A Narrative Mini Review on Current Status of Hypoallergenic Wheat Development for IgE-Mediated Wheat Allergy, Wheat-Dependent Exercise-Induced Anaphylaxis.

Immunoglobulin E (IgE)-mediated food allergies to wheat that develop after school age typically shows a type of wheat-dependent exercise-induced anaphylaxis (WDEIA). At present, avoidance of wheat products or postprandial rest after ingesting wheat is recommended for patients with WDEIA, depending on the severity of the allergy symptoms. ω5-Gliadin has been identified as the major allergen in WDEIA. In addition, α/ß-, γ-, and ω1,2-gliadins, high and low molecular weight-glutenins, and a few water-soluble wheat proteins have been identified as IgE-binding allergens in a small proportion of patients with IgE-mediated wheat allergies. A variety of approaches have been manufactured to develop hypoallergenic wheat products that can be consumed by patients with IgE-mediated wheat allergies. In order to analyze such approaches, and to contribute to the further improvement, this study outlined the current status of these hypoallergenic wheat productions, including wheat lines with a reduced allergenicity that are mostly constructed for the patients sensitized to ω5-gliadin, hypoallergenic wheat by enzymic degradation/ion exchanger deamidation, and hypoallergenic wheat by thioredoxin treatment. The wheat products obtained by these approaches significantly reduced the reactivity of Serum IgE in wheat-allergic patients. However, either these were not effective on some populations of the patients, or low-level IgE-reactivity to some allergens of the products was observed in the patients. These results highlight some of the difficulties faced in creating hypoallergenic wheat products or hypoallergenic wheat lines through either traditional breeding or biotechnology approaches in developing hypoallergenic wheat completely safe for all the patients allergic to wheat.

Efficacy and safety of omalizumab in adult patients with wheat-dependent exercise-induced anaphylaxis: Reduction of in vitro basophil activation and allergic reaction to wheat.

BACKGROUND: In patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA. METHODS: In this phase 2, multicentre single-arm trial, 20 adult patients with WDEIA were enrolled (UMIN 000019250). All patients were administered 150-600 mg of omalizumab subcutaneously and evaluations (basophil activation and blood examination) were performed at regular intervals during administration period (0-48 weeks) and observation period (48-68 weeks). Primary endpoint was proportion of the patients who achieved a basophil activation rate below 10% with fractionated wheat preparations, and secondary endpoint was proportion of the patients with no allergic reactions after wheat products ingestion. RESULTS: During the omalizumab treatment, more than 80% of the patients achieved the basophil activation rate less than 10% against all fractionated wheat preparations, and 68.8% of the patients who achieved the primary endpoint experienced no allergic reaction. During the observation period, the proportion of the patients who achieved a basophil activation rate below 10% decreased gradually, and the proportion of patients with positive allergic reactions increased gradually thereafter and reached maximum of 46.7%. Severe adverse events were not observed during the study. CONCLUSIONS: Long-term omalizumab treatment is safe and effective for adult patients with WDEIA when assessed by basophil activation rate with wheat allergens as well as allergic reactions after lifting of restrictions on wheat intake. However, this is not enough to achieve desensitization.

Effect of Multimorbidity on Fragility Fractures in Community-Dwelling Older Adults: Shimane CoHRE Study.

Fragility fractures (FFxs), which are a common musculoskeletal injury in older adults, is associated with an increased frequency of falls. Both FFxs and falls may result from drugs, habits, and co-occurring diseases. We aimed to evaluate the effects of various diseases on the risk of FFx. This retrospective study included 1420 individuals aged ≥60 years. We evaluated the history of clinical FFx and diseases using a detailed questionnaire and a health examination. The risk of comorbidities was assessed using the Age-Adjusted Charlson Comorbidity (AAC) Index. We performed binary logistic regression analysis to determine the risk of FFx and falls after adjusting for covariates. In elderly men, the incidence of FFx positively correlated with rheumatoid arthritis and parent's hip fracture. For elderly women, the incidence of FFx positively correlated with rheumatoid arthritis and antihypertensive drugs but was inversely associated with dyslipidemia and antilipidemic drugs. The FFX risk of older adults with an AAC Index ≥6 was higher than those with an AAC Index of 1-3. In addition, the AAC Index and falls were independently and strongly associated with a higher risk of FFx. Taken together, multimorbidity increases the risk of clinical FFx independent of falls in the community-dwelling elderly population.

J-curve association between alcohol intake and varicose veins in Japan: The Shimane CoHRE Study.

The effect of alcohol intake on varicose veins (VV) has not been determined by its consumption level. The aim of this study was to investigate the association between alcohol intake and VV in an elderly general population. Using a cross-sectional approach, the Shimane CoHRE Study data, comprising a total of 1060 participants, were analyzed. By multivariate regression analysis adjusted with basic characteristics, past work history, lifestyle-related factors and medical history, compared with non-drinkers, mild drinkers (<20.0 g/day) showed a significantly lower adjusted odds ratio (aOR) of VV (aOR = 0.64, P = 0.036). In a similar way, regular drinkers (1-5 days/week) showed a significantly lower aOR of VV when compared with occasional drinkers (aOR = 0.57, P = 0.032). VV and alcohol intake showed J-curve relationships. In a stratified analysis by alcohol consumption levels, the association of smoking and VV were also observed in moderate to heavy drinkers and habitual drinkers. These findings can provide better understanding of pathophysiological mechanism and be used for evidence-based patient education.

Surgical methods and clinical results of subfascial endoscopic perforator surgery in Japan.

OBJECTIVES: To clarify the surgical methods and the clinical results of subfascial endoscopic perforator surgery in Japan. METHODS: This study included 1287 limbs of 1091 patients who underwent subfascial endoscopic perforator surgery in 14 hospitals. Simultaneous saphenous vein treatment was performed in 1079 limbs (83.8%), and 118 limbs (9.2%) had deep venous lesions. The venous clinical severity score was calculated before and 6 to 12 months after surgery. The ulcer healing rate and ulcer recurrence rate were calculated cumulatively. RESULTS: Preoperative venous clinical severity score was significantly decreased from 10.0 ± 6.6 to 3.1 ± 3.4 ( P < .0001) postoperatively. The primary ulcer healing rate was 96.2% (332/345 C6 limbs) at an average follow-up of 47.7 months, and the ulcer recurrence rate was 12.0% (49/393 C5, C6 limbs) at the average follow-up of 46.0 months after the ulcer healed. CONCLUSION: These results indicate that subfascial endoscopic perforator surgery is an alternative to improve the long-lasting disease severity and/or clinical outcome.

Familial Transmission of Hospital-Treated Varicose Veins in Adoptees: A Swedish Family Study.

BACKGROUND: Varicose veins (VVs) cluster in families, but the familial risk of VVs has not been determined among adoptees. The aim was to estimate whether the familial transmission of VVs is related to disease in biological and/or adoptive parents. STUDY DESIGN: The Swedish Multi-Generation Register and the Swedish Patient Register were used to follow all Swedish-born adoptees (born 1932 through 2004) that could be linked to both their biological and their adoptive parents (n = 80,214; 50% females). The risk of VVs was estimated in adoptees with at least 1 biological parent with VVs, but no adoptive parent with VVs (n = 187) compared with adoptees without a biological or adoptive parent with VVs (n = 1,758). The risk of VVs was also determined in adoptees with at least 1 adoptive parent, but no biological parent with VVs (n = 87), and in adoptees with both biological and adoptive parents affected (n = 21). RESULTS: Adoptees from an affected biological parent, but no adoptive parent, were more likely to have VVs than adoptees from an unaffected biological or adoptive parent (standard incidence ratio [SIR] = 2.21; 95% CI, 1.91-2.55). The familial SIR for adoptees with both an affected biological parent and an adoptive parent was 4.58 (95% CI, 2.83-7.01). Adoptees with an affected adoptive parent but no biological parent were not at increased risk of VVs (SIR = 1.15; 95% CI, 0.92-1.42). CONCLUSIONS: These novel findings suggest that genetic factors make a strong contribution to the familial transmission of VVs from parents to offspring, although familial environmental factors might contribute.

Characterization of a hypoallergenic wheat line lacking ω-5 gliadin.

BACKGROUND: There is no curative treatment for wheat-dependent exercise-induced anaphylaxis (WDEIA). ω-5 Gliadin is one of the dominant allergens affecting WDEIA patients. The use of ω-5 gliadin-free wheat flour in the regular diet is considered one of the prophylactic approaches against the elicitation of allergic symptoms and sensitization to ω-5 gliadin. We sought to find hypoallergenic bread wheat (or common wheat) that lacked the genes encoding ω-5 gliadin and to evaluate its in vitro allergenicity. We also aimed to evaluate the sensitization ability of one of the selected hypoallergenic wheat lines by using a possible animal model of wheat allergy. METHODS: We screened the deletion lines of bread wheat by western blotting to ascertain common wheat lines lacking the ω-5 gliadin locus. The deletion lines we used have partial deficiency of chromosome 1B (Endo and Gill, 1996). To assess sensitization ability of gluten from the selected deletion line, guinea pigs were fed with either the gluten from the selected deletion line or commercially available gluten, and allergic score was evaluated after challenging the same gluten preparations. RESULTS: We found that a deletion line 1BS-18 had the least deficiency of chromosome 1B among the deletion stocks lacking the ω-5 gliadin locus. The challenge test using the guinea pigs revealed that the symptoms induced by application of the 1BS-18 gluten were much less than that of commercially available gluten. CONCLUSIONS: The deletion line 1BS-18, which lacked the ω-5 gliadin locus, is likely to have a low sensitization capacity in the guinea pig. The use of the wheat products of the 1BS-18 line in daily life may provide a feasible solution for the onset of wheat allergy.

Altitudes of residential areas affect salt intake in a rural area in Japan: a Shimane CoHRE Study.

There is increasing evidence of an association between residential environments and hypertension. As shown in our previous study, the inconvenience of the locations of residential areas may be one of the factors influencing the blood pressures of inhabitants. Salt intake is one of the likely mediators between inconvenience and hypertension. Therefore, in this study, we evaluated the association between the altitudes of residential areas and salt intake in a rural Japanese region because altitude may be one of the proxies for inconvenience. In this cross-sectional study, 1016 participants living in a mountainous region in Japan were recruited during health examinations. The altitude of each participant's residence was estimated using a geographic information system. Subjects were divided into quartile groups according to the altitudes of their residences. To evaluate salt intake, we employed the 24-h salt intake estimation of Kawano et al. (e24-h salt intake) and the urinary sodium-to-potassium ratio (uNa/K). Linear regression analyses indicated that altitude was an independent factor influencing both e24-h salt intake and uNa/K after adjustments for age, sex, body mass index, physical activity, alcohol consumption, triglycerides and county of residence. The same result was observed when the subjects who did not take antihypertensive medications were analyzed (N=633). The present study indicated that altitude of residence had a significant positive influence on salt intake in a rural area of Japan.

Association Between Geographic Elevation, Bone Status, and Exercise Habits: The Shimane CoHRE Study.

In recent years, there has been growing interest in the association between the residential environment and health. The association between residential environment (i.e., geographic elevation) and bone status is unknown. Furthermore, these associations could differ by exercise habits due to the chronically greater daily activity caused by steep slopes in mountainous areas. The aim of this study was to test whether the association between bone status of elderly people measured using quantitative ultrasound (QUS) and elevation varied according to the exercise habits in a mountainous area population. Data were collected from a cross-sectional study conducted during 2012-2013. QUS value was expressed as a proportion of the young adult mean (%YAM), with higher scores donating better bone status. After excluding subjects with missing data, we analyzed the data for 321 men and 500 women. Our results indicate that %YAM was not associated with elevation among men, or among women with exercise habits. However, elevation was associated with %YAM among women without exercise habits. Our results highlight the importance of considering residential environment and exercise habits when establishing promotion strategies to maintain bone status of the elderly people who live in rural mountainous areas.

Standing posture at work and overweight exacerbate varicose veins: Shimane CoHRE Study.

Varicose veins (VV) in legs are commonly observed in the general global population. However, the prevalence of and risk factors for VV in Japan are not clear. This study aimed at clarifying the risk factors for VV in traditional rural areas of Shimane prefecture. Subjects (113 men and 205 women aged ≥45 years) were recruited from health examinations in those areas in 2012. VV were defined as a reflux of blood in the great and/or small saphenous vein and incompetent perforating veins detected by ultrasonography. Risk factors for VV were analyzed using logistic regression models that included various parameters. We also investigated the possible interaction between standing at work and overweight and calculated the synergistic index. VV were found in 20.1% of the subjects (12.4% of men and 24.4% of women). The previously known risk factors of prolonged upright standing posture during work, higher body mass index (BMI), female sex, and age were also significant factors for VV. There was a significant combined effect of overweight (BMI ≥25) and prolonged upright standing posture at work [adjusted odds ratio = 3.42; 95% confidence interval (CI), 1.07-10.89], although the synergistic effect was not significant [synergistic index = 1.3; 95% CI, 0.2-8.7]. The prevalence of VV in the traditional rural area of Shimane prefecture was comparable to that reported previously in European countries. Our results confirm that exposure to both prolonged standing at work and overweight exacerbate VV development. This finding is useful to develop strategies for VV prevention.

Simple and rapid detection of HLA-A*31:01 for prediction of carbamazepine-induced hypersensitivity using loop-mediated isothermal amplification method.

BACKGROUND: Carbamazepine (CBZ), which is widely used in management of epilepsy or neuropathic pain, causes fatal severe cutaneous adverse reactions (SCARs). CBZ-induced SCARs are known to occur in strong association with human leukocyte antigen (HLA)-A*31:01 in Japanese and European populations. HLA genotyping is currently used to detect human HLA-A*31:01. OBJECTIVE: To establish a simple and rapid screening assay specific for HLA-A*31:01, the loop-mediated isothermal amplification (LAMP) method was employed on a sample Japanese population. METHODS: A set of LAMP primers targeting exon 2 of HLA-A*31:01 were designed. Thirty-two clinical samples including the representative HLA-A allele in Japan were used to assess the specificity of LAMP primers in the detection of HLA-A*31:01. RESULTS: The HLA-A*31:01-specific LAMP assay showed consistency with polymerase chain reaction reverse sequence-specific oligonucleotide probe (PCR-rSSO) and polymerase chain reaction-sequence based typing (PCR-SBT) results. CONCLUSION: High sensitivity and specificity of the HLA-A*31:01 LAMP assay was confirmed. Considering its convenience, the assay can be widely used to screen patients at high genetic risk of CBZ-induced SCARs.

Serum gliadin monitoring extracts patients with false negative results in challenge tests for the diagnosis of wheat-dependent exercise-induced anaphylaxis.

BACKGROUND: Challenge testing with wheat plus exercise and/or aspirin is a gold standard for the diagnosis of wheat-dependent exercise-induced anaphylaxis (WDEIA); however, the test may often yield false-negative results. Our previous study suggested that an increase in serum wheat gliadin levels is required to induce allergic symptoms in patients with WDEIA. Based on this knowledge, we sought to extract the patients with false negative results in the challenge tests of WDEIA. METHODS: Thirty-six patients with suspected WDEIA were enrolled. First, group categorizations-Group I, challenge tests were positive; Group II, challenge tests were negative and serum gliadin were undetectable; Group III, challenge tests were negative and serum gliadin were detectable-were given according to the results of wheat plus exercise and/or aspirin challenge testing and serum gliadin levels. Second, diagnoses were made using retests and/or dietary management in Group II and III. RESULTS: Positive results for wheat plus exercise and/or aspirin challenge tests gave a diagnosis of definite WDEIA in 17 of 36 patients (Group I). Of the remaining 19 challenge negative patients, serum gliadin was undetectable in ten patients (Group II). Of the ten patients (Group II), three of them were diagnosed as definite WDEIA by retesting and six of them were diagnosed as probable WDEIA using a wheat elimination diet, whereas one patient was non-WDEIA. In the rest of the nine challenge negative patients, serum gliadin was detectable (Group III). No allergic episodes with a normal diet provided a diagnosis of non-WDEIA in seven of the nine patients, whereas the remaining two patients were probable WDEIA or had another food allergy because of repeated episodes. CONCLUSIONS: Our study revealed that serum gliadin monitoring during challenge testing is useful.

Characterization of two isozymes of coniferyl alcohol dehydrogenase from Streptomyces sp. NL15-2K.

We purified two isozymes of coniferyl alcohol dehydrogenase (CADH I and II) to homogeneity from cell-free extracts of Streptomyces sp. NL15-2K. The apparent molecular masses of CADH I and II were determined to be 143 kDa and 151 kDa respectively by gel filtration, whereas their subunit molecular masses were determined to be 35,782.2 Da and 37,597.7 Da respectively by matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Thus, it is probable that both isozymes are tetramers. The optimum pH and temperature for coniferyl alcohol dehydrogenase activity were pH 9.5 and 45 °C for CADH I and pH 8.5 and 40 °C for CADH II. CADH I oxidized various aromatic alcohols and allyl alcohol, and was most efficient on cinnamyl alcohol, whereas CADH II exhibited high substrate specificity for coniferyl alcohol, and showed no activity as to the other alcohols, except for cinnamyl alcohol and 3-(4-hydroxy-3-methoxyphenyl)-1-propanol. In the presence of NADH, CADH I and II reduced cinnamaldehyde and coniferyl aldehyde respectively to the corresponding alcohols.

Usability of Fag e 2 ImmunoCAP in the diagnosis of buckwheat allergy.

Currently, the detection of crude buckwheat extract-specific IgE by ImmunoCAP (f11) (Phadia AB, Uppsala, Sweden) is widely used to diagnose buckwheat allergy. However, the results of this test do not always correlate with the development of allergic symptoms. This study aimed to evaluate the diagnostic usefulness of specific IgE antibody titers for the major buckwheat allergens Fag e 1 and Fag e 2. Specific IgE antibodies were determined using the ImmunoCAP method for native Fag e 1 and Fag e 2, recombinant Fag e 1 and Fag e 2, and crude buckwheat extract (f11) in 10 buckwheat allergy patients, 14 atopic dermatitis patients, and 15 healthy subjects. All buckwheat allergy patients showed positive results for native Fag e 1- and Fag e 2-specific IgE tests and for ImmunoCAP (f11). In contrast, the rates of atopic dermatitis patients with positive results for native Fag e 1- and Fag e 2-specific IgE tests were 64.2% (9/14) and 57.1% (8/14), respectively. The sensitivities of the test using recombinant proteins were lower than those of the test using native proteins. The area under the curve (AUC) as determined by receiver operating characteristic (ROC) curve analysis was the largest for the native Fag e 2-specific IgE test (0.967), with a sensitivity of 90% and a specificity of 89.6% (cut-off: 2.74 kUa/L). Thus, the native Fag e 2-specific IgE antibody titer obtained using the ImmunoCAP method is more reliable than the buckwheat ImmunoCAP (f11) value for predicting buckwheat allergy.

[Analysis of causative allergen of the patient with baker's asthma and wheat-dependent exercise-induced anaphylaxis (WDEIA)].

A 47 years-old woman suffering from baker's asthma for several years developed anaphylaxis when she was walking hard after taking wheat. On the provocation test, neither wheat alone nor exercise alone induced any symptoms. The combination of exercise, wheat and aspirin induced urticaria and marked elevation of blood gliadin levels. According to the high titer of omega-5 gliadin specific IgE in her serum and the result of challenge test, we diagnosed wheat-dependent exercise-induced anaphylaxis (WDEIA). By means of western blotting of soluble and insoluble wheat proteins, we detected several bands which were supposed to be beta-, gamma- and omega-5 gliadin by their relative molecular mass. Wheat gliadins might be causative allergen of both baker's asthma and WDEIA in our case.