Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway epithelial cells from asthmatic patients.

BACKGROUND: Genetic and genomic data increasingly point to the airway epithelium as critical to asthma pathogenesis. Epithelial growth factor (EGF) family members play a fundamental role in epithelial differentiation, proliferation, and repair. Although expression of erythroblastosis oncogene B2 (ErbB2) mRNA, an EGF family receptor, was reported to be lower in asthmatic patients, little is understood about its functional role. OBJECTIVE: We sought to determine whether decreased ErbB2 activation in freshly isolated human airway epithelial cells (HAECs) from asthmatic patients associated with impaired wound closure in vitro. METHODS: An in vitro scratch-wound model of air-liquid interface cultured and freshly isolated HAECs were compared between HAECs from healthy control subjects (HCs) and asthmatic patients in relation to ErbB2. RESULTS: Freshly brushed HAECs from asthmatic patients had impaired ErbB2 activation compared with those from HCs. In an in vitro scratch-wound model, HAECs from asthmatic patients showed delayed wound closure compared with HAECs from HCs. Cell proliferation, as assessed based on [3H] thymidine incorporation after wounding, and expression or activation of ErbB2 and cyclin D1 at the leading edge of the wound were lower in HAECs from asthmatic patients and HCs. A selective ErbB2 tyrosine kinase inhibitor, mubritinib, impaired wound closure and decreased cyclin D1 expression in healthy HAECs, with less effect on cells from asthmatic patients, supporting diminished activity in asthmatic patients. CONCLUSION: These results implicate a primary defect in the ErbB2 pathway as constraining epithelial repair processes in asthmatic patients. Restoration of homeostatic ErbB2 function should be considered a novel asthma therapeutic target.

Resolution rate of pulmonary sarcoidosis and its related factors in a Japanese population.

BACKGROUND AND OBJECTIVE: A number of previous studies have reported on the rate of resolution of pulmonary sarcoidosis and its associated factors. However, most of the studies were conducted several decades ago and no similar surveys have been conducted in recent years. The aim of this study was to evaluate the rate of resolution of pulmonary sarcoidosis and its related factors in recently diagnosed patients, and to compare the results with those from previous studies. METHODS: This study included 306 patients who had been newly diagnosed with pulmonary sarcoidosis between 2000 and 2009 in Sapporo, Japan. Chest radiographical findings were assessed at the initial visit and at the 2- or 5-year observation points. The rates of resolution on chest radiographs and the association with clinical manifestations were evaluated. RESULTS: The resolution rates were 17.9% at the 2-year and 29.9% at the 5-year observation point. These rates were lower than those reported in the earlier surveys. Younger subjects (aged <40 years) showed resolution more often (P < 0.05). The absence of extra-pulmonary organ involvement was associated with resolution at 5 years (P < 0.05). CONCLUSION: The clinical course of pulmonary sarcoidosis may be changing, showing a tendency not to resolve. At least in part, this may be due to the ageing of the Japanese population.

Association of the CAT-262C>T polymorphism with asthma in smokers and the nonemphysematous phenotype of chronic obstructive pulmonary disease.

BACKGROUND: Catalase (CAT) is a part of the active antioxidant defense system and has been studied with regard to its association with asthma and chronic obstructive pulmonary disease (COPD), which are heterogeneous obstructive pulmonary diseases characterized by chronic airway inflammation. We hypothesized that the CAT gene might be involved in the common pathogenesis underlying asthma and COPD. OBJECTIVE: To evaluate the association of CAT polymorphisms with specific phenotypes of asthma and COPD to identify the common underlying pathophysiologic mechanisms of these 2 diseases. METHODS: The -262C>T and -21A>T polymorphisms in the CAT gene were genotyped in 493 individuals with asthma, 265 with COPD, and 1,076 healthy controls. Asthmatic patients were categorized according to smoking status (smokers and nonsmokers) and age at onset (early onset and adult onset) as part of a case-control study. In patients with COPD, visual scoring (computed tomographic score) was assessed to determine emphysema severity, which was used to evaluate associations with CAT gene polymorphisms. RESULTS: Overall, the -262C>T and -21A>T polymorphisms were not associated with asthma. However, the -262CT+TT genotype was significantly associated with adult-onset asthma in smokers (P = .005), and a significant interaction between smoking status and the effect of -262C>T genotype on asthma were observed (P = .01). In patients with COPD, this genotype was significantly associated with a low computed tomographic score (P = .03), which indicates a nonemphysematous type of COPD. CONCLUSION: The present study indicates that the CAT gene is involved in the common pathogenesis underlying adult-onset asthma in smokers and the nonemphysematous type of COPD.

[Prevalence of adult asthma and allergic rhinitis in Kamishihoro, Hokkaido -trends from 2006 through 2011-].

PURPOSE: To investigate changes in the prevalence of adult asthma and allergic rhinitis from 2006 to 2011 in Kamishihoro, a town in Hokkaido, Japan. METHODS: The Japanese edition of the European Community Respiratory Health Survey questionnaire was completed by 1472 residents aged from 20 to 81 years old. (718 men, 749 women). The age and gender distribution of respondents matched that of respondents in 2006. RESULTS: Response rates were 98.1% in 2011 and 95.8% in 2006. Wheezing in the last 12 months was reported by 10.7% of men and 8.3% of women in 2011, compared to 12.9% and 9.8%, respectively, in 2006. The questions "Have you ever had asthma?" followed by "Was this confirmed by a doctor?" both received positive answers from 7.9% of men and 7.5% of women in 2011, compared to 5.7% and 6.3%, respectively, in 2006. The rate of current smoking was 34.8% in men and 14.7% in women in 2011, compared to 42.8% and 17.2%, respectively, in 2006. A "Yes" answer to the questionnaire item, "Do you have any nasal allergies, including hay fever?" (defining allergic rhinitis) was given by 23.2% of men and 25.4% of women in 2011, compared to 17.6% and 23.0%, respectively, in 2006. The prevalence of allergic rhinitis was increased, particularly among younger respondents. CONCLUSION: Rates of current asthma and allergic rhinitis increased, whereas the rate of wheezing in the past 12 months decreased from 2006 to 2011. Optimal treatment of asthma might be related to these trends.

The CC16 A38G polymorphism is associated with asymptomatic airway hyper-responsiveness and development of late-onset asthma.

BACKGROUND: Clara cell secretory protein (CC16) is expressed primarily in the respiratory tract and is a potent anti-inflammatory agent that protects the airway from inflammation. The associations of the A38G polymorphism in this gene with asymptomatic airway hyper-responsiveness (AHR), which is considered a risk factor for future asthma in adults, and the development of adult-onset asthma are unclear. OBJECTIVE: To evaluate the association of the CC16 A38G polymorphism with asymptomatic AHR in healthy young adults and the development of adult-onset asthma and the association between plasma CC16 level according to this genotype and asymptomatic AHR. METHODS: Nonspecific AHR was measured in 154 asymptomatic, young, healthy adults using a continuous methacholine inhalation method. The cumulative dose values of inhaled methacholine measured at the inflection point at which respiratory conductance started to decrease (Dmin) were used as an index of AHR. Case-control analysis was performed for the association between this polymorphism and the development of asthma in 1,086 unrelated Japanese subjects (504 subjects with asthma and 582 healthy subjects). RESULTS: The 38AA + AG genotype was associated with lower Dmin values and lower plasma CC16 levels (P = .012 and .020). There was a significant positive correlation between Dmin values and plasma CC16 levels (P = .012). In the case-control study, the 38AA + AG genotype was significantly associated with late-onset asthma (onset at >40 years; odds ratio, 1.63; P = .016). CONCLUSION: These results suggest that the CC16 A38G polymorphism may play a role in asymptomatic AHR and contribute to the development of late-onset asthma.

Increased prevalence of cigarette smoking in Japanese patients with sarcoidosis.

BACKGROUND AND OBJECTIVE: Several studies have shown that individuals with sarcoidosis in Western populations are less likely to have smoked before diagnosis. Epidemiological characteristics of sarcoidosis are known to differ between Japanese and Westerners. Therefore, the relationship between cigarette smoking and sarcoidosis in a Japanese population was investigated. METHODS: Three hundred eighty-eight patients newly diagnosed with sarcoidosis between 2000 and 2008 were retrospectively identified. The results of two large surveys of smoking prevalence in Japan provided reference data. Specific clinical manifestations of sarcoidosis were compared between current smokers and never-smokers, after excluding former smokers. RESULTS: The prevalence of current smokers at the time of the diagnosis of sarcoidosis was 59.6% in men and 27.9% in women. With the exception of men in their 30s, the prevalence was higher in all age groups compared with the general Japanese population. The prevalence of lung parenchymal involvement tended to be higher in current smokers than in never-smokers (odds ratio = 1.33 (0.99-1.77), P = 0.054). CONCLUSIONS: This retrospective cohort study suggests that smoking prevalence is higher in Japanese sarcoidosis patients than that reported in Western sarcoidosis patients and that there could be different relationships between smoking and the development of sarcoidosis in these populations.

High-precision rapid testing of omicron SARS-CoV-2 variants in clinical samples using AI-nanopore.

A digital platform that can rapidly and accurately diagnose pathogenic viral variants, including SARS-CoV-2, will minimize pandemics, public anxiety, and economic losses. We recently reported an artificial intelligence (AI)-nanopore platform that enables testing for Wuhan SARS-CoV-2 with high sensitivity and specificity within five minutes. However, which parts of the virus are recognized by the platform are unknown. Similarly, whether the platform can detect SARS-CoV-2 variants or the presence of the virus in clinical samples needs further study. Here, we demonstrated the platform can distinguish SARS-CoV-2 variants. Further, it identified mutated Wuhan SARS-CoV-2 expressing spike proteins of the delta and omicron variants, indicating it discriminates spike proteins. Finally, we used the platform to identify omicron variants with a sensitivity and specificity of 100% and 94%, respectively, in saliva specimens from COVID-19 patients. Thus, our results demonstrate the AI-nanopore platform is an effective diagnostic tool for SARS-CoV-2 variants.

Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer.

PURPOSE: Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer. METHODS: Eligibility criteria included histologically proven, locally advanced or metastatic pancreatic cancer. Gemcitabine was administered intravenously at a dose of 1000 mg/m(2) on days 1, 8, and 15 every 4 weeks. Regional hyperthermia was performed once weekly, 1 day preceding or following gemcitabine administration. The primary end point was the 1-year survival rate. Secondary objectives were determination of tumour response and safety. RESULTS: We enrolled 18 patients with advanced pancreatic cancer between November 2008 and May 2010. The major grade 3-4 adverse events were neutropenia and anaemia; however, there were no episodes of infection. The objective response rate (ORR) and disease control rate (ORR + stable disease) were 11.1% and 61.1%, respectively. Median overall survival (OS) was 8 months, and the 1-year survival rate was 33.3%. Median OS of patients with locally advanced pancreatic cancer was 17.7 months. CONCLUSIONS: Regional hyperthermia combined with gemcitabine is well tolerated and active in patients with locally advanced pancreatic cancer.

Total serum IgE levels and atopic status in patients with sarcoidosis.

To date, two studies have reported lower total serum immunoglobulin E (IgE) levels and lower prevalence of atopy in patients with sarcoidosis compared with healthy subjects. However, those reports did not consider age or gender differences between cases and controls. In addition, the association between total serum IgE levels and clinical manifestations of sarcoidosis has not been clarified. This study assessed total serum IgE levels and prevalence of atopy in patients with sarcoidosis after taking age and sex differences into account and evaluated associations between total serum IgE levels and clinical manifestations of sarcoidosis. Total serum IgE levels and prevalence of atopy on initial visits were compared between 189 patients with sarcoidosis and 378 age- and sex-matched controls. Associations between total serum IgE levels and involvement of each affected organ were evaluated. Changes in total serum IgE levels during the clinical course of sarcoidosis were also evaluated. Total serum IgE levels were significantly lower in patients with sarcoidosis than in controls, independent of atopic status (atopic subjects, p = 0.025; nonatopic subjects, p < 0.001). Total serum IgE levels did not differ according to the involvement of different organs. Total serum IgE levels decreased further, albeit only slightly, after disease remission (p < 0.001). Increased susceptibility to sarcoidosis may be attributable to several underlying genetic or environmental factors that result in lower total serum IgE levels.

Multiple Routes of Antibody-Dependent Enhancement of SARS-CoV-2 Infection.

Antibody-dependent enhancement (ADE) of infection is generally known for many viruses. A potential risk of ADE in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has also been discussed since the beginning of the coronavirus disease 2019 (COVID-19) pandemic; however, clinical evidence of the presence of antibodies with ADE potential is limited. Here, we show that ADE antibodies are produced by SARS-CoV-2 infection and the ADE process can be mediated by at least two different host factors, Fcγ receptor (FcγR) and complement component C1q. Of 89 serum samples collected from acute or convalescent COVID-19 patients, 62.9% were found to be positive for SARS-CoV-2-specific IgG. FcγR- and/or C1q-mediated ADE were detected in 50% of the IgG-positive sera, whereas most of them showed neutralizing activity in the absence of FcγR and C1q. Importantly, ADE antibodies were found in 41.4% of the acute COVID-19 patients. Neutralizing activity was also detected in most of the IgG-positive sera, but it was counteracted by ADE in subneutralizing conditions in the presence of FcγR or C1q. Although the clinical importance of ADE needs to be further investigated with larger numbers of COVID-19 patient samples, our data suggest that SARS-CoV-2 utilizes multiple mechanisms of ADE. C1q-mediated ADE may particularly have a clinical impact since C1q is present at high concentrations in plasma and its receptors are ubiquitously expressed on the surfaces of many types of cells, including respiratory epithelial cells, which SARS-CoV-2 primarily infects. IMPORTANCE Potential risks of antibody-dependent enhancement (ADE) in the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been discussed and the proposed mechanism mostly depends on the Fc gamma receptor (FcγR). However, since FcγRs are exclusively expressed on immune cells, which are not primary targets of SARS-CoV-2, the clinical importance of ADE of SARS-CoV-2 infection remains controversial. Our study demonstrates that SARS-CoV-2 infection induces antibodies that increase SARS-CoV-2 infection through another ADE mechanism in which complement component C1q mediates the enhancement. Although neutralizing activity was also detected in the serum samples, it was counteracted by ADE in the presence of FcγR or C1q. Considering the ubiquity of C1q and its cellular receptors, C1q-mediated ADE may more likely occur in respiratory epithelial cells, which SARS-CoV-2 primarily infects. Our data highlight the importance of careful monitoring of the antibody properties in COVID-19 convalescent and vaccinated individuals.

Characteristics of COVID-19 patients admitted into two hospitals in sapporo, Japan: Analyses and insights from two outbreak waves.

BACKGROUND: Coronavirus disease (COVID-19) emerged in January 2020 in Sapporo city, and the outbreak has shown two peaks. METHODS: A total of 260 COVID-19 patients were enrolled and categorized into three groups according to the pandemic pattern, jobs and situation, and disease severity. We compared clinical characteristics according to these categories. RESULTS: We found two pandemic peaks, and the proportion of patients and health providers who were infected in other hospitals had increased in the latter two periods (period 2: 49.6%, period 3: 32.7%). Particularly, the proportion of infected health providers was 27% in period 2, and they tended to be younger females with a mild condition. Severity of the disease (requirement of oxygen and/or mechanical ventilation) was associated with advanced age, and all the patients who died during admission were over 60 years old. CONCLUSIONS: We reported the temporal dynamics and characteristics of the COVID-19 pandemic in Sapporo city, Japan. This survey from the viewpoint of the hospital provides a new insight into and a better guide for the further management of the COVID-19 pandemic.

Equivalent SARS-CoV-2 viral loads by PCR between nasopharyngeal swab and saliva in symptomatic patients.

Emerging evidences have shown the utility of saliva for the detection of SARS-CoV-2 by PCR as alternative to nasopharyngeal swab (NPS). However, conflicting results have been reported regarding viral loads between NPS and saliva. We conducted a study to compare the viral loads between NPS and saliva in 42 COVID-19 patients. Viral loads were estimated by the cycle threshold (Ct) values. SARS-CoV-2 was detected in 34 (81%) using NPS with median Ct value of 27.4, and 38 (90%) using saliva with median Ct value of 28.9 (P = 0.79). Kendall's W was 0.82, showing a high degree of agreement, indicating equivalent viral loads in NPS and saliva. After symptom onset, the Ct values of both NPS and saliva continued to increase over time, with no substantial difference. Self-collected saliva has a detection sensitivity comparable to that of NPS and is a useful diagnostic tool with mitigating uncomfortable process and the risk of aerosol transmission to healthcare workers.

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis.

BACKGROUND: Mannose receptor (MR) is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition and thought to be critical in shaping host immune response. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with sarcoidosis. METHODS: Nine single nucleotide polymorphisms (SNPs), encompassing the MRC1 gene, were genotyped in a total of 605 Japanese consisting of 181 sarcoidosis patients and 424 healthy controls. RESULTS: Suggestive evidence of association between rs691005 SNP and risk of sarcoidosis was observed independent of sex and age in a recessive model (P = 0.001). CONCLUSIONS: These results suggest that MRC1 is an important candidate gene for sarcoidosis. This is the first study to imply that genetic variants in MRC1, a major member of the C-type lectin, contribute to the development of sarcoidosis.

A functional polymorphism (-603A --> G) in the tissue factor gene promoter is associated with adult-onset asthma.

Tissue factor (TF) is important for initiation of coagulation and for the increased thrombin activity observed at sites of inflammation. Thrombin activity is induced by allergen challenge in asthmatic airways and is involved in the pathogenesis of asthma. A -603A --> G polymorphism (rs1361600) in the promoter region of the TF gene has been associated with serum TF levels and with the development of cardiovascular diseases. The aim of this study was to determine whether the functional -603A --> G polymorphism has genetic influences on the development of asthma. Case-control analysis was performed of the association between six common single-nucleotide polymorphisms (SNPs), including the -603A --> G polymorphism, at the TF gene, and the development of asthma, using two unrelated Japanese populations. In the primary population (n=826), the GG genotype at the -603A --> G polymorphism was associated with adult-onset asthma (onset at >or=21 years of age) (odds ratio (OR) 2.886, P=0.0231). A second population showed a similar tendency (n=1654, OR 1.602, P=0.064). Transcriptional activity of promoters with -603A --> G genotypes were examined using luciferase promoter assays. The -603G allele was associated with higher promoter activity (P<0.05). The association between the functional polymorphism (-603A --> G) in the TF gene promoter and adult-onset asthma indicates that TF is a candidate gene contributing to asthma susceptibility.

Gene expression profiles of diabetic mice treated with whole body hyperthermia: A high-density DNA microarray analysis.

Previously we have demonstrated that whole body hyperthermia (WBH) improves insulin resistance in diabetic mice. The aim of the present study was to perform a gene expression analysis of the liver and adipose tissue of obesity-induced insulin resistant diabetic mice (db/db mice) after WBH and to define the molecules that play the important role in improvement of insulin resistance by WBH. Male db/db mice were treated with WBH 3 times per week for 12 weeks. Total RNA was extracted from the liver and adipose tissue of db/db mice, and differences in the gene expression profiles among db/+ mice, untreated db/db mice, and WBH-treated db/db mice were investigated using a high-density DNA microarray. WBH directly targets liver and adipose tissue, resulting in modifications in NF-kappaB and IL-6 signalling pathways, as well as lipid metabolism. Although the mechanisms have not yet been completely investigated, we can conclude that WBH may provide a new therapeutic or preventive modality against type 2 diabetes mellitus and metabolic or insulin resistance syndrome through the modification of several signalling pathways.

Levels of transferrin in bronchoalveolar lavage fluid in sarcoidosis.

There has been only one report showing high levels of transferrin (Tf) in bronchoalveolar lavage fluid (BALF) in patients with sarcoidosis. This study was designed to assess the levels of Tf in both BALF and serum and to examine the relationship between the levels of Tf and other disease markers in sarcoidosis. Subjects were 64 sarcoidosis and 10 healthy controls. Tf in BALF and serum was measured by nephelometric assay. Median Tf levels in BALF from sarcoidosis was 0.70 (range, 0.00-3.97) mg/dl, which was significantly higher compared with controls (0.36 (range, 0.00-1.02) mg/dl; p = 0.005). In contrast, median Tf levels in serum from sarcoidosis was 258 (range, 171- 383) mg/dl, which was significantly lower compared with controls (322 (range, 234-356) mg/dl; p = 0.003). Tf levels in BALF were significantly correlated with both the percentage of lymphocytes (r = 0.617, p = 0.001) and serum angiotensin-converting enzyme activity (r = 0.363, p = 0.003) and serum soluble interleukin-2 receptor (r = 0.450, p = 0.001) in sarcoidosis. Levels of Tf in BALF from patients with sarcoidosis were not influenced by smoking status. The levels of Tf in sarcoidosis are high in BALF, but low in serum. Increased levels of Tf in BALF may reflect the disease activity.

The role of atopy in the clinical course of pulmonary sarcoidosis in the Japanese population.

Sarcoidosis is a multisystem disorder characterized by a T-helper 1 (Th1)-mediated immune response. Conversely, atopy is characterized by the presence of a specific immunoglobulin E (IgE) E response in association with a Th2-type immune response. Several epidemiological studies have shown that atopic status influences disease activity and clinical course for several Th1-mediated diseases. The aim of this study was to evaluate associations between atopic status and clinical findings of sarcoidosis. We further evaluated the impact of atopic status on the clinical course of pulmonary sarcoidosis. We defined atopy as a positive specific IgE response to at least one common inhaled allergen (multiple antigen simultaneous test scores, lumicount of >1.01). Subjects comprised 134 patients given a diagnosis of sarcoidosis between 2000 and 2006, divided into atopic and nonatopic groups. Several clinical findings were compared between the two groups. Furthermore, 100 subjects observed 2 years after diagnosis were divided into resolving and persistent clinical course groups according to chest radiography and associations with atopic status were evaluated. Atopy was more prevalent among men than women (p = 0.009) and subjects with atopy were younger (p = 0.002) and showed less frequent lung parenchymal lesions (stages II and III; p = 0.018) compared with subjects without atopy. The prevalence of atopy was higher in the resolving clinical course group than in the persistent clinical course group (p = 0.002) and this association was independent of sex, age, presence of lung parenchymal lesions, and presence of extrapulmonary lesions (p = 0.037). Classification of sarcoidosis based on atopic status might be useful for predicting the clinical course of pulmonary sarcoidosis.

[Evaluating total serum IgE levels and peripheral eosinophil count in asthma and rhinitis].

BACKGROUND: Total serum immunoglobulin (Ig)E levels and peripheral blood eosinophil counts are widely examined to evaluate patients with various allergic diseases. Asthma and allergic rhinitis often coexist. However, the significance of these indices for asthma and rhinitis under consideration of the status of co-existence has not been fully elucidated and was therefore examined in the present study. METHODS: Subjects comprised 347 adult residents in Kamishihoro town, Hokkaido. Relationships between two indices and asthma, rhinitis and their coexistence were analyzed. RESULTS: Serum IgE (sIgE) levels were significantly higher in asthma with (p<0.01) or without (p<0.01) rhinitis, regardless of atopic status, but not in rhinitis alone. Peripheral eosinophil counts were significantly higher only in asthma with rhinitis (p<0.005). CONCLUSION: Compared with rhinitis, non-antigen-specific IgE production may contribute more to elevated levels of sIgE in asthma. In addition, the significance of sIgE and peripheral eosinophil count as indices of evaluating asthma and rhinitis might differ.

Genetic variants in the mannose receptor gene (MRC1) are associated with asthma in two independent populations.

Mannose receptor is a member of the C-type lectin receptor family involved in pathogen molecular pattern recognition and thought to be critical in shaping host immune responses and maintaining homeostasis. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with asthma in two independent populations. Seven single-nucleotide polymorphisms (SNPs; rs2477637, rs2253120, rs2477631, rs2477664, rs692527, rs1926736, and rs691005) in the MRC1 gene locus were genotyped and evaluated regarding association with asthma in 870 unrelated Japanese subjects (446 asthmatics, 424 controls). The same markers were validated in 176 unrelated African-American subjects (86 asthmatics, 90 controls). Suggestive evidence of association between five SNPs (rs2477637, rs2253120, rs2477664, rs692527, and rs1926736) and asthma was observed in the analysis of the Japanese population independent of sex, age, smoking status, and atopic status. SNPs rs692527 and rs691005 showed significant association with asthma in the African-American population. Haplotypes containing two linked SNPs (rs692527 and rs1926736) were significantly associated with asthma in both Japanese and African-American populations. Our results suggest that sequence variations in the MRC1 gene are associated with the development of asthma in two independent and ethnically diverse populations.

Severity and progression rate of cerebellar ataxia in 16q-linked autosomal dominant cerebellar ataxia (16q-ADCA) in the endemic Nagano Area of Japan.

16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5' untranslated region of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding's ADCA III, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using international cooperative ataxia rating scale and scale for the assessment and rating of ataxia and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 +/- 9.8 years, n = 66) than in SCA6 patients (41.1 +/- 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant.