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Background Previous population-based studies in western countries had revealed increased skin cancer risk among transplant recipients compared to the general population. However, population-based studies in Asia on skin cancer among recipients of different transplanted organs were lacking in the literature. Aims This study aims to estimate skin cancer risk among recipients in Taiwan, examine the association between each specific type of skin cancer and each type of transplanted organ, and compare skin cancer risk between different immunosuppressive regimens. Methods This population-based retrospective cohort study identified 7550 patients with heart, lung, kidney or liver transplantation and 30,200 controls matched for gender, age and comorbidity index from the National Health Insurance Research Database in Taiwan between 2000 and 2015. Using multivariable Cox proportional hazard models, we estimated the hazard ratios and 95% confidence intervals for the correlation of skin cancer with organ transplantation as well as immunosuppressive regimen. Results Organ transplant recipients in Taiwan had an increased risk of skin cancer with adjusted hazard ratios of 4.327 (95% confidence intervals 2.740-6.837, P < 0.001), with the greatest risk, observed among heart recipients (adjusted hazard ratios 6.348, 95% confidence intervals 3.080-13.088, P < 0.001). The risk of non-melanoma skin cancer and melanoma was 4.473 (95% confidence intervals 2.568-7.783, P < 0.001) and 3.324 (95% confidence intervals 1.300-8.172, P < 0.001), respectively. When comparing immunosuppressants, those with calcineurin inhibitors carried the highest risk of skin cancer (adjusted hazard ratios 4.789, 95% confidence intervals 3.033-7.569, P < 0.001), followed by those with antimetabolites (adjusted hazard ratios 4.771, 95% confidence intervals 3.025-7.541, P < 0.001). Limitations We could not evaluate confounding behavioural risk factors of skin cancers that were not documented in the database, nor could we recognize patients’ compliance with immunosuppressants. Conclusion Organ recipients have a greater risk of skin cancer. Clinicians should inform recipients of the importance of photoprotection and regular dermatologic follow-up.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse reactions to drugs and psychological sequelae are also observed to follow the trauma of widespread epidermal necrolysis. To delineate the association between SJS and TEN, and psychiatric disorders, we conducted a retrospective population-based cohort study by including 212 patients diagnosed with first-time SJS or TEN in Taiwan between 2000 and 2013 and 669 population controls. Adjusted hazard ratios were calculated after adjusting for sex, age, comorbidity in the form of Charlson comorbidity index, and facility level of care. Overall, SJS or TEN was associated with an increased risk of developing psychiatric disorders including schizophrenia, major depressive disorder, mania, anxiety, and bipolar with an adjusted hazard ratio of 1.392 (95% CI, 1.192-1.625; p 0.001). Particularly, the adjusted hazard ratios of psychiatric disorders were 1.290 (95% CI, 1.105-1.506; p 0.001) for SJS and 1.855 (95% CI, 1.587-2.167; p 0.001) for TEN.

Orchestrated control of multiple overlapping and sequential processes is required for the maintenance of epidermal homeostasis and the response to and recovery from a variety of skin insults. Previous studies indicate that membrane-associated serine protease matriptase and prostasin play essential roles in epidermal development, differentiation, and barrier formation. The control of proteolysis is a highly regulated process, which depends not only on gene expression but also on zymogen activation and the balance between protease and protease inhibitor. Subcellular localization can affect the accessibility of protease inhibitors to proteases and, thus, also represents an integral component of the control of proteolysis. To understand how membrane-associated proteolysis is regulated in human skin, these key aspects of matriptase and prostasin were determined in normal and injured human skin by immunohistochemistry. This staining shows that matriptase is expressed predominantly in the zymogen form at the periphery of basal and spinous keratinocytes, and prostasin appears to be constitutively activated at high levels in polarized organelle-like structures of the granular keratinocytes in the adjacent quiescent skin. The membrane-associated proteolysis appears to be elevated via an increase in matriptase zymogen activation and prostasin protein expression in areas of skin recovering from epidermal insults. There was no noticeable change observed in other regulatory aspects, including the expression and tissue distribution of their cognate inhibitors HAI-1 and HAI-2. This study reveals that the membrane-associated proteolysis may be a critical epidermal mechanism involved in responding to, and recovering from, damage to human skin.

Genital warts are a common sexually transmitted disease caused by human papillomavirus (HPV) infections. The prevalence of dementia is 4-8% in those aged 65 years or older in Taiwanese community studies, with a high social and economic burden for patients, family caregivers, the community and society. Previous studies have shown that viral infections such as herpes simplex and herpes zoster were associated with dementia. This study aimed to investigate the association between dementia and HPV infections. A population-based cohort study using data from Taiwan's National Health Insurance Research Database was conducted. Fine and Grays's survival analysis was employed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between genital warts and dementia. From all of the potential participants aged 50 years or more, a total of 16 116 patients were enrolled, including 4029 genital warts-infected patients, with 12 087 sex-, age- and indexed date-matched controls (1:3). The cumulative incidences of dementia were 10.72 per 103 person-years and 6.43 per 103 person-years in the genital warts and control group, respectively. There were 475 dementia cases from the genital warts cohort during the follow-up period of 15 years. The adjusted HR for dementia was 1.485 (95% CI, 1.321-1.668; P

Recent studies revealed the risk of bullous pemphigoid (BP) in patients with diabetes mellitus (DM) taking dipeptidyl peptidase 4 (DPP-4) inhibitors. To clarify the relationship between taking DPP-4 inhibitors and the risk of BP among patients with DM, we conducted a cohort study by using the National Health Insurance Research Database of Taiwan from 1 January 2009 to 31 December 2015. We identified 6340 patients with DM taking DPP-4 inhibitors and 25 360 DM patients who had not taken DPP-4 inhibitors during the 7-year follow-up period. Compared with the non-DPP-4 inhibitor group, patients taking DDP-4 inhibitors had a higher risk of BP (adjusted hazard ratio [aHR], 2.382; 95% confidence interval (CI), 1.163-4.883; P = 0.017]. Among the DPP-4 inhibitors available in Taiwan, vildagliptin showed the highest risk of BP (aHR, 2.849; 95% CI, 1.893-4.215; P < 0.001), followed by saxagliptin (aHR, 2.657; 95% CI, 1.770-3.934; P < 0.001). Subgroup analysis revealed that the higher risk of BP was observed in patients older than 65 years (aHR, 2.403; 95% CI, 1.590-3.627; P < 0.001). This study revealed that treatment with DPP-4 inhibitors, especially vildagliptin, was significantly associated with an increased risk of BP among DM patients.

Rosacea has been reported to be associated with psychiatric disorders. Nevertheless, a nationwide study of the relationship between rosacea and comorbid psychiatric diseases in an Asian population has not been conducted. The aim of this study was to clarify the role of rosacea in the various psychiatric disorders by using a nationwide database in Taiwan. Data were obtained from the National Health Insurance Research Database of Taiwan from 2000 to 2013. In total, 7881 patients with rosacea and 31 524 age- and sex-matched controls were enrolled. Patients with rosacea tended to have more coexisting psychiatric disorders. After adjusting for age, sex, comorbidity and residence/regions, the adjusted hazard ratio (HR) of psychiatric disorders for patients with rosacea was 2.761 (95% CI = 2.650-2.877, P < 0.001). Among them, the highest adjusted HR are phobic disorder and obsessive-compulsive disorder of 7.841 (95% CI = 7.526-8.170, P < 0.001) and 6.389 (95% CI = 6.132-6.657, P < 0.001), respectively. The National Health Insurance Research Database of Taiwan does not include the information about rosacea subtypes, severity and laboratory parameters. In conclusion, rosacea is related to various psychiatric disorders. In addition to anxiety and depression, patients are also at increased risk of phobic disorder and obsessive-compulsive disorder.

Orchestrated control of multiple overlapping and sequential processes is required for the maintenance of epidermal homeostasis and the response to and recovery from a variety of skin insults. Previous studies indicate that membrane-associated serine protease matriptase and prostasin play essential roles in epidermal development, differentiation, and barrier formation. The control of proteolysis is a highly regulated process, which depends not only on gene expression but also on zymogen activation and the balance between protease and protease inhibitor. Subcellular localization can affect the accessibility of protease inhibitors to proteases and, thus, also represents an integral component of the control of proteolysis. To understand how membrane-associated proteolysis is regulated in human skin, these key aspects of matriptase and prostasin were determined in normal and injured human skin by immunohistochemistry. This staining shows that matriptase is expressed predominantly in the zymogen form at the periphery of basal and spinous keratinocytes, and prostasin appears to be constitutively activated at high levels in polarized organelle-like structures of the granular keratinocytes in the adjacent quiescent skin. The membrane-associated proteolysis appears to be elevated via an increase in matriptase zymogen activation and prostasin protein expression in areas of skin recovering from epidermal insults. There was no noticeable change observed in other regulatory aspects, including the expression and tissue distribution of their cognate inhibitors HAI-1 and HAI-2. This study reveals that the membrane-associated proteolysis may be a critical epidermal mechanism involved in responding to, and recovering from, damage to human skin.

A number of studies investigating mutations of genes involved in MAPK and PI3K pathways in melanoma patients have been performed, most of which were based on Caucasian populations. We sought to identify BRAF, NRAS, MEK1, PI3K, and PTEN mutations and further determine possible correlations with clinicopathological parameters in Taiwanese patients with acral, non-chronic sun damaged (NCSD), or mucosal melanoma. Forty melanocytic nevi, 24 dysplastic nevi, and 175 melanomas from Taiwanese patients were analysed for mutations in BRAF, NRAS, MEK1, PI3K, and PTEN genes by PCR and direct sequencing. Immunohistochemical analysis of the respective proteins in nevi and melanomas were also performed to determine possible clinicopathological characteristics. In addition to the classic BRAFV600E mutation, a novel BRAFV600L mutation was identified in acral and sinonasal melanomas. A significantly reduced frequency of NRAS and BRAF mutations was noted compared with Caucasian-based studies. Increased immunohistochemical scores for pan-RAS and MEK1 and less nodal metastasis were associated with enhanced survival rates in acral and NCSD melanoma patients. Our findings suggest that oncogenic events may differ among melanomas in Asian patients geographically (e.g. between Japanese and Taiwanese patients). Moreover, distinct genetic alterations were noted among acral, NCSD, and mucosal melanoma patients in our study, and the expression of biomarkers correlated with clinical survival rates differentially among the various melanoma groups.

This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan’s National Health Insurance Research Database (NHIRD). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351-2.795, P

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (CTCL); it rarely exhibits a predilection for hair follicle infiltration. We describe a patient with preferential localization of skin lesions in the head and neck region with eyelid involvement, grouped follicular papules and acneiform lesions, severe pruritus and secondary bacterial infections. The histological presentation showed folliculotropic neoplastic lymphoid cells instead of epidermotropic infiltrates. The final diagnosis was folliculotropic mycosis fungoides (FMF), a rare, more aggressive variant of CTCL. Clinical manifestations of FMF may be challenging; thus, multiple, deep biopsy containing adnexal structures, are required to make this crucial diagnosis.

// Yu-Wen Yeh 1, 2 , Ching-Chia Cheng 3, 4 , Shu-Ting Yang 4 , Chi-Feng Tseng 4 , Ting-Yu Chang 4 , Sin-Ying Tsai 5 , Earl Fu 6 , Chien-Ping Chiang 7 , Li-Chuan Liao 8 , Pei-Wen Tsai 9 , Yung-Luen Yu 5, 10, 11 , Jen-Liang Su 4, 5, 10, 11 1 Division of Dermatology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 10581, Taiwan 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan 3 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan 4 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan 5 Department of Biotechnology, Asia University, Taichung 41354, Taiwan 6 Department of Periodontology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan 7 Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan 8 Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu 30062, Taiwan 9 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan 10 Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan 11 Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan Correspondence to: Jen-Liang Su, email: jlsu@nhri.org.tw Yung-Luen Yu, email: ylyu@mail.cmu.edu.tw Keywords: VEGF-C, YAP1, metastasis, cancer stemness, skin cancer Received: August 08, 2016 Accepted: November 07, 2016 Published: November 25, 2016 ABSTRACT Vascular endothelial growth factor-C (VEGF-C) has been implicated in epithelial-mesenchymal transition (EMT) processes and various human cancers, including skin cancer. Skin cancer is an aggressive human malignancy with increasing incidence worldwide; however, the underlying mechanisms involved in VEGF-C-induced skin cancer stemness and metastasis remain unclear. Here, we report that VEGF-C enhances skin cancer migration, invasion and stemness through Slug up-regulation. Oncomine database analysis indicated that the KRAS/MAPK (mitogen-activated protein kinases) pathway and YAP1 (yes-associated protein 1) expression are positively correlated with metastatic skin cancer. We show that VEGF-C triggers the activation of KRAS/MAPK signaling to increase YAP1 and downstream Slug expression, which are suppressed by an anti-VEGFR3 (VEGF receptor 3) peptide, a specific peptide targeting VEGFR3. The VEGF-C-induced migration, invasion and stemness of skin cancer cells are also abrogated by the anti-VEGFR3 peptide. Based on these data, we reveal the role of the VEGF-C/VEGFR3-mediated KRAS/MAPK-YAP1/Slug pathway in skin cancer progression and propose that the VEGF-C/VEGFR3 axis is a promising target for the anti-VEGFR3 peptide.

Alcohol dehydrogenase (ADH) is the principal enzyme responsible for metabolism of ethanol. Human ADH constitutes a complex isozyme family with striking variations in kinetic function and tissue distribution. Liver and gastrointestinal tract are the major sites for first-pass metabolism (FPM). Their relative contributions to alcohol FPM and degrees of the inhibitions by aspirin and its metabolite salicylate, acetaminophen and cimetidine remain controversial. To address this issue, mathematical organ modeling of ethanol-oxidizing activities in target tissues and that of the ethanol–drug interactions were constructed by linear combination of the corresponding numerical rate equations of tissue constituent ADH isozymes with the documented isozyme protein contents, kinetic parameters for ethanol oxidation and the drug inhibitions of ADH isozymes/allozymes that were determined in 0.1 M sodium phosphate at pH 7.5 and 25 °C containing 0.5 mM NAD+. The organ simulations reveal that the ADH activities in mucosae of the stomach, duodenum and jejunum with ADH1C*1/*1 genotype are less than 1%, respectively, that of the ADH1B*1/*1–ADH1C*1/*1 liver at 1–200 mM ethanol, indicating that liver is major site of the FPM. The apparent hepatic KM and Vmax for ethanol oxidation are simulated to be 0.093 ± 0.019 mM and 4.0 ± 0.1 mmol/min, respectively. At 95% clearance in liver, the logarithmic average sinusoidal ethanol concentration is determined to be 0.80 mM in accordance with the flow-limited gradient perfusion model. The organ simulations indicate that higher therapeutic acetaminophen (0.5 mM) inhibits 16% of ADH1B*1/*1 hepatic ADH activity at 2–20 mM ethanol and that therapeutic salicylate (1.5 mM) inhibits 30–31% of the ADH1B*2/*2 activity, suggesting potential significant inhibitions of ethanol FPM in these allelotypes. The result provides systematic evaluations and predictions by computer simulation on potential ethanol FPM in target tissues and hepatic ethanol–drug interactions in the context of tissue ADH isozymes.

Hidradenitis suppurativa (HS) has been reported to be associated with metabolic syndrome and coronary artery disease (CAD). Nevertheless, a nationwide study of this relationship in the Asian population has not been conducted. The aim of the present study was to clarify the cardiovascular disease risk factors, and the occurrence of CAD and cerebral infarction among patients with HS by using a nationwide database in Taiwan. We obtained data from the National Health Insurance Research Database of Taiwan. After adjusting for confounding factors, we used Cox proportional hazards analysis to reveal the risk of incident hypertension (HTN), diabetes mellitus (DM), dyslipidemia, CAD and cerebral infarction in HS patients. We identified 478 patients with newly diagnosed HS and 1912 patients in the control cohort during the 10-year follow-up period. Compared with the controls, HS patients had a higher risk of dyslipidemia (adjusted hazard ratio [aHR], 3.858; 95% confidence interval [CI], 2.785-5.346; P

This study aimed to evaluate the association of autoimmune bullous diseases [bullous pemphigoid (BP) and pemphigus vulgaris (PV)] with radiotherapy (RT) among patients with breast cancer from a population-based Taiwanese database. The case–control study included 365 women with BP or PV and 1460 randomly selected propensity score-matched controls without BP or PV. We compared the prevalences of prior RT and breast cancer between the cases and controls. In addition, we performed multivariable logistic regression analysis to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for developing BP or PV according to previous RT and/or breast cancer status. Among the 1825 subjects, 680 patients (37.16%) had previously undergone RT, including 196 cases (53.41%) and 484 controls (33.08%) (P

OBJECTIVE Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for the metabolism of ethanol. East Asian populations are unique in that they carry both a prevalent ADH1B*2 and a dominant-negative ALDH2*2 allele. A systematic investigation of ethanol-metabolizing activities in normal livers correlated with the corresponding functional allelic variations and protein contents of the relevant isozymes in respective enzyme families has been lacking. MATERIALS AND METHODS To obtain a reasonable sample size encompassing all possible genetic allelotypes of the ADH1B and ALDH2, 141 surgical liver specimens from adult Han Chinese were studied. Expression patterns and activities of ADH and ALDH were determined with stratification of the genetic phenotypes. Absolute protein contents as well as cellular localization of the activity and protein of ADH/ALDH isozymes were also investigated. RESULTS The activities of ADH1B*1/*2 and ADH1B*2/*2 allelic phenotypes were 5-6-fold those of the ADH1B*1/*1, suggesting that ADH1B*2 allele-encoded subunits are dominant over expression of hepatic ADH activity. The activities of the ALDH2-active phenotype were 90% higher than those of the ALDH2-inactive phenotype. Sex and age did not significantly influence the hepatic ADH and ALDH activities with specified genetic phenotypes. The isozyme protein contents were as follows in decreasing order: ADH1, ADH2, ALDH1A1, ALDH2, and ADH3. Both ADH1, but not ADH2/3, and ALDH1A1/2 showed a preferential expression in perivenular hepatocytes. CONCLUSION Functional correlations of ADH1B*2 and ALDH2*2 variant alleles in the liver provide a biochemical genetic basis suggesting their contribution toward variability in ethanol metabolism as well as susceptibility to alcoholism and alcohol-related diseases in East Asians.

Photoaging, the premature aging of skin induced by ultraviolet rays, is characterized by wrinkling, roughness, laxity, and pigmentary changes. Various natural and synthetic retinoids have been explored for the treatment of aging. Among retinoids, adapalene (Ada, 0.3%) is one of the most potent and widely used drugs to treat photoaging. However, it causes irritant reactions that limit its acceptance by patients. Several studies have shown the applicability of Lysozyme (Lys)-shelled microbubbles (MBs) for drug delivery through sonophoresis, and recently we have shown its efficiency to treat inflammatory skin disease. Here, we report the construction of novel Ada-LysMBs based on opposite electric charges for combined effects to treat photoaging. The Ada-LysMBs were self-assembled and had a mean diameter of 2857 nm. The maximum loading efficiency of Ada onto LysMBs was 13.99 ± 0.59%. An acoustic power density of 3 W/cm2 for 1 min revealing maximum penetration depth of LysMBs was optimized for further in vitro and in vivo studies of Ada-LysMBs. It was observed that in vitro Ada release from Ada-LysMBs at 6 h after ultrasound (US) treatment was more rapid at pH 7.4 (82%) than at pH 5.5 (73%). Franz diffusion experiments on isolated porcine skin indicated that US approximately doubled Ada delivery by Ada-LysMBs and Ada + LysMBs at 12 h and six-fold Lys permeation by LysMBs at 6 h, compared to these treatments alone. A 5-week in vivo study in mice identified significant wrinkle reduction in animals treated with US plus Ada-LysMBs. Our findings indicate that US may be used with Ada-LysMBs in the water phase to treat photoaging by normalizing hyperkeratinization and promoting collagen synthesis.

Secondary syphilis represents a diagnostic challenge due to its varied clinical manifestations. Co-infection with human immunodeficiency virus (HIV) adds to the diversity of the clinical presentation of syphilis. We herein report a case of secondary syphilis as an arthropod bite-like eruption in a previously undiagnosed HIV-coinfected patient. A 24-year-old homosexual male presented with multiple corticosteroid-resistant insect bite-like nodules on his trunk and bilateral arms. Skin biopsy disclosed plasma cell infiltration and positive Treponema pallidum staining. His symptoms got dramatic remission after benzathine penicillin G therapy. The presented case extends the clinical spectrum of secondary syphilis in HIV patient.