Cardiovascular comorbidities in patients with rosacea: A nationwide case-control study from Taiwan.

BACKGROUND: Rosacea is a chronic inflammatory skin disease. Inflammation plays a prominent role in atherosclerosis and its complications. OBJECTIVE: We sought to investigate the associations of rosacea with cardiovascular disease risk factors and cardiovascular diseases from a nationwide population-based database. METHODS: A total of 33,553 patients with rosacea and 67,106 age- and gender-matched control subjects were identified from the National Health Insurance Research Database in Taiwan from 1997 to 2010. Multivariate logistic regressions were performed to compare the odds of comorbidities between the 2 groups. RESULTS: Dyslipidemia (odds ratio 1.41; 95% confidence interval 1.36-1.46), coronary artery disease (odds ratio 1.35, 95% confidence interval 1.29-1.41), and hypertension (odds ratio 1.17, 95% confidence interval 1.12-1.21) were significantly associated with rosacea. Coronary artery disease remained independently associated with rosacea after adjustment for hypertension, diabetes mellitus, and dyslipidemia. Male patients with rosacea had higher risks for all comorbidities than female patients with rosacea. LIMITATIONS: The National Health Insurance Research Database does not contain information regarding rosacea subtypes or disease severity, or laboratory data. CONCLUSION: Patients with rosacea are more likely to have dyslipidemia and hypertension. They are also at increased risk of coronary artery disease after adjustment for cardiovascular disease risk factors.

Thyroid disease as a risk factor for cerebrovascular disease.

BACKGROUND: Thyroid disease is the medical condition impairing function of the thyroid. Among this disorder category, hyperthyroidism is that the thyroid gland produces excessive amounts of thyroid hormones whereas hypothyroidism is that the thyroid gland does not produce enough thyroid hormone. Various studies have supported the comorbid association between thyroid disease and cardiovascular disorder. However, there is insufficient evidence to prove the relationship between cerebrovascular disease (CVD) and thyroid disease. METHODS: In this study, we tried to verify that thyroid disease increases the risk of CVD development employing a population-based database, National Health Insurance Research Database of Taiwan. A total of 16,808 hyperthyroidism cases and 5793 hypothyroidism patients with corresponding control subjects were studied, respectively. Hazard ratio (HR) by the Cox regression was used to quantify risk of CVD in different groups of subjects, that is, case patients versus matched controls. Further stratification studies for risk factors of CVD were performed to evaluate the comorbid association between CVD and hyperthyroidism/hypothyroidism. RESULTS: Evaluation results have shown that hyperthyroidism increased 38% of the hazard of developing follow-up CVD (adjusted HR, 1.38) whereas hypothyroidism increased even higher the risk (adjusted HR, 1.89). Further stratification studies for risk factors of CVD suggested that the comorbid association between hypothyroidism and CVD was comparable to those influences from cardiac risk factors, such as diabetes mellitus, hyperlipidemia, hypertension, or renal failure and so forth. CONCLUSIONS: Thyroid disease may predispose to onset of CVD. Advanced analysis is required to investigate the pathologic mechanism underlying the association between CVD and thyroid disease.

De novo motif discovery facilitates identification of interactions between transcription factors in Saccharomyces cerevisiae.

MOTIVATION: Gene regulation involves complicated mechanisms such as cooperativity between a set of transcription factors (TFs). Previous studies have used target genes shared by two TFs as a clue to infer TF-TF interactions. However, this task remains challenging because the target genes with low binding affinity are frequently omitted by experimental data, especially when a single strict threshold is employed. This article aims at improving the accuracy of inferring TF-TF interactions by incorporating motif discovery as a fundamental step when detecting overlapping targets of TFs based on ChIP-chip data. RESULTS: The proposed method, simTFBS, outperforms three naïve methods that adopt fixed thresholds when inferring TF-TF interactions based on ChIP-chip data. In addition, simTFBS is compared with two advanced methods and demonstrates its advantages in predicting TF-TF interactions. By comparing simTFBS with predictions based on the set of available annotated yeast TF binding motifs, we demonstrate that the good performance of simTFBS is indeed coming from the additional motifs found by the proposed procedures. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Atopic diathesis in patients with Kawasaki disease.

OBJECTIVE: To determine the association between Kawasaki disease (KD) and atopic diathesis (atopic dermatitis [AD], allergic rhinitis, and asthma) in children younger than 5 years of age. STUDY DESIGN: In this nationwide study, we aimed to analyze the association and temporal relationship between KD and atopic diathesis. Data were obtained from the National Health Insurance Research Database of Taiwan from 1997 to 2010. In total, 200 patients with KD younger than 5 years of age and 800 age- and sex-matched control subjects were enrolled. RESULTS: In the whole study population, an increased risk of any concomitant atopic diseases was observed in patients with KD (OR 1.61, 95% CI 1.15-2.26). The risk of AD was increased in male patients between 1 and 5 years of age (OR 3.02, 95% CI 1.22-7.50). More than 60% of the patients developed atopic diseases after the diagnosis of KD. CONCLUSION: There appears to be an association between KD and risk of AD. Most of the atopic diseases occurred after the episode of KD.

Increased risk of sexual dysfunction in male patients with psoriasis: a nationwide population-based follow-up study.

INTRODUCTION: An association between psoriasis and sexual dysfunction (SD) has been explored. However, the risk of SD after the diagnosis of psoriasis relative to the age-matched general population remains unknown. Aim. To clarify the risk of developing SD in male patients with psoriasis. METHODS: From 2000 to 2001, we identified 12,300 male patients with newly diagnosed psoriasis and 61,500 matching controls from National Health Insurance Database in Taiwan. MAIN OUTCOME MEASURES: The two cohorts were followed up until 2008, and we observed the occurrence of SD by registry of SD diagnosis in the database. Stratified Cox proportional hazard regressions were used to calculate the 7-year SD risk for these two groups. RESULTS: Of the 73,800 sampled patients, 1,812 patients (2.46%) experienced SD during the 7-year follow-up period, including 373 (3.03% of patients with psoriasis) in the study group and 1,439 (2.34% of patients without psoriasis) in the comparison group. The hazard ratio (HR) for SD for patients with psoriasis was 1.27 times (95% confidence interval [CI], 1.11-1.46; P = 0.001) as high as that for patients without psoriasis after adjusting for age, monthly income, number of health-care visits, systemic treatment, and other comorbidities. Stratified analysis showed that the risk of SD was higher in patients older than 60 years old (HR: 1.42, 95% CI: 1.12-1.81) and patients with psoriatic arthritis (HR: 1.78, 95% CI: 1.08-2.91). However, the risk of SD was not significantly elevated in patients receiving systemic treatment, including retinoid, methotrexate, and cyclosporine. CONCLUSIONS: Male patients with psoriasis are at increased risk of developing SD. Physicians should pay attention to the impact of psoriasis on psychosocial and sexual health, especially in old-aged patients.

Cancer risk in patients with allergic rhinitis, asthma and atopic dermatitis: a nationwide cohort study in Taiwan.

It has long been a debate that whether atopy is a risk factor or protective factor for cancer. However, no large-scale study of different cancers in patients with atopic diseases has been conducted among Asians. Here, we conducted a nationwide study to evaluate the cancer risk in patients with allergic rhinitis (AR), asthma and atopic dermatitis (AD). Drawing on Taiwan's National Health Insurance Research Database, 225,315 patients with AR, 107,601 patients with asthma and 34,263 patients with AD without prior cancers were identified in the period from 1996 to 2008. The standard incidence ratio (SIR) of each cancer was calculated. Although the overall cancer risks in patients with atopic symptoms were not increased, the risks were slightly elevated in female patients with AR or asthma (SIR: 1.13 and 1.08, AR and asthma, respectively) and slightly decreased in males patients with AR. Those aged 20-39 years-old possessed the highest risk. A higher risk of developing brain cancer was found in patients with atopic diseases, and patient with AR or asthma also had an elevated risk of developing cancer of kidney and urinary bladder. In contrast, the risk of nonmelanoma skin cancer was lower in patients with AR and asthma. Compared to patients with only one atopic disease, those with more than one atopic disease had lower cancer risks. Our data suggests that the association between atopy and cancer is site-specific.

Malignancies after renal transplantation in Taiwan: a nationwide population-based study.

BACKGROUND: Renal transplantation has been regarded as the treatment of choice for end-stage renal disease. Renal transplantation increases the risk of cancers due to long-term immunosuppression. The types of post-transplantation malignancies may vary among different geographic regions and ethnic populations. To date, large population-based studies of post-transplantation malignancies in Asian renal transplant recipients (RTRs) have rarely been reported. METHODS: To investigate the patterns of post-transplantation malignancies in Chinese RTRs, we performed a nationwide population-based cohort study between 1997 and 2008 based on data from the National Health Insurance Database in Taiwan. Patterns of cancer incidence in RTRs were compared with those of the general population using standardized incidence ratios (SIRs). RESULTS: Among the 4716 RTRs (2475 males and 2241 females; mean age 44.1 ± 12.4 years) and 22 556 person-years of observation, 320 post-transplant cancers were diagnosed. The SIR of all cancers was 3.75 (95% confidence interval 3.36-4.18). Women had a higher risk than men for the development of malignancies (SIR 5.04 for women and SIR 2.88 for men). Renal, bladder and liver cancers were the most common cancers, with SIRs of 44.29, 42.89 and 5.07, respectively. When stratified by age, RTRs of young age at transplant (<20 years) had the highest risk of post-transplantation malignancies. CONCLUSIONS: This study demonstrates different patterns of malignancies after renal transplantation in Chinese RTRs, with higher incidences of kidney and bladder cancers. Physicians should be more vigilant in examining RTRs for post-transplantation malignancies especially in younger patients.

Comorbidity profiles among patients with alopecia areata: the importance of onset age, a nationwide population-based study.

BACKGROUND: Alopecia areata (AA) is considered an autoimmune disease with undetermined pathogenesis. Age at onset predicts distinct outcomes. A nationwide study of the relationship of AA with associated diseases stratified by onset age has rarely been reported. OBJECTIVE: We sought to clarify the role of atopic and autoimmune diseases in AA, thereby better understanding its pathogenesis. METHODS: A total of 4334 patients with AA were identified from the National Health Insurance Database in Taiwan from 1996 to 2008. A national representative cohort of 784,158 persons served as control subjects. RESULTS: Among patients with AA, there were significant associations with vitiligo, lupus erythematosus, psoriasis, atopic dermatitis, autoimmune thyroid disease, and allergic rhinitis. Different ages at onset resulted in disparate comorbidities. Increased risk of atopic dermatitis (odds ratio [OR] 3.82, 95% confidence interval 2.67-5.45) and lupus erythematosus (OR 9.76, 95% confidence interval 3.05-31.21) were found in childhood AA younger than 10 years. Additional diseases including psoriasis (OR 2.43) and rheumatoid arthritis (OR 2.57) appeared at onset age 11 to 20 years. Most atopic and autoimmune diseases were observed at onset ages of 21 to 60 years. With onset age older than 60 years, thyroid disease (OR 2.52) was highly related to AA. Moreover, patients with AA had higher risk for more coexisting diseases than control subjects. LIMITATIONS: We could not differentiate hypothyroidism from hyperthyroidism. CONCLUSIONS: AA is related to various atopic and autoimmune diseases. Different associated diseases in each onset age group of AA can allow clinician to efficiently investigate specific comorbidities.

Insights into the mechanism of Piper betle leaf-induced contact leukomelanosis using C57BL/6 mice as the animal model and tyrosinase assays.

BACKGROUND/OBJECTIVES: Steamed piper betle leaves (PBL) were once used by many Taiwanese women to treat pigment disorders on the face. Most women claimed a quick, favourable response at first, only to be overcome with facial leukomelanosis later. METHODS: C57BL/6 mice were randomly assigned to different groups to study if PBL could cause the following effects: contact dermatitis, leukomelanosis, or hair bleaching. Intracellular melanin content was measured by tyrosinase assays. RESULTS: Most steamed PBL-treated mice developed contact dermatitis and postinflammatory hyperpigmentation (PIH) on their shaved backs. About half developed bleached hair to varying extents. The steamed PBL did not only bleach the hairs, but also, unexpectedly, stimulated melanocyte replication, indicated by the fact that the number of functional melanocytes in the tail epidermis increased significantly after treatment (P = 0.007). Using tyrosinase assays PBL extract at the undiluted concentration showed limited inhibition of melanogenesis, probably via melanocytotoxicity. CONCLUSIONS: The leukomelanosis observed in patients might be the consequence of PIH combined with a mixed reaction (hyper- and hypopigmentation), probably due to the different volatile chemicals that surface after steaming the PBL. This conflicting mixed reaction suggests that counteractive ingredients might exist in PBL. PBL, if purified, might be a promising source of a novel bleaching agent.

Prevalence of atopic dermatitis, allergic rhinitis and asthma in Taiwan: a national study 2000 to 2007.

To study the prevalence of atopic dermatitis, allergic rhinitis, and asthma in Taiwan, we analysed the claims data of a nationally representative cohort of 997,729 enrolees from the National Health Insurance register from 2000 to 2007. Overall, 66,446 patients were diagnosed with atopic dermatitis, and 49.8% of them had concomitant allergic rhinitis and/or asthma. The overall 8-year prevalences of atopic dermatitis, allergic rhinitis, and asthma were 6.7%, 26.3% and 11.9%, respectively. Children and adolescents had significantly higher prevalences of these atopic diseases. The prevalence of atopic dermatitis in females was lower than that in males before the age of 8 years, but became higher after that. Patients with atopic dermatitis were more likely to have allergic rhinitis and asthma. Those having both atopic dermatitis and allergic rhinitis possessed an even higher risk for asthma (odds ratio 9.04). The numbers of visits for atopic dermatitis were highest in late spring to mid-summer. These data suggest that atopic diseases are common in Taiwan.

Retinoid-responsive transcriptional changes in epidermal keratinocytes.

Retinoids (RA) have been used as therapeutic agents for numerous skin diseases, from psoriasis to acne and wrinkles. While RA is known to inhibit keratinocyte differentiation, the molecular effects of RA in epidermis have not been comprehensively defined. To identify the transcriptional targets of RA in primary human epidermal keratinocytes, we compared the transcriptional profiles of cells grown in the presence or absence of all-trans retinoic acid for 1, 4, 24, 48, and 72 h, using large DNA microarrays. As expected, RA suppresses the protein markers of cornification; however the genes responsible for biosynthesis of epidermal lipids, long-chain fatty acids, cholesterol, and sphingolipids, are also suppressed. Importantly, the pathways of RA synthesis, esterification and metabolism are activated by RA; therefore, RA regulates its own bioavailability. Unexpectedly, RA regulates many genes associated with the cell cycle and programmed cell death. This led us to reveal novel effects of RA on keratinocyte proliferation and apoptosis. The response to RA is very fast: 315 genes were regulated already after 1 h. More than one-third of RA-regulated genes function in signal transduction and regulation of transcription. Using in silico analysis, we identified a set of over-represented transcription factor binding sites in the RA-regulated genes. Many psoriasis-related genes are regulated by RA, some induced, others suppressed. These results comprehensively document the transcriptional changes caused by RA in keratinocytes, add new insights into the molecular mechanism influenced by RA in the epidermis and demonstrate the hypothesis-generating power of DNA microarray analysis.

Epidemiological features and costs of herpes zoster in Taiwan: a national study 2000 to 2006.

To analyse the epidemiological characteristics and related costs of herpes zoster in Taiwan, a nationally representative cohort of 1,000,000 individuals from the National Health Insurance register was followed up from 2000 to 2006 and their claims data analysed. Overall, 34,280 patients were diagnosed with zoster (incidence 4.89/1000 person-years) and 2944 patients (8.6%) developed post-herpetic neuralgia 3 months after the start of the zoster rash (incidence 0.42/1000 person-years). People with older age, diabetes, and immunocompromising conditions were at higher risk of developing zoster and post-herpetic neuralgia. The overall hospitalization rate for zoster was 16.1 cases per 100,000 person-years. The cost for each home care case and per hospitalized case were approximately 53.30 euro and 1224.70 euro, respectively. Further research into the cost-effectiveness of zoster vaccine is needed.

Cancer Risks in Vitiligo Patients: A Nationwide Population-Based Study in Taiwan.

Vitiligo is an autoimmune disease characterized by destruction of melanocytes and associated with other autoimmune disease. Whether the dysregulation of immune system enhances oncogenesis or not remains obscure. Until now, no nationwide population-based study has been conducted regarding this. As such, this paper aims to clarify cancer risk in vitiligo patients. A retrospective nationwide population-based cohort study between 2000 and 2010 was performed based on data from the National Health Insurance Research Database of Taiwan. Standardized incidence ratios (SIRs) of cancers were analyzed. Among the 12,391 vitiligo patients (5364 males and 7027 females) and 48,531.09 person-years of observation, a total of 345 cancers were identified. Significantly increased SIRs were observed for prostate cancer in male patients, thyroid cancer and breast cancer in female patients and bladder cancers in both male and female patients. Unfortunately, the low incidence rate of certain cancers limited the power of our statistical analyses. This study demonstrated the patterns of malignancies in vitiligo patients of Taiwan. Compared with the general population, male patients had higher risks of prostate cancer and female patients had higher risks of thyroid cancer and breast cancer. The risks of bladder cancer were also increased in both male and female patients.

Senile gluteal dermatosis: a clinical study of 137 cases.

BACKGROUND: Senile gluteal dermatosis (SGD) is a common genital dermatosis but has gained little attention before. A large-scale clinical study of this disease is lacking. MATERIALS AND METHODS: We examined 162 consecutive outpatients with gluteal skin diseases of different causes. Fourteen skin biopsies were performed. Patient's age, gender, body mass index (BMI), way of sitting or lying, treatment response, and underlying systemic diseases were recorded. RESULTS: About 137 (85%) patients could be defined as SGD. These patients, with a mean age of 79.4 ± 40.7 years and a mean BMI of 21.7 ± 10.8, presented with either partial (n = 43, 31%) or full-blown (n = 94, 69%) SGD lesions characterized by the sign of so-called "three corners of a triangle": brownish plaques on the gluteal cleft and each side of the buttocks. Male/female ratio was 130/7. Itching or pain of varying intensity was reported by 50 patients (36%) and 14 patients (10%), respectively. Eighty-six patients (53%) presented with horizontal hyperkeratotic ridges, a characteristic sign of SGD. Most patients spent most of the day sitting but reported no special way of sitting or lying. More than half of patients with SGD claimed no response to topical steroids and/or keratolytics. In comparison with patients with SGD, SGD-free patients were younger (61.3 ± 36 years, P = 0.0005) and heavier (BMI 26.2 ± 15.6, P < 0.0001) but showed no significant difference in the frequency of underlying systemic diseases. CONCLUSIONS: SGD is a common dermatosis, mostly affecting the thinner elderly. Friction, pressures and long hours sitting seemed to be important factors to trigger this dermatosis.

Analysis and meta-analysis of transcriptional profiling in human epidermis.

Because of its accessibility, skin has been among the first organs analyzed using DNA microarrays; psoriasis, melanomas, carcinomas, chronic wounds, and responses of epidermal keratinocytes in culture have been intensely investigated. Skin has everything: stem cells, differentiation, signaling, inflammation, hereditary diseases, etc. Here we provide step-by-step instructions for bioinformatics analysis of transcriptional profiling of skin. We also present methods for meta-analysis of transcription profiles from multiple contributors, available in public data repositories. Specifically, we describe the use of GCOS and RMAExpress programs for initial normalization and selection of differentially expressed genes and RankProd for meta-analysis of multiple related studies. We also describe DAVID and Lists2Networks programs for annotation of genes, and for statistically relevant identification of over- and underrepresented functional and biological categories in identified gene sets, as well as oPOSSUM for analysis of transcription factor binding sites in the promoter regions of gene sets. This work can serve as a primer for researchers embarking on skinomics, the comprehensive analysis of transcriptional changes in skin.

Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study.

PURPOSE: Systemic sclerosis is a life-threatening autoimmune disease characterized by vasculopathy, which results in myocardial involvement in an extremely high percentage of patients. Nevertheless, there have been no large-scale epidemiological studies about the risk of acute myocardial infarction in patients with systemic sclerosis. The aims of this study were to evaluate the hazard ratio (HR) and risk factors of acute myocardial infarction in patients with systemic sclerosis, as well as to compare the risks of acute myocardial infarction among systemic sclerosis patients taking different immunosuppressors. METHODS: The study cohort included 1344 patients with systemic sclerosis and 13,440 (1:10) age-, sex-, and comorbidity-matched controls during the period between 1997 and 2006, from the National Health Insurance Research Database. We compared the risk of acute myocardial infarction between patients with systemic sclerosis and controls and calculated the adjusted HRs for acute myocardial infarction in systemic sclerosis patients taking immunosuppressors and not taking immunosuppressors. RESULTS: The incidence rates of acute myocardial infarction were 535 and 313 cases per 100,000 person-years for systemic sclerosis cohort and reference cohort, respectively (P <.001, unadjusted). After adjusting for age, sex, and underlying medical diseases on Cox proportional hazards model, systemic sclerosis was found to be an independent risk factor for acute myocardial infarction (HR 2.45). Other risk factors included hypertension (HR 2.08) and diabetes (HR 2.14). The multivariate adjusted HR for acute myocardial infarction did not decrease among the systemic sclerosis patients taking systemic steroids, penicillamine, cyclophosphamide, azathioprine, methotrexate, or cyclosporine. CONCLUSION: Systemic sclerosis is independently associated with an increased risk of acute myocardial infarction. Immunosuppressors do not lower the risk of acute myocardial infarction in our study.

Comprehensive transcriptional profiling of human epidermis, reconstituted epidermal equivalents, and cultured keratinocytes using DNA microarray chips.

Because of its accessibility, skin has been among the first organs analyzed using DNA microarrays; psoriasis, melanomas, carcinomas, chronic wound biopsies, and epidermal keratinocytes in culture have been intensely investigated. Skin has everything: stem cells, differentiation, signaling, inflammation, diseases, cancer, etc. Here we provide step-by-step instructions for bioinformatics analysis of transcriptional profiling of skin. Specifically, we describe the use of GCOS and RMA programs for initial normalization and selection of differentially expressed genes, DAVID and LOLA programs for annotation of genes, and statistically relevant identification of over- and under-represented functional and biological categories in identified gene sets, L2L and Venn diagrams for comparing multiple lists of genes, and oPOSSUM for identification of statistically over-represented transcription factor binding sites in the promoter regions of gene sets. The work can be a primer for researchers embarking on skinomics, the comprehensive analysis of transcriptional changes in the skin.