Healthcare use and prescription patterns associated with adult asthma in Korea: analysis of the NHI claims database.

BACKGROUND: National Health Insurance (NHI) claim records could provide valuable data for epidemiological studies of asthma in Korea. The aim of this study is to estimate the prevalence of adult asthma and to investigate asthma-related healthcare use and prescription patterns in Korea over 5 years. METHODS: National Health Insurance claim records from January 1, 2006 to December 31, 2010 were analyzed in a retrospective, population-based study. Outcome measures included asthma prevalence, healthcare use, and prescription patterns over time, by type of hospital, and by medical specialty. Additionally, we assessed differences in healthcare use between newly diagnosed and previously diagnosed patients in 2009. RESULTS: Over 5 years, the prevalence of asthma among Korean adults increased from 4944 to 5707 cases per 100,000 population (from 3760 to 4445 in men and from 6108 to 6951 in women). Asthma-related outpatient visits decreased from 4.82 ± 8.02 to 3.44 ± 5.50. Approximately 3% of all patients were hospitalized and 2.4% received asthma-related emergency treatment each year. Pulmonary function tests were performed in 10-11% of patients an average of 1.3 times per year. Newly diagnosed patients experienced fewer asthma-related hospitalizations (1.78% vs 4.35%) and emergency department visits (0.80% vs 2.11%) than the previously diagnosed group. Prescriptions of inhaled corticosteroids-based inhalers were maintained with about 20% of average of all types of hospitals. CONCLUSIONS: The prevalence of asthma in Korea has increased over a recent 5-year period, and asthma is still suboptimally controlled. Public health strategies are needed to improve the management of asthma in adults.

Validation of the cephalosporin intradermal skin test for predicting immediate hypersensitivity: a prospective study with drug challenge.

BACKGROUND: Cephalosporin is a major offending agent in terms of drug hypersensitivity along with penicillin. Cephalosporin intradermal skin tests (IDTs) have been widely used; however, their validity for predicting immediate hypersensitivity has not been studied. This study aimed to determine the predictive value of cephalosporin intradermal skin testing before administration of the drug. METHODS: We prospectively conducted IDTs with four cephalosporins, one each of selected first-, second-, third-, or fourth-generation cephalosporins: ceftezol; cefotetan or cefamandole; ceftriaxone or cefotaxime; and flomoxef, respectively, as well as with penicillin G. After the skin test, whatever the result, one of the tested cephalosporins was administered intravenously and the patient was carefully observed. RESULTS: We recruited 1421 patients who required preoperative cephalosporins. Seventy-four patients (74/1421, 5.2%) were positive to at least one cephalosporin. However, none of responders had immediate hypersensitivity reactions after a challenge dose of the same or different cephalosporin, which were positive in the skin test. Four patients who suffered generalized urticaria and itching after challenge gave negative skin tests for the corresponding drug. The IDT for cephalosporin had a sensitivity of 0%, a specificity of 97.5%, a negative predictive value of 99.7%, and a positive predictive value (PPV) of 0%, when challenged with the same drugs that were positive in the skin test. CONCLUSION: Routine skin testing with a cephalosporin before its administration is not useful for predicting immediate hypersensitivity because of the extremely low sensitivity and PPV of the skin test (CRIS registration no. KCT0000455).

Lessons from two cases of anaphylaxis to proton pump inhibitors.

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors (PPIs), which are widely used for the treatment of peptic ulcers and gastroesophageal diseases, reduce both basal and stimulated gastric acid secretion by inhibiting the parietal cell enzyme H(+)-K(+)-adenosine triphosphatase. There have been several reports of hypersensitivity reactions to PPIs but anaphylaxis is very rare. We report on two cases of anaphylaxis to PPIs. CASE SUMMARY: Our two interesting and instructive cases of anaphylaxis to PPIs relate to the orally disintegrating form of lansoprazole and omeprazole. The first patient had taken esomeprazole 20 mg/day for 1 month without any side effects before experiencing anaphylaxis to lansoprazole. To our knowledge, this is the first report of anaphylaxis to the orally disintegrating form of lansoprazole. In the second case, the patient was misdiagnosed with penicillin allergy which she suffered from earlier. WHAT IS NEW AND CONCLUSION: Physicians need to be more aware of the possibility of hypersensitivity to PPIs.

Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response.

BACKGROUND: Recent findings have raised new interests about the use of anticholinergics, especially tiotropium, for the treatment of asthma. This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics, and to identify factors capable of predicting the response to tiotropium, using a pharmacogenetic approach. METHODS: A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited. Tiotropium 18 microg was added once a day and lung functions were measured every 4 weeks. Responders were defined as those with an improvement of > or = 15% (or 200 ml) in the forced expiratory volume in 1 s (FEV1) that was maintained for at least 8 successive weeks. Eleven single nucleotide polymorphisms (SNPs) in CHRM1-3 (coding muscarinic receptors one to three) which were identified by re-sequencing, and Arg16Gly and Gln27Glu in ADRB2 (coding beta(2) adrenoreceptor) were scored in 80 of the 138 asthmatics. RESULTS: Forty-six of the 138 asthmatics (33.3%) responded to tiotropium treatment. Logistic regression analyses (controlled for age, gender, and smoking status) showed that Arg16Gly in ADRB2 [P = 0.003, OR (95% CI) = 0.21 (0.07-0.59) in a minor allele-dominant model] was significantly associated with response to tiotropium. CONCLUSIONS: As many as 30% of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium. The presence of Arg16Gly in ADRB2 may predict response to tiotropium.

Polymorphisms in the neurokinin-2 receptor gene are associated with angiotensin-converting enzyme inhibitor-induced cough.

BACKGROUND AND OBJECTIVE: Treatment with angiotensin-converting enzyme (ACE) inhibitors can induce chronic cough in many patients. Genetic variations in the neurokinin 2 receptor gene (NK2R) are significantly associated with cough sensitivity to capsaicin. METHODS: This study assessed the relationship between genetic polymorphisms in the NK2R gene and chronic cough in 91 patients taking ACE inhibitors. Patients included in the study did not have chest abnormalities, postnasal drip, gastroesophageal reflux or a recent history of upper respiratory infection. RESULTS: We detected two single nucleotide polymorphisms in the NK2R gene (i.e., Gly231Glu and Arg375His). The allelic frequencies at amino acid 231 were 36.3% for Gly/Gly, 49.5% for Gly/Glu and 14.3% for Glu/Glu. The allelic frequencies at amino acid 375 were 74.7% for Arg/Arg, 24.2% for Arg/His and 1.1% for His/His. The prevalence of chronic cough in patients with the amino acid 231 genotype was 33.3% in Gly/Gly homozygotes, 24.4% in Gly/Glu heterozygotes and 0% in Glu/Glu homozygotes. There was a statistically significant association between chronic cough and the Glu/Glu allele (P = 0.028) when the data were analyzed with a recessive model. In addition, there was a significant inverse linear association between the number of Glu231 alleles and ACE inhibitor-related cough (P = 0.026). The prevalence of chronic cough in patients with the amino acid 375 genotype was 22.1% in Arg/Arg homozygotes, 31.8% in Arg/His heterozygotes and 0% in His/His homozygotes, although none of these association were statistically significant. CONCLUSION: Our findings indicate that the Gly231Glu polymorphism is associated with a lower prevalence of ACE inhibitor-related cough.

Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes.

OBJECTIVE: Advanced glycation end products (AGE) accumulate in articular cartilage with age. We investigated the effects of AGE in primary-cultured human OA chondrocytes. METHODS: Chondrocytes were cultured with/or without AGE-bovine serum albumin (AGE-BSA) and the expression levels of inducible nitric oxide (iNOS), cyclooxygenase (COX)-2 microsomal prostaglandin E synthase-1 (mPGES-1) were evaluated using RT-PCR and western blot analysis. Prostaglandin E(2) (PGE(2)) was analysed by ELISA and nitric oxide (NO) was analysed by Griess reaction assay. Pharmacological studies to elucidate the involved pathway were executed using specific inhibitors of MAPK and receptor for AGE (RAGE). RESULTS: We found that treatment of OA chondrocytes with AGE-BSA increased COX-2, mPGES-1 and iNOS mRNA and protein, as well as elevating production of PGE(2) and NO. Pre-treatment with the MAPK inhibitors SP600125 (JNK inhibitor), SB202190 (p38 inhibitor) or PD98059 (ERK inhibitor) significantly inhibited AGE-BSA induction of COX-2 expression and production of PGE(2). In contrast, SN50, a nuclear factor-kappaB (NF-kappaB) inhibitor, had no effect on levels of COX-2 and PGE(2). SB202190 and SN50, but not SP600125 and PD98059, decreased AGE-BSA-induced production of NO. Pre-treatment with soluble receptor for AGE (sRAGE) also reduced AGE-stimulated COX-2, iNOS and PGE(2), implicating the involvement of RAGE. CONCLUSIONS: These results show that AGE may augment inflammatory responses in OA chondrocytes by increasing PGE(2) and NO levels, possibly via the MAPK pathway for PGE(2) and the NF-kappaB pathway for NO.

Corticotomy-/osteotomy-assisted tooth movement microCTs differ.

Corticotomy-assisted and osteotomy-assisted tooth movement involves surgical incisions through the alveolar bone. To ascertain whether teeth move by distraction osteogenesis or by regional accelerated phenomenon (RAP), we randomly assigned 30 Sprague-Dawley rats to one of 5 experimental groups: corticotomy alone, corticotomy-assisted tooth movement, osteotomy alone, osteotomy-assisted tooth movement, or tooth movement alone. Each animal was imaged by microtomography immediately after surgery, after 21 days, and after 2 months. After 21 days, regional accelerated phenomenon was observed in the alveolar bone of the corticotomy-treated animals and distraction osteogenesis in the osteotomy-assisted tooth movement animals. Pixel count data were analyzed by nested ANOVA for 5 experimental groups, split-mouth controls, 3 levels along the root, and 5 sites per level. The most demineralized sites after 21 days differed for each of the experimental groups. Our study indicates that osteotomies and corticotomies induce different alveolar bone reactions, which can be exploited for tooth movement.

Nuclear matrix of calreticulin in hepatocellular carcinoma.

Nuclear matrix protein profiles of malignant cells vary from their normal counterparts. By two-dimensional gel electrophoresis, we analyzed nuclear matrix proteins in 11 hepatocellular carcinomas and compared them with corresponding non-neoplastic liver tissue. Although the compositions were mostly similar, several peptides were noted predominantly in the former. The most prominent one was an acidic protein of apparent Mr 62,000, which was identified to be calreticulin upon NH2-terminal amino acid sequencing. By immunoblotting, calreticulin was confirmed to be present abundantly in the nuclear matrix fraction of carcinomas but not in that of the nonmalignant liver tissue. Interestingly, the total content of calreticulin was similar between them. By immunofluorescence microscopy, evident nuclear immunostaining was detected in carcinomas. Calreticulin was also found to be in the nuclear matrices of various carcinoma cell lines. We conclude that calreticulin is a component of the nuclear matrix. The formation and/or expansion of the calreticulin-nuclear matrix may be related to the activated cell growth.

Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice.

To investigate the role of membrane-type matrix metalloproteinase-1 (MT1-MMP) in mammary gland development and tumorigenesis, transgenic mice overexpressing MT1-MMP in mammary gland under the control of the mouse mammary tumor virus long terminal repeat-promoter were generated. The mouse mammary tumor virus/MT1-MMP transgenic mice displayed abnormalities in 82% of female mammary glands. The abnormalities were verified as lymphocytic infiltration, fibrosis, hyperplasia, alveolar structure disruption, dysplasia, and adenocarcinoma. Northern and reverse transcription-PCR analyses demonstrated that MT1-MMP mRNA was overexpressed in mammary glands exhibiting abnormalities. Western blot analysis and immunohistochemical studies have revealed that the protein expression level was also increased in these glands. In addition, the beta-casein gene as a functional epithelial cell marker was poorly expressed in the mammary glands of transgenic mice exhibiting abnormalities. Gelatin zymography showed significantly increased MMP-2 activation in these mammary glands. These results showed that overexpression of MT1-MMP induced remodeling of the extracellular matrix and tumor formation in the mammary glands of transgenic mice. Therefore, we suggest that overexpression of MT1-MMP may play a key role in development and tumorigenesis in mammary glands.

Translocation of lipocortin (annexin) 1 to the membrane of U937 cells induced by phorbol ester, but not by dexamethasone.

1. Induction of lipocortin 1 secretion by dexamethasone has been demonstrated, although the secretory mechanism is still unknown. We have studied the effects of 12-tetradecanoyl phorbol 13-acetate (TPA) and/or dexamethasone on the expression, translocation, and secretion of lipocortin 1 in U937 cells. 2. The expression of lipocortin 1 and its mRNA increased during TPA-induced differentiation of U937 cells to a maximum of 1.9 fold and 8.2 fold, respectively, after 48 h. Both the protein and the mRNA levels decreased after 48 h. 3. TPA caused the translocation of lipocortin 1 from the cytosol to the membrane of U937 cells in a time-dependent manner, as determined by Western blot analysis. The translocation was concurrent with the differentiation of the cells. After 48 h of TPA treatment, 82.6 +/- 6.5% of lipocortin 1 was present in the membrane fraction compared to 41.6 +/- 1.7% in untreated cells. 4. The amount of lipocortin 1 that was externally bound (associated) with the membrane increased to 3.2 fold as the cytosol to membrane translocation of lipocortin 1 increased. 5. Dexamethasone decreased the externally bound lipocortin 1, but had no effect on the cytosol to membrane translocation. 6. This offers a model system with which the function and the secretion mechanism of lipocortin 1 can be studied. Our data is consistent with the hypothesis that the secretory mechanism is through an unknown pathway, involving the translocation of lipocortin 1 from the cytosol to the internal membranes, and then, its secretion to the external membrane.

Detection of the H1-j strain of Salmonella typhi among Korean isolates by the polymerase chain reaction.

Salmonella typhi, the etiologic agent of typhoid fever, typically has only a phase-1 flagellar antigen, H1-d (fliC). While most strains of S. typhi have H1-d antigen, 10-20% of Indonesian isolates have been reported to possess H1-j antigen instead. To investigate the presence H1-j strains of S. typhi isolates in Korea, where typhoid fever is still a common infectious problem, we used the polymerase chain reaction (PCR) with a pair of oligonucleotides primers that specifically amplified the flagellin gene of S. typhi. Of 375 isolates of S. typhi tested, only one was shown to possess the H1-j antigen, which was shown by the presence of a 1,269-basepair fragment on agarose gel electrophoresis after the PCR. The isolate with the H1-j antigen was cultured from a Korean-Indonesian man who was already symptomatic in Indonesia and was thought to be an Indonesian strain. Because 375 strains tested in this study were collected from cases with typhoid fever in different regions of Korea during the period from 1986 to 1991, it could be concluded that the mutation rate to j antigen is negligible among S. typhi endemic in Korea.

Matrix attachment region sequences enhanced the expression frequency of a whey acidic protein/human lactoferrin fusion gene in the mammary gland of transgenic mice.

To elevate the expression frequency of transgenes in transgenic mice, the chicken lysozyme matrix attachment region (MAR) sequence was used by combining it with a transgene. The whey acidic protein (WAP) promoter/human lactoferrin (hLF) cDNA fusion transgene (pWL) was connected to the chicken lysozyme MAR sequence at its 5'-end (pMWL). While only two of three mice became transgenic from the pWL vector expressed hLF, all seven mice from the pMWL vector expressed the transgene in their lactating mammary glands. To evaluate the effect of lactogenic hormones on transgene expression, experiments with the primary culture of transgenic mammary explants were performed. It was revealed that the expression of transgenes was slightly increased by insulin plus dexamethasone or insulin plus prolactin treatment. However it was not increased by insulin, dexamethasone or prolactin (IDP) treatment alone. In contrast, the endogenous WAP gene was expressed only in the IDP treated group. These results demonstrate that MAR sequences are effective in improving the expression frequency of transgenes in transgenic mice although the developmental and hormonal regulations are not the same as those of the endogenous WAP gene.

Expression of insulin-like growth factor-II and insulin-like growth factor binding protein-1 in the placental basal plate from pre-eclamptic pregnancies.

OBJECTIVES: To determine whether expressions of insulin-like growth factor-II (IGF-II) and insulin-like growth factor binding protein-1 (IGFBP-1) are altered in pre-eclamptic placenta and to elucidate the possible relationship between their expressions and a mechanism for inadequate trophoblast invasion in pre-eclampsia. METHODS: Placental tissues were obtained at cesarean delivery from five normotensive, nine mild pre-eclamptic and five severe pre-eclamptic women at 33-39 completed weeks of gestation. After total ribonucleic acid was extracted, reverse transcriptase-polymerase chain reaction was performed to determine IGF-II and IGFBP-1 mRNA expression. Product bands were quantitated by scanning densitometry and results were expressed as ratio of cytokines/beta-actin. Western blot analysis was also done to determine IGF-II and IGFBP-1 protein expression. Statistical analysis was determined by Kruskal-Wallis analysis of variance with the Scheffe multiple post-hoc test. RESULTS: The IGF-II mRNA levels of mild and severe pre-eclamptic placenta were significantly lower than that of uncomplicated placenta (P<0.005, P<0.001, respectively), with the level of severe pre-eclamptic placenta being significantly lower than that of mild pre-eclamptic placenta (P<0.05). As for the IGF-II protein expression, a significant decrease was found among the three groups (P<0.001), correlating with the IGF-II mRNA results. However, the mean IGFBP-1 mRNA levels of mild and severe pre-eclamptic placenta were significantly higher than that of uncomplicated placenta (P<0.05, P<0.005, respectively), with the level of severe pre-eclamptic placenta being significantly raised compared with that of mild pre-eclamptic placenta (P<0.05). Finally, a significant increase of IGFBP-1 protein expression was noted among the three groups (P<0.001), correlating with the IGFBP-1 mRNA results. CONCLUSIONS: This study suggests that IGF-II and IGFBP-1 might be associated with the impaired trophoblastic invasion that may lead to pathogenesis of pre-eclampsia.

The impact of total antioxidant capacity on pulmonary function in asthma patients.

BACKGROUND: Oxidative stress, mediated by an imbalance between oxidants and antioxidants, contributes significantly to the pathogenesis of asthma. OBJECTIVE: To evaluate the impact of serum total antioxidant capacity (TAC) on the pulmonary function of Korean asthma patients. METHOD: A total of 104 adult asthma patients enrolled from the COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) programme participated in the study. Baseline clinical parameters at enrolment, and the results of pulmonary function tests at baseline and 1 and 2 years after enrolment were collected. TAC at baseline was measured using a Trolox-equivalent antioxidant capacity assay. Patients were divided into two groups based on TAC levels, and various clinical parameters were compared. RESULT: Serum TAC levels correlated with forced expiratory volume in 1 second (FEV(1)) at baseline (r = 0.22, P = 0.03). The group with higher baseline TAC levels maintained greater mean FEV(1) both 1 and 2 years after enrolment, even after adjusting for sex, age, height, weight, body mass index and smoking status. CONCLUSION: These results suggest an important link between serum TAC levels and pulmonary function, indicating that higher TAC levels may be a biomarker for favourable prognosis in asthma patients.

Reliability and validity of the St George's Respiratory Questionnaire for asthma.

BACKGROUND: The St George's Respiratory Questionnaire (SGRQ) is a self-administered questionnaire that has been used to evaluate the health-related quality of life of patients with chronic respiratory diseases. OBJECTIVE: To assess the validity and reliability of the SGRQ for a large population with asthma. DESIGN: We used the previously developed Korean version of the SGRQ (SGRQ-K) to assess 676 asthma patients enrolled from the Cohort for Reality and Evolution of Adult Asthma in Korea study. Cronbach's α was used to assess test reliability and Pearson's correlation coefficient was used to assess the correlation between SGRQ scores and various clinical factors. RESULTS: The total SGRQ-K score had acceptable reliability (Cronbach's α = 0.92). The total SGRQ-K score was significantly correlated with symptom duration (r = 0.157, P < 0.001), pulmonary function (% FEV(1) of predicted r = -0.314, P < 0.001; % FVC of predicted r = -0.224, P < 0.001; FEV(1)/FVC r = -0.224, P < 0.001), asthma severity (r = 0.278, P < 0.001) and history of asthma exacerbation. CONCLUSION: With the exception of the SGRQ-K symptoms, SGRQ-K is a reliable and valid test for evaluation of the quality of life of patients with asthma. Scores were well correlated with duration of symptoms, lung function and previous history of asthma exacerbation.