Atopy in chronic urticaria: an important yet overlooked issue.

Chronic urticaria (CU) is one of the most common dermatological diseases and has a significant impact on the quality of life of patients. However, the pathogenesis of this disease remains unclear. Autoimmunity in chronic spontaneous urticaria (CSU) has received considerable attention and has been studied previously. Atopy is an important characteristic of CU; however, it has not been fully recognized. Atopy predisposes individuals to immune responses to allergens, leading to type 2 inflammation and immunoglobulin E (IgE) overproduction. Compared with healthy individuals, patients with CU have a higher proportion of atopy, and an atopic background is correlated with the clinical characteristics of CU. The total IgE levels in patients with CU is significantly higher than those in healthy individuals. Although its level is not higher than that in classic allergic diseases, it is closely related to CU. Exogenous allergens, auto-allergens, and specific IgEs, which are closely related to atopy, have been reported, and their roles in CU pathogenesis are also being studied. Local and systemic atopic inflammation is present in patients with CU. This review summarizes the current knowledge regarding atopy and CU, speculating that there are CU subtypes, such as atopic CSU or atopic chronic inducible urticaria (CIndU) and that atopy may be involved in the pathogenesis of CU. These findings provide a new perspective for a comprehensive understanding of the clinical features of CU and further research regarding its pathogenesis.

Biomarkers of Autologous Whole Blood Injection Efficacy in Patients with Chronic Spontaneous Urticaria with Autoreactivity: A Preliminary Study.

INTRODUCTION: Chronic spontaneous urticaria (CSU) with autoreactivity is often resistant to antihistamines. Autologous whole blood injection (AWBI) has shown potential efficacy in the treatment of this disease, but it is controversial. It is necessary to screen patients who are suitable for this therapy in advance. This study aimed to identify biomarkers that predict the efficacy of AWBI treatment in CSU patients with autoreactivity. METHODS: A total of 30 patients with autologous serum skin test-positive CSU treated with AWBI were included in this study; urticaria activity score (UAS7) was recorded and the treatment response was judged based on it. Levels of total serum IgE, anti-high-affinity IgE receptor (FcεRI) IgG, and basophils CD63 and FcεRI expressions, and D-dimer of all patients were determined and analyzed. RESULTS: Baseline levels of total IgE, D-dimer, basophil FcεRI and CD63 expressions showed good correlations with UAS7 variations. D-dimer, basophil FcεRI and CD63 expressions changed significantly before and after AWBI treatment in AWBI responders, and the basophil FcεRI and CD63 expressions consistently and dynamically decreased in AWBI responders during the treatment. Baseline levels of total IgE, D-dimer, basophil FcεRI and CD63 expressions showed certain predictive values for AWBI response. CONCLUSIONS: Baseline levels of total IgE, D-dimer, basophil FcεRI and CD63 expressions could be biomarkers of predicting AWBI efficacy in patients with CSU with autoreactivity.

Atopy Does Not Influence the Clinical Outcome of Acute Urticaria: A Retrospective Study.

BACKGROUND: Acute urticaria (AU) may be associated with atopy, but the relationship between atopic status and the clinical features of the disease has not been fully described. OBJECTIVES: The aim of the study was to determine the proportion of atopy in AU patients and to see whether atopy is related to the clinical characteristics of AU and whether it has an impact on the outcome of the disease. MATERIALS AND METHOD: A retrospective analysis of patients with AU was performed. Demographic data, clinical features, and laboratory results were compared and analyzed between the atopic and non-atopic AU (napAU). RESULTS: In total, 139 participants were included. 54 (38.8%) patients were atopic AU (apAU) and 85 (61.2%) were napAU. Compared with napAU patients, apAU patients were more likely to have anaphylaxis, higher levels of C4, and lower levels of antistreptolysin. There were no significant differences between the two groups in terms of other clinical features, laboratory tests, the natural course of the disease, or disease outcomes. CONCLUSION: Atopy does exist in some patients with AU, and AU patients with an atopic background are at higher risk for anaphylaxis. Atopy does not influence the clinical outcome of AU and is not correlated with other clinical features and laboratory results of AU.

Dupilumab and subcutaneous immunotherapy for the treatment of refractory moderate to severe atopic dermatitis: A preliminary report.

Subcutaneous immunotherapy (SCIT) and dupilumab are important treatments for patients with moderate to severe atopic dermatitis (AD). However, in clinical practice, poor response to allergen immunotherapy (AIT) or dupilumab has been observed in some patients. It is unknown whether combining dupilumab and SCIT can improve treatment responses in patients with moderate to severe AD that is resistant to dupilumab or SCIT monotherapy. This single-centre, retrospective, observational, real-world study evaluated the efficacy and safety of dupilumab and SCIT for refractory moderate to severe AD. The data of ten patients with moderate to severe atopic dermatitis who were treated with dupilumab and SCIT were retrospectively analysed. The scoring atopic dermatitis (SCORAD) score, numerical rating scale (NRS), and atopic dermatitis control test (ADCT) scores and eosinophil and total IgE levels before and after add-on therapy were compared and analysed. The SCORAD, NRS, and ADCT scores decreased significantly at four and 12 weeks after the initiation of add-on therapy and plateaued during maintenance treatment. The eosinophil and total IgE levels were not significantly different before and after add-on therapy. No serious adverse reactions were reported in any patient during add-on therapy. This study indicates that the combination of dupilumab and SCIT safely improves the treatment response of patients with moderate to severe AD who are resistant to dupilumab or SCIT monotherapy.

Establishing induced pluripotent stem cell lines from two dominant optic atrophy patients with distinct OPA1 mutations and clinical pathologies.

Dominant optic atrophy (DOA) is an inherited disease that leads to the loss of retinal ganglion cells (RGCs), the projection neurons that relay visual information from the retina to the brain through the optic nerve. The majority of DOA cases can be attributed to mutations in optic atrophy 1 (OPA1), a nuclear gene encoding a mitochondrial-targeted protein that plays important roles in maintaining mitochondrial structure, dynamics, and bioenergetics. Although OPA1 is ubiquitously expressed in all human tissues, RGCs appear to be the primary cell type affected by OPA1 mutations. DOA has not been extensively studied in human RGCs due to the general unavailability of retinal tissues. However, recent advances in stem cell biology have made it possible to produce human RGCs from pluripotent stem cells (PSCs). To aid in establishing DOA disease models based on human PSC-derived RGCs, we have generated iPSC lines from two DOA patients who carry distinct OPA1 mutations and present very different disease symptoms. Studies using these OPA1 mutant RGCs can be correlated with clinical features in the patients to provide insights into DOA disease mechanisms.

Symptomatic dermographism induced by oral minocycline: A report of four cases.

Symptomatic dermographism (SD) is the most common form of chronic inducible urticarias. The etiology of this disease has rarely been reported in the literature. Minocycline is widely used in the treatment of acne, rosacea, and other inflammatory skin diseases. Herein we report four cases of SD onset during minocycline administration. These were young women in their 20s to 30s who were taking minocycline orally for acne vulgaris or rosacea. They all experienced the onset of SD 2-3 weeks after taking the drug, and then the complete disappearance of SD 1 month after stopping the drug. Minocycline was thought to be the culprit drug in these cases as other drugs were ruled out on clinical grounds. Our small series suggests that oral minocycline may induce SD, thus raising the awareness of this association in clinical practice. More research is needed to further confirm this association and reveal the underlying mechanism(s).

Acute Generalized Pustular Psoriasis Developed Resistance to Adalimumab Was Successfully Treated with Narrowband Ultraviolet B and Acitretin: A Case Report.

Acute generalized pustular psoriasis (GPP) is a severe but rare variant of psoriasis, characterized by an acute eruption of extensive erythema with numerous non-follicular pustules. In rare cases, local pustular psoriasis like acrodermatitis continua of Hallopeau (ACH) may progress into acute GPP if improperly treated. ACH and GPP are rare in the clinic and their treatment is more complex and often treatment-resistant compared to psoriasis vulgaris (PV). A variety of anti-psoriasis biologics emerging in recent years have been reported for the treatment of ACH and acute GPP. Biologics is considered to be an upgraded treatment option for traditional anti-psoriasis agents. But there are few reports of GPP patients developing resistance to biologics, or what if biologics fails. Herein, we report a case of acute GPP that developed from ACH, initially responded extremely well to adalimumab, but the treatment failed when the patient treated with the drug again, which is thought to have developed resistance to adalimumab, finally successfully treated with narrowband ultraviolet B (NB-UVB) and acitretin.

Ciliary neurotrophic factor-mediated neuroprotection involves enhanced glycolysis and anabolism in degenerating mouse retinas.

Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective cytokine in multiple models of retinal degeneration. To understand mechanisms underlying its broad neuroprotective effects, we have investigated the influence of CNTF on metabolism in a mouse model of photoreceptor degeneration. CNTF treatment improves the morphology of photoreceptor mitochondria, but also leads to reduced oxygen consumption and suppressed respiratory chain activities. Molecular analyses show elevated glycolytic pathway gene transcripts and active enzymes. Metabolomics analyses detect significantly higher levels of ATP and the energy currency phosphocreatine, elevated glycolytic pathway metabolites, increased TCA cycle metabolites, lipid biosynthetic pathway intermediates, nucleotides, and amino acids. Moreover, CNTF treatment restores the key antioxidant glutathione to the wild type level. Therefore, CNTF significantly impacts the metabolic status of degenerating retinas by promoting aerobic glycolysis and augmenting anabolic activities. These findings reveal cellular mechanisms underlying enhanced neuronal viability and suggest potential therapies for treating retinal degeneration.

Chronic Non-Healing Ulcers Associated with Atopic Inflammation: A Case Report.

Chronic non-healing ulcers are the undesirable outcome of delayed wound healing influenced by many factors. It can be seen in patients with diabetes, autoimmune conditions and multiple primary skin conditions. But chronic non-healing ulcers secondary to atopic inflammation are rarely reported in the literature. In this study, we reported a case with wounds caused by the wrong tattoo and surgery, activation of atopic inflammation caused delayed wound healing and the formation of chronic non-healing ulcers. The patient's atopic inflammation was relieved and stabilized with oral cyclosporine and topical application of halometasone cream and subsequently 0.1% tacrolimus cream, and then the chronic non-healing ulcers healed well, without recurrence at a follow-up visit 3 months later.

Generation of a homozygous LRPAP1 knockout human embryonic stem cell line (FDCHDPe009-B) by CRISPR/Cas9 system.

The homozygous autosomal recessive truncating mutations of LDL receptor related protein associated protein 1 (LRPAP1) is a possible reason for Nonsyndromic Extreme Myopia, patients with which show typical chorioretinal degeneration. We generated an LRPAP1 knockout FDCHDPe009-B embryonic stem cell line to study mechanisms of retinal degeneration underlying LRPAP1 deficiency with the help of the CRISPR/Cas9 system. Two distinct biallelic deletions in the cell line have been confirmed, which causing a frameshift and premature stop codons thus influence the translation of LRPAP1. FDCHDPe009-B has maintained normal stem cell morphology, pluripotent gene expression, parental karyotype, and ability to differentiate into three germ layers.

Single Cell Transcriptomic Analyses Reveal the Impact of bHLH Factors on Human Retinal Organoid Development.

The developing retina expresses multiple bHLH transcription factors. Their precise functions and interactions in uncommitted retinal progenitors remain to be fully elucidated. Here, we investigate the roles of bHLH factors ATOH7 and Neurog2 in human ES cell-derived retinal organoids. Single cell transcriptome analyses identify three states of proliferating retinal progenitors: pre-neurogenic, neurogenic, and cell cycle-exiting progenitors. Each shows different expression profile of bHLH factors. The cell cycle-exiting progenitors feed into a postmitotic heterozygous neuroblast pool that gives rise to early born neuronal lineages. Elevating ATOH7 or Neurog2 expression accelerates the transition from the pre-neurogenic to the neurogenic state, and expands the exiting progenitor and neuroblast populations. In addition, ATOH7 and Neurog2 significantly, yet differentially, enhance retinal ganglion cell and cone photoreceptor production. Moreover, single cell transcriptome analyses reveal that ATOH7 and Neurog2 each assert positive autoregulation, and both suppress key bHLH factors associated with the pre-neurogenic and states and elevate bHLH factors expressed by exiting progenitors and differentiating neuroblasts. This study thus provides novel insight regarding how ATOH7 and Neurog2 impact human retinal progenitor behaviors and neuroblast fate choices.

Generation of a homozygous LRP2 knockout human embryonic stem cell line (FDCHDPe010-A-56) by CRISPR/Cas9 system.

LRP2 is mainly expressed in the cell membrane of epithelia, maintaining normal endocytosis of nutrients from the extracellular microenvironment and mediating growth factor signals. The deficiency of LRP2 can result in abnormal lysosomal and mitochondrial function as well as insufficient resistance to oxidative stress. LRP2-KO animals show enlarged eyes and malfunction of the retinal pigment epithelium (RPE). We were able to generate an LRP2-KO human embryonic stem (ES) cell line using CRISPR/Cas9 gene editing and differentiate the mutant ES cells into RPE cells. Thus, this LRP2-KO human ES line will facilitate studying cellular mechanisms of eye disease due to LRP2 deficiency.

Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration.

Ciliary neurotrophic factor (CNTF) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, we performed high-throughput RNA sequencing analyses using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. In the absence of CNTF treatment, transcriptome alterations were detected at the onset of rod degeneration compared with wild type mice, including reduction of key photoreceptor transcription factors Crx, Nrl, and rod phototransduction genes. Short-term CNTF treatments caused further declines of photoreceptor transcription factors accompanied by marked decreases of both rod- and cone-specific gene expression. In addition, CNTF triggered acute elevation of transcripts in the innate immune system and growth factor signaling. These immune responses were sustained after long-term CNTF exposures that also affected neuronal transmission and metabolism. Comparisons of transcriptomes also uncovered common pathways shared with other retinal degeneration models. Cross referencing bulk RNA-seq with single-cell RNA-seq data revealed the CNTF responsive cell types, including Müller glia, rod and cone photoreceptors, and bipolar cells. Together, these results demonstrate the influence of exogenous CNTF on the retinal transcriptome landscape and illuminate likely CNTF impacts in degenerating human retinas.

Single-Cell RNA Sequencing of hESC-Derived 3D Retinal Organoids Reveals Novel Genes Regulating RPC Commitment in Early Human Retinogenesis.

The development of the mammalian retina is a complicated process involving the generation of distinct types of neurons from retinal progenitor cells (RPCs) in a spatiotemporal-specific manner. The progression of RPCs during retinogenesis includes RPC proliferation, cell-fate commitment, and specific neuronal differentiation. In this study, by performing single-cell RNA sequencing of cells isolated from human embryonic stem cell (hESC)-derived 3D retinal organoids, we successfully deconstructed the temporal progression of RPCs during early human retinogenesis. We identified two distinctive subtypes of RPCs with unique molecular profiles, namely multipotent RPCs and neurogenic RPCs. We found that genes related to the Notch and Wnt signaling pathways, as well as chromatin remodeling, were dynamically regulated during RPC commitment. Interestingly, our analysis identified that CCND1, a G1-phase cell-cycle regulator, was coexpressed with ASCL1 in a cell-cycle-independent manner. Temporally controlled overexpression of CCND1 in retinal organoids demonstrated a role for CCND1 in promoting early retinal neurogenesis. Together, our results revealed critical pathways and novel genes in early retinogenesis of humans.

Generation of an integration-free induced pluripotent stem cell line (FDEENTi003-A) from a patient with pathological myopia.

Pathological myopia (PM) is a major cause of irreversible vision impairment worldwide. We have successfully reprogrammed the peripheral blood mononuclear cells (PBMCs) from a PM patient to induced pluripotent stem cells and characterized their pluripotency and genetic stability, as well as the potential to differentiate to retinal pigment epithelium (RPE). This line may serve as a useful tool to explore the pathogenesis of PM.

Establishment of an induced pluripotent stem cell line (FDEENTi002-A) from a patient with Best's disease carrying c.888C > A mutation in BEST1 gene.

Best's disease (BD) is an inherited retinal degenerative disease caused by mutations in BEST1 gene. A human induced pluripotent stem cell (iPSC) line has been generated with integration-free Sendai virus method from peripheral blood mononuclear cells (PBMCs) of a BD patient carrying c.888C > A mutation in BEST1 gene. This cell line may serve as a model for the study of pathogenesis of BD.

Establishment of an induced pluripotent stem cell line (FDEENTi001-A) from a patient with pathological myopia.

Pathological myopia (PM) is a retinal degenerative disease with an increasing prevalence in Asia. The peripheral blood mononuclear cells (PBMCs) from a patient with PM were successfully reprogrammed to induced pluripotent stem cells (iPSCs) using integration-free method, Sendai viral (SeV) vectors expressing OCT4, SOX2, KLF4 and C-MYC. This line may provide a useful resource for exploring the pathogenesis of PM.

Tobacco and Alcohol Consumption Rates among Chinese Women of Reproductive Age in 2004⁻2011: Rate and Sociodemographic Influencing Factors.

Background: Smoking and alcohol consumption have become major public health problems among Chinese women. In this study we explore the behavioral trends in smoking and alcohol consumption of Chinese women. We also explored the changes in the sociodemographic factors that affect the smoking and alcohol consumption behaviors of Chinese women at different reproductive stages. Methods: We used the Chinese Health and Nutrition Survey data for 2004 to 2011 to investigate the trends and influential factors of tobacco and alcohol consumption among Chinese women. Data for tobacco and alcohol consumption (consumption of beer or any other alcoholic beverage and smoking of cigarettes) were extracted using questionnaires. We applied the χ² test to examine the trends of alcohol and tobacco consumption among Chinese women over the period of 2004 to 2011. We conducted two penalized logistic regressions with age as the continuous and classification variable (18⁻23, 24⁻29, 30⁻44, and 45⁻49 years), and independent variables included residence, age, and marital status. Results: Drinking rates among Chinese women significantly changed over the period of 2004 to 2011 (p = 0.018). Age was related to tobacco consumption rates for 2009 and 2011 (p < 0.05). Marital status was associated with tobacco consumption rates for 2004, 2009, and 2011 (p < 0.05). Tobacco and alcohol consumption rates from 2004 to 2011 were positively correlated (p < 0.05). Over the period of 2004 to 2011, alcohol consumption rates were higher among women living in urban areas than those among women living in rural areas (p < 0.05). High educational attainment was related to alcohol consumption. Educational attainment levels of secondary or primary schooling and university or above were related to alcohol consumption rates for 2004 to 2011 (p < 0.05). Employed women were more likely to consume alcohol than unemployed women in 2004, 2006, and 2011 (p < 0.05). Data from 2004 to 2011 showed that tobacco and alcohol use were correlated (p < 0.05) and that women aged 45⁻49 years old were more likely to consume tobacco than other women (p < 0.05); Conclusions: The drinking behavior of Chinese women changed considerably over the period of 2004 to 2011. Our results provide further insight on the smoking and drinking behaviors of Chinese women at different reproductive stages and the factors that influence such behaviors. Therefore, our findings on trends and factors that influence rates of tobacco and alcohol use allow for a better understanding of the smoking and drinking behaviors of Chinese women.

Elevated expression of human bHLH factor ATOH7 accelerates cell cycle progression of progenitors and enhances production of avian retinal ganglion cells.

The production of vertebrate retinal projection neurons, retinal ganglion cells (RGCs), is regulated by cell-intrinsic determinants and cell-to-cell signaling events. The basic-helix-loop-helix (bHLH) protein Atoh7 is a key neurogenic transcription factor required for RGC development. Here, we investigate whether manipulating human ATOH7 expression among uncommitted progenitors can promote RGC fate specification and thus be used as a strategy to enhance RGC genesis. Using the chicken retina as a model, we show that cell autonomous expression of ATOH7 is sufficient to induce precocious RGC formation and expansion of the neurogenic territory. ATOH7 overexpression among neurogenic progenitors significantly enhances RGC production at the expense of reducing the progenitor pool. Furthermore, forced expression of ATOH7 leads to a minor increase of cone photoreceptors. We provide evidence that elevating ATOH7 levels accelerates cell cycle progression from S to M phase and promotes cell cycle exit. We also show that ATOH7-induced ectopic RGCs often exhibit aberrant axonal projection patterns and are correlated with increased cell death during the period of retinotectal connections. These results demonstrate the high potency of human ATOH7 in promoting early retinogenesis and specifying the RGC differentiation program, thus providing insight for manipulating RGC production from stem cell-derived retinal organoids.