Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals ...involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell-mediated cytotoxicity that does not require direct cellular contact.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening ...adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs.
We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids.
Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN.
The anti-TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs.
ClinicalTrials.gov NCT01276314.
Ministry of Science and Technology of Taiwan.
Specific ethnic genetic backgrounds are associated with the risk of Stevens–Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, ...multiple‐country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998–2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX‐II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta‐lactam antibiotics, quinolones were also a common cause. Only one acetaminophen‐induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.
Abstract Background Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine ...(CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Objective To carry out a comprehensive analysis on the clinical spectrum and HLA genotype–phenotype correlations in CBZ-induced hypersensitivity reactions. Methods We analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects. Results CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc = 5.8 × 10−43 ; odds ratio (OR) (95% CI) = 97.6(42.0–226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc = 8.3 × 10−5 ; OR (95% CI) = 0.22(0.1–0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02 , but linked to HLA-A*31:01 (Pc = 2.7 × 10−3 ; OR (95% CI) = 6.86(2.4–19.9), and HLA-B*51:01 (Pc = 0.01; OR (95% CI) = 4.56(2.0–10.5)). No gene dosage or CBZ dosage effects was observed. Conclusion This study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype–phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.
OBJECTIVE:To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in ...Asian populations (Chinese and Thai).
METHODS:We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)–induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database.
RESULTS:We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10; odds ratio 27.90; 95% confidence interval CI 7.84–99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077–0.584).
CONCLUSIONS:Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.
Travel time is a fundamental measure in transportation. Accurate travel-time prediction also is crucial to the development of intelligent transportation systems and advanced traveler information ...systems. We apply support vector regression (SVR) for travel-time prediction and compare its results to other baseline travel-time prediction methods using real highway traffic data. Since support vector machines have greater generalization ability and guarantee global minima for given training data, it is believed that SVR will perform well for time series analysis. Compared to other baseline predictors, our results show that the SVR predictor can significantly reduce both relative mean errors and root-mean-squared errors of predicted travel times. We demonstrate the feasibility of applying SVR in travel-time prediction and prove that SVR is applicable and performs well for traffic data analysis.
IMPORTANCE: The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with ...eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. OBJECTIVE: To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. MAIN OUTCOMES AND MEASURES: Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. RESULTS: The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10−17). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. CONCLUSIONS AND RELEVANCE: This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.
Few previous studies have established Snaith-Hamilton Pleasure Scale (SHAPS) cut-off values using receiver operating characteristic curve analysis and applied these values to compare predictors of ...anhedonia between clinical and nonclinical groups.
To determine the optimal cut-off values for the SHAPS and use them to identify predictors of anhedonia in clinical and nonclinical groups in Taiwan.
This cross-sectional and correlational study used convenience sampling to recruit 160 patients from three hospitals and 412 students from two universities in northern Taiwan. Data analysis included receiver operating characteristic curve, univariate and multivariate analyses.
The optimal SHAPS cut-off values were 29.5 and 23.5 for the clinical and nonclinical groups, respectively. Moreover, two-stage analysis revealed that participants in the clinical group who perceived themselves as nondepressed, and participants in the nonclinical group who did not skip classes and whose fathers exhibited higher levels of care and protection were less likely to attain the cut-off values. Conversely, participants in the nonclinical group who reported lower academic satisfaction and were unwilling to seek help from family or friends were more likely to attain the cut-off values.
Our findings highlight the importance of optimal cut-off values in screening for depression risk within clinical and nonclinical groups. Accordingly, the development of comprehensive, individualised programmes to monitor variation trends in SHAPS scores and relevant predictors of anhedonia across different target populations is crucial.
A novel coral-like perovskite nanostructured layer was grown on a compact perovskite foundation layer by the facile surface modification with dimethylformamide/isopropanol (DMF/IPA) as co-solvent. ...Surface morphological characterizations with SEM and XRD analyses revealed a growing mechanism of the new morphology, which was composed of the perovskite decomposition and recrystallization, excessive-PbI2 extraction, and sequential formation of coral-like nanostructured perovskite layer. The coral-like perovskite nanostructures resulted in significant light scattering, enhancing the light-harvesting efficiency, and thus augmenting the photocurrent density. Moreover, the geometric configuration of the perovksite solar cells was changed from planar to bulk heterojunction, which results in the acceleration of charge separation and extraction due to the high surface area at the interface between the obtained perovskite and hole-transport layers. The optimal perovskite solar cell exhibited an impressive power conversion efficiency (PCE) of 19.47%, as compared to that of the pristine cell (17.19%).
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•The novel coral-like perovskite nanostructures were first introduced into PSCs.•The growing mechanism of the coral-like perovskite nanostructures was proposed.•The light harvesting efficiency was improved due to the coral-like nanostructures.•The coral-like nanostructures resulted in an accelerated charge extraction.•PSCs with coral-like perovskite nanostructures shows a high efficiency of 19.47%.
In order to optimize the working electrode for dye-sensitized solar cells (DSSCs), three kinds of stacked-film structures with the same overall thickness of 13 μ m were prepared by using spray ...coating system, including pure TiO 2 film, TiO 2 -Graphene (TG) film and TiO 2 /TG (TTG) bilayer film. To increase light path and excite more dye molecules, the bilayer structure of TTG film is composed with TiO 2 main layer and TG scattering layer, which provide pores to adsorb N719 dye molecules. The DSSCs with pure TiO 2 , TG, and TTG working electrodes exhibit the efficiencies of 3.07%, 2.48%, and 4.49%, respectively. From the results, the DSSCs with TG film working electrode had the lowest efficiency, because the TG film had the defects which led to higher interfacial charges than the pure TiO 2 . Moreover, TTG working electrode contained a TiO 2 main layer and a TG scattering layer in which the graphene material could increase the electron transport and reduce the recombination, and it was also due to the stacked structure, which could improve the light utilization and enhance the light transmitting distance. In this article, the working electrode of DSSCs was successfully modified by using TTG stacked structure with an improved efficiency of 46.25% higher than that of TiO 2 working electrode.
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