Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel.

BACKGROUND: A transition from a subtyping to a phenotyping approach in rosacea is underway, allowing individual patient management according to presenting features instead of categorization by predefined subtypes. The ROSacea COnsensus (ROSCO) 2017 recommendations further support this transition and align with guidance from other working groups. OBJECTIVES: To update and extend previous global ROSCO recommendations in line with the latest research and continue supporting uptake of the phenotype approach in rosacea through clinical tool development. METHODS: Nineteen dermatologists and two ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and management. Voting was electronic and blinded. RESULTS: Delphi statements on which the panel achieved consensus of ≥ 75% voting 'Agree' or 'Strongly agree' are presented. The panel recommends discussing disease burden with patients during consultations, using four questions to assist conversations. The primary treatment objective should be achievement of complete clearance, owing to previously established clinical benefits for patients. Cutaneous and ocular features are defined. Treatments have been reassessed in line with recent evidence and the prior treatment algorithm updated. Combination therapy is recommended to benefit patients with multiple features. Ongoing monitoring and dialogue should take place between physician and patients, covering defined factors to maximize outcomes. A prototype clinical tool (Rosacea Tracker) and patient case studies have been developed from consensus statements. CONCLUSIONS: The current survey updates previous recommendations as a basis for local guideline development and provides clinical tools to facilitate a phenotype approach in practice and improve rosacea patient management. What's already known about this topic? A transition to a phenotype approach in rosacea is underway and is being recommended by multiple working groups. New research has become available since the previous ROSCO consensus, necessitating an update and extension of recommendations. What does this study add? We offer updated global recommendations for clinical practice that account for recent research, to continue supporting the transition to a phenotype approach in rosacea. We present prototype clinical tools to facilitate use of the phenotype approach in practice and improve management of patients with rosacea.

The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner.

Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2.1). For we believe the first time, we show that N-methyl-d-aspartate (NMDA) receptor-dependent Ca2+ transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4-associated psychiatric disorders.

Applying the phenotype approach for rosacea to practice and research.

BACKGROUND: Rosacea diagnosis and classification have evolved since the 2002 National Rosacea Society expert panel subtype approach. Several working groups are now aligned to a more patient-centric phenotype approach, based on an individual's presenting signs and symptoms. However, subtyping is still commonplace across the field and an integrated strategy is required to ensure widespread progression to the phenotype approach. OBJECTIVES: To provide practical recommendations that facilitate adoption of a phenotype approach across the rosacea field. METHODS: A review of the literature and consolidation of rosacea expert experience. RESULTS: We identify challenges to implementing a phenotype approach in rosacea and offer practical recommendations to overcome them across clinical practice, interventional research, epidemiological research and basic science. CONCLUSIONS: These practical recommendations are intended to indicate the next steps in the progression from subtyping to a phenotype approach in rosacea, with the goals of improving our understanding of the disease, facilitating treatment developments and ultimately improving care for patients with rosacea.

Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel.

BACKGROUND: Rosacea is currently diagnosed by consensus-defined primary and secondary features and managed by subtype. However, individual features (phenotypes) can span multiple subtypes, which has implications for clinical practice and research. Adopting a phenotype-led approach may facilitate patient-centred management. OBJECTIVES: To advance clinical practice by obtaining international consensus to establish a phenotype-led rosacea diagnosis and classification scheme with global representation. METHODS: Seventeen dermatologists and three ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and severity evaluation. All voting was electronic and blinded. RESULTS: Consensus was achieved for transitioning to a phenotype-based approach to rosacea diagnosis and classification. The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes. Flushing, telangiectasia, inflammatory lesions and ocular manifestations were not considered to be individually diagnostic. The panel reached agreement on dimensions for phenotype severity measures and established the importance of assessing the patient burden of rosacea. CONCLUSIONS: The panel recommended an approach for diagnosis and classification of rosacea based on disease phenotype.

Hepatitis C may enhance key amplifiers of psoriasis.

BACKGROUND: Multiple studies have noted an association between hepatitis C and psoriasis, but it is not known whether psoriasis is a result of treatment modalities for hepatitis C or a result of hepatitis C alone. OBJECTIVE: To examine the relationship between psoriasis and hepatitis C by measuring the expression of cathelicidin, TLR9 and IFNγ in psoriatic lesional and non-lesional skin in HCV-positive and negative psoriatic patients. METHODS: Two 2 mm punch biopsies of lesional and non-lesional skin in 10 patients who were HCV-negative psoriatics and seven HCV-positive psoriatics were used to measure cathelicidin, TLR9 and IFNγ mRNA expression by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). RESULTS: The mRNA levels of cathelicidin, TLR9 and IFNγ were significantly higher in both non-lesional and lesional skin of HCV-positive patients with psoriasis as compared to HCV-negative psoriatic patients. Additionally, the IFNγ level in lesional skin of HCV-positive psoriatic patients was higher than the IFNγ level seen in non-lesional skin of those same patients. CONCLUSION: These findings suggest that HCV infection upregulates these inflammatory cytokines, possibly increasing susceptibility to developing psoriasis.

European Surveillance System on Contact Allergies (ESSCA): results with the European baseline series, 2013/14.

BACKGROUND: Contact allergy is a common condition and can severely interfere with daily life or professional activities. Due to changes in exposures, such as introduction of new substances, new products or formulations and regulatory intervention, the spectrum of contact sensitization changes. OBJECTIVE: To evaluate the current spectrum of contact allergy to allergens present in the European baseline series (EBS) across Europe. METHODS: Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (ESSCA, www.essca-dc.org) in consecutively patch-tested patients, 2013/14, in 46 departments in 12 European countries. RESULTS: Altogether, 31 689 patients were included in the analysis. Compared to a similar analysis in 2004, the prevalence of contact allergy to methylisothiazolinone went up to around 20% in several departments. In comparison, contact allergy to the metals nickel, cobalt and chromium remained largely stable, at 18.1%, 5.9% and 3.2%, respectively, similar to mostly unchanged prevalence with fragrance mix I, II and Myroxylon pereirae (balsam of Peru) at 7.3%, 3.8% and 5.3%, respectively. In the subgroup of departments diagnosing (mainly) patients with occupational contact dermatitis, the prevalence of work-related contact allergies such as epoxy resin or rubber additives was found to be increased, compared to general dermatology departments. CONCLUSION: Continuous surveillance of contact allergy based on network data offers the identification of time trends or persisting problems, and thus enables focussing in-depth research (subgroup analyses, exposure analysis) on areas where it is needed.

Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

BACKGROUND AND OBJECTIVES: Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis. MATERIALS AND METHODS: Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay. RESULTS: Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects. CONCLUSIONS: Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

Clinical epidemiology of hand eczema in patients accessing dermatological reference centres: results from Italy.

BACKGROUND: Data on the epidemiological impact and clinical characteristics of chronic hand eczema in Southern Europe are lacking. OBJECTIVES: To estimate the prevalence of chronic hand eczema in its different stages of severity and refractoriness to standard therapy in patients accessing Italian dermatological reference centres, and to evaluate sociodemographic and clinical factors associated with each stage. METHODS: A cross-sectional multicentre study was conducted. Adult patients with hand eczema, consecutively accessing 14 centres over a 6-month period, were enrolled. Patients were classified according to disease duration, severity and response to standard therapy with potent topical corticosteroids. Logistical regression was performed to investigate the relationship between sociodemographic and clinical data with different stages of eczema. RESULTS: The total number of participants was 981. Hand eczema was chronic in 83·5% of patients; 21·3% had severe eczema, with 62·0% of these patients refractory to standard therapy. Food processing and related work, the health professions, craft and related trade works (building, plumbing, electrical), hairdressing/beauty and handicraft work were most frequently associated with chronic hand eczema. Severe chronic hand eczema was more likely to be seen in men, older patients and those with less education. Severe and refractory hand eczema was also more likely among the unemployed and patients with allergic rhinitis and/or atopic dermatitis. CONCLUSIONS: Chronic hand eczema is frequent among patients with hand eczema accessing dermatology centres. Many patients were severe and refractory to standard therapy. The appropriate identification of hand eczema is the first step in implementing effective and efficient treatments.

A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis.

BACKGROUND: Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production. OBJECTIVE: To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin. METHODS: This was a multi-centre, placebo-controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained. RESULTS: At baseline, 20% of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13 or EASI scores. CONCLUSIONS: This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted.

Modeling the current and projected distribution of Brazilian peppertree Schinus terebinthifolia Raddi (Anacardiaceae) in the Americas.

Global biodiversity is under substantial threat due to biological invasions, a problem exacerbated by climate change. Such invasions have detrimental effects on the environment, economy, and human health, resulting in significant financial burdens. Recently, understanding these challenges has become a highlighted priority within the scientific community. This study focuses on the evaluation of Schinus terebinthifolia, native to South America, and its invasive spread into North and Central America, which has resulted in wide distribution and considerable impact. The primary objectives of this study include analyzing the potential distribution of the species under current and future climate scenarios, identifying the areas where its climatic niche is changing. Data collection encompassed a vast dataset of over 30,000 occurrence records of this species, from the following databases: (1) The Global Biodiversity Information Facility provided 22,163 records (GBIF), (2) The virtual Herbarium Reflora contributed 1,438 records, and NeoTropTree made available 6,591 records. Following a rigorous filtering process, 992 occurrences were considered for modeling. In this process, we utilized climate data and climate projections, employing various algorithms, with an emphasis on the consensus model methodology. The research results reveal a clear trend of reduced habitat suitability for S. terebinthifolia, especially under scenarios of high global warming. This accentuates the urgency of implementing emission control measures and mitigation strategies. Additionally, the study underscores the crucial importance of continuous monitoring, as well as actions for controlling and restoring affected ecosystems. The significant role played by S. terebinthifolia in both its native and invaded areas highlights the need for comprehensive management approaches. In the face of climate change and biodiversity threats, this study provides insightful observations on the dynamics of biological invasions. Success in addressing these issues relies on close cooperation between the scientific community, policymakers, land managers, and local communities. This collaboration is essential for guiding and conducting conservation and biodiversity management efforts in an ever-evolving world.

Floral Morphometry and Sexual System Determination in Pink Pepper (Schinus terebinthifolia - Anacardiaceae).

The increasing global importance of pink peppertree (Schinus terebinthifolia, Anacardiaceae) as a high-value commercial crop and its potential for expansion in production demand appropriate management due to uncertainties regarding its sexual system. This study focused on evaluating the morphology of sterile and fertile floral whorls, as well as analyzing the sexual system of pink pepper in two populations in northeastern Brazil. The results revealed no significant differences in the morphological characteristics of the flowers between the studied areas, suggesting that the species possesses notable adaptability to environmental conditions. However, a significant difference in the proportion of staminate individuals was observed in both areas, representing over 88% and 72%, respectively. A correlation was observed between the size of the stamens and the presence of apparently atrophied pistils (r=0.275; df=178; p<0.001), along with the occurrence of fruits in these hermaphroditic plants. In this context, the species should be considered gynodioecious due to the presence of plants with hermaphroditic flowers and plants with pistillate flowers. However, further research is essential to elucidate the role of pollinators, especially bees and wasps, and to better understand the fruiting process in hermaphroditic flowers. These insights have the potential to significantly enhance management aiming for efficient fruit production, promoting its economic and ecological relevance.

Intrarectal administration of mCRAMP-encoding plasmid reverses exacerbated colitis in Cnlp(-/-) mice.

Cathelicidin is a pleiotropic host defense peptide secreted by epithelial and immune cells. Whether endogenous cathelicidin is protective against ulcerative colitis, however, is unclear. Here we sought to delineate the role of endogenous murine cathelicidin (mCRAMP) and the therapeutic efficacy of intrarectal administration of mCRAMP-encoding plasmid in ulcerative colitis using dextran sulfate sodium (DSS)-challenged cathelicidin-knockout (Cnlp(-/-)) mice as a model. Cnlp(-/-) mice had more severe symptoms and mucosal disruption than the wild-type mice in response to DSS challenge. The tissue levels of interleukin-1ß and tumor necrosis factor-α, myeloperoxidase activity and the number of apoptotic cells were increased in the colon of DSS-challenged Cnlp(-/-) mice. Moreover, mucus secretion and mucin gene expression were impaired in Cnlp(-/-) mice. All these abnormalities were reversed by the intrarectal administration of mCRAMP or mCRAMP-encoding plasmid. Taken together, endogenous cathelicidin may protect against ulcerative colitis through modulation of inflammation and mucus secretion.

Cathelicidin protects against Helicobacter pylori colonization and the associated gastritis in mice.

Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.

Localized salt-dependent aquagenic urticaria: a subtype of aquagenic urticaria?

Aquagenic urticaria is a rare form of inducible urticaria characterized by wealing at the site of contact of the skin with water, regardless of its temperature, within minutes of exposure. We describe six young women who reported urticarial rashes, triggered mostly by sea bathing, characteristically localized on the inferior facial contours and neck. In four of the six patients, this was the only localization. All six reacted with erythema and wealing to challenge tests with hypertonic saline (3.5% NaCl) applied to the submandibular area and/or neck. Two patients reacted also to tap water or to normal saline, but less intensely. Challenge tests with different hypertonic water solutions, performed in one patient, showed that both salinity and hypertonicity may be pathogenically relevant. Response to antihistamines was poor in three patients. Our experience suggests the existence of a distinct salt-dependent subtype of aquagenic urticaria (SDAU) that affects young women, with a characteristic localization on the inferior facial contours and neck. SDAU is possibly under-recognized and under-reported.

Induction and exacerbation of psoriasis with Interferon-alpha therapy for hepatitis C: a review and analysis of 36 cases.

BACKGROUND: Interferon-alpha (IFN-α) therapy is used to treat hepatitis C infection. The exacerbation and occurrence of psoriasis in hepatitis C patients treated with IFN-α is increasingly recognized, but the distinct associated features, aetiology and management have not been reviewed. OBJECTIVE: To review all published cases of hepatitis C patients who developed psoriasis while receiving IFN-α therapy. METHODS: The review was conducted by searching the PubMed database using the keywords 'hepatitis C' AND 'psoriasis.' In addition, references to additional publications not indexed for PubMed were followed to obtain a complete record of published data. RESULTS: We identified 32 publications describing 36 subjects who developed a psoriatic eruption while receiving IFN-α therapy for hepatitis C. Topical therapies were a commonly employed treatment modality, but led to resolution in only 30% of cases in which they were employed solely. Cessation of IFN-α therapy led to resolution in 93% of cases. Hundred per cent of those who developed psoriasis while on IFN-α therapy responded to systemic therapy and were able to continue the drug. CONCLUSION: Further studies and analysis of IFN-α-induced lesions are necessary to clarify the role of IFN-α and the hepatitis C virus in the development of psoriatic lesions.

Human retroviruses in the second decade: a personal perspective.

Human retroviruses have developed novel strategies for their propagation and survival. A consequence of their success has been the induction of an extraordinarily diverse set of human diseases, including AIDS, cancers and neurological and inflammatory disorders. Early research focused on their characterization, linkage to these diseases, and the mechanisms involved. Research should now aim at the eradication of human retroviruses and on treatment of infected people.

The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection.

The ability of CD8 T cells derived from human immunodeficiency virus (HIV)-infected patients to produce soluble HIV-suppressive factor(s) (HIV-SF) has been suggested as an important mechanism of control of HIV infection in vivo. The C-C chemokines RANTES, MIP-1 alpha and MIP-1 beta were recently identified as the major components of the HIV-SF produced by both immortalized and primary patient CD8 T cells. Whereas they potently inhibit infection by primary and macrophage-tropic HIV-1 isolates, T-cell line-adapted viral strains tend to be insensitive to their suppressive effects. Consistent with this discrepancy, two distinct chemokine receptors, namely, CXCR4 (ref. 7) and CCR5 (ref. 8), were recently identified as potential co-receptors for T-cell line-adapted and macrophage-tropic HIV-1 isolates, respectively. Here, we demonstrate that the third hypervariable domain of the gp 120 envelope glycoprotein is a critical determinant of the susceptibility of HIV-1 to chemokines. Moreover, we show that RANTES, MIP-1 alpha and MIP-1 beta block the entry of HIV-1 into cells and that their antiviral activity is independent of pertussis toxin-sensitive signal transduction pathways mediated by chemokine receptors. The ability of the chemokines to block the early steps of HIV infection could be exploited to develop novel therapeutic approaches for AIDS.

Intracellular expression of antibody fragments directed against HIV reverse transcriptase prevents HIV infection in vitro.

We have tested a novel strategy of intracellular immunization to block human immunodeficiency virus (HIV) infection. The expression of a specific antibody within a cell was achieved by transduction of genes that encode for immunoglobulin chains with specificity to viral reverse transcriptase. We demonstrated that inhibition of this enzyme makes cells resistant to HIV infection by blocking an early stage of viral replication. If high efficiency transduction with a stable vector into lymphohaematopoietic stem cells or mature lymphocytes can be achieved, gene transfer-mediated intracellular immunization might be a feasible treatment strategy in AIDS.

Effects of a urinary factor from women in early pregnancy on HIV-1, SIV and associated disease.

The effects of clinical grade crude preparations of human chorionic gonadotropin (hCG) on Kaposi's sarcoma, HIV, SIV and hematopoiesis were examined in vitro and in vivo. In contrast to previous studies, we report that the antiviral activity of hCG associated factors is not due to the native hCG heterodimer, including its purified subunits or its major degradation product, the beta-core. Using gel permeation chromatography of the clinical grade hCG and urine concentrates from pregnant women, we demonstrate that an as yet unidentified hCG associated factor (HAF) with anti-HIV, anti-SIV, anti-KS and pro-hematopoietic activities elutes as two peaks corresponding to 15-30 kDa and 2-4 kDa.