Mas-related G protein-coupled receptor X2 and its activators in dermatologic allergies.

The Mas-related G protein-coupled receptor X2 (MRGPRX2) is a multiligand receptor responding to various exogenous and endogenous stimuli. Being highly expressed on skin mast cells, MRGPRX2 triggers their degranulation and release of proinflammatory mediators, and it promotes multicellular signaling cascades, such as itch induction and transmission in sensory neurons. The expression of MRGPRX2 by skin mast cells and the levels of the MRGPRX2 agonists (eg, substance P, major basic protein, eosinophil peroxidase) are upregulated in the serum and/or skin of patients with inflammatory and pruritic skin diseases, such as chronic spontaneous urticaria or atopic dermatitis. Therefore, MRGPRX2 and its agonists might be potential biomarkers for the progression of cutaneous inflammatory diseases and the response to treatment. In addition, they may represent promising targets for prevention and treatment of signs and symptoms in patients with skin diseases or drug reactions. To assess this possibility, this review explores the role and relevance of MRGPRX2 and its activators in cutaneous inflammatory disorders and chronic pruritus.

Predictors of treatment response in chronic spontaneous urticaria.

The current therapeutic algorithm for chronic spontaneous urticaria (CSU), endorsed by the international guideline, entails treatment escalation from second-generation H1 -antihistamines (sgAHs) to omalizumab and cyclosporine until complete response is achieved. Recently, several predictors of response to these treatment options have been described. Here, we discuss the most promising predictors of response and nonresponse to these treatments in CSU. A systematic search was performed by two independent researchers using the MEDLINE/PubMed database with specific keywords and 73 studies included in the review. Levels of evidence were categorized as strong (robust predictors), weak (emerging predictors) or no association, based on the outcome and number of studies available. High disease activity, high levels of C-reactive protein and D-dimer are robust predictors for a poor or no response to sgAHs. Poor or no response to omalizumab is robustly predicted by low serum levels of total IgE. A good response to cyclosporine is robustly predicted by a positive basophil histamine release assay, whereas low total IgE is an emerging predictor. The response to treatment with sgAHs, omalizumab and cyclosporine can be predicted by the use of markers that are readily available in routine clinical practice. Further studies are needed to confirm these predictors.

The role of eosinophils in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is considered to be primarily a mast cell-driven disease. However, recent evidence suggests that eosinophils may also have an axial role in symptomology. Histologic studies have demonstrated the presence of both eosinophils and eosinophil granules, indicative of activation, in CSU lesions. Although many allergic and inflammatory conditions are associated with a peripheral blood eosinophilia, the converse appears to be the case in CSU, with a peripheral blood eosinopenia being observed in many patients. Possible mechanisms include the depletion of blood eosinophils by recruitment into the skin during active disease and immunologic destruction in the blood. We also address in some detail the interactions between eosinophils and mast cells, particularly the cytokine cross-talk of these cells and mediator release possibly leading to clinical symptoms. Also, activation by eosinophil proteins of the coagulation pathway leads to the generation of thrombin and increased mast cell degranulation. Finally, treatments aimed at reducing eosinophil accumulation and activation, such as the anti-IL-5 antibodies mepolizumab, reslizumab, and benralizumab, have been reported to reduce CSU symptoms. Clearly, a new picture of an important role of eosinophils in the pathogenesis of CSU is emerging.

Angioedema Masqueraders.

Angioedema is a common reason for referral to immunology and allergy specialists. Not all cases are in fact angioedema. There are many conditions that may mimic its appearance, resulting in misdiagnosis. This may happen when a clinician is unfamiliar with conditions resembling angioedema or when there is a low index of clinical suspicion. In this article, we explore a list of differential diagnoses based on body parts, including the lips, the limbs, periorbital tissues, the face, epiglottis and uvula, as well as the genitalia, that may pose as a masquerader even to an experienced eye.

Adipose-derived stem cells seeded in Pluronic F-127 hydrogel promotes diabetic wound healing.

BACKGROUND: Chronic nonhealing wound is a multifactorial complication of diabetes that results specifically as a consequence of impaired angiogenesis and currently lacks in effective treatments. Although a stem cell-based therapy may provide a novel treatment to augment diabetic wound healing, inferior cell survival at the diabetic skin wound is one of the key causes that are responsible for the low efficacy of the stem cell therapy. MATERIALS AND METHODS: In this work, we used an injectable, biocompatible, and thermosensitive hydrogel Pluronic F-127 to encapsulate allogeneic nondiabetic adipose-derived stem cells (ADSCs) and topically applied the cells to a full-thickness cutaneous wound in the streptozotocin-induced diabetic model in rats. RESULTS: The cells seeded in the hydrogel enhanced angiogenesis (CD31 marker) and promoted the cell proliferation (Ki67 marker) at the wound site and significantly accelerated wound closure, which was accompanied by facilitated regeneration of granulation tissue. Consistently, levels of the messenger RNA expression of key angiogenesis growth factor, vascular endothelial growth factor, and key wound healing growth factor, transforming growth factor beta 1, were also upregulated in the cell-treated wounds when compared with untreated wounds. CONCLUSIONS: The results indicated that the transplantation of allogeneic ADSCs via the hydrogel improves the efficiency of cell delivery and optimizes the performance of ADSCs for augmenting diabetic wound healing. In conclusion, this ADSC-based therapy may provide a novel therapeutic strategy for the treatment of nonhealing diabetic foot ulcers.

Case report of an unusual allergic reaction to a routine skin prick test performed in an outpatient clinic: Diagnosis, management, and knowledge gaps.

BACKGROUND: The skin prick test (SPT) is a standard procedure in allergy/immunology clinics, crucial for evaluating conditions like allergic rhinitis and food allergies. As a cornerstone in investigating immunoglobulin E-mediated allergy, it plays a vital role in diagnosing allergies, including those triggered by common dust mites like Dermatophagoides pteronyssinus, Dermatophagoides farinae, Euroglyphus maynei, and Blomia tropicalis. Despite its widespread use, adverse reactions to SPT are uncommon (15 per 100,000 patients), though the procedure is not entirely risk-free. This article presents a clinical case involving a 17-year-old female who experienced a moderately delayed allergic reaction 120 minutes post-SPT, managed effectively with subsequent symptom resolution. METHODS: The patient, with a history of persistent rhinorrhea, itchy nose, eyes, and postnasal drip, sought consultation due to worsening symptoms. Diagnostic measures, including patient-reported outcomes and SPT with a standard aeroallergen panel, revealed sensitization to various allergens. RESULTS: Post-test, the patient reported ocular pruritus, left eyelid swelling, and moderate rhinorrhea, persisting for about 24 hours. On the subsequent medical visit, the patient received rupatadine and deflazacort, leading to symptom resolution within 3 hours. CONCLUSION: This article delves into a systemic allergic reaction post-SPT, emphasizing the 2 main stages of type I hypersensitivity reactions. While the acute phase involves mast cell-driven mediators within 15 minutes, the delayed phase (4-8 hours) includes de novo cytokine release. Vigilance regarding symptom onset and differentiation between mild and severe reactions is crucial. Notably, the absence of specific waiting time guidelines post-SPT underscores the need for reporting to enhance understanding and subsequent management. Performing these procedures in specialized centers with qualified professionals is essential for effectively managing potential anaphylactic reactions. Addressing these knowledge gaps will contribute to enhanced patient safety during diagnostic procedures.

Effect of moxibustion on expression profile of miRNAs in Tripterygium glycoside-induced decreased ovarian reserve.

OBJECTIVE: To explore the possible regulatory mechanism of microRNA (miRNA) in moxibustion treatment for decreased ovarian reserve (DOR). METHODS: The DOR model was constructed by intragastrical Tripterygium glycoside suspension administration, and moxibustion therapy was simultaneously given. The morphological ovarian changes were observed by hematoxylin and eosin staining. The miRNA expression profile was detected by RNA sequencing, and bioinformatics analysis was performed. Cytoscape software 3.6.1 was used to establish a regulatory network and differentially expressed miRNAs were verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: Decreased number of mature follicles, increased atresia follicles, and abnormal granulosa cell morphology were observed in the model group compared with the control group. The moxibustion group demonstrated increased mature follicles, decreased atretic follicles, and significantly decreased abnormal morphology of granulosa cells compared with the model group. Additionally, RNA sequencing results manifested significantly up-regulated miRNA expressions (miR-92b-3p, miR-26-5p_R + 1_1ss10TC, miR-206-3p, miR-9993b-3p_1ss6GA, miR-7857-3p_R-1, miR-219a-2-3p_1ss10GC, miR-3968-p5_1ss10AT, and PC-5p-6478_1795) and down-regulated miR-664-2-5p_R + 1 in the model group, compared with the control group, and the moxibustion group reversed abnormal disorder levels of these miRNAs. Moreover, these differentially expressed miRNAs were mainly involved in the phosphatidylinositol-3-kinase / protein kinase B signaling pathway and nuclear factor erythropoietin-2-related factor 2 / heme oxygenase 1 signaling pathway. Finally, network and RT-qPCR verification revealed miR-9993b-3p_1ss6GA as the most critical miRNA. CONCLUSION: This experiment proved the effectiveness of moxibustion in improving the ovarian reserve of rats by regulating miRNA expression, especially miR-9993b-3p_1ss6GA.

Advancements in Antiviral Drug Development: Comprehensive Insights into Design Strategies and Mechanisms Targeting Key Viral Proteins.

Viral infectious diseases have always been a threat to human survival and quality of life, impeding the stability and progress of human society. As such, researchers have persistently focused on developing highly efficient, low-toxicity antiviral drugs, whether for acute or chronic infectious diseases. This article presents a comprehensive review of the design concepts behind virus-targeted drugs, examined through the lens of antiviral drug mechanisms. The intention is to provide a reference for the development of new, virus-targeted antiviral drugs and guide their clinical usage.

An update on the use of antihistamines in managing chronic urticaria.

INTRODUCTION: Urticaria, a mast cell-mediated skin disease, manifests as acute or chronic, with the latter divided into spontaneous and inducible types and requires individualized management, including identifying triggers and comorbidities. Antihistamines, particularly the second generation group, form the mainstay of primary treatment plans consisting of dosage adjustments and/or in combination with other treatment modalities depending on underlying disease control. AREAS COVERED: A literature search was conducted using 'antihistamines,' 'urticaria,' 'pharmacogenomics,' 'genomics,' 'biomarkers' and 'treatment response' as key words. In this review, we focus on the comprehensive understanding and application of antihistamines in managing adult and adolescent patients with chronic urticaria. EXPERT OPINION: Using antihistamines to treat urticaria is set to change significantly, focusing more on personalized medicine and identifying key biomarkers to enhance treatment response prediction. These changes aim to make treatments more specific and cost-effective by avoiding unnecessary tests. Applying new approaches in everyday clinical care faces challenges like proving the biomarkers' reliability, updating current guidelines, and incorporating individualized treatments into standard procedures. Efforts should now concentrate on finding easy-to-use biomarkers, improving access to pharmacogenomics, understanding why some patients are resistant to treatment, and creating more specific treatment options based on patient needs.

Urticaria and mimickers of urticaria.

Urticaria is a common skin condition encountered across various specialties in medicine, especially in dermatology and allergy/immunology practice. It has a heterogeneous presentation hence it is unsurprising that many skin conditions may be confused with urticaria. Urticaria may present as acute or chronic urticaria, the latter can be further categorised into chronic spontaneous and chronic inducible. In this article, we explore, explain, and summarise various skin lesions that are considered mimickers of urticaria, to promote understanding of each of the conditions highlighted, improve recognition, and reduce misdiagnosis.

Luftsichel sign.

Here we present a case of a patient with breathlessness and cough admitted to the COVID ward. Chest radiography demonstrates findings consistent with lobar collapse, giving rise to the 'Luftsichel sign'. This sign has been described in the literature and highlights the importance of recognition and prompt further investigation.

Induced membrane technique versus one-stage autografting in management of atrophic nonunion of long bone in the lower limb: clinical and health burden outcomes.

OBJECTIVE: In this study, we aimed to compare the outcomes of the two-stage induced membrane technique (IMT) and one-stage autografting in the treatment of aseptic atrophic nonunion in lower limb long bones. METHODS: From January 2014 to January 2022, we reviewed all surgically treated long bone nonunion patients, including patients aged 18 years or older with atrophic nonunion, who were either treated with the two-stage induced membrane technique (IMT) or one-stage autografting. Outcome parameters interns of clinical, quality of life and healthcare burden were recorded and retrospectively analysed between the two treatment populations. The follow-up time was at least 1 year. RESULTS: In total, 103 patients who met the criteria for aseptic atrophic nonunion were enrolled. Among them, 41 (39.8%) patients were treated with two-stage IMT, and 62 (60.2%) patients were treated with one-stage autologous bone grafting. The follow-up time was 12 to 68 months, with an average of 28.4 months. The bone healing rate was comparable in both groups (IMT: 92.7% vs. one-stage grafting: 91.9%, P = 0.089) at 12 months post-operation, and the bone healing Lane-Sandhu score was superior in the IMT group (mean: 8.68 vs. 7.81, P = 0.002). Meanwhile, the SF-12 scores of subjective physical component score (PCS) (mean: 21.36 vs. 49.64, P < 0.01) and mental health component score (MCS) (mean: 24.85 vs. 46.14, P < 0.01) significantly increased in the IMT group, as well as in the one-stage grafting group, and no statistically significant difference was found within groups. However, the total hospital stays (median: 8 days vs. 14 days, P < 0.01) and direct medical healthcare costs (median: ¥30,432 vs. ¥56,327, P < 0.05) were greater in the IMT group, while the complications (nonunion 8, infection 3, material failure 2, and donor site pain 6) were not significantly different between the two groups (17.1% vs. 19.4, P = 0.770). CONCLUSION: The data indicate that two-stage method of IMT serves as an alternative method in treating atrophic nonunion; however, it may not be a preferred option, in comprehensive considering patient clinical outcomes and healthcare burden. More evidence-based research is needed to further guide clinical decision-making.

Epidemiology, Management, and Treatment Access of Hereditary Angioedema in the Asia Pacific Region: Outcomes From an International Survey.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease with significant morbidity and mortality for which early diagnosis and effective therapy are critical. Many Asia Pacific (AP) countries still lack access to diagnostic tests and evidence-based therapies. Epidemiologic data from the AP is needed to formulate regional guidelines to improve standards of care for HAE. OBJECTIVE: To investigate the estimated minimal prevalence, needs, and potential interventions for the diagnosis and management of HAE in the AP. METHODS: A structured questionnaire was distributed to representative experts from member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology. Patient profiles and the presence of diagnostic facilities or tests, regional and national HAE guidelines, and patient support groups were reported and compared. RESULTS: Completed questionnaires were received from 14 representatives of 12 member countries and territories, representing 46% of the world population. Overall minimal prevalence of HAE in the AP region was 0.02/100,000 population, with significant heterogeneity across different centers. Only one-half and one-third had registered on-demand and prophylactic medications, respectively. Few had patient support groups (58%) or regional guidelines (33%), and their existence was associated with the availability of HAE-specific medications. Availability of C1-inhibitor level testing was associated with a lower age at HAE diagnosis (P = .017). CONCLUSIONS: Hereditary angioedema in the AP differs from that in Western countries. Hereditary angioedema-specific medications were registered in only a minority of countries and territories, but those with patient support groups or regional guidelines were more likely to have better access. Asia Pacific-specific consensus and guidelines are lacking and urgently needed.

The Melbourne epidemic thunderstorm asthma event 2016: a 5-year longitudinal study.

Background: In 2016, Melbourne was struck by the world's largest and most devastating epidemic thunderstorm asthma (ETSA) episode. While affected individuals displayed worsened short-term asthma control, little is known about their longer-term natural history, nor about interventions that restore control. Objective: We assessed the asthma symptomatology and related behaviours of ETSA-affected individuals through a single-centre prospective 5-year longitudinal study. We embedded an open-label observational trial investigating the role of grass pollen sublingual tablet (Oralair) allergen immunotherapy in improving asthma and allergic rhinitis symptoms. Methods: Allergic rhinitis symptom severity, frequency of asthma symptoms and inhaled corticosteroid usage were assessed via questionnaire yearly. In 2018, a subgroup of participants was enrolled in an observational study of Oralair treatment compared to control. The active group received Oralair from 2019 to 2021; both groups were followed-up for 5 years. Subgroup analyses were performed for participants with complete datasets, and who completed the trial per-protocol. Results: Year-on-year data across 5 years was available for 30 participants. The rate of persistent asthma symptoms declined from 37% to 7% in 2016 to 2021. Only 10%-27% of participants reported being completely asymptomatic in any given year. The inhaled preventer prescription rate was 67%, with only 35% being adherent. Twenty-seven participants with available data completed the Oralair trial per-protocol. No significant difference was noted between control and active groups for allergic rhinitis symptoms or asthma control, although the Oralair group saw a significant improvement in asthma control comparing 2019 with 2021. Conclusion: This is the longest documented follow-up of ETSA-affected individuals. Five years following sentinel event, there was progressive reduction but some persistence in asthma symptoms. Oralair allergen immunotherapy did not further improve allergic rhinitis or asthma symptoms compared to control, but there were no further ETSA events to test a protective effect during the study period.

Mast Cell Diseases in Practice and Research: Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond.

BACKGROUND: Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes. OBJECTIVE: This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community's efforts to improve diagnosis, management, therapy, and patients' quality of life by addressing unmet needs. METHODS: In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs. RESULTS: Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research. CONCLUSIONS: Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders.

Roles of PDGF receptor-beta in the structure and function of postnatal kidney glomerulus.

BACKGROUND: Mesangial cell functions are critically regulated by platelet-derived growth factor receptor (PDGFR)-ß signals. In contrast to the well-established role of PDGFR-ß in the development of kidney glomerulus, its role in adult kidney glomerulus remains controversial. METHODS: We deleted the PDGFR-ß gene postnatally using the Cre-loxP system and analysed the long-term effects of PDGFR-ß inhibition on glomerular changes associated with ageing and subtotal nephrectomy. RESULTS: Mice depleted of PDGFR-ß (Deletant) survived without showing apparent abnormalities. In glomerulus of Deletant, mesangial PDGFR-ß expression was decreased. The glomerular cell numbers were low, and the ageing-associated increment of mesangial matrix area was suppressed in Deletant as compared with control mice with conserved PDGFR-ß expression (Floxed) at 48 weeks of age. At 2 weeks after subtotal nephrectomy, albuminuria and the elevation of blood urea nitrogen were aggravated in Deletant. At this time, Deletant showed specific glomerular changes that included many hypertrophic podocytes and collapsed capillaries. At 12 weeks after subtotal nephrectomy, the kidney function in Deletant restored to the level of Floxed; however, the Deletant glomeruli showed dilated capillaries, decreased cell number and reduced mesangial matrix area with less extended mesangial cell processes as compared with Floxed. CONCLUSIONS: The long-term inhibition of mesangial PDGFR-ß prevented age-related mesangial expansion. On the other hand, the kidney glomeruli with decreased PDGFR-ß showed increased vulnerability to the acute nephron loss, and showed mesangial insufficiency in the following adaptive process.

Quantity and quality: Normative open-access neuroimaging databases.

The focus of this article is to compare twenty normative and open-access neuroimaging databases based on quantitative measures of image quality, namely, signal-to-noise (SNR) and contrast-to-noise ratios (CNR). We further the analysis through discussing to what extent these databases can be used for the visualization of deeper regions of the brain, such as the subcortex, as well as provide an overview of the types of inferences that can be drawn. A quantitative comparison of contrasts including T1-weighted (T1w) and T2-weighted (T2w) images are summarized, providing evidence for the benefit of ultra-high field MRI. Our analysis suggests a decline in SNR in the caudate nuclei with increasing age, in T1w, T2w, qT1 and qT2* contrasts, potentially indicative of complex structural age-dependent changes. A similar decline was found in the corpus callosum of the T1w, qT1 and qT2* contrasts, though this relationship is not as extensive as within the caudate nuclei. These declines were accompanied by a declining CNR over age in all image contrasts. A positive correlation was found between scan time and the estimated SNR as well as a negative correlation between scan time and spatial resolution. Image quality as well as the number and types of contrasts acquired by these databases are important factors to take into account when selecting structural data for reuse. This article highlights the opportunities and pitfalls associated with sampling existing databases, and provides a quantitative backing for their usage.

Extracorporeal Membrane Oxygenation for Acute Toxic Inhalations: Case Reports and Literature Review.

Previous studies have shown that poisoning is a major threat to human health. Inhalation of acute toxic gas has been linked to serious health consequences. Among the antidotes for poisoning currently used, supportive care is the most common intervention in clinical practice. Severe acute respiratory distress syndrome (ARDS) and/or refractory cardiogenic shock or cardiac arrest caused by toxins are associated with high mortality and are difficult to treat. Extracorporeal membrane oxygenation (ECMO) is an aggressive supportive measure used to manage severely poisoned patients. This study presents two cases of acute toxic gases inhalation, severe ARDS and circulatory instability induced by bromine inhalation, and ARDS induced by nitric acid inhalation which were successfully treated with ECMO. The ECMO techniques used in the animal models and in human cases to treat severe poisoning are described as well as the indications, contraindications, complications, and weaning of ECMO.

Total IgE as a Marker for Chronic Spontaneous Urticaria.

OBJECTIVE: Immunoglobulin E (IgE) and its receptor, FcɛRI, importantly contribute to the pathophysiology of chronic spontaneous urticaria (CSU). Recent findings point to a possible role of total IgE as a marker of CSU disease activity, endotypes, and responses to treatment. The evidence in support of total IgE included in the diagnostic workup of patients with CSU has not yet been reviewed. METHODS: Publications were searched via PubMed. The search terms used were "chronic urticaria" and "total IgE." Studies were screened by titles and abstracts, and 141 were used in the review. RESULTS: CSU patients frequently had elevated total IgE serum levels (up to 50%), but normal or very low total IgE levels also occurred. High total IgE may represent high disease activity, longer disease duration, high chance of responding to omalizumab treatment, quick relapse after stopping omalizumab, and lower chance of responding to cyclosporine. Low IgE, in contrast, may suggest Type IIb autoimmune CSU, poor response to treatment with omalizumab and a better chance to benefits from cyclosporine treatment. Furthermore, IgE in different CSU cohorts may have different physicochemical properties that could explain differences in treatment responses to IgE-directed therapies. CONCLUSION: The results of our review suggest that total IgE is a valuable marker for CSU, and we recommend its assessment in the routine diagnostic workup of CSU patients.