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Background: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. Methods: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). Results: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about “diagnosis-probable” patient cohort (n = 402) and the “diagnosis-confirmed” patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. Conclusions: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Gastrointestinal (GI) allergies are broadly associated with food allergies and divided into groups based on the degree of allergen-specific immunoglobulin E (IgE) involvement: IgE-mediated, non-IgE-mediated, and mixed. Non-IgE-mediated GI food allergies are mostly observed in neonates and infants and include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). In addition to the classical phenotype, unique phenotypes such as vomiting and bloody stool, suspected sepsis, and overlapping eosinophilic GI disorders (EGIDs) have increased in Japan over the past 2 decades. Some of these cases were defined as having chronic FPIES. More recently, cases of hen’s-egg FPIES in Japan have increased dramatically since 2018, albeit for unknown reasons. Typical mixed-type food allergies are EGIDs, characterized by prominent eosinophil infiltration in the GI tract leading to GI symptoms. EGIDs are broadly classified into eosinophilic esophagitis (EoE) and non-EoE EGIDs that involve the GI tract with the exception of the esophagus. Of the EGIDs, EoE is the best known, as the number of cases has increased dramatically in Western countries, whereas pediatric EoE remains rare in Asia and non-EoE EGIDs may be more prevalent in Japan. A recent Japanese national survey showed that pediatric non-EoE EGIDs were persistent and severe compared to those in adults, possibly requiring further effective therapeutic options. Among the EGIDs, FPIAP is pathologically diagnosed as an infantile form of eosinophilic colitis. In addition, recent FPIES and FPE cases also involved eosinophilic inflammation. Recent cases of GI allergies may be associated with type 2 inflammation. A better understanding of the interactions between GI allergies and type 2 inflammation may clarify the pathogenesis of the recent increase in GI allergies.

This article covers the salient and updated themes of the Japanese Pediatric Guidelines for the Treatment and Management of Asthma (JPGL) 2020 published by the Japanese Society of Pediatric Allergy and Clinical Immunology. In the 2020 guidelines, five new clinical questions (CQs) have been added to address the 12 CQs regarding the treatment of childhood asthma. “Infant and preschool asthma” is diagnosed when young children (

Reports of food protein–induced enterocolitis syndrome (FPIES) in Japan have been increasing. However, the disease itself and the treatment options are poorly understood by both patients and medical professionals. The objective of this study is to develop an action plan for acute FPIES in Japan. We prepared a single–sheet action plan that describes the management of acute FPIES episodes for caregivers on one side and medical professionals on the reverse side. To evaluate the content of the action plan, we distributed a questionnaire to caregivers of patients with FPIES and to physicians who would encounter patients with FPIES. Changes to the FPIES action plan were made based on the feedback from the participants. The Delphi method was utilized to finalize the action plan. The participants of the initial survey found the action plan to be useful but the process for determining severity to be impractical. After discussion, the authors made appropriate improvements. By the Delphi method, consensus was reached on the revised FPIES action plan. In conclusion, this Japanese FPIES action plan was created by physicians from multiple subspecialties and caregivers of patients with FPIES. The action plan may improve the management of acute FPIES reactions in the Japanese community.

Abstract Cambodia has one of the highest tuberculosis (TB) incidence rates in the WHO Western Pacific region. Remarkably though, the prevalence of multidrug-resistant TB (MDR-TB) remains low. We explored the genetic diversity of Mycobacterium tuberculosis (MTB) circulating in this unique setting using whole-genome sequencing (WGS). From October 2017 until January 2018, we collected one hundred sputum specimens from consenting adults older than 21 years of age, newly diagnosed with bacteriologically confirmed TB in 3 districts of Phnom Penh and Takeo provinces of Cambodia before they commence on their TB treatment, where eighty MTB isolates were successfully cultured and sequenced. Majority of the isolates belonged to Lineage 1 (Indo-Oceanic) (69/80, 86.25%), followed by Lineage 2 (East Asian) (10/80, 12.5%) and Lineage 4 (Euro-American) (1/80, 1.25%). Phenotypic resistance to both streptomycin and isoniazid was found in 3 isolates (3/80, 3.75%), while mono-resistance to streptomycin and isoniazid was identical at 2.5% (N = 2 each). None of the isolates tested was resistant to either rifampicin or ethambutol. The specificities of genotypic prediction for resistance to all drugs tested were 100%, while the sensitivities of genotypic resistance predictions to isoniazid and streptomycin were lower at 40% (2/5) and 80% (4/5) respectively. We identified 8 clusters each comprising of two to five individuals all residing in the Takeo province, making up half (28/56, 50%) of all individuals sampled in the province, indicating the presence of multiple ongoing transmission events. All clustered isolates were of Lineage 1 and none are resistant to any of the drugs tested. This study while demonstrating the relevance and utility of WGS in predicting drug resistance and inference of disease transmission, highlights the need to increase the representation of genotype–phenotype TB data from low and middle income countries in Asia and Africa to improve the accuracies for prediction of drug resistance.

Background: IgE-mediated egg allergy is a common food allergy worldwide. Patients with egg allergy are known to easily achieve tolerance compared to other allergens such as nuts. Oral food challenge (OFC) is often performed on patients diagnosed with or suspected of having IgE-mediated food allergy, but whether hen's egg OFC is useful in IgE-dependent egg allergy patients to avoid complete elimination remains unknown. Methods: We identified articles in which OFCs were performed in Japanese patients diagnosed with or suspected of having IgE-mediated egg allergy. We evaluated whether the OFCs were useful to avoid the complete elimination of eggs by assessing the following: (1) the number of patients who could avoid complete elimination; (2) the number of patients who experienced serious adverse events (SAEs); or (3) adverse events (AEs); (4) improvement in quality of life (QOL); and (5) immunological changes. Results: Fifty-nine articles were selected in the study; all the references were case series or case studies in which OFC was compared to pre-challenge conditions. The overall negative ratio against egg OFC was 62.7%, but an additional 71.9% of OFC-positive patients could take eggs when expanded to partial elimination. Of the 4182 cases, 1146 showed AEs in the OFC, and two cases reached an SAE. Two reports showed an improvement in QOL and immunological changes, although the evidence was weak. Conclusions: OFCs against eggs may be useful to avoid complete elimination, but medical professionals should proceed with the test safely and carefully.

Background: Cow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known. Methods: After setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events. Results: Forty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%). Conclusions: This analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.

ABSTRACT The dioxonaphthoimidazolium scaffold is a novel, highly bactericidal redox cycling antituberculosis chemotype that is reliant on the respiratory enzyme Type II NADH dehydrogenase (NDH2) for the generation of reactive oxygen species (ROS). Here, we employed Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) reporter strains to show that ROS generated by the redox cycler SA23 simulated an iron deficient state in the bacteria, which led to a compensatory increase in the expression of the iron acquisition mbtB gene while collaterally reducing the expression of the iron storage bfrB gene. Exacerbating the iron deficiency via the inclusion of an iron chelator or aggravating oxidative stress by deploying a catalase (KatG) loss-of-function mutant strain enhanced the activity of SA23, whereas a combined approach of treating the katG mutant strain with an iron chelator led to even greater gains in activity. Our results support the notion that the activity of SA23 pivots on a vicious cycle of events that involve the derailment of iron homeostasis toward greater acquisition of the metal, overwhelmed oxidative stress defenses due to enhanced Fenton reactivity, and, ultimately, self-inflicted death. Hence, we posit that redox cyclers that concurrently perturb the iron equilibrium and cellular respiration are well-positioned to be potent next-generation anti-tubercular drugs. IMPORTANCE Cellular respiration in mycobacteria is a potentially rich target space for the discovery of novel drug entities. Here, we show that a redox cycling bactericidal small molecule that selectively activates a respiratory complex in mycobacteria has the surprising effect of disrupting iron homeostasis. Our results support the notion that the disruption of cellular respiration is a potent driver of reactive oxygen species (ROS) generation by the redox cycling molecule. Mycobacteria respond by acquiring iron to restore the levels depleted by the prevailing oxidizing conditions, which inadvertently trigger the compensatory acquisition of the metal. This leads to overwhelmed oxidative stress defenses and yet more iron depletion. For organisms that are unable to break out of this pernicious cycle of events, cell death is the inevitable outcome. Hence, aberrant ROS production by a redox cycling bactericidal agent inflicts a plethora of damaging effects on mycobacteria, including the derailment of iron homeostasis.

The Japanese Guideline for Childhood Asthma (JGCA) 2020 is a translation of the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2017 into English, which was published by the Japanese Society of Pediatric Allergy and Clinical Immunology. It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. These guidelines will be of interest to non-specialist physicians involved in the care of children with asthma. In JPGL, JPGL2017 is the first evidence-based guidelines updated according to the GRADE system and Minds approach, and it addresses eight clinical questions about the treatment of childhood asthma. In children aged ≤5 years, infant and preschool asthma is diagnosed according to the response to short acting beta2 agonists or the effect of a therapeutic trial during 1 month with controller treatment and worsening after treatment cessation. Long-term management both promotes pharmacological therapy and measures against risk factors that induce exacerbation, better patient education and a partnership with trinity. In addition, long-term management should not be carried out without review but rather be based on a cycle of evaluation, adjustment and treatment. In JPGL2017, the transdermal patch and oral beta2 agonists are positioned as drugs within the concept of “short-term additional treatment” to be used until the symptoms are stabilized when the control state transiently deteriorates.

Five years have passed since the Japanese Pediatric Guideline for Food Allergy (JPGFA) was first revised in 2011 from its original version. As many scientific papers related to food allergy have been published during the last 5 years, the second major revision of the JPGFA was carried out in 2016. In this guideline, food allergies are generally classified into four clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type of food allergy (urticaria, anaphylaxis, etc.), and (4) special forms of immediate-type of food allergy such as food-dependent exercise-induced anaphylaxis and oral allergy syndrome (OAS). Much of this guideline covers the immediate-type of food allergy that is seen during childhood to adolescence. Infantile atopic dermatitis associated with food allergy type is especially important as the onset of most food allergies occurs during infancy. We have discussed the neonatal and infantile gastrointestinal allergy and special forms of immediate type food allergy types separately. Diagnostic procedures are highlighted, such as probability curves and component-resolved diagnosis, including the recent advancement utilizing antigen-specific IgE. The oral food challenge using a stepwise approach is recommended to avoid complete elimination of causative foods. Although oral immunotherapy (OIT) has not been approved as a routine treatment by nationwide insurance, we included a chapter for OIT, focusing on efficacy and problems. Prevention of food allergy is currently the focus of interest, and many changes were made based on recent evidence. Finally, the contraindication between adrenaline and antipsychotic drugs in Japan was discussed among related medical societies, and we reached an agreement that the use of adrenaline can be allowed based on the physician's discretion. In conclusion, this guideline encourages physicians to follow the principle to let patients consume causative foods in any way and as early as possible.

Antibodies expressed in the cytosol often form insoluble aggregates, which makes it hard to target intracellular proteins. Here the authors engineer an ultra-stable cytoplasmic antibody (STAND) with a low isoelectric point that can be used in vivo.

A recent report showed that most pediatric cases of non-eosinophilic esophagitis (EoE) eosinophilic gastrointestinal disorders (EGIDs) (non-EoE EGIDs) are persistent and severe compared with those of EoE, thus requiring further effective therapeutic approaches. In this study, we present the first case based on a systematic search of non-EoE EGID for which tolerance to causative foods and histological and symptomatic improvements were achieved following dupilumab administration, after elimination diets and omalizumab and mepolizumab treatments. Driven by this case, we investigated the efficacies of biological treatments in non-EoE EGID cases based on the patient studied herein, and other patients identified in the conducted systematic review. Seven articles, including five different biologics, were reviewed. Both clinical efficacies and impact differences among the targeted molecules are demonstrated in this study. Our findings show that dupilumab may affect mechanisms that can suppress symptoms induced by offending foods that are different from those induced by other biologics as identified in the conducted systematic review. Additional studies are required to address the unmet needs of non-EoE EGID treatments.

Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms Charcot–Leyden crystals, which are observed in various eosinophilic diseases. Accumulating studies have indicated that galectin-10 acts as a new biomarker for disease activity, diagnosis, and treatment effectiveness in asthma, eosinophilic esophagitis, rhinitis, sinusitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis. The extracellular release of galectin-10 is not mediated through conventional secretory processes (piecemeal degranulation or exocytosis), but rather by extracellular trap cell death (ETosis), which is an active cell death program. Eosinophils undergoing ETosis rapidly disintegrate their plasma membranes to release the majority of galectin-10. Therefore, elevated galectin-10 levels in serum and tissue suggest a high degree of eosinophil ETosis. To date, several studies have shown that galectin-10/Charcot–Leyden crystals are more than just markers for eosinophilic inflammation, but play functional roles in immunity. In this review, we focus on the close relationship between eosinophils and galectin-10, highlighting this protein as a potential new biomarker in eosinophilic diseases.

Background: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GI-FAs) are one type of food allergy found in neonates and infants. Few reports have defined the severity of non-IgE-GI-FAs in these populations. Methods: Grading scales of the severity of non-IgE-GI-FAs according to extra-GI symptoms, such as poor weight gain, as well as systemic symptoms, including fever and shock, were developed and retrospectively applied to patients with non-IgE-GI-FAs. The relationship between the severity of non-IgE-GI-FAs and both clinical and laboratory findings were examined. Results: Elevation of C-reactive protein levels and a decrease in total protein and albumin were observed in accordance with allergy severity. In an endoscopic examination, inflammatory findings were confirmed in large areas of the colonic mucosa in case of higher severity levels, and infiltration of inflammatory cells other than eosinophils was found in the severest grade. Extensively hydrolyzed milk or amino acid-based milk was required for all patients with the severest grade. In addition, the timing of acquiring tolerance tended to be late for this grade. Conclusions: Classification and determination of the severity of non-IgE-GI-FAs in neonates and infants may not only contribute to elucidation of the pathogenesis but may also be useful in the clinical setting. Keywords: Food hypersensitivity, Gastroenteritis, Infant, Milk, Prognosis

ABSTRACT Indole propionic acid (IPA), produced by the gut microbiota, is active against Mycobacterium tuberculosis in vitro and in vivo. However, its mechanism of action is unknown. IPA is the deamination product of tryptophan (Trp) and thus a close structural analog of this essential aromatic amino acid. De novo Trp biosynthesis in M. tuberculosis is regulated through feedback inhibition: Trp acts as an allosteric inhibitor of anthranilate synthase TrpE, which catalyzes the first committed step in the Trp biosynthesis pathway. Hence, we hypothesized that IPA may mimic Trp as an allosteric inhibitor of TrpE and exert its antimicrobial effect by blocking synthesis of Trp at the TrpE catalytic step. To test our hypothesis, we carried out metabolic, chemical rescue, genetic, and biochemical analyses. Treatment of mycobacteria with IPA inhibited growth and reduced the intracellular level of Trp, an effect abrogated upon supplementation of Trp in the medium. Missense mutations at the allosteric Trp binding site of TrpE eliminated Trp inhibition and caused IPA resistance. In conclusion, we have shown that IPA blocks Trp biosynthesis in M. tuberculosis via inhibition of TrpE by mimicking the physiological allosteric inhibitor of this enzyme. IMPORTANCE New drugs against tuberculosis are urgently needed. The tryptophan (Trp) analog indole propionic acid (IPA) is the first antitubercular metabolite produced by human gut bacteria. Here, we show that this antibiotic blocks Trp synthesis, an in vivo essential biosynthetic pathway in M. tuberculosis. Intriguingly, IPA acts by decoupling a bacterial feedback regulatory mechanism: it mimics Trp as allosteric inhibitor of anthranilate synthase, thereby switching off Trp synthesis regardless of intracellular Trp levels. The identification of IPA’s target paves the way for the discovery of more potent TrpE ligands employing rational, target-based lead optimization.

To identify novel inhibitors of Mycobacterium tuberculosis cell envelope biosynthesis, we employed a two-step approach. First, we screened the diverse synthetic small molecule 71,544-compound Enamine library for growth inhibitors using the non-pathogenic surrogate Mycobacterium bovis BCG as screening strain and turbidity as readout. Second, 16 confirmed hits were tested for their ability to induce the cell envelope stress responsive promoter piniBAC controlling expression of red fluorescent protein in an M. bovis BCG reporter strain. Using a fluorescence readout, the acetamide E11 was identified. Resistant mutant selection and whole genome sequencing revealed the mycolic acid transporter Mmpl3 as a candidate target of E11. Biochemical analysis using mycobacterial spheroplasts and various membrane assays suggest that E11 indirectly inhibits MmpL3-facilitated translocation of trehalose monomycolates by proton motive force disruption. E11 showed potent bactericidal activity against growing and non-growing M. tuberculosis, low cytotoxic, and hemolytic activity and a dynamic structure activity relationship. In addition to activity against M. tuberculosis, E11 was active against the non-tuberculous mycobacterium M. abscessus, an emerging opportunistic pathogen. In conclusion, we identified a novel bactericidal anti-mycobacterial lead compound targeting MmpL3 providing an attractive starting point for optimization.

ABSTRACT The mycobacterial caseinolytic protease ClpP1P2 is a degradative protease that recently gained interest as a genetically and pharmacologically validated drug target for tuberculosis. The first whole-cell active ClpP1P2 inhibitor, the human proteasome inhibitor bortezomib, is currently undergoing lead optimization to introduce selectivity for the bacterial target. How inhibition of ClpP1P2 translates into whole-cell antimicrobial activity is little understood. Previous work has shown that the caseinolytic protease gene regulator ClgR is an activator of the clpP1P2 genes and also suggested that this transcription factor may be a substrate of the protease. Here, we employ promoter activity reporters and direct mRNA level measurements showing that bortezomib treatment of Mycobacterium bovis BCG increased transcription of clpP1P2 and other ClgR-dependent promoters, suggesting that inhibition of ClpP1P2 increases cellular ClgR levels. Then, we carried out red fluorescent protein-ClgR fusion analyses to show that ClgR is indeed a substrate of ClpP1P2 and to identify ClgR’s C-terminal nonapeptide APVVSLAVA as the signal sufficient for recognition and efficient protein degradation by ClpP1P2. Interestingly, accumulation of ClgR appears to be toxic for bacilli, suggesting a mechanism for how pharmacological inhibition of ClpP1P2 protease activity by bortezomib translates into whole-cell antibacterial activity. IMPORTANCE With 9 million new cases and more than 1 million deaths per year, tuberculosis, caused by Mycobacterium tuberculosis, is the biggest infectious disease killer globally. New drugs for the treatment of the drug-resistant forms of the disease are needed. Recently, a new target-lead couple, the mycobacterial protease ClpP1P2 and the human anticancer drug bortezomib, was identified. However, we know little about how expression of this protease is regulated, which proteins in the bacterium it degrades, how the protease recognizes its target proteins, and how the inhibition of ClpP1P2 exerts whole-cell antimicrobial activity. Here, we show that the ClpP1P2 protease regulates its own expression, and we identified a new substrate and a new substrate recognition sequence and a mechanism for how ClpP1P2 inhibition causes bacterial growth inhibition.

Background: Epidemiological evidence indicates that the age at onset of asthma and allergen sensitization in early life is decreasing in people from Western countries. To explore latent trends, we conducted a retrospective examination of the age at onset of asthma and specific IgE antibodies against inhalant allergens in Japanese asthmatic children. Methods: We conducted a case series study of 103 consecutive children with atopic type of asthma (aged 2 years to 16 years, mean age 9.4 ± 3.4 years). Diagnoses of asthma and allergic rhinitis were defined according to Japanese guidelines. The onset of asthma and allergic rhinitis was also defined as any report of asthma and allergic rhinitis confirmed by a physician. Allergen sensitization was evaluated as specific serum IgE levels for 9 common inhalant allergens in peripheral blood. Atopic type of asthma was defined as a being positive for at least one aeroallergen. Results: Mean age at asthma onset was 2.3 ± 1.9 years, which is slightly lower than that of previous reports, including those published in Japan. A high prevalence rate of up to 80% was found for perennial antigens including Dermatophagoides spp. and house dust, as reported previously. Notably, some of the children aged at 1 year tested positive for these allergens. Conclusions: The age at onset of asthma seems to be decreasing in comparison with previous reports. Furthermore, the age at onset of allergen sensitization against inhalant allergens appears to follow this trend.

Background: Little information is available regarding eosinophil activation and cytokine profiles in relation to age in virus-induced bronchial asthma. We therefore explored the association between age, respiratory viruses, serum eosinophil cationic protein (ECP), and cytokines/chemokines in acute exacerbations of childhood asthma. Methods: We investigated viruses in nasal secretions from 88 patients with acute exacerbation of childhood asthma by using antigen detection kits and/or RT-PCR, followed by direct DNA sequencing analysis. We also measured peripheral eosinophil counts, and the serum levels of ECP and 27 types of cytokines/chemokines in 71 virus-induced acute asthma cases and 13 controls. Results: Viruses were detected in 71(80.7%) of the 88 samples. The three major viruses detected were rhinoviruses, RS viruses, and enteroviruses; enteroviruses were found to be dominant in patients aged ≥3 years. There was no change in the levels of rhinoviruses and RS viruses between the two age groups, defined as children aged

Whole mitochondrial DNA of the Silkie fowl (Gallus gallus var. domesticus) was sequenced in order to elucidate the genetic position of the Silkie fowl in its related species based on mitochondrial DNA sequence. The length of Silkie mitochondrial DNA was found to be 16,784 base pairs. The similarity between Silkie and White Leghorn was found to be 99.77% (39 nucleotide differences in 16,784 base pairs). Since the sequences of NADH dehydrogenase subunit 2 and cytochrome b genes have been reported in six species [Japanese quail : Coturnix japonica, Ring-neck pheasant : Phasianus colchicus, Grey partridge : Perdix perdix, Chinese bamboo partridge : Bambusicola thoracia, Chicken (White Leghorn) : Gallus gallus var. domesticus, and Redhead : Aythya americana], nucleotide sequences of these two genes were used for a phylogenetic analysis of Silkie against these six species using neighbor joining and maximum likelihood methods. The Silkie and White Leghorn are in the same phylogenetic cluster with a bootstrap value of 1000/1000.

Background: Recently, a second prostaglandin D2 (PGD2) receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), was identified. Because PGD2 was reported to have chemotactic activity on eosinophils, CRTH2 expressed on eosinophils attracted interest as a receptor associated with eosinophil migration to, and accumulation at, inflammatory sites. To elucidate the mechanism regulating the expression of CRTH2 on eosinophils, the effects of PGD2, interleukin (IL)-4, IL-5 and interferon (IFN)-γ on CRTH2 expression were investigated. Methods: Blood eosinophils were purified using Percoll and anti-CD16 antibody coated magnetic beads. Eosinophils were incubated with PGD2 and/or IL-4, IL-5 and IFN-γ. The expression of CRTH2 on eosinophils was measured using a FACScan cytometer (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA). Results: Prostaglandin D2 and IL-5, but not IL-4 and IFN-γ, downregulated the expression of CRTH2 on eosinophils. Furthermore, PGD2- and IL-5-induced downregulation of CRTH2 on human eosinophils was inhibited by phenylarsine oxide, a receptor internalization inhibitor. Conclusions: These results suggest that PGD2 and IL-5 regulate CRTH2 expression on eosinophils through CRTH2 internalization. The decreased expression of CRTH2 on tissue eosinophils may make these cells remain at the site of allergic inflammation.

Evidence suggests that cytokines may be one of the major factors influencing cognitive development in those with autism spectrum disorder (ASD). To shed light on the neural and cognitive mechanisms of ASD, we investigated the association between peripheral cytokine levels and cognitive profiles in children with ASD. The serum levels of 10 cytokines (granulocyte macrophage colony-stimulating factor, interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-α) were examined in 14 children with ASD using the Human Ultrasensitive Cytokine Magnetic 10-Plex Panel for the Luminex platform. The Wechsler Intelligence Scale for Children (WISC) was administered to each subject, and the relationships between WISC scores and serum levels of the cytokines were examined. The full-scale intelligence quotient (IQ) was significantly negatively correlated with the levels of IL-6 (Spearman’s rank, p < 0.0001, false discovery rate q < 0.01). The levels of IL-6 and IFN-γ showed significant negative correlations with the verbal comprehension index (p < 0.001, q < 0.01) and working memory index (p < 0.01, q < 0.05), respectively. No other cytokines were significantly correlated with full-scale IQ or with any of the subscale scores of the WISC. The present results suggest negative correlations of IL-6 and IFN-γ levels with cognitive development of children with ASD. Our preliminary findings add to the evidence that cytokines may play a role in the neural development in ASD.

With the incessant challenge of exposure to the air we breathe, lung tissue suffers the highest levels of oxygen tension and thus requires robust antioxidant defenses. Furthermore, following injury or infection, lung tissue faces the additional challenge of inflammation-induced reactive oxygen and nitrogen species (ROS/RNS). Little is known about the identity or distribution of lung antioxidant enzymes under normal conditions or during infection-induced inflammation. Using a mouse model of influenza (H1N1 influenza virus A/PR/8/34 [PR8]) in combination with bioinformatics, we identified seven lung-abundant antioxidant enzymes: Glutathione peroxidase 3 (Gpx3), Superoxide dismutase 3 (Sod3), Transferrin (Tf), peroxyredoxin6 (Prdx6), glutathione S-transferase kappa 1 (Gstk1), Catalase (Cat), and Glutathione peroxidase 8 (Gpx8). Interestingly, despite the demand for antioxidants during inflammation, influenza caused depletion in two key antioxidants: Cat and Prdx6. As Cat is highly expressed in Clara cells, virus-induced Clara cell loss contributes to the depletion in Cat. Prdx6 is also reduced due to Clara cell loss, however there is a coincident increase in Prdx6 levels in the alveoli, resulting in only a subtle reduction of Prdx6 overall. Analogously, Gpx3 shifts from the basement membranes underlying the bronchioles and blood vessels to the alveoli, thus maintaining balanced expression. Taken together, these studies identify key lung antioxidants and reveal their distribution among specific cell types. Furthermore, results show that influenza depletes key antioxidants, and that in some cases there is coincident increased expression, consistent with compensatory expression. Given that oxidative stress is known to be a key risk factor during influenza infection, knowledge about the antioxidant repertoire of lungs, and the spatio-temporal distribution of antioxidants, contributes to our understanding of the underlying mechanisms of influenza-induced morbidity and mortality.

Coronavirus host and cell specificities are determined by specific interactions between the viral spike (S) protein and host cell receptor(s). Avian coronavirus infectious bronchitis (IBV) has been adapted to embryonated chicken eggs, primary chicken kidney (CK) cells, monkey kidney cell line Vero, and other human and animal cells. Here we report that acquisition of the cell-cell fusion activity by amino acid mutations in the S protein determines the infectivity of IBV in cultured cells. Expression of S protein derived from Vero- and CK-adapted strains showed efficient induction of membrane fusion. However, expression of S protein cloned from the third passage of IBV in chicken embryo (EP3) did not show apparent syncytia formation. By construction of chimeric S constructs and site-directed mutagenesis, a point mutation (L857-F) at amino acid position 857 in the heptad repeat 1 region of S protein was shown to be responsible for its acquisition of the cell-cell fusion activity. Furthermore, a G405-D point mutation in the S1 domain, which was acquired during further propagation of Vero-adapted IBV in Vero cells, could enhance the cell-cell fusion activity of the protein. Re-introduction of L857 back to the S gene of Vero-adapted IBV allowed recovery of variants that contain the introduced L857. However, compensatory mutations in S1 and some distant regions of S2 were required for restoration of the cell-cell fusion activity of S protein carrying L857 and for the infectivity of the recovered variants in cultured cells. This study demonstrates that acquisition of the cell-cell fusion activity in S protein determines the selection and/or adaptation of a coronavirus from chicken embryo to cultured cells of human and animal origins.

In response to viral infection, the expression of numerous host genes, including predominantly a number of proinflammatory cytokines and chemokines, is usually up-regulated at both transcriptional and translational levels. It was noted that in cells infected with coronavirus, transcription and translation of some of these genes were differentially induced. Drastic induction of their expression at the transcriptional level was observed in cells infected with coronavirus. However, induction of the same genes at the translational level was usually found to be minimal to moderate. To investigate the underlying mechanisms, yeast two-hybrid screen was carried out using SARS-CoV proteins as baits, revealing that a subunit of the eukaryotic initiation factor 3 (eIF3), eIF3f, may interact with the N-terminal region of the SARS-CoV spike (S) protein. This interaction was subsequently confirmed by co-immunoprecipitation and immunofluorescent staining. Meanwhile, parallel experiments confirmed that eIF3f could also interact with the S protein of another coronavirus, the avian coronavirus infectious bronchitis virus (IBV). These interactions led to the inhibition of translation of a reporter gene in both in vitro expression system and intact cells. Interestingly, IBV-infected cells stably expressing a Flag-tagged eIF3f showed much higher translation of IL-6 and IL-8, suggesting that the interaction between coronavirus S protein and eIF3f plays a functional role in controlling the expression of host genes, especially genes that are induced during coronavirus infection cycles. This study reveals a novel mechanism exploited by coronavirus to regulate viral pathogenesis.

Panniculitis is an inflammation that occurs in subcutaneous adipose tissue. Panniculitis includes physical panniculitis (e.g., traumatic) and infectious panniculitis (e.g., bacterial, fungal, subcutaneous panniculitis-like T cell lymphoma [SPCTL], etc.). Accurate diagnosis is crucial due to similar clinical presentation of all types of panniculitis. Here, we report a case of SPCTL which was initially diagnosed with traumatic panniculitis. A 15-year-old male patient was admitted to a previous hospital due to a progressively enlarged right flank and inguinal mass after an abdominal bruise. He was initially diagnosed with traumatic panniculitis, but the mass expanded throughout the chest and abdomen accompanied by a fever of over 11 months. Computed tomography (CT) revealed a subcutaneous mass in the anterior chest and abdominal wall. Fludeoxyglucose F18 (FDG) uptake was observed at those lesions using FDG-positron emission tomography (PET). A biopsy of the mass lesion was performed, during which SPCTL was diagnosed based on pathological examination. He was initially treated with prednisolone and cyclosporine A for two weeks. His fever went down, but subcutaneous mass in the chest and abdominal wall persisted. Therefore, he received a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen. After 6 courses of CHOP, CT revealed no disease evidence. He remained in complete remission at 30 months of therapy. [ABSTRACT FROM AUTHOR]

Bezold's abscess is an extracranial complication of otitis media, in which a cervical abscess forms from the mastoid process through an ostial fistula, and is a rare condition in recent years. In this study, we experienced a X-linked agammaglobulinemia, which was discovered due to Bezold's abscess. Case: A 12-year-old boy suffering from recurrent right suppurative otitis media for three months was treated with tympanostomy and oral antibacterial therapy at a local otorhinolaryngology clinic. The patient visited the clinic due to a recurrence of symptoms. CT showed bony defects in the cortical bone and mastoid process of the lateral side of the right mastoid cell. The patient was referred to our hospital, admitted the same day and underwent emergency surgery. Intraoperative findings led to the diagnosis of acute mastoiditis and Bezold's abscess caused by mastoiditis spreading to the s ternocleidomastoid muscle. After drainage and administration of ABPC/SBT, the abscess disappeared, and the patient's general condition improved. Subsequently, a blood typing test performed on admission suggested the influence of low immunoglobulin levels. A close examination by the pediatric department led to a diagnosis of X-linked agammaglobulinemia. As a result, the patient receives regular immunoglobulin therapy and has been free of infection, including Bezold's abscess. CONCLUSIONS: In the case of recurrent otitis media and rare infections, congenital immune abnormalities should be considered. [ABSTRACT FROM AUTHOR]

Although Burkitt lymphoma (BL) usually arises in the abdomen or pelvis, it can also arise in the epidural space as a primary or secondary site and present with back pain or limb weakness. Emergency management is necessary to relieve spinal cord compression (SCC). Herein, we report a case of BL with metastatic spinal lesions in a 16-year-old female who presented with sudden-onset progressive walking difficulty. She was admitted to a previous hospital where she presented with abdominal pain and vomiting and was diagnosed with intussusception via a computed tomography scan. Laparoscopic small bowel resection was performed, during which a diagnosis of BL was made on the basis of pathological examination. Sudden numbness in the extremities and the complete inability to walk occurred ten days after surgery. Thoracolumbar MRI revealed a metastatic mass extending from C7 to T6 with evidence of SCC. Emergency decompressive laminectomies (from C7 to T6) and partial debulking of the tumor were performed 12 hours after the onset of her neurologic symptoms. She was subsequently treated with chemotherapy, and she made a complete neurologic recovery. Emergency decompressive laminectomies for BL with spinal lesions could effectively lead to the recovery of neurologic symptoms. [ABSTRACT FROM AUTHOR]