Laundry detergents and surfactants-induced eosinophilic airway inflammation by increasing IL-33 expression and activating ILC2s.

INTRODUCTION: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated. METHODS: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC). RESULTS: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2-/- Il2rg-/- , Il33-/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes. CONCLUSION: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life.

Direct platelet adhesion potentiates group 2 innate lymphoid cell functions.

BACKGROUND: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved. METHODS: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl-/- mice were evaluated. Both purified CD41+ and CD41- ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41+ and CD41- ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues. RESULTS: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl-/- mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level. CONCLUSION: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33.

Verruciform xanthoma accompanying a cystic growth: A case report.

Verruciform xanthoma, an uncommon, benign lesion with characteristic histopathological features, usually develops on the oral mucosa or genital area. We present an unusual case of verruciform xanthoma observed on the inguinal skin of a 52-year-old healthy man along with an underlying cystic component. The superficial lesion was a pedunculated nodule with a fissured surface and an 18-mm mound-like pigmented tumor underneath it. The histopathologically deep lesion was continuously attached to the superficial lesion. It was composed of fistula or sinus-like spaces and covered with acanthotic epithelium. The epidermis and upper dermis of both lesions showed identical histopathological findings: varying degrees of acanthosis, elongation of rete ridges, eosinophilic parakeratotic layer extending toward the dermis, and densely infiltrating foam cells confined to the papillary layer of the dermis. This finding of a cystic component in the deep dermis expands the histopathologic features of verruciform xanthoma.

Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity.

Endogenous and exogenous androgens induce masculinization of external genitalia through binding to the androgen receptor (AR). The target genes of androgens in external genitalia remain to be determined, although previous studies have shown that the apolipoprotein D gene (APOD) was significantly upregulated by dihydrotestosterone (DHT), the most potent androgen in humans. In the present study, we performed microarray analysis for genital skin fibroblasts obtained from four boys with buried penis (the control individuals) and a patient with partial androgen insensitivity syndrome (PAIS) due to a hypomorphic mutation in AR (the PAIS patient). We identified 24 transcripts that were upregulated or downregulated by DHT in all samples of control individuals and, to a lesser extent, in the sample of the PAIS patient. Differences between DHT-treated and -untreated samples were small; the results of 24 transcripts did not reach statistical significance. The 24 transcripts included CYP1B1, a gene possibly involved in the development of genital tubercle in mice, and APOD, as well as several genes that have been reported as androgen targets in prostate or other tissues. The results of this study indicate that androgen-mediated masculinization of external genitalia is unlikely to depend on massive transcriptional changes in specific AR target genes. Rather, minor transcriptional changes of several genes, and/or a complex molecular network may play a major role in penile development. Importantly, our data suggest the possible involvement of CYP1B1 in human genital development and confirm the clinical importance of APOD as a biomarker for AR function.

Predicting postoperative fever and bacterial colonization on packing material following endoscopic endonasal surgery.

Postoperative fever following endoscopic endonasal surgery is a rare occurrence of concern to surgeons. To elucidate preoperative and operative predictors of postoperative fever, we analyzed the characteristics of patients and their perioperative background in association with postoperative fever. A retrospective review of 371 patients who had undergone endoscopic endonasal surgery was conducted. Predictors, including intake of antibiotics, steroids, history of asthma, preoperative nasal bacterial culture, duration of operation, duration of packing and intraoperative intravenous antibiotics on the occurrence of postoperative fever, and bacterial colonization on the packing material, were analyzed retrospectively. Fever (≥38 °C) occurred in 63 (17 %) patients. Most incidences of fever occurred on postoperative day one. In majority of these cases, the fever subsided after removal of the packing material without further antibiotic administration. However, one patient who experienced persistent fever after the removal of packing material developed meningitis. History of asthma, prolonged operation time (≥108 min), and intravenous cefazolin administration instead of cefmetazole were associated with postoperative fever. Odds ratios (ORs) for each were 2.3, 4.6, and 2.0, respectively. Positive preoperative bacterial colonization was associated with postoperative bacterial colonization on the packing material (OR 2.3). Postoperative fever subsided in most patients after removal of the packing material. When this postoperative fever persists, its underlying cause should be examined.

[Tonsillectomy in Cases with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome].

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease, characterized, as its name suggests, by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. This syndrome is the most common cause of recurrent fever in children, however the rate of recognition of this syndrome is still low. Tonsillectomy has been suggested as an effective treatment, even though the precise, pathophysiology underlying this syndrome remains unknown. In this study, we investigated the outcomes in patients who underwent tonsillectomy. In particular, we examined the surgical outcomes and clinical features of the patients who underwent tonsillectomy. A total of 19 patients with PFAPA syndrome underwent tonsillectomy at our hospital from July 2013 to May 2016. Before the surgery, while all the patients had received medications, none showed complete resolution of the syndromes. However, of the 19 patients, 15 showed complete resolution of the syndrome immediately after the surgery. Four patients had fever even after the surgery. Three patients showed partial remission, with the frequency and duration of the episodes decreasing after the surgery. However, in one patient, the fever persisted as before the surgery. There were no significant differences in the clinical characteristics, such as the age at onset, fever episodes, associated symptoms, or age at surgery among the three groups. However, we observed a trend towards a higher frequency of a family history in patients with persistent symptoms after surgery. Tonsillectomy was highly effective against PFAPA syndrome, however, some patients failed to respond to the procedure. Therefore, it is important to carefully evaluate the risks and benefits in each case. The indications for tonsillectomy have not yet been clearly established. It is essential to continue further investigations to establish effective therapeutic strategies for this syndrome.

Specific amyloid ß clearance by a catalytic antibody construct.

Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid ß (Aß)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Aß C terminus noncovalently and hydrolyzed Aß rapidly, with no reactivity to the Aß precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Aß dipeptide unit. The catabody dissolved preformed Aß aggregates and inhibited Aß aggregation more potently than an Aß-binding IgG. Intravenous catabody treatment reduced brain Aß deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Aß hydrolysis appears to be an innate immune function that could be applied for therapeutic Aß removal.

Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded ß-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid ß peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function.

[A Retrospective Series of 77 Pediatric Patients with Vertigo at a National Center for Child Health and Development].

The evaluation and management of vertigo in children varies among institutional and medical specialties. The aim of this study was to describe the characteristics of vertigo in children presenting at a national pediatric center. Patients < 16 years old presenting with vertigo to the department of otolaryngology at a national center for child health and development from April 2004 to October 2009 were included (N = 77; 42 males and 35 females; average age, 8.7 ± 3.4 years) in this study. The most common diagnoses were vestibular migraine (VM; N = 21), benign paroxysmal vertigo (BPV; N =16), unilateral vestibulopathy (N = 12), and psychogenic vertigo (N = 8). Significant differences were observed in the frequency of the diagnoses between children aged older and younger than 7 years: BPV was most common in children < 7 years of age (p < 0.01) and VM was most common in ≥ 27 years of age (p < 0.05). Because obtaining adequate information from children for making a correct diagnosis is sometimes difficult, acquiring sufficient information from the parents is important. In addition, getting the parents to record the nystagmus during a vertigo attack with a digital camera or cellular phone can be useful because observing the nystagmus recorded on the video is helpful for making a diagnosis. Furthermore, the parents are participating in their child's care by attempting to record the attack, strengthening the relationship between the parents and the child. The incidence of psychogenic vertigo is low (less than 10%). Therefore, although physicians have recently tended to define the disorder as psychogenic when no objective abnormality is found in a patient, making a diagnosis of psychogenic vertigo is not recommended. Because vertigo can sometimes make a child anxious, delivering the correct diagnosis and treatment at the early stage is important for preventing anxiety in affected children.

Antibodies to a superantigenic glycoprotein 120 epitope as the basis for developing an HIV vaccine.

Failure to induce synthesis of neutralizing Abs to the CD4 binding determinant (CD4BD) of gp120, a central objective in HIV vaccine research, has been alternately ascribed to insufficient immunogen binding to Abs in their germline V region configuration expressed as BCRs, insufficient adaptive mutations in Ab V regions, and conformational instability of gp120. We employed peptide analogs of gp120 residues 421-433 within the CD4BD (CD4BD(core)) to identify Abs produced without prior exposure to HIV (constitutive Abs). The CD4BD(core) peptide was recognized by single-chain Fv fragments from noninfected humans with lupus that neutralized genetically diverse strains belonging to various HIV subtypes. Replacing the framework region (FR) of a V(H)4-family single-chain Fv with the corresponding V(H)3-family FRs from single-chain Fv JL427 improved the CD4BD(core) peptide-binding activity, suggesting a CD4BD(core) binding site outside the pocket formed by the CDRs. Replacement mutations in the FR site vicinity suggested the potential for adaptive improvement. A very small subset of serum CD4BD(core)-specific serum IgAs from noninfected humans without autoimmune disease isolated by epitope-specific chromatography neutralized the virus potently. A CD4BD(core)-specific, HIV neutralizing murine IgM with H and L chain V regions (V(H) and V(L) regions) free of immunogen-driven somatic mutations was induced by immunization with a CD4BD(core) peptide analog containing an electrophilic group that binds B cells covalently. The studies indicate broad and potent HIV neutralization by constitutive Abs as an innate, germline-encoded activity directed to the superantigenic CD4BD(core) epitope that is available for amplification for vaccination against HIV.

Fallopian canal dehiscence at pediatric cholesteatoma surgery.

The objectives of the study were to investigate the characteristics of ears with dehiscence of the fallopian canal at the time of cholesteatoma surgery and the relationship between dehiscence and age, and to consider the reasons why the fallopian canal tends to be preserved in pediatric patients. This study included 37 ears with cholesteatoma in pediatric patients (mean age 9.2 years, age range 4-14 years) and 273 ears with cholesteatoma in non-pediatric patients (mean age 45 years, age range 15-84 years). Patients were treated between January 2006 and April 2012. All patients had undergone prior tympanoplasty under general anesthesia at our institution. Facial canal dehiscence was evaluated by inspection and through palpation by blunt picking after the pathological tissues had been removed. The size of fallopian canal dehiscence was not investigated in this study. The frequency of dehiscence of the fallopian canal according to the type of cholesteatoma and coexisting pathological conditions, including destruction of the stapes, presence of a labyrinthine fistula, and dural exposure, were compared between the pediatric and non-pediatric groups. The frequency of dehiscence in cases with destruction of the stapes was also compared between the pediatric and non-pediatric groups. Dehiscence of the fallopian canal occurred in 6 of 37 ears (16.8 %) in the pediatric group and 91 of 273 ears (33.3 %) in the non-pediatric group (p < 0.05). In congenital cholesteatoma, the frequency of dehiscence was lower in the pediatric group than in the non-pediatric group (p < 0.05). However, in other types of cholesteatoma there was no statistically difference between the two types of cholesteatoma. The frequency of the destruction of the stapes was higher in the pediatric group than in the non-pediatric group (43.2 vs. 16.5 %, p < 0.001). In patients with severe destruction of the stapes, the fallopian canal was preserved more frequently in the pediatric group than in the non-pediatric group (p < 0.05). The frequency of dehiscence of the fallopian canal at the time of cholesteatoma surgery was lower in the ears of pediatric patients than in the ears of non-pediatric patients. This is probably due to the difference in types of cholesteatoma between the two groups and other unknown mechanisms.

Differences in clinical characteristics of fallopian canal dehiscence associated with pars flaccida and pars tensa cholesteatomas.

This study investigated the difference in clinical characteristics of fallopian canal dehiscence associated with pars flaccida and pars tensa cholesteatomas for the purpose of increasing the preoperative detectability of dehiscence. A total of 189 ears of patients 7-80 years of age (mean 42 years) with pars flaccida cholesteatoma and 63 ears of patients 9-84 years of age (mean 50 years) with pars tensa cholesteatoma were studied. All patients had undergone prior surgical management at our institution from January 2006 to April 2012. The incidence of fallopian canal dehiscence and its location were compared between pars flaccida and pars tensa cholesteatomas. Intraoperative findings of coexistent pathologies, including destruction of the stapes superstructure, labyrinthine fistula, and dural exposure, were compared between the dehiscence and no-dehiscence groups for the two types of cholesteatomas. The incidence of dehiscence was significantly higher in patients with pars tensa cholesteatoma (55.6 %) than in patients with pars flaccida cholesteatoma (26.5 %). Dehiscence located posterior to the cochleariform process occurred slightly more frequently in patients with pars tensa cholesteatoma than in those with pars flaccida cholesteatoma. In patients with pars flaccida cholesteatoma, labyrinthine fistulas and dural exposure were significantly more frequent in the dehiscence group than in the no-dehiscence group. Fallopian canal dehiscence is more frequent in patients with pars tensa cholesteatoma than in those with pars flaccida cholesteatoma. Especially in patients with pars flaccida cholesteatoma, paying special attention to these coexisting pathologies is important to increase preoperative detectability of dehiscence.

Predictive Models for Palliative Care Needs of Advanced Cancer Patients Receiving Chemotherapy.

CONTEXT: Early palliative care is recommended within eight-week of diagnosing advanced cancer. Although guidelines suggest routine screening to identify cancer patients who could benefit from palliative care, implementing screening can be challenging due to understaffing and time constraints. OBJECTIVES: To develop and evaluate machine learning models for predicting specialist palliative care needs in advanced cancer patients undergoing chemotherapy, and to investigate if predictive models could substitute screening tools. METHODS: We conducted a retrospective cohort study using supervised machine learning. The study included patients aged 18 or older, diagnosed with metastatic or stage IV cancer, who underwent chemotherapy and distress screening at a designated cancer hospital in Japan from April 1, 2018, to March 31, 2023. Specialist palliative care needs were assessed based on distress screening scores and expert evaluations. Data sources were hospital's cancer registry, health claims database, and nursing admission records. The predictive model was developed using XGBoost, a machine learning algorithm. RESULTS: Out of the 1878 included patients, 561 were analyzed. Among them, 114 (20.3%) exhibited needs for specialist palliative care. After under-sampling to address data imbalance, the models achieved an Area Under the Curve (AUC) of 0.89 with 95.8% sensitivity and a specificity of 71.9%. After feature selection, the model retained five variables, including the patient-reported pain score, and showcased an 0.82 AUC. CONCLUSION: Our models could forecast specialist palliative care needs for advanced cancer patients on chemotherapy. Using five variables as predictors could replace screening tools and has the potential to contribute to earlier palliative care.

Large carcinoma ex pleomorphic adenoma of the parotid gland: a case report and review of literature.

Pleomorphic adenoma (PA) is one of the most common benign tumors of the parotid gland. PA usually grows slowly and is painless. Surgery is necessary for treating PA. Facial palsy, salivary fistula, and Frey syndrome have been reported as complications of tumor resection. PA can transform into a carcinoma ex pleomorphic adenoma (CXPA) over time and as it enlarges. This report describes a case of a large CXPA that transformed from a PA that had developed over 17 years and caused withdrawal from social contact because fear of surgery made the patient refuse treatment. The tumor gradually enlarged without any pain for a decade, but rapid growth and bleeding began a year before admission. Postoperative facial function and local control of the tumor were excellent, but the patient required adjuvant chemotherapy for lung and mediastinum lymph node metastasis leading to dyspnea from tracheal stenosis. This case indicates the importance of adequate explanation and advice when choosing therapy for PA, especially given the risk of a PA transforming to a CXPA.

Can the effectiveness of tonsillectomy for PFAPA syndrome be predicted based on clinical factors.

OBJECTIVES: To evaluate the clinical factors associated with the outcome of tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, thereby clarifying who would most likely benefit from that surgery. METHODS: This was a case-control study of 53 PFAPA patients who underwent tonsillectomy and were divided into a complete-resolution group and a postoperative-fever group. Logistic regression analyses were performed using 17 clinical factors as variables to identify factors associated with the surgical outcome. Hierarchical cluster analysis was also performed to evaluate for relationships between phenotypes and surgical outcomes. RESULTS: Thirty-nine (73.6%) patients had complete resolution after tonsillectomy. In simple logistic regression analysis, the surgical outcome showed significant positive trends with late-onset (odds ratio [OR] 7.1, P = 0.02) and presence of headache (OR 6.5, P = 0.01). In stepwise multiple logistic regression analysis adjusted for age at onset, presence of headache was significantly associated with complete resolution (OR 6.5, P = 0.01). The complete resolution rates for each combination of headache status and age at onset were as follows: presence of headache/age at onset ≥36 months, 100% (14/14); presence of headache/age at onset <36 months, 76.9% (10/13); absence of headache/age at onset ≥36 months, 75.0% (6/8); and absence of headache/age at onset <36 months, 43.8% (7/16). In hierarchical cluster analysis, complete resolution, age at onset, and headache were in the same cluster. CONCLUSIONS: PFAPA patients with headache and late onset responded well to tonsillectomy. The mechanisms underlying this association may warrant further investigation.

Roles of human trophoblasts' pattern recognition receptors in host defense and pregnancy complications.

The immune system in pregnancy is able to protect pregnant mothers and fetuses from pathogenic microorganisms even while permitting the mother to tolerate the semi-allogenic fetus. Trophoblasts, which are fetal-derived placental cells, play a central role on both sides of this duality at the maternal-fetal interface. In brief, the trophoblasts express pattern recognition receptors (PRRs) and are involved in the local innate immune response in the placenta. That response eliminates pathogenic microbes but also causes tissue damage. In this review, we summarize the research findings to date regarding the roles of those human trophoblast PRRs. Multiple types of PRRs (Toll-like receptors, Nod-like receptors, and RIG-I-like receptors) are expressed in the placenta and on trophoblasts. Trophoblasts' PRRs participate in protecting the fetus against viruses, bacteria, and parasites by triggering production of proinflammatory cytokines and chemokines in the placenta. On the negative side, PRR signaling in trophoblasts can also initiate inflammation and trophoblast cell death, which can lead to placental inflammation-associated pregnancy complications such as preeclampsia, anti-phospholipid antibody syndrome, and miscarriage. Further elucidation of these dual roles of trophoblasts' PRRs may shed light on the mechanisms by which fetuses are protected against congenital infections and also give us a better understanding of the etiologies of pregnancy complications, which can help us prevent/reduce adverse prenatal/neonatal outcomes.

Clinical Risk Factors for Dysphagia and Esophageal Dysmotility in Systemic Sclerosis.

Systemic sclerosis (SSc) is often associated with dysphagia and esophageal dysmotility; however, only a few clinical studies on this topic have been conducted. Patients with SSc who underwent swallowing examinations and esophagography at our institution between 2010 and 2022 were included. A retrospective evaluation of the patients' backgrounds, autoantibody positivity, swallowing function, and esophageal motility was performed using medical charts. The association between dysphagia and esophageal dysmotility in patients with SSc and respective risk factors was investigated. Data were collected from 50 patients. Anti-topoisomerase I antibodies (ATA) and anti-centromere antibodies (ACA) were detected in 21 (42%) and 11 (22%) patients, respectively. Dysphagia was present in 13 patients (26%), and esophageal dysmotility in 34 patients (68%). ATA-positive patients had a higher risk for dysphagia (p = 0.027); ACA-positive patients had a significantly lower risk (p = 0.046). Older age and laryngeal sensory deficits were identified as risk factors for dysphagia; however, no risk factors for esophageal dysmotility were identified. No correlation was found between dysphagia and esophageal dysmotility. Esophageal dysmotility is more common in patients with SSc than in those with dysphagia. Autoantibodies can be predictors of dysphagia, and dysphagia must be carefully considered in ATA-positive and elderly patients with SSc.