection, increased hospitalization, and mortality rates. We reported only an isolated positivity of COVID-19 in the overall group; whereas none suffered from upper airway symptoms associated with COVID-19 (fever, cough, dyspnoea, sore throat, anosmia, and/or ageusia). Even though the demographic characteristics pose a substantial risk for such a population, we suggest that a regular administration of VIT may help in the development of an immunological milieu able to down modulate the Th1/Th17 environment that has been linked to inflammatory manifestations of COVID-19. To the best of our knowledge, this is the first description of the incidence of COVID-19 infection in Hymenoptera venom allergic patients treated with VIT, suggesting indirectly that venom immune tolerance-inducing treatment may be capable of reducing the aberrant inflammatory response induced by the virus in this specific population.

Curvature is one of many visual features shown to be important for visual perception. We recently showed that curvilinear features provide sufficient information for categorizing animate vs. inanimate objects, while rectilinear features do not (Zachariou et al., 2018). Results from our fMRI study in rhesus monkeys (Yue et al., 2014) have shed light on some of the neural substrates underlying curvature processing by revealing a network of visual cortical patches with a curvature response preference. However, it is unknown whether a similar network exists in human visual cortex. Thus, the current study was designed to investigate cortical areas with a preference for curvature in the human brain using fMRI at 7T. Consistent with our monkey fMRI results, we found a network of curvature preferring cortical patches—some of which overlapped well-known face-selective areas. Moreover, principal component analysis (PCA) using all visually-responsive voxels indicated that curvilinear features of visual stimuli were associated with specific retinotopic regions in visual cortex. Regions associated with positive curvilinear PC values encompassed the central visual field representation of early visual areas and the lateral surface of temporal cortex, while those associated with negative curvilinear PC values encompassed the peripheral visual field representation of early visual areas and the medial surface of temporal cortex. Thus, we found that broad areas of curvature preference, which encompassed face-selective areas, were bound by central visual field representations. Our results support the hypothesis that curvilinearity preference interacts with central-peripheral processing biases as primary features underlying the organization of temporal cortex topography in the adult human brain.

Allergic sensitization to the major allergen Bet v 1 represents the dominating factor inducing a vast variety of allergic symptoms in birch pollen allergic patients worldwide, including the pollen food allergy syndrome. In order to overcome the huge socio-economic burden associated with allergic diseases, allergen-specific immunotherapy (AIT) as a curative strategy to manage the disease was introduced. Still, many hurdles related to this treatment exist making AIT not the patients’ first choice. To improve the current situation, the development of hypoallergen-based drug products has raised attention in the last decade. Herein, we investigated the efficacy of the novel AIT candidate BM4, a hypoallergenic variant of Bet v 1, to induce treatment-relevant cross-reactive Bet v 1-specific IgG antibodies in two different mammals, Wistar rats and New Zealand White rabbits. We further analyzed the cross-reactivity of BM4-induced Wistar rat antibodies with the birch pollen-associated food allergens Mal d 1 and Cor a 1, and the functional capability of the induced antibodies to act as IgE-blocking IgG antibodies. Enzyme-linked immunosorbent assay (ELISA) was used to determine the titers of rat IgG1, IgG2a, IgG2b, and IgE, as well as rabbit IgG and IgE antibodies. To address the functional relevance of the induced IgG antibodies, the capacity of rat sera to suppress binding of human IgE to Bet v 1 was investigated by using an inhibition ELISA and an IgE-facilitated allergen-binding inhibition assay. We found that the treatment with BM4 induced elevated Bet v 1-specific IgG antibody titers in both mammalian species. In Wistar rats, high BM4-specific IgG1, IgG2a, and IgG2b titers (104 to 106) were induced, which cross-reacted with wild-type Bet v 1, and the homologous allergens Mal d 1 and Cor a 1. Rat allergen-specific IgG antibodies sustained upon treatment discontinuation. Sera of rats immunized with BM4 were able to significantly suppress binding of human IgE to the wild-type allergens and CD23-mediated human IgE-facilitated Bet v 1 binding on B cells. By contrast, treatment-induced IgE antibody levels were low or undetectable. In summary, BM4 induced a robust IgG immune response that efficiently blocked human IgE-binding to wild-type allergens, underscoring its potential therapeutic value in AIT.

Allergic diseases represent a global health and economic burden of increasing significance. The lack of disease-modifying therapies besides specific allergen immunotherapy (AIT) which is not available for all types of allergies, necessitates the study of novel therapeutic approaches. Exosomes are small endosome-derived vesicles delivering cargo between cells and thus allowing inter-cellular communication. Since immune cells make use of exosomes to boost, deviate, or suppress immune responses, exosomes are intriguing candidates for immunotherapy. Here, we review the role of exosomes in allergic sensitization and inflammation, and we discuss the mechanisms by which exosomes could potentially be used in immunotherapeutic approaches for the treatment of allergic diseases. We propose the following approaches: (a) Mast cell-derived exosomes expressing IgE receptor FcεRI could absorb IgE and down-regulate systemic IgE levels. (b) Tolerogenic exosomes could suppress allergic immune responses via induction of regulatory T cells. (c) Exosomes could promote TH1-like responses towards an allergen. (d) Exosomes could modulate IgE-facilitated antigen presentation.

Abstract Background Hymenoptera venom immunotherapy (VIT) is a clinically effective treatment. However, little is known about its long-term clinical efficacy and biological effects. Several mechanisms have been proposed to account for VIT efficacy, including reduction of specific IgE and induction of allergen-specific IgG4, but the overall picture remains elusive. We investigated Vespula VIT clinical efficacy up to 8 years after discontinuation and the kinetics of Vespula-specific IgE and IgG4. Out of 686 consecutive patients we retrospectively selected and analysed a series of 23 patients with Vespula allergy that underwent a 5-year IT course, followed by a prolonged follow-up. Methods Clinical efficacy of VIT was assessed as number and severity of reactions to Vespula re-stinging events. The presence of Vespula-specific IgE and IgG4 was also monitored over time. Results During the VIT treatment, patients were protected, reporting no reactions or mild reactions in occasion of re-stinging events. This protection was entirely maintained during the follow-up, up to 8 years. Skin reactivity (reflecting mast cell-bound Vespula-specific IgE) and circulating Vespula-specific IgE levels declined substantially during VIT. Notably, this reduction was maintained over time during the follow-up. Moreover, all the patients were analysed for IgG4. A robust induction of Vespula-specific IgG4 was observed during the VIT course, with a substantial decline during the follow-up. Conclusions We conclude that Vespula VIT is a clinically effective treatment, which induces long-term protection after discontinuation. The reduction of specific IgE, assessed by skin tests and RAST, closely matches the VIT- induced protection, while the IgG4 induction seems not to be associated with VIT clinical efficacy in the long term.

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Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)