[STATE-OF-THE-ART OF GLOBAL START-UP INVESTMENT FOR ALLERGY AND IMMUNOLOGY 2022].

BACKGROUND: In 2022, the "New Capitalism Grand Design and Implementation Plan" was adopted in Japan, emphasizing the promotion and environmental development of startups. Given this context, an investigation into the startup and investment landscape in the allergy sector, both domestically and internationally, becomes imperative. METHODS: We analyzed 156 allergy-related startups from Japan, the US, and Europe from 2010 to 2021. Data on corporate information and investment trends were extracted from databases and VC websites. RESULTS: The total investment reached approximately 7.2 billion USD, with a ratio of 20:6:1 for the US, Europe, and Japan, respectively. The US showed a decline post its peak from 2016-2018, while Europe and Japan experienced growth. Notably, the US primarily invested in biopharmaceuticals for atopic dermatitis and food allergies, Europe in asthma-related apps, and Japan in healthcare apps and cross-border startups. DISCUSSION AND CONCLUSION: While Japan's investment environment in the allergy sector remains in its nascent stages and has room for development, the US and Europe are evidently ahead. Considering the rise of startups and funding limitations in Japan, external funding from regions like the US becomes a potential avenue. These findings are anticipated to contribute to the strategic activation of startups in allergy research and development.

Maternal Dietary Vitamin D Intake during Pregnancy Is Associated with Allergic Disease Symptoms in Children at 3 Years Old: The Japan Environment and Children's Study.

INTRODUCTION: Vitamin D plays an important role in the immune system, and postnatal vitamin D insufficiency is one of the risk factors for the development of allergic disease. However, the effects of women's vitamin D intake during pregnancy on the prevalence of allergic disease in their children remain controversial. METHODS: From the Japan Environment and Children's Study, an ongoing nationwide birth cohort study, we obtained information on maternal dietary vitamin D intake determined using a food frequency questionnaire and parent-reported allergic disease symptoms based on the ISAAC questionnaire in children at 3 years of age. RESULTS: From the full dataset of 103,060 pregnancies, we analyzed complete data for 73,309 mother-child pairs. The prevalence of current wheeze, current rhinitis, current rhino-conjunctivitis, current eczema, ever asthma, ever pollinosis, and ever atopic dermatitis in the children was 17.2%, 29.7%, 3.8%, 15.2%, 9.6%, 3.7%, and 11.0%, respectively. The ORs for current rhinitis were significantly lower in the 3rd, 4th, and 5th quintiles than in the 1st quintile after adjustment for various covariates and showed a linear association. The ORs for ever pollinosis were significantly lower in the 2nd, 3rd, and 4th quintiles than in the 1st quintile, showing a U-shaped curve. There was no clear association between mothers' dietary vitamin D intake and symptoms of asthma or atopic dermatitis in their 3-year-old children. CONCLUSION: Maternal dietary vitamin D intake during pregnancy is associated with the ORs for nasal allergies in children at the age of 3 years. Further studies are warranted to evaluate the appropriate intake dose of vitamin D for pregnant women to prevent the development of nasal allergies in their children.

[A YOUNG CHILD WITH ALLERGIC SYMPTOMS DUE TO INGESTION OF EDIBLE CRICKETS].

In recent years, the consumption of edible insects has gained attention, and the potential allergic risks associated with their ingestion have been pointed out, though there are limited case reports. A 3-year-old boy exhibited an immediate allergic reaction, showing symptoms of sneezing, nasal discharge, coughing, and eyelid edema after ingesting two cricket crackers. He had previously consumed shrimp but had never eaten edible insects. Given his lack of a history of allergic diseases, the onset of this allergy was unexpected. Subsequent prick tests and oral food challenge tests confirmed that the Two-spotted cricket (Gryllus bimaculatus) was the allergen responsible for his symptoms. The IgE inhibition test indicated that the cricket significantly suppressed the specific IgE levels for moth, shrimp, and mite (Dermatophagoides pteronyssinus). This incident marked the first time in the patient's life that he exhibited allergic symptoms, and it serves as a significant case highlighting the risks of allergies from edible insects. Known allergens in insects include tropomyosin and arginine kinase, which are common in arthropods, but there are reports of other allergens as well, suggesting potential sensitization from cross-reactions. As the consumption of insects becomes more widespread, the number of allergic cases may increase, and food labeling and preventive measures should be considered.

Maternal exposure to smoking and infant's wheeze and asthma: Japan Environment and Children's Study.

BACKGROUND: Evidence regarding independent effects of maternal smoking in different time frames of pregnancy and maternal exposure to secondhand smoke on the development of wheeze/asthma in her offspring is limited. We aimed to investigate the effect of maternal exposure to tobacco smoke on wheeze/asthma development at 1 year of age in her offspring using data from the nationwide birth cohort study in Japan. METHODS: Pregnant women who lived in the 15 designated regional centers throughout Japan were recruited. We obtained information about maternal smoking or secondhand smoke status and wheeze/asthma development in the offspring from a self-administered questionnaire. RESULTS: We analyzed 90,210 singleton births. Current maternal smoking during pregnancy increased the risks of wheeze/asthma in the offspring compared with no maternal smoking (wheeze: 1-10 cigarettes/day: adjusted odds ratio (aOR) 1.436, 95% CI 1.270-1.624; ≧11 cigarettes/day: aOR 1.669, 95% CI 1.341-2.078; asthma: 1-10 cigarettes/day: aOR 1.389, 95% CI 1.087-1.774; ≧11 cigarettes/day: aOR 1.565, 95% CI 1.045-2.344). Daily maternal exposure to secondhand smoke during pregnancy also increased the risks of wheeze/asthma in her offspring compared with no secondhand smoke exposure (wheeze: aOR 1.166, 95% CI 1.083-1.256; asthma: aOR 1.258, 95% CI 1.075-1.473). The combination of current maternal smoking during pregnancy and maternal history of allergy increased the risks of wheeze/asthma in her offspring (wheeze: aOR 2.007, 95% CI 1.739-2.317; asthma: aOR 1.995, 95% CI 1.528-2.605). CONCLUSIONS: We found that current maternal smoking and maternal secondhand smoke exposure during pregnancy increased the risks of wheeze and asthma in her offspring.

In-utero arsenic exposure and growth of infants from birth to 6 months of age: a prospective cohort study in rural Bangladesh.

Arsenic exposure in postnatal life impacts the growth of children, but little is known about the effect of in-utero arsenic exposure on growth very early in childhood. The aim of this study was to examine the associations between in-utero arsenic exposure and the growth of infants from birth to 6 months of age using monthly follow-up data. A prospective cohort study was conducted in rural areas of Bangladesh with 108 mother-infant pairs. This study identified a negative association between in-utero arsenic exposure and head circumference of infants 1-6 months of age (coefficient = -1.20, 95% confidence interval [CI]: -1.97, -0.42), and the effect was more pronounced in the earlier ages of 1-3 months (coefficient = -0.88, 95% CI: -1.70, -0.05). Because head circumference is considered as a surrogate of brain size, our findings suggest that in-utero arsenic exposure influences brain growth during an important developmental period.

Neutrophilia and hyperamylasemia in patients with immediate food allergy.

BACKGROUND: Presently, little is known about the laboratory data several hours after oral food challenge (OFC) in patients with immunoglobulin (Ig)E-mediated immediate food allergy (FA). METHODS: One hundred and twelve subjects who underwent OFC at the present institute between 1 June 2016 and 31 March 2018, were enrolled in this study. Changes in laboratory data several hours after OFC were examined. RESULTS: OFC was positive in 76 patients and negative in 36. Increase in absolute neutrophil count (ANC) was significantly higher in OFC-positive than in OFC-negative subjects (median, 2,306/µL vs 637/µL; P < 0.00001). On multivariate regression analysis, a significant correlation was seen between neutrophilia and the development of gastrointestinal symptoms (t = 3.63; P < 0.001). Serum interleukin-6 increased in 43.8% of the patients with marked neutrophilia and had a significant positive correlation with ANC (r = 0.64; P < 0.001). Serum amylase increased in 33.3% of the OFC-positive patients and was >100 U/L (median, 642 U/L) in five patients in whom serum lipase also increased markedly (1,197 U/L). There was a significant negative correlation between increase in serum amylase and decrease in absolute eosinophil count (r = -0.36, P < 0.01). CONCLUSIONS: Marked neutrophilia was seen after OFC in patients with immediate FA presenting gastrointestinal symptoms, which may provide an insight into the relationship between symptoms and laboratory data. A considerable increase in serum amylase after OFC was also seen in patients with immediate FA, suggesting that the pancreas is a target organ for immediate FA.

Increased serum cortisol on oral food challenge in infants with food protein-induced enterocolitis syndrome.

BACKGROUND: An increase in absolute neutrophil count (ANC) is seen after oral food challenge test (OFC) in patients with food protein-induced enterocolitis syndrome (FPIES). Although it has been suggested that interleukin (IL)-8 is involved in this phenomenon, a possible role for cortisol has not yet been studied. METHODS: Six positive OFC in five patients with FPIES due to cows' milk (CM) proteins, and two negative OFC in two patients with suspected FPIES were analyzed. Absolute neutrophil count, serum IL-8, and serum cortisol were measured before OFC, 6 and 24 h after the ingestion of CM formula. RESULTS: For the positive OFC, ANC measured 6 h after the ingestion of CM formula was significantly higher than that measured before the OFC (median, 8,761 versus 2,297/µL; P < 0.05). Significant increases in serum cortisol and IL-8 were observed 6 h after OFC (cortisol, median 1,119 pg/mL before versus 2,141 pg/mL after, P < 0.05; IL-8, median 15.5 pg/mL before versus 165.3 pg/mL after, P < 0.05). The change ratio (i.e. ratio of that after OFC to that before OFC) of ANC was significantly correlated not only with that of serum IL-8 (r = 0.90, P < 0.01) but also with that of serum cortisol (r = 0.76, P < 0.05). Moreover, the serum cortisol change ratio was significantly higher in subjects with vomiting than in those without (median, 2.5 versus 1.0, P < 0.05). CONCLUSIONS: Serum cortisol, in combination with IL-8, affects the increase in ANC after OFC.

Cytokine profile after oral food challenge in infants with food protein-induced enterocolitis syndrome.

BACKGROUND: Although food protein-induced enterocolitis syndrome (FPIES) is supposed to be caused by inflammation, the role of cytokines has not yet been clarified. METHODS: To elucidate the role of cytokines in the development of symptoms and abnormal laboratory findings at an oral food challenge (OFC), changes in serum cytokine levels were analyzed for 6 OFCs in 4 patients with FPIES. The result of OFC was judged positive if any gastrointestinal (GI) symptoms (vomiting, diarrhea, or bloody stool) were induced. RESULTS: Among 11 cytokines profiled, serum levels of interleukin (IL)-2, IL-5, and IL-8 were clearly increased in all 4 positive OFCs in which elevations of the serum level of C-reactive protein (CRP) and peripheral blood neutrophilia were also seen. The level of serum IL-10 also rose in 2 positive OFCs. Remarkable increases in the serum level of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-12 were observed in a positive OFC where the serum level of CRP rose markedly (6.75 mg/dL). The serum levels of IL-5 were also elevated in 2 negative OFCs. No apparent specific correlations were found between cytokines and GI symptoms. CONCLUSIONS: These results suggest that IL-2 and IL-8 are involved in the antigen-specific immune responses in most patients with FPIES. Further studies are needed to elucidate the significance of these cytokine in the pathogenesis of FPIES.

Increased C-reactive protein and fever in Japanese infants with food protein-induced enterocolitis syndrome.

BACKGROUND: Increased C-reactive protein (CRP) and fever are observed in some infants with food protein-induced enterocolitis syndrome (FPIES) in Japan, but the reproducibility of these findings has not yet been confirmed on oral food challenge (OFC). METHODS: Fourteen infants with FPIES induced by cow's milk (CM) formula were enrolled. OFC using CM formula was performed on each infant once or repeatedly (total 18 tests), with a stepwise incremental protocol in an infection-controlled setting. CRP was measured 24 h after the last ingestion of the CM formula. RESULTS: Increased CRP was observed in 11 of the 18 OFC conducted (median, 2.60 mg/dL; range, 0.22-4.84 mg/dL). Fever was induced in six occasions during OFC. Serum CRP in the patients with fever increased to median 3.76 mg/dL (range, <0.7-4.84 mg/dL), which was significantly higher than that of the patients without fever (median <0.1 mg/dL; range, <0.1-2.6 mg/dL; P < 0.001). CRP during OFC significantly correlated with that at disease onset (rs = 0.62, P < 0.02). Three of the four patients with fever at disease onset also had fever during OFC. CONCLUSIONS: Increased CRP and fever are reproducible during OFC in some infants with FPIES, suggesting that these are not accidental phenomena, but instead are associated with FPIES itself in Japanese patients.

Close Positive Correlation between the Lymphocyte Response to Hen Egg White and House Dust Mites in Infants with Atopic Dermatitis.

BACKGROUND: It was recently hypothesized that food allergens sensitize infants with atopic dermatitis (AD) via the skin. If this is the case, an intimate positive correlation should be observed between immune responses to both food and indoor allergens. METHODS: One hundred and seven infants with AD and 32 controls were enrolled. The proliferation of lymphocytes stimulated with hen egg white (EW) or house dust mite (HDM) allergens was measured by means of an allergen-specific lymphocyte stimulation test (ALST). Cytokine production was measured in 13 patients and 4 controls. RESULTS: ALST responses for EW (EW-ALST) were significantly higher in AD infants than in control subjects (stimulation index: 7.98 vs. 2.54, p < 0.0001). HDM-ALST responses were also significantly higher in AD infants than in controls (stimulation index: 5.09 vs. 1.44, p < 0.0001). A significant positive correlation was seen between HDM-ALST and EW-ALST responses in AD infants aged 5-6 months (rs = 0.77, p < 0.000001). Serum levels of EW-specific IgE (EW-IgE) were significantly correlated with both EW-ALST (rs = 0.43, p < 0.05) and HDM-ALST levels (rs = 0.47, p < 0.05) in AD patients aged 3-4 months. Serum EW-IgE levels in AD infants were significantly correlated with the ratio of IL-4/IFN-γ production from lymphocytes stimulated with EW (rs = 0.62, p < 0.01) and with HDM (rs = 0.67, p < 0.005). CONCLUSIONS: This study describes the close positive correlation between EW- and HDM-specific immune responses in infants with AD. These results may support the hypothesis that both food and indoor allergens concurrently sensitize infants via the skin.

Single-shot dual-wavelength phase unwrapping in parallel phase-shifting digital holography.

We propose a single-shot phase-unwrapping method using two wavelengths in parallel phase-shifting digital holography (PPSDH). The proposed method enables one to solve the phase ambiguity problem in PPSDH. We conducted an experiment of the proposed method using two lasers whose wavelengths are 473 and 532 nm. An object having about 1.9 µm step, which is 7.1 times larger than the half wavelength of one of the lasers (266 nm), was fabricated by using vapor deposition of aluminum. Single-shot measurement of the height of the object was successfully demonstrated, and the validity of the proposed method was verified.

Superresolution of interference fringes in parallel four-step phase-shifting digital holography.

A superresolution method for interference fringes obtained by parallel four-step phase-shifting digital holography is proposed. A complex amplitude distribution of an object wave is derived from a recorded hologram by parallel phase-shifting interferometry using two pixels without any interpolation procedures. Multiple distributions are derived by changing one of the two pixels when conducting phase-shifting interferometry. The angular spectrum distribution of the object wave is obtained by both the Fourier transforms and synthesis of the spectrum distribution from the Fourier-transformed images in the spatial frequency domain. Available space bandwidth is extended to half of that of an image sensor.

Intrauterine growth restriction modifies gene expression profiling in cord blood.

BACKGROUND: Small-for-gestational-age (SGA) newborns are at an increased risk for perinatal morbidity and mortality and development of metabolic syndromes such as cardiovascular disease and type 2 diabetes mellitus (T2DM) in adulthood. The mechanism underlying this increased risk remains unclear. In this study, genetic modifications of cord blood were investigated to characterize fetal change in SGA newborns. METHODS: Gene expression in cord blood cells was compared between 10 SGA newborns and 10 appropriate-for-gestational-age (AGA) newborns using microarray analysis. Pathway analysis was conducted using the Ingenuity Pathways Knowledge Base. To confirm the microarray analysis results, quantitative real-time polymerase chain reaction (RT-PCR) was performed for upregulated genes in SGA newborns. RESULTS: In total, 775 upregulated and 936 downregulated probes were identified in SGA newborns and compared with those in AGA newborns. Of these probes, 1149 were annotated. Most of these genes have been implicated in the development of cardiovascular disease and T2DM. There was good agreement between the RT-PCR and microarray analyses results. CONCLUSIONS: Expression of certain genes was modified in SGA newborns in the fetal period. These genes have been associated with metabolic syndrome. To clarify the association between modified gene expression in cord blood and individual vulnerability to metabolic syndrome in adulthood, these SGA newborns will be have long-term follow up for examination of genetic and postnatal environmental factors. Gene expression of cord blood can be a useful and non-invasive method of investigation of genetic alterations in the fetal period.

[Evaluation of the allergenicity of ß-casein in Japanese children with cow milk allergy by using the basophil activation test].

BACKGROUND: Among the casein components, αs-casein (αs-CAS) is considered the major allergen in Japan, and there are very few reports on the allergenicity of ß-casein (ß-CAS). In this study, we compared the allergenicity of ß-CAS with that of αs-CAS in Japanese children with cow milk allergy (CMA). METHOD: The allergenicity of αs-CAS and ß-CAS in 29 CMA patients and 11 control subjects was assessed using the basophil activation test (BAT). The accuracy of the BAT to distinguish the patients with CMA from the control subjects was estimated using a receiver operating characteristic (ROC) analysis and was expressed as the area under the curve (AUC). RESULTS: BAT results for CM were positive in 93.1% of the CMA patients. The results of the ß-CAS-BAT and αs-CAS-BAT were found to be positive in 86.2% and 69.0% of the CMA patients, respectively, however, the difference was not significant. The AUC for the ß-CAS-BAT was 0.893, which was not significantly different from that for the αs-CAS-BAT (0.859). CONCLUSIONS: These results suggest that the allergenicities of ß-CAS and αs-CAS are similar in Japanese patients with CMA.

Space-bandwidth extension in parallel phase-shifting digital holography using a four-channel polarization-imaging camera.

We propose a method for extending the space bandwidth (SBW) available for recording an object wave in parallel phase-shifting digital holography using a four-channel polarization-imaging camera. A linear spatial carrier of the reference wave is introduced to an optical setup of parallel four-step phase-shifting interferometry using a commercially available polarization-imaging camera that has four polarization-detection channels. Then a hologram required for parallel two-step phase shifting, which is a technique capable of recording the widest SBW in parallel phase shifting, can be obtained. The effectiveness of the proposed method was numerically and experimentally verified.

Multiwavelength parallel phase-shifting digital holography using angular multiplexing.

We propose a single-shot digital holography for recording multiwavelength and complex amplitude information by using a single monochromatic image sensor. The zeroth-order wave and conjugate image in each wavelength are removed from a recorded single hologram by applying parallel phase-shifting interferometry. Angular multiplexing is utilized to record the complex amplitude of an object wave in each wavelength separately, and no color filter is required. The effectiveness of the proposed technique was experimentally verified.

A case of mite-ingestion-associated exercise- induced anaphylaxis mimicking wheat-dependent exercise-induced anaphylaxis.

We present a case of mite-ingestion-associated exercise-induced anaphylaxis mimicking wheat-dependent exercise-induced anaphylaxis (WDEIA). A 17-year-old boy was referred for an episode of anaphylaxis while jogging, 1.5 h after having eaten okonomiyaki (a Japanese pancake). Laboratory measures revealed a slightly elevated specific immunoglobulin E (IgE) antibody against omega-5 gliadin (0.41 kUA/l) and a marked elevation of specific IgE antibody against house-dust mite, Dermatophagoides farinae (142 kUA/l). A detailed interview revealed that, in spite of the referring doctor's advice to discontinue postprandial exercises, he continued his jogging routine after consuming foods containing wheat and also that his younger brother, who had mild intermittent asthma, had suffered a mild asthma attack 2 h after eating the same food. We therefore examined the okonimiyaki mix, which had been stored for several months after opening the package until this episode, under a microscope, and we found an abundant number of live mites, D. farinae. Finally, a diagnosis of mite-ingestion-associated exercise-induced anaphylaxis was made. This clinical entity should be excluded when making a diagnosis of WDEIA.

Aerosol characteristics of admixture of budesonide inhalation suspension with a beta2-agonist, procaterol.

BACKGROUND: Nebulized drugs for asthma treatment are often mixed together in order to simplify inhalation regimens, although not recommended. We therefore evaluated aerosol characteristics and physicochemical stability of the admixture of an inhaled corticosteroid suspension with a beta2-agonist solution. METHODS: An 8-stage cascade impactor was used to measure the particle size distribution of admixture of Pulmicort® Respules® (budesonide, 0.5mg/2mL) with Meptin® Inhalation Solution Unit (procaterol hydrochloride, 30µg/0.3mL) from a jet nebulizer, PARI LC Plus®. Concentration of each drug was assayed with high-pressure liquid chromatography. Physicochemical compatibility was also assessed up to 24 hours after mixing. RESULTS: With regard to budesonide, impactor parameters such as mass median aerodynamic diameter (MMAD) and respirable mass (RM) were comparable between admixtures and single-drug preparations (2.92 ± 0.03 vs 2.99 ± 0.14µm, 146.8 ± 2.9 vs 147.6 ± 8.2µg, respectively). On the other hand, delivery rates of procaterol increased when admixed with budesonide suspension, resulting in significantly higher RM (15.1 ± 0.8 vs 10.2 ± 0.5µg, p < 0.01). Variations from initial concentration in the percentages of drug remaining at any time point were less than 10%, and there were no appreciable changes in pH of the admixtures for up to 24 hours. CONCLUSIONS: There is a possibility that admixture might influence of aerodynamic characteristics of procaterol, but not budesonide. In vivo data will be needed for the clinical implications of our findings.