Atopic dermatitis complicated by recurrent eczema herpeticum is characterized by multiple, concurrent epidermal inflammatory endotypes.

BACKGROUND: A subgroup of atopic dermatitis (AD) patients suffer from recurrent, disseminated herpes simplex virus (HSV) skin infections, termed eczema herpeticum (EH), which can be life-threatening and contribute to AD morbidity. The pathobiology underlying ADEH is unknown. OBJECTIVE: To determine transcriptional mechanisms of skin and immune system pathobiology that underlie ADEH disease. METHODS: We performed whole transcriptome RNA-sequencing of non-lesional skin samples (epidermis, dermis) of AD patients with (ADEH + , n=15) and without (ADEH - , n=13) recurrent EH history, and healthy controls (HC, n=15). We also performed RNA-sequencing on plasmacytoid dendritic cells (pDCs) collected from these participants and infected in vitro with HSV-1. Differential expression, gene set enrichment, and endotyping analyses were performed. RESULTS: ADEH + disease was characterized by dysregulation in skin gene expression, which was limited in dermis (differentially expressed genes [DEGs]=14) and widespread in epidermis (DEGs=129). ADEH + -upregulated epidermal DEGs were enriched in type 2 cytokine (T2) ( IL4R, CCL22, CRLF2, IL7R ), interferon ( CXCL10, ICAM1, IFI44 , and IRF7) , and IL-36γ ( IL36G ) inflammatory pathway genes. At a person-level, all ADEH + participants exhibited T2 and interferon endotypes and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH - participants. ADEH + patient skin also exhibited dysregulation in epidermal differentiation complex (EDC) genes within the LCE, S100 , and SPRR families, which are involved in skin barrier function, inflammation, and antimicrobial activities. pDC transcriptional responses to HSV-1 infection were not altered by ADEH status. CONCLUSIONS: ADEH + pathobiology is characterized by a unique, multi-faceted epidermal inflammation that accompanies dysregulation in the expression of EDC genes. Key Messages: AD patients with a history of recurrent EH exhibit molecular skin pathobiology that is similar in form, but more severe in degree, than in AD patients without this complication. Non-lesional skin of ADEH + patients concurrently exhibits excessive type 2 cytokine, interferon, and IL-36γ-driven epidermal inflammation. Expression of these inflammatory skin endotypes among ADEH + patients is associated with dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity. Capsule Summary: AD patients with a history of recurrent disseminated HSV-1 skin infections form a unique molecular skin endotype group that concurrently exhibits type 2 cytokine, interferon, and IL-36γ-driven skin inflammation, accompanied by dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity.

Dupilumab Inhibits Vascular Leakage of Blood Proteins Into Atopic Dermatitis Skin.

BACKGROUND: Atopic dermatitis (AD) skin lesions are associated with oozing, bleeding, and erythema. This suggests that AD is associated with vascular changes. Dupilumab is an antibody to the alpha subunit of IL-4 receptor that demonstrates strong efficacy in the treatment of AD. IL-4 is known to reduce the permeability barrier function of vascular endothelium. OBJECTIVE: To examine the effects of dupilumab on vascular barrier function in AD skin. METHODS: Using proteomic analysis, we evaluated the plasma protein composition in skin tapes of lesional and nonlesional skin of adults and adolescents with moderate to severe AD over the course of a 16-week treatment with dupilumab and compared those with matched healthy subjects. RESULTS: At baseline, 115 plasma proteins were detected in AD skin and globally increased (1.5-fold or greater) compared with healthy skin. Functionally, these proteins included immunoglobulins, proteins involved in the coagulation process, enzymes, protease inhibitors, transport proteins, acute-phase proteins, complement proteins, and other pleiotropic proteins. Noteworthy, fibrinogens, fibronectin, and heme-binding proteins haptoglobin and hemopexin were among the top proteins originating from plasma and were increased in AD lesional versus healthy skin at baseline (P < .0001). Dupilumab treatment resulted in significantly reduced levels of plasma proteins in AD skin (P < .0001), with most dropping to levels seen in healthy skin or no longer detectable at week 16. CONCLUSIONS: Inhibition of IL-4/IL-13 action by dupilumab significantly reduces the efflux of plasma proteins into AD skin. Several of these proteins, such as fibrinogens and fibronectin, are known to enhance Staphylococcus aureus colonization and are associated with AD skin severity.

Anti-IL17A Halts the Onset of Diabetic Retinopathy in Type I and II Diabetic Mice.

There are ~463 million diabetics worldwide, and more than half have diabetic retinopathy. Yet, treatments are still lacking for non-proliferative diabetic retinopathy. We and others previously provided evidence that Interleukin-17A (IL-17A) plays a pivotal role in non-proliferative diabetic retinopathy. However, all murine studies used Type I diabetes models. Hence, it was the aim of this study to determine if IL-17A induces non-proliferative diabetic retinopathy in Type II diabetic mice, as identified for Type I diabetes. While examining the efficacy of anti-IL-17A as a potential therapeutic in a short-term Type I and a long-term Type II diabetes model; using different routes of administration of anti-IL-17A treatments. Retinal inflammation was significantly decreased (p < 0.05) after Type I-diabetic mice received 1 intravitreal injection, and Type II-diabetic mice received seven intraperitoneal injections of anti-IL-17A. Further, vascular tight junction protein Zonula Occludens-1 (ZO-1) was significantly decreased in both Type I and II diabetic mice, which was significantly increased when mice received anti-IL-17A injections (p < 0.05). Similarly, tight junction protein Occludin degradation was halted in Type II diabetic mice that received anti-IL-17A treatments. Finally, retinal capillary degeneration was halted 6 months after diabetes was confirmed in Type II-diabetic mice that received weekly intraperitoneal injections of anti-IL-17A. These findings provide evidence that IL-17A plays a pivotal role in non-proliferative diabetic retinopathy in Type II diabetic mice, and suggests that anti-IL-17A could be a good therapeutic candidate for non-proliferative diabetic retinopathy.

IL-17A Enhances Retinal Neovascularization.

Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays a pivotal role in the onset and progression of non-proliferative diabetic retinopathy in diabetic mice. Unfortunately, none of our diabetic murine models progress to proliferative diabetic retinopathy. Hence, the role of IL-17A in vascular angiogenesis, neovascularization, and the onset of proliferative diabetic retinopathy was unclear. In the current study, we determined that diabetes-mediated IL-17A enhances vascular endothelial growth factor (VEGF) production in the retina, Muller glia, and retinal endothelial cells. Further, we determined that IL-17A can initiate retinal endothelial cell proliferation and can enhance VEGF-dependent vascular angiogenesis. Finally, by utilizing the oxygen induced retinopathy model, we determined that IL-17A enhances retinal neovascularization. Collectively, the results of this study provide evidence that IL-17A plays a pivotal role in vascular proliferation in the retina. Hence, IL-17A could be a potentially novel therapeutic target for retinal neovascularization, which can cause blindness in multiple ocular diseases.

Development of the Italian version of the Consultation and Relational Empathy (CARE) measure: translation, internal reliability, and construct validity in patients undergoing rehabilitation after total hip and knee arthroplasty.

PURPOSE: To translate and cross-culturally adapt the Consultation and Relational Empathy (CARE) measure into Italian, examine its internal reliability, and construct validity in a rehabilitation setting. MATERIALS AND METHODS: The translation process consisted of two forward translations, a pre-final version, a back-translation, and a final version, in accordance with available guidelines. We administered the Italian version of the CARE measure to 101 patients hospitalised for rehabilitation after total hip or total knee arthroplasty (THA and TKA). We assessed face validity, internal reliability, and construct validity. RESULTS: Face validity was high. Patients answered all questions and the "does not apply" option was never selected. Internal reliability (Cronbach's α = 0.962) resulted in line with the original version. The exploratory factor analysis confirmed the unidimensional structure of the CARE measure with 74.82% of variance explained by the first factor. CONCLUSIONS: The Italian version of the CARE measure showed high face validity. Internal reliability and construct validity were in line with the original version in patients undergoing rehabilitation after THA and TKA.IMPLICATIONS FOR REHABILITATIONInternal reliability and construct validity of the Italian version of the CARE measure are in line with those of the original version of the CARE measure.The Italian CARE measure can be used to assess patient's perceived therapist's empathy in patients undergoing physical therapy after THA and TKA.Physiotherapists should use the CARE measure with more caution in other rehabilitative contexts.

Inhibition of CD40-TRAF6-dependent inflammatory activity halts the onset of diabetic retinopathy in streptozotocin-diabetic mice.

Diabetes initiates inflammation that can impair the retinal vasculature, and lead to diabetic retinopathy; one of the leading causes of blindness. Inflammatory pathways have been examined as potential therapeutic targets for diabetic retinopathy, but there is still a need for early-stage treatments. We hypothesized that the CD40-TNF Receptor Associated Factor 6 (TRAF6) axis plays a pivotal role in the onset of diabetic retinopathy, and that the CD40-TRAF6 axis would be a prime therapeutic target for early-stage non-proliferative diabetic retinopathy. The CD40-TRAF6 complex can initiate NFκB activation, inflammation, and tissue damage. Further, CD40 and TRAF6 are constitutively expressed on Muller glia, and upregulated in the diabetic retina. Yet the role of the CD40-TRAF6 complex in the onset of diabetic retinopathy is still unclear. In the current study, we examined the CD40-TRAF6 axis in diabetic retinopathy using a small molecule inhibitor (SMI-6877002) on streptozotocin-induced diabetic mice. When CD40-TRAF6-dependent inflammation was inhibited, retinal vascular leakage and capillary degeneration was ameliorated in diabetic mice. Collectively, these data suggest that the CD40-TRAF6 axis plays a pivotal role in the onset of diabetic retinopathy, and could be a novel therapeutic target for early diabetic retinopathy.

Dupilumab significantly improves skin barrier function in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α-subunit of interleukin (IL)-4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored. METHODS: We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non-lesional skin of adults and adolescents with moderate-to-severe AD over the course of 16-week treatment with dupilumab and compared those values with that of matched healthy volunteers. RESULTS: Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL-4/IL-13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non-hydroxy fatty acids and C18-sphingosine and increased the level of esterified omega-hydroxy fatty acid-containing ceramides) and increased ceramide chain length in lesional as well as non-lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment. CONCLUSIONS: Inhibition of IL-4/IL-13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate-to-severe AD.

Diabetes Aggravates Photoreceptor Pathologies in a Mouse Model for Ocular Vitamin A Deficiency.

Emerging evidence indicates that diabetes disturbs photoreceptor function and vitamin A homeostasis. However, the biochemical basis of this phenotype is not well established. Here, we compared the effects of streptozotocin-induced diabetes in wild-type (WT) mice and Stra6-/- mice, a mouse model for ocular vitamin A deficiency. After 8 weeks, diabetes increased serum retinyl esters in mice of both genotypes. The eyes of diabetic WT mice displayed increased superoxide levels but no changes in retinoid concentrations. Diabetic Stra6-/- mice showed increased ocular retinoid concentrations, but superoxide levels remained unchanged. After 30 weeks, significant alterations in liver and fat retinoid concentrations were observed in diabetic mice. Diabetic WT mice exhibited a decreased expression of visual cycle proteins and a thinning of the photoreceptor layer. Stra6-/- mice displayed significantly lower ocular retinoid concentration than WT mice. An altered retinal morphology and a reduced expression of photoreceptor marker genes paralleled these biochemical changes and were more pronounced in the diabetic animals. Taken together, we observed that diabetes altered vitamin A homeostasis in several organ systems and aggravated photoreceptor pathologies in the vitamin-deficient mouse eyes.

Infraestructura oncológica en el Sistema de Salud Mexicano.

No disponible.

Signaling sphingolipids are biomarkers for atopic dermatitis prone to disseminated viral infections.

BACKGROUND: Life-threatening viral diseases such as eczema herpeticum (EH) and eczema vaccinatum (EV) occur in <5% of individuals with atopic dermatitis (AD). The diagnosis of AD, however, excludes all individuals with AD from smallpox vaccination. OBJECTIVES: We sought to identify circulatory and skin lipid biomarkers associated with EH and EV. METHODS: Stratum corneum and plasma samples from 15 subjects with AD and a history of EH, 13 age- and gender-matched subjects with AD and without EH history, and 13 healthy nonatopic (NA) controls were analyzed by liquid chromatography tandem mass spectrometry for sphingolipid content. Sphingosine-1-phosphate (S1P) and ceramide levels were validated in plasma samples from the Atopic Dermatitis Vaccinia Network/Atopic Dermatitis Research Network repository (12 NA, 12 AD, 23 EH) and plasma from 7 subjects with EV and 7 matched subjects with AD. S1P lyase was downregulated in human primary keratinocytes to evaluate its effect on herpes simplex virus 1 (HSV-1) replication in vitro. RESULTS: The stratum corneum of patients with EH demonstrated significantly higher levels of free sphingoid bases than those in patients who were NA, indicating enhanced sphingolipid turnover in keratinocytes (P < .05). Plasma from 2 independent cohorts of patients with EH had a significantly increased S1P/ceramide ratio in subjects with EH versus those with AD and or who were NA (P < .01). The S1P level in plasma from subjects with EV was twice the level in plasma from subjects with AD (mean = 1,533 vs 732 pmol/mL; P < .001). Downregulation of S1P lyase expression with silencing RNA led to an increased S1P level and doubled HSV-1 titer in keratinocytes. CONCLUSIONS: Our data point to long-term abnormalities in the S1P signaling system as a biomarker for previous disseminated viral diseases and a potential treatment target in recurring infections.

Integrated People-Centred Care in Canada - Policies, Standards, and Implementation Tools to Improve Outcomes.

INTRODUCTION: Despite the national and international policy commitment to implement integrated health systems, there is an absence of national standards that support evidence-based design, implementation, and monitoring for improvement. Health Standards Organization (HSO)'s CAN/HSO 76000:2021 - Integrated People-Centred Health Systems (IPCHS) National Standard of Canada (NSC) has been developed to help close this gap. This manuscript outlines the policy context and the process taken to develop the IPCHS standard. DESCRIPTION: The IPCHS standard is built around 10 design principles with detailed, action-oriented criteria and guidance for policy makers and health system partners. The IPCHS standard was co-designed with a technical committee that included balanced representation of policy makers, health system decision-makers, Indigenous leaders, providers, patients, caregivers, and academics. Additional feedback was received from a diverse audience during two public review periods and targeted consultation via interviews. This qualitative feedback, combined with the evidence reviews completed by the technical committee, informed the final content of the IPCHS standard. DISCUSSION: The IPCHS standard was developed through a co-design process and complements existing frameworks by providing 66 detailed, action-oriented criteria, with specific guidance. The co-design process and consultations resulted in increased awareness and capacity among policy makers and health system partners. Supplementary tools are also in development to facilitate implementation and monitoring of progress and outcomes. This manuscript was developed in collaboration with technical committee members and HSO staff who led the targeted consultation and adoption of the IPCHS standard in six integrated care networks. CONCLUSION: Implementing integration strategies requires that we create and sustain a culture of continuous improvement and learning. Key lessons from the development process focused on the importance of co-design, embedding people-centred practices throughout the standard, formal yet iterative methodology inclusive of broad consultation, clear accountability for both policy makers and system partners, tools that support action and can be adapted to local context and level of integrated system maturity.

P63 targeted deletion under the FOXN1 promoter disrupts pre-and post-natal thymus development, function and maintenance as well as induces severe hair loss.

Progressive immune deficiency of aging is characterized by severe thymic atrophy, contracted T cell repertoire, and poor immune function. p63 is critical for the proliferative potential of embryonic and adult stem cells, as well as thymic epithelial cells (TECs). Because p63 null mice experience rapid post-natal lethality due to epidermal and limb morphogenesis defects, studies to define a role for p63 expression in TEC biology focused on embryonic thymus development and in vitro experiments. Since post-natal thymic stromal development and function differs from that of the embryo, we assessed the impact of lineage-restricted p63 loss on pre- and post-natal murine TEC function by generating mice with a loss of p63 function targeted to TEC, termed p63TECko mice. In adult p63TECko mice, severe thymic hypoplasia was observed with a lack in a discernable segregation into medullary and cortical compartments and peripheral T cell lymphopenia. This profound thymic defect was seen in both neonatal as well as embryonic p63TECko mice. In addition to TECs, p63 also plays in important role in the development of stratified epithelium of the skin; lack of p63 results in defects in skin epidermal stratification and differentiation. Interestingly, all adult p63TECko mice lacked hair follicles despite having normal p63 expression in the skin. Together our results show a critical role of TEC p63 in thymic development and maintenance and show that p63 expression is critical for hair follicle formation.

Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment.

The global number of diabetics continues to rise annually. As diabetes progresses, almost all of Type I and more than half of Type II diabetics develop diabetic retinopathy. Diabetic retinopathy is a microvascular disease of the retina, and is the leading cause of blindness in the working-age population worldwide. With such a significant health impact, new drugs are required to halt the blinding threat posed by this visual disorder. The cause of diabetic retinopathy is multifactorial, and an optimal therapeutic would halt inflammation, cease photoreceptor cell dysfunction, and ablate vascular impairment. XMD8-92 is a small molecule inhibitor that blocks inflammatory activity downstream of ERK5 (extracellular signal-related kinase 5) and BRD4 (bromodomain 4). ERK5 elicits inflammation, is increased in Type II diabetics, and plays a pathologic role in diabetic nephropathy, while BRD4 induces retinal inflammation and plays a role in retinal degeneration. Further, we provide evidence that suggests both pERK5 and BRD4 expression are increased in the retinas of our STZ (streptozotocin)-induced diabetic mice. Taken together, we hypothesized that XMD8-92 would be a good therapeutic candidate for diabetic retinopathy, and tested XMD8-92 in a murine model of diabetic retinopathy. In the current study, we developed an in vivo treatment regimen by administering one 100 µL subcutaneous injection of saline containing 20 µM of XMD8-92 weekly, to STZ-induced diabetic mice. XMD8-92 treatments significantly decreased diabetes-mediated retinal inflammation, VEGF production, and oxidative stress. Further, XMD8-92 halted the degradation of ZO-1 (zonula occludens-1), which is a tight junction protein associated with vascular permeability in the retina. Finally, XMD8-92 treatment ablated diabetes-mediated vascular leakage and capillary degeneration, which are the clinical hallmarks of non-proliferative diabetic retinopathy. Taken together, this study provides strong evidence that XMD8-92 could be a potentially novel therapeutic for diabetic retinopathy.

Aryl Hydrocarbon Receptor Agonist VAF347 Impedes Retinal Pathogenesis in Diabetic Mice.

Diabetic retinopathy is the leading cause of blindness in the working-age population worldwide. Although the cause of diabetic retinopathy is multifactorial, IL-17A is a prevalent inflammatory cytokine involved in the promotion of diabetes-mediated retinal inflammation and the progression of diabetic retinopathy. The primary source of IL-17A is Th17 cells, which are T helper cells that have been differentiated by dendritic cells in a proinflammatory cytokine environment. Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can manipulate dendritic cell maturation, halt the production of IL-6 (a proinflammatory cytokine), and suppress Th17 cell differentiation. In the current study, we examined the efficacy of an AhR agonist, VAF347, as a potential therapeutic for the onset of non-proliferative diabetic retinopathy in streptozotocin (STZ)-induced diabetic C57BL/6 mice. We determined that diabetes-mediated leukostasis, oxidative stress, and inflammation in the retina of STZ-diabetic mice were all significantly lower when treated with the AhR agonist VAF347. Furthermore, when VAF347 was subcutaneously injected into STZ-diabetic mice, retinal capillary degeneration was ameliorated, which is the hallmark of non-proliferative diabetic retinopathy in this diabetes murine model. Collectively, these findings provide evidence that the AhR agonist VAF347 could be a potentially novel therapeutic for non-proliferative diabetic retinopathy.

One country's journey to interoperability: Tanzania's experience developing and implementing a national health information exchange.

BACKGROUND: Robust, flexible, and integrated health information (HIS) systems are essential to achieving national and international goals in health and development. Such systems are still uncommon in most low and middle income countries. This article describes a first-phase activity in Tanzania to integrate the country's vertical health management information system with the help of an interoperability layer that enables cross-program data exchange. METHODS: From 2014 to 2019, the Tanzanian government and partners implemented a five-step procedure based on the "Mind the GAPS" (governance, architecture, program management, and standards) framework and using both proprietary and open-source tools. In collaboration with multiple stakeholders, the team developed the system to address major data challenges via four fully documented "use case scenarios" addressing data exchange among hospitals, between services and the supply chain, across digital data systems, and within the supply chain reporting system. This work included developing the architecture for health system data exchange, putting a middleware interoperability layer in place to facilitate the exchange, and training to support use of the system and the data it generates. RESULTS: Tanzania successfully completed the five-step procedure for all four use cases. Data exchange is currently enabled among 15 separate information systems, and has resulted in improved data availability and significant time savings. The government has adopted the health information exchange within the national strategy for health care information, and the system is being operated and managed by Tanzanian officials. CONCLUSION: Developing an integrated HIS requires a significant time investment; but ultimately benefit both programs and patients. Tanzania's experience may interest countries that are developing their HIS programs.

Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial.

Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 (ShA9), a bacterium isolated from healthy human skin, as a topical therapy for AD. ShA9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus (psmα) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical ShA9 or vehicle on the forearm skin of 54 adults with S. aureus-positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving ShA9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with ShA9 but a significant decrease in S. aureus and increased ShA9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by ShA9, but expression of mRNA for psmα was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by ShA9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.

Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum.

BACKGROUND: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). METHODS: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. RESULTS: Eight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). CONCLUSION: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.

Skin tape proteomics identifies pathways associated with transepidermal water loss and allergen polysensitization in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) and food allergy (FA) are associated with skin barrier dysfunction. OBJECTIVE: Skin biomarkers are needed for skin barrier interventions studies. METHODS: In this study, skin tape strip (STS) samples were collected from nonlesional skin of 62 children in AD FA+, AD FA-, and nonatopic groups for mass spectrometry proteomic analysis. transepidermal water loss and allergic sensitization were assessed. STS proteomic analysis results were validated in an independent cohort of 41 adults with AD with and without FA versus nonatopic controls. RESULTS: A group of 45 proteins was identified as a principal component 1 (PC1) with the highest expression in AD FA+ STSs. This novel set of STS proteins was highly correlative to skin transepidermal water loss and allergic sensitization. PC1 proteins included keratin intermediate filaments; proteins associated with inflammatory responses (S100 proteins, alarmins, protease inhibitors); and glycolysis and antioxidant defense enzymes. Analysis of PC1 proteins expression in an independent adult AD cohort validated differential expression of STS PC1 proteins in the skin of adult patients with AD with the history of clinical reactions to peanut. CONCLUSIONS: STS analysis of nonlesional skin of AD children identified a cluster of proteins with the highest expression in AD FA+ children. The differential expression of STS PC1 proteins was confirmed in a replicate cohort of adult AD patients with FA to peanut, suggesting a unique STS proteomic endotype for AD FA+ that persists into adulthood. Collectively, PC1 proteins are associated with abnormalities in skin barrier integrity and may increase the risk of epicutaneous sensitization to food allergens.

RORγt Inhibitor-SR1001 Halts Retinal Inflammation, Capillary Degeneration, and the Progression of Diabetic Retinopathy.

Diabetic retinopathy is a diabetes-mediated retinal microvascular disease that is the leading cause of blindness in the working-age population worldwide. Interleukin (IL)-17A is an inflammatory cytokine that has been previously shown to play a pivotal role in the promotion and progression of diabetic retinopathy. Retinoic acid-related orphan receptor gammaT (RORγt) is a ligand-dependent transcription factor that mediates IL-17A production. However, the role of RORγt in diabetes-mediated retinal inflammation and capillary degeneration, as well as its potential therapeutic attributes for diabetic retinopathy has not yet been determined. In the current study, we examined retinal inflammation and vascular pathology in streptozotocin-induced diabetic mice. We found RORγt expressing cells in the retinal vasculature of diabetic mice. Further, diabetes-mediated retinal inflammation, oxidative stress, and retinal endothelial cell death were all significantly lower in RORγt-/- mice. Finally, when a RORγt small molecule inhibitor (SR1001) was subcutaneously injected into diabetic mice, retinal inflammation and capillary degeneration were ameliorated. These findings establish a pathologic role for RORγt in the onset of diabetic retinopathy and identify a potentially novel therapeutic for this blinding disease.