A survey on prevalence and parents' perceptions of food allergy in 3- to 16-year-old children in Wuhan, China.

Background: The prevalence of food allergy (FA) has risen in recent decades, yet there is limited data on the cognition and beliefs of FA among the parents of FA children. Objective: To investigate the prevalence of FA and assess the knowledge and perception of FA among parents of FA children in Wuhan, China. Methods: Online questionnaires were conducted for the parents of 3- to 16-year-old children. They reported symptoms of suspected FA in the screening questionnaire were interviewed for further diagnostic evaluation. All the parents of the suspected FA children completed the subsequent assessments of the knowledge and perception on FA as well as their attitude towards the current online platforms. Results: A total of 1963 children were recruited. The prevalence of self-reported FA was 10.2% (95% CI: 8.1-12.4%) and the physician-diagnosed FA was 6.2% (95% CI: 5.1-7.2%) in 3- to 16-year-olds in Wuhan. And the children with family history (57.9%) were predisposed to developing FA (P＜0.001). The total Brief Illness Perception Questionnaire (B-IPQ) score was 41.3 ± 10.0 among the parents. The B-IPQ scores correlated with symptom onset, but not with family history or other atopic comorbidities. The parents who never sought treatments obtained lower B-IPQ scores on most items compared to those who received treatments. The accuracy rate of the FA knowledge questionnaire was 56.7%. 11.6% of participants reported that children's FA had an impact on their lives. 67.2% of participants had searched information of FA online, among whom 80% expected to obtain professional suggestions on management and prevention strategies of FA from online platform. Conclusion: In 3- to 16-year-old children in Wuhan, the prevalence of self-reported and physician-diagnosed FA was 10.2% and 6.2% respectively. Parents' knowledge of FA was insufficient and only a small proportion of parents perceived that their lives and careers have been affected considerably by FA of their children. Patient education and current online platforms should be improved among parents of FA children.

Low-dose oral immunotherapy in immunoglobulin E-mediated food allergies.

Nowadays, the management of food allergies has increasingly moved from conventional oral immunotherapy (OIT) to low-dose OIT or low-dose OIT utilizing hypoallergenic foods. This shift is largely because the latter appears to induce oral tolerance with fewer adverse effects than the former. However, the mechanisms underpinning such differences remain unclear. To better understand these mechanisms, we conducted a comparative study scrutinizing the mechanisms of OIT, especially those of low-dose desensitization. We also summarized articles on low-dose OIT and low-dose OIT using hypoallergenic foods. We examined the efficacy, safety, and immunological parameters of low-dose OIT and those of low-dose OIT with hypoallergenic foods with the aim of shedding some light on low-dose OIT and its therapeutic application in inducing oral tolerance for individuals with food allergies.

A Survey of Airborne Fungi and Their Sensitization Profile in Wuhan, China.

INTRODUCTION: Airborne fungi induce allergic symptoms in 3-10% of the population worldwide. To better prevent and manage fungi-related allergic diseases, it is essential to identify the genus and the distribution profile of airborne fungi. METHODS: With this purpose in mind, we carried out a 12-month volumetric sampling study to monitor the airborne fungi and retrospectively analyzed the sensitization profile of four dominant fungi (Cladosporium, Alternaria, Aspergillus, and Penicillium) among respiratory allergies during the same study period in Wuhan, China. RESULTS: A total of 29 different fungal genuses were identified, and the peak fungal concentration period was found to be in September and October, followed by May and June. The most prevalent fungi in this area were Cladosporium (36.36%), Ustilago (20.12%), and Alternaria (13.87%). In addition, the skin prick test data from 1,365 respiratory allergies patients showed that 202 (14.80%) of them were sensitized to fungi. The sensitization rates to Cladosporium, Alternaria, Aspergillus, and Penicillium were 11.72%, 4.69%, 1.98%, and 4.76%, respectively. The seasonal fluctuation of Alternaria and Aspergillus correlated with their sensitization rates. Among the fungal sensitized patients, 76 (37.62%) were sensitized to two or more kinds of fungi. The serum-specific IgE tests suggested low to high correlations existed between these fungi; however, these correlations were not found between fungi and other allergens. CONCLUSION: Our study provides the distribution profile and reveals the clinical significance of the airborne fungi in Wuhan, which will facilitate the precise management of fungal allergy.

COVID-19-Associated Disease Course Is Shortened in Moderate-to-Severe Atopic Dermatitis Patients Receiving Dupilumab Treatment: A Retrospective Cross-Sectional Study.

Previous studies suggest that allergic diseases may be a protective factor in SARS-CoV-2 infection. However, data regarding the impact of dupilumab, a widely used immunomodulatory medication, on COVID-19 in an allergic population are very limited. To investigate the incidence and severity of COVID-19 among moderate-to-severe atopic dermatitis (AD) patients treated with dupilumab, a retrospective cross-sectional survey was conducted among patients with moderate-to-severe AD who presented at the Department of Allergy of Tongji Hospital from 15 January 2023 to 31 January 2023. Healthy individuals matched for gender and age were also enrolled as a control. All subjects were asked about their demographic characteristics, past medical history, COVID-19 vaccination history, and medications, as well as the presence and duration of individual COVID-19-related symptoms. A total of 159 moderate-to-severe AD patients and 198 healthy individuals were enrolled in the study. Among the AD patients, 97 patients were treated with dupilumab, and 62 patients did not receive any biologicals or systemic treatments (topical treatment group). The proportions of people who were not infected with COVID in the dupilumab treatment group, topical treatment group and healthy control group were 10.31%, 9.68% and 19.19%, respectively (p = 0.057). There was no significant difference in COVID-19-related symptom scores among all groups (p = 0.059). The hospitalization rates were 3.58% in the topical treatment group and 1.25% in the healthy control group, and no patient was hospitalized in the dupilumab treatment group (p = 0.163). Compared with healthy control group and topical treatment group, the dupilumab treatment group had the shortest COVID-19-associated disease duration (dupilumab treatment group, 4.15 ± 2.85 d vs. topical treatment group, 5.43 ± 3.15 d vs. healthy control group, 6.09 ± 4.29 d; p = 0.001). Among the AD patients treated with dupilumab for different times, there was no appreciable difference (<0.5 year group, 5 ± 3.62 d vs. 0.5-1 year group, 4.84 ± 2.58 d vs. >1 year group, 2.8 ± 1.32 d; p = 0.183). Dupilumab treatment shortened the duration of COVID-19 in patients with moderate-to-severe AD. AD patients can continue their dupilumab treatment during the COVID-19 pandemic.

Metformin increases bone marrow adipose tissue by promoting mesenchymal stromal cells apoptosis.

Bone marrow adipose tissue (MAT) has the potential to exert both local and systemic effects on metabolic homeostasis. As a first-line drug used to treat type 2 diabetes mellitus, metformin has conflicting effects on MAT and bone marrow mesenchymal stem cell (BM-MSC) differentiation. Through a series of experiments in vivo and in vitro, we found that except improving the glucose and lipid metabolism disorder in ob/ob mice, 200 mg/kg metformin increased MAT in mice tibia, and prompted osteogenic genes (RunX2, OPN, OCN) and lipogenic genes (Ppar-γ, Cebpα, Scd1) expression in mice bone marrow. However, metformin promoted osteogenesis and inhibited lipogenesis of MSC in vitro, which is inconsistent with the results in vivo. Given MAT being considered the "filler" of the space after the apoptosis of bone marrow stroma, the effect of metformin on MSC apoptosis was examined. We discovered that metformin induces MSC apoptosis in vivo and in vitro. Therefore, we speculated that the increased MAT in mice tibia may be attributed to the filling of adipose tissue after apoptosis of bone marrow stromal cells induced by metformin. The increased MAT may be involved in the regulation of metformin on glucose, lipid, and bone metabolism in diabetic mice, providing a new way to understand the metabolic regulation of metformin. While increased MAT-associated insulin resistance and metabolic disorders may account for the poorer clinical benefits in patients with intensive glucose control.

A Questionnaire Survey on the Prevalence and Parents' Perceptions of Respiratory Allergies in a 3- to 16-Year-Old Population in Wuhan, China.

(1) Background: The prevalence of allergic rhinitis (AR) and asthma has increased rapidly in China. However, perceptions of respiratory allergies and barriers to their management have not attracted enough attention. (2) Objective: To investigate the prevalence of, parents' perceptions of and their unmet needs for information concerning respiratory allergies in a 3- to 16-year-old children population. (3) Methods: A cross-sectional survey was conducted from June to July 2021 in three schools in Wuhan, China. A total of 1963 participants were recruited through cluster sampling for their parents to complete an online questionnaire regarding respiratory allergic symptoms. The diagnosis of respiratory allergies was based on self-reported symptoms and face-to-face physician evaluation. All the participants with respiratory allergies were asked to complete the Brief Illness Perception Questionnaire (B-IPQ), the Asthma Knowledge Questionnaire (AKQ) and a questionnaire regarding their unmet needs for disease management. (4) Results: The prevalence of respiratory allergies was 29.3% (576/1963) in the 3- to 16-year-old population, among whom AR accounted for 25.7%; asthma, 1.8% and AR-complicated asthma (AR&Asthma), 1.9%. The total B-IPQ score was 40.2 ± 10.9 in the participants with respiratory allergies, and there were no differences among the AR, asthma and AR&Asthma groups (all p > 0.05). The B-IPQ score correlated significantly with symptom onset time and a history of atopic dermatitis (p < 0.01). Nearly one fifth, 18.9%, of the participants with respiratory allergies never went to hospital for treatment, but those with higher B-IPQ scores were more likely to seek professional treatment (p < 0.001). The accuracy rates of AKQ were 72.5% in the participants with asthma and 76.7% in those without asthma (p = 0.147). Among the 576 participants with respiratory allergies, 568 (98.6%) had tried to obtain disease-management information from online platforms, and 55.5% (315/568) were dissatisfied with current platforms; the reasons included incomprehensive contents of illness (45.7%), lack of voice from leading experts (40.3%), too many advertisements (37.5%) and similar contents on different platforms (36.8%). (5) Conclusions: The prevalence of respiratory allergies is high in the 3- to 16-years old population in Wuhan, China. Yet the parents' perceptions of respiratory allergies and knowledge of asthma are insufficient. It is crucial to increase parents' awareness of the illness and facilitate their access to truly informative and professional platforms.

Clinical and immunological characteristics of Aspergillus fumigatus-sensitized asthma and allergic bronchopulmonary aspergillosis.

Background: Aspergillus fumigatus (A.f) is a common airborne allergen that contributes to allergic asthma. In some patients, A.f can colonize in the airway and lead to allergic bronchopulmonary aspergillosis (ABPA). However, our understanding of the pathogenesis of A.f-sensitized asthma and ABPA remains inadequate. Objective: We aimed to investigate the clinical and immunological characteristics of A.f-sensitized asthma and ABPA. Methods: A total of 64 ABPA and 57 A.f-sensitized asthma patients were enrolled in the study, and 33 non-A.f-sensitized asthma patients served as the control group. The clinical and immunological parameters included lung function, fractional exhaled nitric oxide (FeNO), induced sputum and blood cell analysis, specific IgE/IgG/IgA of A.f and its components, cytokines (IL-33, IL-25, and TSLP) and CD4+T cell subsets. Results: The eosinophils in blood, induced sputum, and FeNO were significantly higher in ABPA patients compared to that in A.f-sensitized patients. The combination of FeNO and eosinophils (EO) parameters presented good diagnostic efficiency in differentiating A.f (+) asthma from ABPA, with a sensitivity of 80% and a specificity of 100%. Specific IgE, IgG, and IgA against A.f also increased in ABPA patients. However, serum IL-25, IL-33, and TSLP showed no significant differences between the two groups. Cell analysis showed an increase in IFN-γ+Th1 cells in the ABPA patients. FlowSOM analysis further confirmed that the frequency of CD3+CD4+PD-1+CD127+IFN-γ+T cells was higher in ABPA patients. Conclusion: Our findings suggest the distinct humoral and cell immunological responses in A.f-sensitized asthma and ABPA patients. ABPA patients have more severe eosinophilic inflammation and enhanced Th1 responses compared with A.f-sensitized asthma patients.

The prevalence of hereditary angioedema in a Chinese cohort with decreased complement 4 levels.

OBJECTIVE: Hereditary angioedema (HAE) is a rare, life-threatening autosomal dominant disorder. We aimed to investigate the prevalence of HAE in a Chinese population with a decreased Complement 4 (C4) level. METHODS: All the patients present in Tongji Hospital with C4 below lower normal range were included from January 2019 to June 2020. The individual data were extracted from the database and categorized by diagnosis. Patients suspected of HAE were further evaluated by C1 inhibitor level and function test to confirm the HAE diagnosis. RESULTS: A total of 8226 patients were enrolled in our study, among whom 18 had symptoms similar to HAE and received C1 inhibitor level and function tests. Two (1 male and 1 female) of the 18 patients were identified as HAE patients. This means the prevalence of HAE was 2.43/10 000 among the C4-decreased population and 10.1/10 000 in the C4-decreased population with etiology undetermined. The 2 HAE patients had experienced skin and oropharynx edema attack and received tracheotomy. The female patient had a family history. Laboratory tests showed significant decrease of C4 and C1 inhibitor levels in the 2 patients, both of whom were diagnosed as type 1 HAE. CONCLUSION: The prevalence of HAE is low in C4-decreased patients. In a large cohort, C4 level can serve as a practical indicator to screen the HAE patients, but further testing of C1 inhibitor activity and levels is needed to confirm the diagnosis of HAE.

IgE and IgG4 Repertoire in Asymptomatic HDM-Sensitized and HDM-Induced Allergic Rhinitis Patients.

INTRODUCTION: Asymptomatic sensitization is defined as the presence of positive skin prick test (SPT) and/or positive serum allergen-specific IgE in the absence of clinical allergic symptoms. Currently, there is no convincing explanation why some people with positive allergen tests do not show symptoms. We aimed to investigate the house dust mite (HDM)-specific IgE and IgG4 repertoire in asymptomatic HDM-sensitized subjects and HDM-induced allergic rhinitis (AR) patients. METHODS: A total of 48 subjects sensitized to HDM were included in this study: 27 had AR with/without asthma (symptomatic group), and 21 had no allergic symptoms (asymptomatic group). Six healthy individuals served as control group. Peripheral blood samples were collected for serum IgE and IgG4 assay and basophil activation tests (BATs). IgE and IgG4 assay included antibodies to Dermatophagoides (Der) p1, 2, 7, 10, 21, 23, and Der f1, 2. RESULTS: AR patients had a larger wheal diameter of SPT (7.0 vs. 3.0 mm, p < 0.0001) and a higher specific IgE to Der p (15.50 vs. 0.70 KU/L, p < 0.0001) than asymptomatic subjects. They also showed more frequent sensitization to Der p1 and Der p2 (both p < 0.05). However, the total IgE and specific IgG4 did not differ significantly between the 2 groups. The basophil activation response after being stimulated with HDM was observed to be higher in AR patients (all p < 0.05). CONCLUSIONS: There are differences in SPT, serum-specific IgE to Der p, component allergen Der p1 and Der p2 level and BAT between AR patients and asymptomatic subjects sensitized to HDM. IgG4 alone cannot differentiate asymptomatic individuals from AR patients.

Safety of house dust mite subcutaneous immunotherapy in preschool children with respiratory allergic diseases.

BACKGROUND: Allergen immunotherapy (AIT) is the only causal therapy for IgE-mediated allergy. There is less evidence about the safety and efficacy of AIT especially subcutaneous immunotherapy (SCIT) in children under 5 years old. We aimed to investigate the side effects and associated risk factors of house dust mite (HDM) SCIT in preschool children with respiratory allergic diseases. METHODS: The preschool children who had HDM-related allergic rhinitis with/without asthma were enrolled and undergone standardized HDM SCIT in our department from June 2013 to December 2019. Local reactions (LRs) and systemic reactions (SRs) were recorded and categorized according to World Allergy Organization recommendations. Demographic data and other therapeutic-related parameters were also recorded to investigate potential risk factors for these side effects. RESULTS: A total of 91 children (60 boys, 65.93%; 31 girls, 34.07%; mean age 4.13 years old) were included in the study. Among the 91 patients, 3109 SCIT injections were recorded, 62/91 (68.13%) experienced 186 immediate LRs, 4 /91(4.40%) experienced 6 delayed LRs, 11/91 (12.09%) children experienced 44 immediate SRs, 21/44 (47.73%) were grade 1 SRs, 21/44 (47.73%) were grade 2, 2/44 (4.55%) were grade 3, no grade 4 or 5 SRs occurred. Furthermore, 1/91 (1.10%) experienced 1 delayed SRs, manifested by urticaria 2 days later after allergen injection. 9/91 (9.89%) experienced 2 or more times SRs. Multivariable logistic regression analysis showed BMI (OR 1.506; 95%CI 1.091 to 2.079; p < 0.05) and sIgE against HDM (OR 1.497; 95%CI 1.082 to 2.071; p < 0.05) were risk factors for LRs. No variable was found to correlate with SRs (all p > 0.05). CONCLUSIONS: HDM subcutaneous immunotherapy is considered to be safe in preschool children with respiratory allergic diseases. Higher BMI and HDM sIgE level in children are risk factors for developing LRs. The incidence of SRs and the rate of severe SRs are low in preschool children.

Specific IgE and IgG4 Profiles of House Dust Mite Components in Allergen-Specific Immunotherapy.

Background: Allergen immunotherapy (AIT) can induce immune tolerance to allergens by activating multiple mechanisms, including promoting IgG4 synthesis and blunting IgE production. However, the longitudinal data of sIgE and sIgG4 to allergen components during AIT are limited. Objective: We sought to investigate the persistence and evolution of sIgE and sIgG4 against house dust mite (HDM) components during AIT and explore their correlation with clinical responses. Methods: Sixty allergic rhinitis (AR) with/without asthma patients receiving AIT for HDM were enrolled in AIT group. Thirty AR patients without receiving AIT served as control group. Blood samples were collected for sIgE, sIgG4 to HDM components (Derp 1, Derf 1, Derp 2, Derf 2, Derp 7, Derp 10, Derp 21 and Derp 23) assay at baseline, Month 6 and Month 18 of AIT. Combined symptom and medication scores (CSMS) were obtained accordingly. Results: In the AIT group, sIgG4 to the HDM components of Derp 1, Derf 1, Derp 2 and Derf 2, Derp 21 significantly increased at Month 18 compared to the baseline (36.2 UA/mL vs 158.8 UA/mL, 46.4 UA/mL vs 94.6 UA/mL, 80.5 UA/mL vs 152.3 UA/mL, 78.3 UA/mL vs 205.1 UA/mL, 42.3 UA/mL vs 59.3 UA/mL, all p<0.05), sIgE to HDM components didn't see differences at baseline and at Month 18 (all p>0.05).The numbers of positive HDM component sIgE and sIgG4 increased from 4.5 to 5 and 0 to 1.5 respectively (both p<0.05). However, the changes of sIgE, sIgG4, sIgE/sIgG4 ratio and the numbers of positive HDM components had no correlations with the improvement of CSMS after AIT (all ρ<0.3). For the control group, the sIgE and sIgG4 did not change significantly during the observational period (all p>0.05). Conclusion: AIT can induce the production of sIgG4 to HDM components. However, the increased sIgG4 levels of HDM component do not correlate with the corresponding sIgE levels at baseline or with AIT response. sIgG4 to HDM components do not qualify as a biomarker to evaluate the efficacy of AIT.

NECI: N-Electron Configuration Interaction with an emphasis on state-of-the-art stochastic methods.

We present NECI, a state-of-the-art implementation of the Full Configuration Interaction Quantum Monte Carlo (FCIQMC) algorithm, a method based on a stochastic application of the Hamiltonian matrix on a sparse sampling of the wave function. The program utilizes a very powerful parallelization and scales efficiently to more than 24 000 central processing unit cores. In this paper, we describe the core functionalities of NECI and its recent developments. This includes the capabilities to calculate ground and excited state energies, properties via the one- and two-body reduced density matrices, as well as spectral and Green's functions for ab initio and model systems. A number of enhancements of the bare FCIQMC algorithm are available within NECI, allowing us to use a partially deterministic formulation of the algorithm, working in a spin-adapted basis or supporting transcorrelated Hamiltonians. NECI supports the FCIDUMP file format for integrals, supplying a convenient interface to numerous quantum chemistry programs, and it is licensed under GPL-3.0.

Hydrogen Sulfide, Adipose Tissue and Diabetes Mellitus.

Hydrogen sulfide (H2S) is now increasingly considered to be the third gasotransmitter alongside other gaseous signaling molecules, nitric oxide (NO) and carbon monoxide (CO). H2S is produced by a variety of endogenous enzymatic and non-enzymatic pathways and acts as a modulator of the physiological and pathological events of the body. Adipocytes express the cystathionine γ lyase (CSE)/H2S system, which modulates a variety of biological activities in adipose tissue (AT), including inflammation, apoptosis, insulin resistance, adipokine secretion and adipocyte differentiation. Abnormalities in the physiological functions of AT play an important role in the process of diabetes mellitus. Therefore, this review provides an overview of the general aspects of H2S biochemistry, the effect of H2S on AT function and diabetes mellitus and its molecular signalling mechanisms as well as the potential application of H2S in pharmacotherapy.

Metformin mitigates autoimmune insulitis by inhibiting Th1 and Th17 responses while promoting Treg production.

Type 1 diabetes mellitus (T1DM) is still one of the major threats on global public health. This autoimmune condition is mainly caused by the imbalance of auto-reactive inflammatory effector T cells (Teffs) and protective regulatory T cells (Tregs). Therefore, inhibiting the development of Teffs and/or promoting Tregs provides a therapeutic strategy for preventing the development of T1DM. Pathways of energy metabolism have been shown to play a pivotal role in dictating the activation, differentiation and immune function of T cells. Studies have shown that inhibition of glycolysis suppresses the development of Th1 and Th17 cells, but promotes Treg production. AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy metabolism in mammals, which has also been demonstrated to interfere with T cell differentiation and effector function through inhibiting mammalian target of rapamycin (mTOR) and subsequent inhibition of glycolysis, and enhancement of lipid oxidation. In this study, we found that AMPK activator metformin suppresses T cell proliferation and inhibits the differentiation of Th1 and Th17 cells while promoting the development of Tregs in vitro in a dose-dependent manner. Treatment of NOD mice with metformin significantly mitigated autoimmune insulitis and substantially decreased the number of pro-inflammatory IFN-γ+ as well as IL17+ CD4 T cells in the spleens of NOD mice. However, a significantly increased percentage of regulatory IL-10+ and Foxp3+ CD4 T cells were seen. We provided a novel potential therapeutic method--by regulating T cell metabolism through targeting AMPK, to reduce the severity of autoimmune insulitis.

Alternaria B Cell Mimotope Immunotherapy Alleviates Allergic Responses in a Mouse Model.

Alternaria is a major outdoor allergen. Immunotherapy with Alternaria extracts has been documented to be effective in the sensitized patients. However, Alternaria extracts are notoriously difficult to standardize. Our aim is to screen the B cell mimotopes of Alternaria and to evaluate the therapeutic effects of B cell mimotope peptides on a BALB/c mouse model of Alternaria allergy. After a human sera pool from Alternaria monosensitized patients was established, B cell mimotopes were screened by a phage-displayed random heptamer peptide library that was identified via mixed Alternaria-specific IgE in the sera pool. B cell mimotopes with phage as a carrier were used to perform immunotherapy in an Alternaria allergy mouse model. Serological Ab levels, lung histology, and cytokine profiles were compared in the mimotope immunotherapy group, natural extract immunotherapy group, irrelevant phage control group, Alternaria-sensitized model group, and saline-blank group. Two mimotopes (MISTSRK and QKRNTIT) presented high binding ability with the sera of the Alternaria-allergic patients and mice and, therefore, were selected for immunotherapy in the mouse model. Compared with irrelevant phage control, model, and natural extract immunotherapy group, mimotope immunotherapy group significantly reduced serum IgE levels, inflammatory cells infiltration in the lung tissue, and IL-4 levels in bronchoalveolar lavage fluid, whereas serum IgG1 and IFN-γ levels in bronchoalveolar lavage fluid were increased. Our results indicate that B cell mimotopes of Alternaria alleviates allergic response in a mouse model and have potential as novel therapeutic agents for IgE-mediated Alternaria-allergic diseases.

Liraglutide, a Glucagon-like Peptide-1 Receptor Agonist, Attenuates Development of Cardiac Allograft Vasculopathy in a Murine Heart Transplant Model.

BACKGROUND: Advances in immunosuppressive therapy have significantly improved short-term but not long-term survival of cardiac transplant recipients; this is largely due to severe cardiac allograft vasculopathy (CAV). Glucagon-like peptide-1 receptor (GLP-1R)-based therapy exerts physiological effects on the cardiovascular system in addition to its traditional role in controlling glucose. We have investigated the effects of liraglutide, a GLP-1R agonist, on the development of CAV in a murine heart transplant model. METHODS: Heterotopic murine cardiac transplantation was performed with a major histocompatibility complex class II-mismatched model. Recipient mice were subcutaneously administered vehicle (0.9% saline solution) or liraglutide (300 µg·kg every 12 hours) from the day of transplantation. Allografts were harvested at 2 or 8 weeks and histologically analyzed. Inflammatory infiltrates were measured by immunohistochemistry, and immunofluorescence and western blotting analyzes were used to evaluate GLP-1R expression and markers of endothelial-to-mesenchymal transition (EndMT) in cardiac allografts and human coronary artery endothelial cells challenged with transforming growth factor-beta 1. RESULTS: Glucagon-like peptide-1 receptor was predominantly localized to vascular endothelial cells and was upregulated in cardiac allografts after liraglutide treatment. Liraglutide ameliorated CAV and cardiac fibrosis with reduced inflammatory cell infiltration and downregulated expression of adhesion molecules. Liraglutide inhibited EndMT in allografts and attenuated EndMT by inhibiting Smad3 activation in transforming growth factor-beta 1-treated human coronary artery endothelial cells. CONCLUSIONS: Administration of liraglutide from the time of transplantation upregulated GLP-1R in the transplanted heart and reduced cardiac fibrosis, inflammation, and CAV development. Therefore, liraglutide may be a novel therapy for CAV.

The Allergic Rhinitis Control Test Questionnaire Is Valuable in Guiding Step-Down Pharmacotherapy Treatment of Allergic Rhinitis.

BACKGROUND: Allergic Rhinitis Control Test (ARCT) has been validated in the allergic rhinitis (AR) step-up pharmacotherapy management approach. OBJECTIVE: The aim of our study was to evaluate the potential of ARCT in AR step-down pharmacotherapy. METHODS: In an open-labeled randomized controlled study, patients with AR controlled with intranasal corticosteroid (INS) plus antihistamine (step 4) were included and randomized into an ARCT or a control group. In the ARCT group, the patients were followed up every 15 days; if the ARCT score was ≥20 (controlled AR), the patient would step down to step 3 (INS), step 2 (daily antihistamine), step 1 (antihistamine as needed), and step 0 (no medication) consecutively; if the ARCT score was strictly <20, the treatment would not be adjusted. In the control group, patients would be treated with step 4 medications during the whole study. Rhinitis Quality-of-Life Questionnaire (RQLQ), Morisky Questionnaire, and Brief Illness Perception Questionnaire (B-IPQ) were completed at baseline and the end of the study. Medication use and side effects were recorded. RESULTS: A total of 255 patients with AR were enrolled into the study; 27 patients dropped out. The control rates at day 45 were 77.8% in the ARCT group and 85.8% in the control group (P > .05). The ARCT group had less mean medication use than the control group (INS 1.27 vs 2.22 bottle, antihistamines 35.9 vs 61.4 tablets) (P < .05). RQLQ, Morisky, and B-IPQ score were significantly improved in both groups after treatment (P < .05). CONCLUSIONS: Stepping down AR medications in controlled patients led to similar clinical outcomes at reduced cost compared with those who maintained their current treatment level. ARCT is an optimal tool for evaluating the step-down eligibility.

Mesenchymal stem cells in combination with low-dose rapamycin significantly prolong islet allograft survival through induction of regulatory T cells.

We previously demonstrated the protective effect of MSCs in an adaptive transfer mouse model. However, their therapeutic potential in an allogeneic immunocompetent setting mimicking clinical context of islet transplantation remained unknown. The aim of this study was to determine whether MSCs therapy, either by itself, or combined with Rapamycin could benefit the allograft survival of fully MHC-mismatched mouse islet transplant. Combination therapy of MSCs and low-dose Rapamycin significantly prolonged the survival of islet allografts, whereas treatment of MSCs, or Rapamycin alone, had no impact. Interestingly, this protective effect was associated with an induced expansion of regulatory T cells in islet grafts and draining lymph nodes, a skewed T-cell differentiation toward immunotolerance, and a profound suppression of alloreactivity against donor antigen. Our study suggests that a combination therapy of MSCs and low-dose Rapamycin can prolong the survival and preserve the function of islet allograft in the MHC-mismatched mouse model of islet transplantation.

The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis.

Renal fibrosis is recognized as the common route of all chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Additionally, accumulating evidence suggests that epithelial-mesenchymal transition (EMT) plays a significant role in the process of renal fibrogenesis. Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been widely used to treat type 2 diabetes. Recent studies have demonstrated that the GLP-1 analogs could also exert protective effects in cardiac fibrosis models. However, the effects of liraglutide on the progression of CKD remain largely unknown. In the present study, we investigated the effects of liraglutide on the progression to renal fibrosis induced by unilateral ureteral obstruction (UUO) and EMT of rat renal tubular epithelial cells (NRK-52E) induced with recombinant transforming growth factor-beta 1 (TGF-ß1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1α1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (α-SMA), and downregulation of E-cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-ß1 and its receptor (TGF-ß1R) and inhibited the activation of its downstream signaling molecules (pSmad3 and pERK1/2). The in vitro results showed that the EMT and extracellular matrix (ECM) secretion of NRK-52E cells were induced by TGF-ß1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-ß1. All these effects were attenuated by liraglutide treatment. However, the protective effects of liraglutide were abolished by co-incubation of the GLP-1 receptor (GLP-1R) antagonist exendin-3 (9-39). These results suggest that liraglutide attenuates the EMT and ECM secretion of NRK-52E cells induced by TGF-ß1 and EMT and renal fibrosis induced by UUO. The potential mechanism involves liraglutide binding to and activating GLP-1R, which prevents EMT by inhibiting the activation of TGF-ß1/Smad3 and ERK1/2 signaling pathways, thereby decreasing the ECM secretion and deposition. Therefore, liraglutide is a promising therapeutic agent that may halt the progression of renal fibrosis.

Pushing configuration-interaction to the limit: Towards massively parallel MCSCF calculations.

A new large-scale parallel multiconfigurational self-consistent field (MCSCF) implementation in the open-source NWChem computational chemistry code is presented. The generalized active space approach is used to partition large configuration interaction (CI) vectors and generate a sufficient number of batches that can be distributed to the available cores. Massively parallel CI calculations with large active spaces can be performed. The new parallel MCSCF implementation is tested for the chromium trimer and for an active space of 20 electrons in 20 orbitals, which can now routinely be performed. Unprecedented CI calculations with an active space of 22 electrons in 22 orbitals for the pentacene systems were performed and a single CI iteration calculation with an active space of 24 electrons in 24 orbitals for the chromium tetramer was possible. The chromium tetramer corresponds to a CI expansion of one trillion Slater determinants (914 058 513 424) and is the largest conventional CI calculation attempted up to date.