HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy.

BACKGROUND: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). OBJECTIVES: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy. METHODS: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects. RESULTS: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10-24 for rs9271588 and P = 2.96 × 10-24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10-9). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQß1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10-8). CONCLUSIONS: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.

Comparing the efficacy of continuous erythropoietin receptor activator and darbepoetin Alfa treatments in Japanese patients with chronic kidney disease during the predialysis period: A propensity-matched analysis.

AIM: Erythropoiesis-stimulating agent (ESA) treatment during the predialysis period can be a strategy to reduce cardiac mortality soon after initiation of dialysis. In this study, we compared the efficacy of continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) in patients with chronic kidney disease (CKD) over 6 months prior to initiation of dialysis. METHODS: This study was a retrospective propensity score-matched study conducted at a single center in Japan that analyzed the effects of CERA and DA therapy on haemoglobin (Hb) changes, ESA resistance index (ERI) changes, and interval of ESA administration during a 6-month observation period prior to initiation of dialysis. Propensity scores were used for matching the patients included in the CERA and DA groups. RESULTS: Among 680 screened, 74 pairs of patients (one in each group) were included in the present analysis after propensity score matching. Mean Hb significantly decreased over 6 months in the DA group compared to that in the CERA group (-0.70 ± 0.23 vs. -0.33 ± 0.22). In the DA group, mean ERI was significantly increased at 4, 3, 2, and 1 month before dialysis and initiation of dialysis, while in the CERA group, mean ERI was significantly increased only at 1 month before dialysis and initiation of dialysis. Moreover, patients administered CERA were required to visit the hospital significantly less frequently for ESA administration than those administered DA. CONCLUSION: Our study showed that CERA may be more effective than DA for management of anaemia during the predialysis period in CKD patients.

Increased ACE and decreased ACE2 expression in kidneys from patients with IgA nephropathy.

BACKGROUND: Angiotensin-converting enzyme (ACE)2 forms angiotensin-1-7 which may protect kidney in a counterregulatory manner to angiotensin II. Recent studies revealed increased ACE and decreased ACE2 expression in kidneys of patients with diabetic nephropathy. However, these changes may not be specific for diabetic nephropathy. We studied ACE and ACE2 expression in patients with IgA nephropathy. METHODS: Renal ACE and ACE2 expression was assessed by immunohistochemistry and in situ hybridization in 30 patients with IgA nephropathy and 21 healthy controls. Correlation between ACE and ACE2 expression and levels of various biochemical parameters was also assessed. Gene expression was also assessed in minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN) as disease controls. RESULTS: Reduced ACE2 expression (p < 0.01) and increased ACE expression in glomeruli (p < 0.001), and reduced ACE2 expression in tubulointerstitium (p < 0.001) were observed in patients with IgA nephropathy compared to healthy controls, although the changes in ACE2 mRNA were not statistically significant. Reduced renal ACE2 expression was also found in MN but not in MCNS. Correlation between renal ACE and ACE2 expression and proteinuria was not observed in IgA nephropathy. CONCLUSION: IgA nephropathy is associated with increased ACE and decreased ACE2 expression in kidneys, as in diabetic nephropathy.

Urinary angiotensin-converting enzyme 2 in patients with CKD.

AIM: Angiotensin-converting enzyme 2 (ACE2) is a type I membrane protein that antagonizes the action of angiotensin II. Because of the need for invasive kidney biopsy, little is known about the role of renal ACE2 in human kidney diseases. The authors studied if urinary ACE2 could provide a novel clue to renal ACE2 in chronic kidney disease (CKD). METHODS: Subjects were 190 patients with CKD including 38 patients with diabetic nephropathy and 36 healthy subjects. Parameters were urinary ACE2 by enzyme-linked immunosorbent assay, blood pressure, casual plasma glucose, proteinuria, microalbuminuria, serum creatinine and estimated glomerular filtration rate. Urine and serum samples were also subjected to western blotting of ACE2. RESULTS: Western blotting confirmed increased urinary ACE2 levels in patients with CKD. Urinary ACE2 was significantly higher in patients with CKD than healthy subjects (median 9.64 (interquartile range, 4.41-16.89) vs 1.50 (0.40-2.33) mg/g·creatinine, P < 0.001) and in patients with diabetic nephropathy than patients without diabetic nephropathy (median 13.16 (interquartile range 6.81-18.70) vs 8.90 (4.19-16.67) mg/g·creatinine, P < 0.05). No significant difference in urinary ACE2 was observed by the use of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker. CONCLUSION: Urinary ACE2 could be used as a non-invasive marker to understand the role of renal ACE2 in CKD.

Effects of new peritoneal dialysis solutions, pyridoxamine and AT1 receptor blocker, on TGF-beta1 and VEGF expression in rat peritoneal mesothelial cells.

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) are involved in peritoneal deterioration in continuous ambulatory peritoneal dialysis. The present study was designed to determine whether new peritoneal dialysis solutions (PDS), pyridoxamine (advanced glycation end products (AGE) inhibitor) or AT1 receptor blocker (ARB), affect the expression of VEGF and TGF-beta1 in rat peritoneal mesothelial cells (RPMC). METHODS: RPMC were stimulated by phosphate-buffered saline (PBS) as control, Dianeal 1.5% (D 1.5%), Dianeal 2.5% (D 2.5%), Dianeal 4.25% (D 4.25%), Dianeal N 1.5% (N 1.5%), Dianeal N 2.5% (N 2.5%) or Extraneal (Ex). In co-incubation experiments, RPMC were stimulated with N 2.5% including pyridoxamine or olmesartan (ARB). VEGF and TGF-beta1 protein and mRNA expression in RPMC were analyzed by ELISA and RT-PCR. RESULTS: Glucose-containing PDS, even N 2.5% diluted twofold with M199 (which contains 1.25% glucose), increased VEGF and TGF-beta1 expression in RPMC (p < 0.05). Ex did not inhibit VEGF expression and did not inhibit TGF- beta1 expression after 24 h in RPMC. Pyridoxamine and ARB significantly reduced N 2.5%-induced VEGF and TGF-beta1 protein and mRNA expression in RPMC (p < 0.01). CONCLUSIONS: Neither new pH-neutral, lactate-buffered, low-GDP, two-chamber bag PDS, nor 7.5% icodextrin PDS alone satisfactorily inhibited VEGF and TGF-beta1 overproduction in RPMC, but ARB or pyridoxamine effectively inhibited glucose-containing PDS (N 2.5%)-induced overproduction.

[Survey of atopic dermatitis and skin barrier functions in Japanese and Chinese school students].

BACKGROUND: The comparative studies of the prevalence of atopic dermatitis and skin barrier functions in Japanese and Chinese were performed. METHODS: Clinical investigations were performed in 68 elementary school students in Lhasa, Tibet Autonomous Region and 67 students in Yixing, Jiangsu Province in China, and 99 students in Nishinomiya, Hyogo in Japan. Transepidermal water loss (TEWL) and capacitance were measured. Questionary survey about bathing frequency was also performed for students in Lhasa, Yixing and Osaka. RESULT: The prevalence rate of atopic dermatitis was 0% in Lhasa, 2.63% in Yixing, 4.26% in Nishinomiya. TEWL of students in Nishinomiya was higher than that in Yixing and Lhasa. Capacitance of students in Lhasa was lower than that in Nishinomiya and Yixing. The frequency of taking a bath in Lhasa was about 2.2 times per month and fewer than that in Nishinomiya and Yixing. CONCLUSION: There was tendency that the prevalence of atopic dermatitis increased according to increase of TEWL. It was thought that more investigations are necessary whether the development of habitat and environment influence the prevalence of atopic dermatitis and skin barrier function.

Association between Low Dietary Protein Intake and Geriatric Nutrition Risk Index in Patients with Chronic Kidney Disease: A Retrospective Single-Center Cohort Study.

Reduced dietary protein intake in malnourished patients with chronic kidney disease (CKD) may be associated with adverse clinical outcomes, which may mask any efficacy of a low-protein diet. The study included 126 patients with CKD who attended a dedicated dietary counseling clinic in 2005-2009 and were systematically followed until January 2015. Of these patients, 20 (15.9%) had moderate or severe nutrition-related risk of geriatric nutritional risk index (GNRI) < 92; these patients were more likely to be older, have a greater proteinuria, and have lower body mass index and serum albumin concentration. Dietary protein intake was significantly lower in older patients (r = -0.33, p < 0.001) and those with lower glomerular filtration rate (r = 0.47, p < 0.001). The non-protein to nitrogen calorie ratio was independently associated with GNRI. Reduced GNRI was significantly associated with mortality (hazard ratio (HR) = 4.94; 95% confidence interval (CI) = 1.61-15.42, p = 0.012) and cardiovascular events (HR = 9.37; 95% CI = 2.49-37.34, p = 0.006), but not with adverse renal outcomes. Restricting protein intake may be harmful to patients with any nutrition-related risk, suggesting that improvement of nutritional status should be a high priority.

Mosquito salivary gland extracts induce EBV-infected NK cell oncogenesis via CD4 T cells in patients with hypersensitivity to mosquito bites.

Severe hypersensitivity to mosquito bites (HMB) is characterized by intense local skin reactions and systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly. Patients with HMB often have natural killer (NK) cell lymphocytosis associated with Epstein-Barr virus (EBV) infection. Here we investigated whether mosquito bites have any influence on the oncogenesis of EBV-infected NK cells. We examined six HMB patients with EBV-infected NK cell lymphocytosis. We first demonstrated that CD4+ T cells, but not NK cells, proliferated well in response to mosquito salivary gland extracts (SGE), especially to SGE of Aedes albopictus. When NK cells were cocultured with autologous CD4+ T cells stimulated by mosquito SGE, the expression of viral oncogene latent membrane protein 1 (LMP1) was remarkably enhanced. Next, we stimulated mononuclear cells of the patients with mosquito SGE, and NK cell counts were monitored for 28 d. The counts changed little from initial levels in the culture with mosquito SGE, whereas they decreased steadily in the culture without the extracts. Furthermore, we detected LMP1 mRNA in the skin lesion induced by mosquito SGE. These results suggest that mosquito bites can induce expression of the viral oncogene LMP1 in NK cells via mosquito antigen-specific CD4+ T cells, which is involved in the oncogenesis of NK cells in vivo.

[The influence of ageing and seasons on infantile eczema - a population-based cohort study of babies aged 4 months and 10 months].

BACKGROUND: This is probably the first report of a population study on infantile eczema performed for 12 months at two ages of 4 months and 10 months on the same infant group. METHODS: The Fujiidera Health Center services the health needs of 181,994 inhabitants of Habikino and Fujiidera cities. Between September 1990 and August 1991,1775 newborns were called for a health check-up performed twice a months when they reached 4 months of age. This was repeated for a year when the infants reached 10 months of age. A total of 1493 4-month old infants and 1264 10-month old infants were examined. An expert dermatologist joined this and performed a complete skin examination throughout the study. The eczematous skin changes were evaluated at 50 different points on the body and scored using an originally made chart. Scratch marks were also evaluated at each area. Based on the scores computed eczema was diagnosed when the total score crossed a threshold number. Based on this the examiner diagnoses were categorized as follows: Degree 1: no need to visit a doctor, Degree 2: visit to doctor required, Degree 3: treatment required. Gender was not considered. The data was analyzed by an originally made software using DEC-7000 computer. RESULTS: Of all the 4-month old infants examined 329 (22.0%) were initially diagnosed to have eczema while of all the 10-month old infants examined 268 (21.2%) were initially diagnosed to have eczema. Further, out of the 329 4-month old infants initially diagnosed with eczema, 228 were again examined when they were 10-months old. Of this sample; 123 (9.7%) infants showed continued symptoms of eczema and 165 (13.1%) infants no longer showed signs of eczema. In addition, out of the 976 4-month old infants initially diagnosed without eczema, 145 (11.5%) newly developed eczema at 10 months. Hence the cumulative diagnosis rate of eczema reached 34.3%. Meanwhile the monthly diagnosis number was significantly higher in Feb (OR 1.84, p=0.031) and significantly lower in Aug (OR 0.21, p<0.001) than the expected number calculated from monthly examination number and the annual diagnosis rate at 4 months. This observation was also the case at 10 months (Feb; OR 2.19, p=0.02, Aug; OR 0.36, p=0.015). The degree of eczema was significantly higher (p<0.001, Mann-Whitney's U test) at 4 months than 10 months. When this was seen monthly, degree 3 was most prevalent in February-March, while degree 2 was most prevalent in October-January for the 4-month olds. For the 10-month olds, both the degree 3 and degree 2 were quite low throughout the year and only degree 1 showed a monthly change similar to degree 2 plus degree 3 of the 4-month olds. CONCLUSION: We therefore conclude that eczematous skin manifestations of infantile eczema are easily changeable by age at less than 1 year and are strongly influenced by seasons.

Atopy-related skin rash in a normal population of infants: Distribution and rates for 50 separate skin regions: Cohort study from 4 months to 3.5 years.

Analysis of the rash in a normal population of infants may give new information that is different from clinical observation of atopic dermatitis (AD). For this purpose, a cohort study was undertaken on infants at 4 months, 10 months and 3.5 years. Infants who attended the local health center for health check were the subjects. Rash related to AD, dryness, scaling, erythema, papules, exudation and crusts was recorded in 50 skin regions and divided into three degrees. Examination was performed twice a month for a year at each age. The 777 infants who attended all three examinations were analyzed in this report. Rash-positive regions were 14.7% on average at 4 months and decreased with age. Prevalence of rash-positive infants was 93.6% at 4 months and also decreased with age. The main findings are as follows. First, rash was more frequent and more severe in younger infants. This seems to suggest that AD in early infancy is initiated and developed by immune immaturity, and is resolved by its maturation. Second, rash involved preferentially air-exposed and air-closed skin in younger infants. This seems to be evidence that the epidermis of young infants is easily responsive to both dryness and wetness. Third, some regions did not show age-dependent reduction of rash rate in younger infants. Those regions are probably irritated by saliva and urine or rubbing and scratching.

[Oral therapy for atopic dermatitis in year 2000. Questionnaire Study to Boarding Members of Japanese Society for Allergology].

Questionnaires were sent to boarding members of Japanese Society for Allergology (response rate 65.2%; 49 dermatologists [Derma] and 101 pediatricians [Pedia] ) to ask the order of choice in therapy attitudes, in the oral in comparison to the local therapy and in the oral therapy only. As for therapy attitudes, "suppress inflammation" (Infla), "reduce staphylococcal colonization" (Staph), "inhibit scratching" (Scrat), "guard skin from irritation" (Guard), "avoid allergen" (Avoid), and "support psychologically" (Psych) were presented. The order of choice was Guard, Infla, Scrat and Avoid for the first four in both Derma and Pedia. The last 2 were Psych and Staph in Derma and vice versa in Pedia. However, the lowest adoption rate was 76.2% in Derma and 85.8% in Pedia. This suggests that wide therapy attitudes were taken in mind in the therapy of atopic dermatitis in the both specialites. The adoption rate was significantly (P>0.05) higher in Pedia than Derma with Staph, Avoid, Scrat and Psych. As for the oral versus local therapy, "antihistamine" (A-hist), "antiallergy" (A-aller), "sedative" (Sedat), "hypnotic" (Hypno), "corticosteroid hormone" (O-steroid) and "antibacterial drug" (A-bact) were presented for the oral therapy, and "skin care medicine" (SkinC), "NSAID" (t-NSAID), "corticosteroid ointment" (S-oint) and "disinfectant" (Disinf) were for the topical therapy. The adoption rate was in the order of SkinC as well as S-oint followed by A-aller and A-hist both in Derma and Pediat. These choices were over 60% in Derma and over 75% in Pediat. Disinf and t-NSAID followed these with over 50% of adoption rate in Pediat, while all others were 30.6% or less in Derma. Thus, in Derma 4 therapies (2 local and 2 oral) were thought to be the first rank therapy but in Pediat additional 2 therapies (Disinf, t-NSAID) were comparable to the first rank therapy in Derma. As for the oral therapy only, A-aller and A-hist were adopted at high rates both in Derma and Pediat, but all other therapies that included 5 additional therapies; "kampo drug", "antimycotic drug", "vitamine", "arachidonic acid cascade controlling drug" and "immunosuppressant" were adopted in only low rates. Experience of oral corticosteroid therapy was about three quarters in Derma but a quarter in Pediat. Conditions for prescribing oral corticosteroid were mostly "extreme severity" and "acute generalized aggravation" both in Derma and Pediat. About 40% of doctors both in Derma and Pediat who ever prescribed oral corticosteroid were afraid that corticosteroid might not be stopped when starting the therapy. However, only short-term oral corticosteroid therapy is described in the guidelines of this society for the treatment of atopic dermatitis (1995). It is hoped to standardized oral corticosteroid therapy for long-lasting extremely severe atopic dermatitis.

Exercise-ankle brachial pressure index with one-minute treadmill walking in patients on maintenance hemodialysis.

BACKGROUND: The ankle-brachial pressure index (ABI) is widely used as a standard screening method for arterial occlusive lesion above the knee. However, the sensitivity of ABI is low in hemodialysis (HD) patients. Exercise stress (Ex-ABI) may reduce the false negative results. PATIENTS AND METHODS: After measuring resting ABI and toe-brachial pressure index (TBI), ankle pressure and ABI immediately after walking (Post-AP, Post-ABI) were measured using one-minute treadmill walking in 52 lower limbs of 26 HD patients. The definition of peripheral arterial occlusive disease (PAD) required an ABI value of less than 0.90, TBI value of less than 0.60, and decrease of more than 15% of the Post-ABI value and 20 mmHg of Post-AP in Ex-ABI. Computed tomographic angiography (CTA) was performed in 32 lower limbs of 16 HD patients. PAD is defined as presence of stenosis of more than 75% in the case of lesions from an iliac artery to knee on CTA. RESULTS: The accuracy of Ex-ABI (Sensitivity, 85.7%; Specificity, 77.7%) was higher than those of ABI (Sensitivity, 42.9%; Specificity, 83.3%) or TBI (Sensitivity, 78.6%; Specificity, 61.1%). CONCLUSION: Ex-ABI with one-minute treadmill walking is the most useful tool for the screening of arterial occlusive lesions above the knee in maintenance HD patients.

English version of the interim report published in 1998 by the members of the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

The Japanese Dermatological Association established an advisory committee in 1995 to set up severity scoring systems for atopic dermatitis (AD). Its interim report was published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998) by Chairman Hikotaro Yoshida. Because of the strong demand for an English version, we have decided to publish the report in English. This prospective study was designed to evaluate the status of 259 AD patients using Method 1, which involves a simple global evaluation of disease severity; Method 2, which involves global evaluation by summing severity scores obtained from five body regions (i.e. the head and neck, anterior and posterior trunks, and upper and lower limbs); Method 3, which consists of both assessment of the extent of involved areas at each of the five body regions and that of the severity scores of each eruption component observed in the most severely affected body region; and Method 4, which consists of the evaluation of only subjective components (daytime pruritus and sleep disturbance). Employing the results obtained with Method 1 as a tentative benchmark, we analyzed its correlation with those of Methods 2, 3 and 4 to statistically assess the validity and reliability of these methods. Method 2, Method 3 and the portion of Method 4 involving evaluation of only the subjective symptom of daytime pruritus but not the sleep disturbance were considered useful in evaluating AD severity.

English version of the concluding report published in 2001 by the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

The Japanese Dermatological Association established an advisory committee in 1995 to develop a severity scoring system for atopic dermatitis (AD). Its interim and concluding reports were published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998 and 111: 2023-2033, 2001). Because of the strong demand for an English version, we have decided to publish the reports in English. This manuscript is the English version of the concluding report. The interim report suggested that eruption components such as erythema, papule, erosion, crust, excoriation and lichenification with extent of involved areas in five body regions, including the head and neck, anterior and posterior trunks, and upper and lower limbs, were important items for assessing AD severity. Additionally, it was recommended that streamlining of eruption components was mandatory for improving the statistical validity and reliability. The committee members subsequently concentrated their efforts on this task, and finally proposed an Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

Urticarial reaction caused by ethanol.

BACKGROUND: We report a case of an urticarial reaction after drinking alcohol beverages. The patient was a 47-year-old man suffering urticarial and anaphylactoid reaction to alcohol for two years. These reactions were observed at every alcohol beverages intake. CASE SUMMARY: We performed a prick test with diluted ethanol, alcohol beverages and their metabolites (acetaldehyde, acetic acid). Only acetic acid showed a positive result. Oral challenge test with diluted-ethanol caused pruritus and swelling of his lips. An oral challenge test with 8% diluted Shochu (Japanese distilled alcohol from rice or wheat) caused wheals on his upper back. DISCUSSION: Only acetic acid, a metabolite of alcohol, induced a positive prick test in the patient with alcohol-induced urticaria. This result was not observed in normal volunteers. An oral challenge test with diluted-alcohol or Shochu showed a positive wheal reaction in a dose dependent-manner which suggests that urticaria seen in this patient might be induced by alcohol-intolerance. However possible allergic reaction to acetaldehyde could not be excluded.