Sensory neuroimmune signaling in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN).

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions often triggered by medications. While the involvement of CD8+ T cells causing keratinocyte death is well recognized, the contribution of neural elements to the persistent skin inflammation has been largely overlooked. OBJECTIVE: To investigate the potential neuroimmune regulation in SJS/TEN. METHODS: Unbiased single-cell RNA sequencing and flow cytometry were performed using circulating CD8+ T cells from healthy controls and patients with SJS/TEN. ELISA and LEGENDplex assays were respectively used to detect neuropeptides and inflammatory mediators. Skin tissues were examined by immunofluorescence staining for neuropeptide-associated nerves and cytokine receptors. Calcium imaging, Smart-seq, and a 3D skin model were employed for cultured human CD8+ T cells. RESULTS: The unbiased RNA-sequencing revealed an upregulation of the receptor for neuropeptide calcitonin gene-related peptide (CGRP), known as RAMP1, in effector CD8+ T cells in SJS/TEN. Increased CGRP+ nerve fibers and CGRP levels, along with upregulated IL-15R and IL-18R on CD8+ T cells, were displayed in the affected skin of SJS/TEN. The CGRP-RAMP1 axis was necessary and sufficient to enhance receptors for IL-15 and IL-18 and cytotoxic activities in CD8+ T cells, ultimately resulting in keratinocyte apoptosis. Calcium influx was detected in CGRP-stimulated CD8+ T cells. HCN2, a hyperpolarization-activated cation channel, was required for this process and the subsequent cytotoxic effects. CONCLUSIONS: Our study highlights the role of neural elements in regulating CD8+ T cell-mediated inflammatory responses and provides new potential translational targets to improve the outcomes of severe cutaneous drug reactions.

Kinetics of Metastable Argon Optical Excitation and Gain in Ar/He Microplasmas.

The optically pumped rare-gas metastable laser is capable of high-intensity lasing on a broad range of near-infrared transitions for excited-state rare gas atoms (Ar*, Kr*, Ne*, Xe*) diluted in flowing He. The lasing action is generated by photoexcitation of the metastable atom to an upper state, followed by collisional energy transfer with He to a neighboring state and lasing back to the metastable state. The metastables are generated in a high-efficiency electric discharge at pressures of ∼0.4 to 1 atm. The diode-pumped rare-gas laser (DPRGL) is a chemically inert analogue to diode-pumped alkali laser (DPAL) systems, with similar optical and power scaling characteristics for high-energy laser applications. We used a continuous-wave linear microplasma array in Ar/He mixtures to produce Ar(1s5) (Paschen notation) metastables at number densities exceeding 1013 cm-3. The gain medium was optically pumped by both a narrow-line 1 W titanium-sapphire laser and a 30 W diode laser. Tunable diode laser absorption and gain spectroscopy determined Ar(1s5) number densities and small-signal gains up to ∼2.5 cm-1. Continuous-wave lasing was observed using the diode pump laser. The results were analyzed with a steady-state kinetics model relating the gain and the Ar(1s5) number density.

Efficacy and associated neurotransmitters of digital cognitive behavior therapy for atopic dermatitis: A comparative effectiveness research.

BACKGROUND: Negative emotions are a major comorbidity of atopic dermatitis (AD). Evidence that supports the effectiveness of digital cognitive behavioral therapy (dCBT) as an adjuvant therapy for AD remains limited. OBJECTIVE: To investigate the preliminary efficacy of additional dCBT and potential neurotransmitter biomarkers for AD accompanied by negative emotions. METHODS: Thirty-two patients with AD were recruited and examined for clinical severity and negative emotions including insomnia, anxiety, and depression. Patients with mild-to-moderate negative emotions were divided into two groups that received standard care (N = 9) or mobile app-delivered CBT plus standard care (N = 11) for 12 weeks. Plasma levels of 40 neurotransmitters were determined using liquid chromatography tandem mass spectrometry pre- and post-treatment. RESULTS: Skin lesions, itch, and insomnia were significantly improved in both treatment groups. Improvements of itch (P = 0.0449) and insomnia (P = 0.0089) were more robust in the combination treatment group than those in the standard treatment group. Neurotransmitters that involve tryptophan, dopamine, and histidine pathways were markedly altered in patients with AD compared with healthy controls. Taurine levels were selectively increased following dCBT plus standard care (P = 0.0259). Baseline levels of L-tyrosine were negatively correlated with the reduction of skin lesions (r = -0.9073, P = 0.0334) and itch intensity (r = -0.9322, P = 0.0210) in the combination therapy group. CONCLUSIONS: dCBT provides an efficacious supplementary approach for AD accompanied by negative emotions. Emotion-related neurotransmitters may contribute to AD and serve as indicators for treatment effects.

Inhibition of tumor necrosis factor improves conventional steroid therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis in a cohort of patients.

BACKGROUND: Systemic steroid therapies for Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been challenged because of their limited benefits. Whether additional tumor necrosis factor (TNF) α inhibition provides an optimized approach remains unexplored. OBJECTIVE: To investigate the efficacy of TNF-α inhibition combined with a steroid to treat SJS/TEN and to identify potential biomarkers. METHODS: Twenty-five patients with SJS/TEN were recruited and divided into 2 groups: 10 patients received methylprednisolone and 15 patients received etanercept plus methylprednisolone. Serum levels of granzyme B, perforin, interferon-γ, interleukin (IL) 6, IL-15, IL-18, macrophage inflammatory protein 1α, macrophage inflammatory protein 1ß, and TNF-α were measured by multiplex cytokine analysis kits during the acute and resolution phases. RESULTS: Compared with the steroid monotherapy, the combination therapy significantly shortened the course of the initial steroid treatment and the duration of the acute stage, hospitalization stay, and skin re-epithelialization. Although both therapies significantly reduced IL-15 levels; the combination therapy also decreased IL-6 and IL-18 levels. While the level of IL-15 was positively correlated with skin re-epithelialization time in both groups, the level of IL-6 served as an additional marker for the course of the disease in the combination therapy group. LIMITATIONS: The cohort size is relatively small. CONCLUSION: Additional TNF-α inhibition to steroid treatment appeared to improve outcomes for SJS/TEN.

Acute pancreatic injuries: A complication of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with cytotoxic immunocell activation.

BACKGROUND: Complications involving internal organs are usually present in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, pancreatic complications are rarely reported and studied. OBJECTIVE: To summarize clinical characteristics of SJS/TEN-associated acute pancreatic injuries and to investigate underlying inflammatory mechanisms. METHODS: Clinical records of 124 inpatients with SJS/TEN were reviewed. Serum levels of tumor necrosis factor α, interleukin (IL) 6, IL-18, IL-15, IL-12p70, and soluble CD56 were determined in 18 healthy donors and 17 patients with SJS/TEN, including 3 with acute pancreatic injuries. RESULTS: Acute pancreatic injury was diagnosed in 7.3% of patients (9/124) in the SJS/TEN cohort. Elevation of serum transaminase level and hypoalbuminemia occurred more frequently in patients with acute pancreatic injuries compared with those without pancreatic symptoms (P = .004 and <.001, respectively). Although acute pancreatic injury did not alter mortality rate of SJS/TEN, it was associated with longer hospitalization stays (P = .008). Within the serum cytokines whose levels were elevated in SJS/TEN, only IL-18 was found to be selectively increased in patients with acute pancreatic injuries compared with those without them (P = .03). LIMITATIONS: Cohort was small. CONCLUSION: Acute pancreatic injury is a gastrointestinal complication of SJS/TEN in which hepatotoxicity is more likely to occur. Overexpression of IL-18 might be involved in this unique entity.

Electronic Spectroscopy and Photoionization of LiMg.

Dimers consisting of an alkali metal bound to an alkaline earth metal are of interest from the perspectives of their bonding characteristics and their potential for being laser cooled to ultracold temperatures. There have been experimental and theoretical studies of many of these species, but spectroscopic data for LiMg and the LiMg+ cation are sparse. In this study, rotationally resolved electronic spectra for LiMg are presented. The ground state is confirmed to be X12Σ+ and observations of low-lying electronically excited states are reported for the first time. Reexamination of transitions in the near-UV spectral range indicates that previous band assignments should be revised. Two-color laser excitation techniques were used to determine an ionization energy of 4.7695(4) eV. This value is 1.2 eV below the previously reported experimental estimate. Vibrationally resolved spectra were obtained for LiMg+, yielding molecular constants that were consistent with a substantial strengthening of the bond on ionization.

Electronic Spectroscopy and Photoionization of LiBe.

LiBe has been the subject of several theoretical investigations and one spectroscopic study. Initially, these efforts were motivated by interest in the intermetallic bond. More recent work has explored the potential for producing LiBe and LiBe+ at ultracold temperatures. In the present study, we have advanced the spectroscopic characterization of several electronic states of LiBe and the ground state of LiBe+. For the neutral molecule, the 12Π, 22Σ+, 32Σ+, and 42Π(3d) states were observed for the first time. Data for the 22Σ+-X2Σ+ transition support a theoretical prediction that this band system is suitable for direct laser cooling. Photoelectron spectroscopy has been used to determine the ionization energy of LiBe and map the low-energy vibrational levels of LiBe+ X1Σ+. Overall, the results validate the predictions of high-level quantum chemistry calculations for both LiBe and LiBe+.

Clinical and pathological findings of chronic actinic dermatitis.

BACKGROUND: Chronic actinic dermatitis (CAD) is a recurrent photosensitive disease occurs predominantly in elderly men on sun-exposed areas, which seriously affect the patient's life quality. The etiology of CAD remains unknown. METHODS: Sixty-six CAD patients, 66 atopic dermatitis (AD) patients, and 46 healthy people were enrolled into this study. Patient-level data were obtained from the electronic medical record and laboratory databases. We also obtained 29 tissue samples including 16 lichenoid lesions, 7 minimal erythematous dose (MED) analysis induced lesions, and 6 normal skin samples. Histopathologic and immunohistochemical analysis were performed. RESULTS: In the clinical characteristics, albumin was lower and uric acid was higher significantly in patients diagnosed as CAD. The infection rate of CAD patient after skin biopsy was considerably high (23.3%). The serum allergen test was prone to be negative in CAD patients. Lymphocytes were the dominate infiltrating cells in early and late CAD lesions, while more CD4+, CD8+, CD69+, and CD103 + cells were found in the late lesions. There is no difference in CD4+/CD8 + ratio and CD69+/CD103 + ratio among groups. More mast cells were observed in the early-stage lesions, and more dendritic cell was observed in the late-stage lesions. CONCLUSIONS: CAD patients have certain oxidative stress and are prone to be infected after skin biopsy. Serum allergen detection is of little significance for CAD diagnosis. Mast cells may be involved in the early process of CAD, while dendritic cells and tissue-resident memory T cell (TRM) may be related to the chronic process of the disease.

Primary Eccrine Porocarcinoma of the Thumb With Metastasis: A Rare Case Report and Literature Review.

ABSTRACT: Eccrine porocarcinoma (EPC) is a rare malignant sweat gland tumor that accounts for approximately 0.005% of all cutaneous carcinomas. It favors the lower extremities. Only 3% of EPCs are on the hand, and only 6 cases occurring specifically on fingers have been previously documented. However, we met a patient with EPC presenting the primary lesion on the left thumb and an extensive cutaneous metastasis on the left forearm. Pathologic findings of axillary lymph nodes confirmed lymphatic metastasis.

Vacuum-Assisted Closure and Skin Grafting Combined with Amphotericin B for Successful Treatment of an Immunocompromised Patient with Cutaneous Mucormycosis Caused by Mucor irregularis: A Case Report and Literature Review.

Cutaneous mucormycosis caused by Mucor irregularis (M. irregularis) is a rare condition that typically occurs in immunocompetent patients. Herein, we describe an immunocompromised patient with cutaneous M. irregularis infection who was successfully treated with debridement combined with vacuum assisted closure (VAC) negative pressure technique and split-thickness skin grafting. We present this case owing to its complexity and rarity and the successful treatment with surgical therapy. A 58-year-old man presented to our hospital with a history of skin ulcers and eschar on the right lower leg since two months. He had been receiving methylprednisolone therapy for bullous pemphigoid that occurred five months prior to the present lesions. Histopathological examination of a right leg lesion showed broad, branching hyphae in the dermis. Fungal culture and subsequent molecular cytogenetic analysis identified the pathogen as M. irregularis. After admission, methylprednisolone was gradually tapered and systemic treatment with amphotericin B (total dose 615 mg) initiated along with others supportive therapies. However, the ulcers showed no improvement, and amphotericin B had to be discontinued owing to development of renal dysfunction. After extensive surgical debridement combined with VAC and skin grafting, his skin ulcers were healed; subsequent fungal cultures of the lesions were negative. The patient exhibited no signs of recurrence at 36-month follow-up. Twenty-six cases with M. irregularis-associated cutaneous mucormycosis in literature were reviewed.

Time-dependent simulations of a CW pumped, pulsed DC discharge Ar metastable laser system.

Optically pumped rare gas lasers have the potential for scaling to output powers above the kW level. In these devices, electrical discharges through He/Rg mixtures (Rg = Ne, Ar, Kr and Xe) are used to generate metastable Rg atoms in the 1s5 state. Optical pumping to the 2p9 level, followed by collisional relaxation to 2p10, is then used to produce lasing on the 2p10-1s5 transition. Several computational models have been developed to analyze CW systems using steady-state approximations for the discharge excitation, optical pumping and lasing processes. However, recent experiments show that repetitively pulsed discharges have advantages for producing larger volume, high-pressure discharges. Here we present dynamic simulations of a CW laser that uses pulsed-discharge production of Ar metastables. Time-dependent equations are solved for both the discharge and lasing process. Two models are investigated. The first considers the conditions within the lasing medium to be spatially uniform (zero-dimensional model). The second allows for spatial variations along the lasing axis (one-dimensional model). The models were evaluated by simulating the performance characteristics of an experimentally demonstrated system that provides time-averaged output energies in the range of 3-4 W. Time-dependent species densities, laser power and longitudinal spatial distributions are presented.

Demonstration of a quasi-CW diode-pumped metastable xenon laser.

In this work, we present the first demonstration of a quasi-continuous-wave diode-pumped metastable xenon laser at atmospheric pressures. Lasing in metastable noble gas species has received increased attention in the last few years as a possible high-power laser source. This demonstration shows that metastable xenon has a sufficiently broad absorption spectrum to be pumped with a broad-bandwidth diode laser. This implies that a high-power metastable xenon gas laser should be achievable using high-power pump diodes.

Human Cutaneous Protothecosis: A Case Report and Review of Cases from Mainland China, Hong Kong, and Taiwan.

We present a case of cutaneous protothecosis caused by Prototheca wickerhamii infection. The patient was a 72-year-old man with hypoalbuminemia. He responded well to fluconazole treatment. We reviewed this case along with 17 other cases of cutaneous protothecosis reported from mainland China, Hong Kong, and Taiwan. Of the 18 cases, 7 each occurred in mainland China and Taiwan, and 4 occurred in Hong Kong. Thirteen cases were caused by P. wickerhamii (72.2%), and three were caused by P. zopfii (16.7%); in two cases, the species was not identified (11.1%). In all, 9 (50%) patients were immunocompromised, and 10 (55.5%) patients denied having a history of trauma. All patients presented with polymorphic skin lesions, and erythematous papules, plaques, or nodules was the most common presentation (15/18, 83.3%). Genotyping was performed in five cases, mostly by means of small subunit ribosomal DNA amplification (four cases). Susceptibility tests (6 patients) showed that P. wickerhamii was sensitive to amphotericin B and voriconazole but resistant to fluconazole or itraconazole. Treatment succeeded in 15 (83.3%) patients and failed in 3 (16.7%). Our data indicate that the number of cutaneous protothecosis cases is underestimated in China, and the skin lesions have some diagnostic value.

Common and uncommon adverse cutaneous reactions to erlotinib: a study of 20 Chinese patients with cancer.

OBJECTIVE: This study presented common lesions with systemic toxicities and uncommon adverse cutaneous reactions such as anaphylactic dermatitis in patients undergoing treatment with erlotinib for the benefit of practicing dermatologists and oncologists. METHODS: Adverse cutaneous reactions associated with erlotinib were reported in 20 Chinese patients with cancer. RESULTS: Adverse cutaneous reactions reported included six cases of anaphylactic dermatitis, 12 cases of acneiform rash, nine cases of xerosis, five cases of nail changes and four cases of hair changes. One case of anaphylactic dermatitis manifested as erythema with swelling on the face and neck, and others as erosive and scaly erythema on the fold of skin, or red macules, papules, plaques and pigmentation on the whole body. Clinical details indicated anaphylactic reactions, including a high percentage of eosinophils in the peripheral blood, eosinophilic infiltration in the dermis layer and good response to antihistamines and topical steroids. Systemic toxicities accompanied by cutaneous reactions occurred in five patients including one case of anaphylactic dermatitis and four cases of acneiform rash. Elevated hepatic enzymes were observed among all the patients with grade-3 or grade-4 acneiform rashes. One patient with anaphylactic dermatitis and one with acneiform rash discontinued erlotinib administration due to severe lesions, high fever or severe elevation of hepatic enzymes. CONCLUSIONS: Anaphylactic cutaneous reactions caused by erlotinib are rarely described hitherto. Systemic toxicities should be emphasized especially in cases with severe skin disorders. Timely detection and appropriate early intervention in patients who develop severe cutaneous reaction while on erlotinib therapy should be considered clinically.

Kinetics of optically pumped Kr metastables.

Optically-pumped atomic gas lasers that utilize metastable excited states of rare gas atoms (Rg(*)) have been demonstrated using both pulsed and CW pump sources. These devices resemble diode-pumped alkali vapor lasers, but have the advantage of using a chemically inert lasing medium. Collisional energy transfer is needed to sustain a population inversion, and He is used as the transfer agent. Consequently, values for the Kr(*)+He state-to-state energy transfer rate constants are needed for the analysis and prediction of laser performance characteristics. In the present study, we report He energy transfer rate constants for Kr(*) in the 5p[5/2](2), 5p[5/2](3), 5p[1/2](1), and 5s[3/2](1) states.

Persistent and acute chlamydial infections induce different structural changes in the Golgi apparatus.

Chlamydia trachomatis causes a wide range of diseases that have a significant impact on public health. Acute chlamydial infections can cause fragmentation of the Golgi compartment ensuring the lipid transportation from the host cell. However, the changes that occur in the host cell Golgi apparatus after persistent infections are unclear. Here, we examined Golgi-associated gene (golga5) transcription and expression along with the structure of the Golgi apparatus in cells persistently infected with Chlamydia trachomatis. The results showed that persistent infections caused little fragmentation of the Golgi. The results also revealed that Golgi fragmentation might be associated with the suppression of transcription of the gene golga5.

Kinetics of optically pumped Ar metastables.

Optically pumped lasers that use metastable excited states of Ar have been demonstrated using both pulsed and CW excitation. In terms of Paschen labeling of the states of Ar, the laser system uses excitation of the 2p9-1s5 transition, and lases on the 2p10-1s5 line. Collisional transfer of population from 2p9 to 2p10 is achieved using He as the buffer gas. For the purpose of modeling and developing this laser, rate constants for state-to-state transfer in Ar(2p(i))+Ar/He mixtures are needed. As the 2p10 level can radiate down to 1s4, this lower level also plays a significant role in the laser kinetics. Consequently, rate constants for the relaxation of 1s4 by Ar and He are also required. In the present study we have used pulsed laser excitation techniques to measure rate constants of relevance to the optically pumped metastable Ar laser.

Toxic epidermal necrolysis complicated with primary cutaneous aspergillosis: A report of four cases.

Primary cutaneous aspergillosis (PCA) is a rare opportunistic infection caused by Aspergillus that can be life-threatening. PCA is mainly reported in immunocompromised hosts such as patients with AIDS, those with hematologic malignancy, or infants with occlusive dressings. However, no study has previously reported PCA associated with toxic epidermal necrolysis (TEN). This study reports four cases of TEN complicated with PCA, presenting with discrete gray or black spots over newly formed epithelia. Risk factors of PCA in patients with TEN include host factors, iatrogenic factors, indoor environment, and wound care. Two of the four cases eventually died, highlighting the importance of further exploring PCA in patients with TEN.

Case report: Rubella virus-associated cutaneous granuloma in an adult with TAP1 deficiency.

Rubella virus-associated granulomas commonly occur in immunocompromised individuals, exhibiting a diverse range of clinical presentations. These manifestations can vary from predominantly superficial cutaneous plaques or nonulcerative nodules to more severe deep ulcerative lesions, often accompanied by extensive necrosis and significant tissue destruction. TAP1 deficiency, an exceedingly rare primary immune-deficiency disorder, presents with severe chronic sino-pulmonary infection and cutaneous granulomas. This report highlights the occurrence of rubella virus-associated cutaneous granulomas in patients with TAP1 deficiency. Notably, the pathogenic mutation responsible for TAP1 deficiency stems from a novel genetic alteration that has not been previously reported. This novel observation holds potential significance for the field of diagnosis and investigative efforts in the context of immunodeficiency disorders.