Journal of Cutaneous Medicine and Surgery, May 1, 2012
Background: Fewer dermatologists than other clinical specialists are entering and being retained ... more Background: Fewer dermatologists than other clinical specialists are entering and being retained as physicians in the Canadian medical workforce. Studies suggest that dermatologist numbers may influence skin disease outcomes. No study has questioned whether the number of clinical dermatologists can influence academic productivity. Objective: To quantify the correlation of the number of dermatologists with biomedical scientific production in this field from 1996 to 2008 in Canada. Methods: Canadian dermatology biomedical scientific production from SClmago Journal & Country Rank (SJR) were merged with Canadian Medical Association ICMA) dermatologist demographic data. linear regression analyses were used to model the relationships. Results: The low growth of dermatologist numbers by 8.16% in Canada from 1996 to 2008 correlates with a small increase in articles by 7.59% published in this subject area during this period. This has reduced the scientific importance of Canadian dermatology in the world. Conclusion: The number of dermatologists was a significant predictor of biomedical research production in the field of derniatQh~QV' Thi § suggests that specialist availability may be one factor influencing dermatology research and publications. Renseignements de base: Parmi Ie personnel medical canadien, un moins grand nombre de dermatologues que d'autres speclallstes cliniques commencent iJ exercer la rnedeclne et continuent de Ie faire. Des etudes donnent iJ penser que Ie nombre de dermatologuas pourrait influer sur I'issue des maladies dermatologiques. Aucune etude n'a pose la question de savoir si Ie nombre de dermatologues cliniquas peut avoir des repercussions sur la productlvite acadernlque. Objectif: Quantifier la correlation entre Ie nombre de dermatologues et la production d'articles scientifiques blornedicaux dans ce domalne, entre 1996 et 2008, au Canada. Methodes: Do a fuslonne la production d'articles scientifiques biornedicaux canadiens en dermatologie de SClmago Journal & Country Rank (SJRI avec les donnees demographiques des dermatologues de I'Association medieale canadienne. On a utilise des analyses de regression lineaire pour etablir Ie modele des relations. Resultats: Une faible augmentation de 8,16 % du nombre de dermatologues au Canada, de 1996 iJ 2008, correspond iJ une faible augmentation de 7,59 % des articles publies dans ce domaine, pendant cette perlode. Ce taux a attenue I'importance scientifique de la dermatologie canadienne dans Ie monde. Conclusion: Le nombre de dermatologues etait un predicteur important de la production de recherches blomadicales dans Ie domaine de la dermatologie. Ceci donne iJ penser que la disponlbilite des specialistes pourrait etre un facteur qui influe sur la recherche et les publications en dermatologie.
American Journal of Tropical Medicine and Hygiene, Jun 1, 1994
The cellular nature of the infiltrate in the skin of patients with American cutaneous leishmanias... more The cellular nature of the infiltrate in the skin of patients with American cutaneous leishmaniasis was characterized by immunohistochemistry. The study population consisted of patients in Ceara, Brazil, an area where Leishmania braziliensis is endemic. Biopsies were taken from lesions present for 0.5â€"4 months duration and sections were stained with antibodies to T cells, T cell subsets, B cells, and macrophage markers to quantitate these cell types. The T cells accounted for 37.0 ±7.6% (mean ± SD) of the infiltrate. The average percentages of CD4-and CD8-positive T cells were similar to each other, 20.4 ±9.0% and 19.9 ±6.7%, respectively. Interleukin-2 receptorâ€"positive cells and B cells were infrequent, 3.7 ± 3.0% and 2.3 ± 3.1%, respectively. When the rela tionship between the age of the lesion at biopsy and the cellular phenotype was examined, it was noted that the percentage of positive cells remained fixed for all cell types except for that of-y3 cells, which decreased with time. It is likely that @ T cells are important in the early phase of the immune response to L braziliensis and may, in general, be important in the early immune response of granulomatous diseases. TIME COURSE OF IMMUNE RESPONSE IN LEISHMANIASIS
ABSTRACT Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropods sal... more ABSTRACT Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropods salivary components. They vary in intensity and quality dependent upon the arthropod species and the individual immune response to specific proteins of the insect’s saliva. Individuals who were not previously exposed show mild localized reactions not beyond those expected by pharmacological substances present in arthropods’ saliva. Allergic reactions are immunological in their nature and the diversity derived from hypersensitivity reactions with different levels of participation of the immune system components. Some are mainly derived from a humoral immune response, and others are based predominantly on T-lymphocyte-mediated. The majority of these undesired biological answers are self-limited, and few may cause a systemic reaction. This article intends to discuss the immunological ingredients of this evolutionary interaction.
Background Granzyme K (GzmK) is a serine protease with minimal presence in healthy tissues while... more Background Granzyme K (GzmK) is a serine protease with minimal presence in healthy tissues while abundant in inflamed tissues. Initially thought to play an exclusive role in immune-mediated cell death, extracellular GzmK can also promote inflammation. Objectives To evaluate the role of GzmK in the pathogenesis of atopic dermatitis (AD), the most common inflammatory skin disease. Methods A panel of human AD and control samples was analysed to determine if GzmK is elevated. Next, to determine a pathological role for GzmK in AD-like skin inflammation, oxazolone-induced dermatitis was induced in GzmK−/− and wild-type (WT) mice. Results In human lesional AD samples, there was an increase in the number of GzmK+ cells compared with healthy controls. GzmK−/− mice exhibited reduced overall disease severity characterized by reductions in scaling, erosions and erythema. Surprisingly, the presence of GzmK did not notably increase the overall pro-inflammatory response or epidermal barrier permeability in WT mice; rather, GzmK impaired angiogenesis, increased microvascular damage and microhaemorrhage. Mechanistically, GzmK contributed to vessel damage through cleavage of syndecan-1, a key structural component of the glycocalyx, which coats the luminal surface of vascular endothelia. Conclusions GzmK may provide a potential therapeutic target for skin conditions associated with persistent inflammation, vasculitis and pathological angiogenesis.
Annals of Allergy Asthma & Immunology, Jun 1, 2009
Background: Nonsedating antihistamines (nsAHs) are recommended as first-line therapeutics for the... more Background: Nonsedating antihistamines (nsAHs) are recommended as first-line therapeutics for the treatment of mast cell-driven disorders, including allergic rhinitis and urticaria. However, their superiority over first-generation AHs (fgAHs) has recently been called into question, mainly because of the lack of supporting head-to-head therapeutic studies. Objective: To compare the effects of 3 modern nsAHs with those of the fgAH hydroxyzine on histamine-and allergen-induced skin reactions in a controlled, double-blind, clinical trial. Methods: Skin prick tests with histamine and Dermatophagoides pteronyssinus extract were performed before and 4 hours after treatment with hydroxyzine, 25 mg; desloratadine, 5 mg; epinastine, 20 mg; fexofenadine, 120 mg; or placebo. Wheal and erythema development was evaluated by digital photography and planimetric analyses. Results: The nsAHs prevented the development of positive reactions to histamine in only 10% to 20% of all individuals tested (n ϭ 75). In contrast, more than 50% of all hydroxyzine-treated individuals showed negative test reactions to histamine (ie, wheals Ͻ7 mm 2 in area or Ͻ3 mm in diameter). Similar differences, although less pronounced, were detected when comparing the effects of nsAHs with hydroxyzine on D pteronyssinus prick testing in a limited number of D pteronyssinus-sensitized individuals. Conclusions: These results indicate that hydroxyzine is more effective than nsAHs when given as recommended in suppressing histamine-induced or allergic skin reactions. Our results suggest that higher doses of nsAHs than those currently recommended are required for the treatment of skin responses to obtain antihistaminic and antiallergic effects that are equivalent to those of fgAHs.
The Journal of Allergy and Clinical Immunology, Feb 1, 2018
RATIONALE: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with itch as its most d... more RATIONALE: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with itch as its most debilitating symptom. Blockade of the type 2 cytokines IL-4 and IL-13 with dupilumab, an anti-IL-4Ra antibody, has demonstrated unprecedented efficacy in treating AD including rapid improvements of itch. However, how disrupting type 2 cytokine signaling improves itch remains unknown. Given the remarkable effects of IL-4Ra blockade on itch, we hypothesized that, in addition to their known proinflammatory functions, IL-4 and IL-13 directly stimulate sensory neurons to mediate chronic itch. METHODS: We investigated the contributions of neuronal IL-4 and IL-13 signaling to chronic itch using sensory neuron-specific genetic deletion of type 2 cytokine signaling components and pharmacologic blockade with JAK inhibitors in a mouse model of AD. We also performed observational studies to explore the anti-itch properties of JAK inhibitors in patients. RESULTS: We found that IL-4 and IL-13 directly activate itch-sensory neurons in mice. Strikingly, we observed that IL-4 also activates human sensory neurons, suggesting that neuronal type 2 cytokine signaling promotes itch across species. Using conditional deletion of IL-4Ra from sensory neurons, we discovered that neuronal IL-4Ra critically mediates AD-associated itch. Additionally, we found that type 2 cytokine responses in neurons were dependent on JAK1, and disruption of neuronal JAK1 signaling reduced chronic itch. Finally, in translational studies, we found that JAK inhibitors markedly improved itch symptoms in chronic itch patients. CONCLUSIONS: The classical immune signaling molecules IL-4Ra and JAK1 represent new targets within the sensory nervous system to treat itch in AD and other chronic itch disorders.
Urticaria or hives is a common skin condition, which can have a significant impact on the individ... more Urticaria or hives is a common skin condition, which can have a significant impact on the individual's quality of life (QOL) and be challenging to treat. Urticaria is divided into acute and chronic, depending on the duration of symptoms. Though urticaria is associated with many different disorders, routine investigations should be limited and guided by history and physical examination. New advances have been made in the classification of chronic urticaria (CU), monitoring of disease activity, QOL, and treatment. An evidence-based approach should be used in the management of these patients.
The Journal of Allergy and Clinical Immunology: In Practice, Jun 1, 2021
Chronic spontaneous urticaria and chronic inducible urticaria are characterized by wheals, angioe... more Chronic spontaneous urticaria and chronic inducible urticaria are characterized by wheals, angioedema, or both, whereas other conditions such as hereditary angioedema present only with angioedema. The unpredictability of outbreaks, disfigurement, pruritus, and associated sleep and work disturbance can cause a significant impact on quality of life (QoL). Significant breakthroughs in the understanding of these conditions in recent years have led to the development of novel therapies. Assessment of patients with these conditions not only focuses on the clinical activity of the condition, but also on the impact on QoL and disease control with treatment. Patient-reported outcome measures, especially if sufficiently validated, give due prominence to the patient's perspective regarding disease impact and treatment outcomes. This article will review the tools readily available to assess activity, impact, and control in patients with recurrent wheals, angioedema, or both.
The objective of the present study was to establish a polymerase chain reaction (PCR) technique f... more The objective of the present study was to establish a polymerase chain reaction (PCR) technique for the diagnosis of cutaneous and mucocutaneous leishmaniosis from autochthonous cases in the state of Paraná in southern Brazil as well as imported cases. We sought to determine its utility and accuracy compared with smears and present culture methods. To standardize PCR samples, skin and mucosal punch biopsies from human lesions were performed on patients living in different regions of the Paraná state (76 cases) and other endemic areas of Brazil and Argentina (7 cases). For PCR standardization, two pairs of primers (MP1L ⁄ MP3H and B1 ⁄ B2) were utilized for amplification of the conserved sequences in the minicircle of kinetoplast DNA (kDNA) for the Leishmania braziliensis complex. Two other primer pairs (b1 ⁄ b2 and a1 ⁄ a2) were species-specific for L. (V.) braziliensis and L. (V.) amazonensis, respectively. After differential diagnosis, eight patients had clinical diagnosis of the cutaneous ulcer changed to others pathologies such as syphilis, baso-cellular carcinoma, varicose ulcer, ecthyma and paracoccidioidomycosis. Of the 75 patients with cutaneous (CL) and mucocutaneous (MCL) lesions who provided samples, 47 (46 CL + 1 MCL) were diagnosed with leishmaniosis by smear and 57 (52 LC + 5 MCL) were diagnosed by culture methods. In contrast, our PCR technique presented higher accuracy when compared to the direct examination and culture of parasites. PCR is applicable both for CL where all 61 lesions were diagnosed, and MCL where 12 of 14 lesions were diagnosed. This molecular biology technique is also a faster and more specific diagnostic method compared with present parasitological procedures.
Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropod salivary comp... more Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropod salivary components. They vary in intensity and quality dependent upon the arthropod specie and the individual immune response to specific proteins of the insect’s saliva. Individuals who were not previously exposed show mild localized reactions not beyond those expected by pharmacological substances present in arthropods’ saliva. Allergic reactions are immunological in their nature and the diversity derived from hypersensitivity reactions with different levels of participation of the immune system components. Some are mainly derived from a humoral immune response, and others are based predominantly on T-lymphocyte-mediated hypersensitivities. The majority of these undesired biological answers are self-limited, and few may cause a systemic reaction. This article intends to discuss the immunological ingredients of this evolutionary interaction.
Background: Allergic rhinitis is a major risk factor for asthma development. Lower airway inflamm... more Background: Allergic rhinitis is a major risk factor for asthma development. Lower airway inflammation and remodeling have been observed in allergic rhinitis subjects without asthma. Tissue repair processes involve the production of extracellular matrix, in which fibroblasts play a major role. These cells originate from bone marrow progenitors called fibrocytes. The number of fibrocytes is increased in asthmatics following allergen exposure. In allergic rhinitis, allergen-induced inflammation has been widely observed, but studies on allergen-induced lower airway remodeling are still limited. The aim of this study is to determine the effect of seasonal allergen exposure on the profile of fibrocytes isolated from blood of allergic rhinitis subjects without asthma. Methods: Non asthmatic subjects with seasonal allergic rhinitis were recruited. At baseline (out of the pollen season), medical history, skin prick tests, spirometry, methacholine bronchoprovocation, blood sampling and sputum induction were performed. At the peak of rhinitis symptoms, the tests were repeated. Fibrocytes number and level of activation were determined in whole blood. Cells were stained for fibrocyte markers (CD34, CD45, CXCR4, collagen I) and analyzed by flow cytometry. Results: Thirty subjects (18F:12M) aged 28 ± 8 years were recruited. Among the 12 subjects that completed the study yet, there were 12.2 ± 7.9 % of fibrocytes at baseline, whereas there were 7.1 ± 3.6 % of fibrocytes during the pollen season. Mean fluorescence of CXCR4 was 1614 ± 646 (arbitrary units) at baseline and 1805 ± 770 during the pollen season. Conclusion: The observed decrease in fibrocytes during allergy season may indicate an active migration of these cells from the periphery to the airways. A change in the number and profile of fibrocytes during natural seasonal exposure in non-asthmatic rhinitic subjects may help direct further studies looking at future outcome of these patients to develop a predictor of asthma onset.
Introduction: Dupilumab was initially approved in 2017 as the first biologic therapy for atopic d... more Introduction: Dupilumab was initially approved in 2017 as the first biologic therapy for atopic dermatitis (AD). We characterized adults with AD initiating dupilumab in a realworld setting in the USA/Canada. Methods: PROSE is an ongoing, longitudinal, prospective, observational, multicenter registry of patients with AD initiating dupilumab per country-specific prescribing information. We report baseline data (day of first dupilumab injection) for patients enrolled from April 2018 through July 2019. Results: Among 315 patients (mean age 42.5 years, 55.2% female), the median AD duration was 17.0 years; 65.4% reported a history of type 2 inflammatory comorbidities (e.g., allergic rhinitis, asthma), and 93.3% reported treatment(s) for AD in the previous year, including topical corticosteroids (90.8%), systemic corticosteroids (36.2%), and nonsteroidal systemic therapies (14.0%). In total, 89.2% had an Overall Disease Severity score of 3 (moderate) or 4 (severe). Other mean disease severity scores included the following: Eczema Area and Severity Index 16.9 (range 0-72), body surface area affected 26.8%, Patient-Oriented Eczema
Revista de Pesquisa: Cuidado é Fundamental Online, 2014
PESQUISA Aspectos clínicos e epidemiológicos da leishmaniose visceral em crianças Clinical and ep... more PESQUISA Aspectos clínicos e epidemiológicos da leishmaniose visceral em crianças Clinical and epidemiological aspects of visceral leishmaniasis in children Aspectos clínicos y epidemiológicos de la leischmaniasis visceral en niños
Journal of Cutaneous Medicine and Surgery, May 1, 2012
Background: Fewer dermatologists than other clinical specialists are entering and being retained ... more Background: Fewer dermatologists than other clinical specialists are entering and being retained as physicians in the Canadian medical workforce. Studies suggest that dermatologist numbers may influence skin disease outcomes. No study has questioned whether the number of clinical dermatologists can influence academic productivity. Objective: To quantify the correlation of the number of dermatologists with biomedical scientific production in this field from 1996 to 2008 in Canada. Methods: Canadian dermatology biomedical scientific production from SClmago Journal & Country Rank (SJR) were merged with Canadian Medical Association ICMA) dermatologist demographic data. linear regression analyses were used to model the relationships. Results: The low growth of dermatologist numbers by 8.16% in Canada from 1996 to 2008 correlates with a small increase in articles by 7.59% published in this subject area during this period. This has reduced the scientific importance of Canadian dermatology in the world. Conclusion: The number of dermatologists was a significant predictor of biomedical research production in the field of derniatQh~QV' Thi § suggests that specialist availability may be one factor influencing dermatology research and publications. Renseignements de base: Parmi Ie personnel medical canadien, un moins grand nombre de dermatologues que d'autres speclallstes cliniques commencent iJ exercer la rnedeclne et continuent de Ie faire. Des etudes donnent iJ penser que Ie nombre de dermatologuas pourrait influer sur I'issue des maladies dermatologiques. Aucune etude n'a pose la question de savoir si Ie nombre de dermatologues cliniquas peut avoir des repercussions sur la productlvite acadernlque. Objectif: Quantifier la correlation entre Ie nombre de dermatologues et la production d'articles scientifiques blornedicaux dans ce domalne, entre 1996 et 2008, au Canada. Methodes: Do a fuslonne la production d'articles scientifiques biornedicaux canadiens en dermatologie de SClmago Journal & Country Rank (SJRI avec les donnees demographiques des dermatologues de I'Association medieale canadienne. On a utilise des analyses de regression lineaire pour etablir Ie modele des relations. Resultats: Une faible augmentation de 8,16 % du nombre de dermatologues au Canada, de 1996 iJ 2008, correspond iJ une faible augmentation de 7,59 % des articles publies dans ce domaine, pendant cette perlode. Ce taux a attenue I'importance scientifique de la dermatologie canadienne dans Ie monde. Conclusion: Le nombre de dermatologues etait un predicteur important de la production de recherches blomadicales dans Ie domaine de la dermatologie. Ceci donne iJ penser que la disponlbilite des specialistes pourrait etre un facteur qui influe sur la recherche et les publications en dermatologie.
American Journal of Tropical Medicine and Hygiene, Jun 1, 1994
The cellular nature of the infiltrate in the skin of patients with American cutaneous leishmanias... more The cellular nature of the infiltrate in the skin of patients with American cutaneous leishmaniasis was characterized by immunohistochemistry. The study population consisted of patients in Ceara, Brazil, an area where Leishmania braziliensis is endemic. Biopsies were taken from lesions present for 0.5â€"4 months duration and sections were stained with antibodies to T cells, T cell subsets, B cells, and macrophage markers to quantitate these cell types. The T cells accounted for 37.0 ±7.6% (mean ± SD) of the infiltrate. The average percentages of CD4-and CD8-positive T cells were similar to each other, 20.4 ±9.0% and 19.9 ±6.7%, respectively. Interleukin-2 receptorâ€"positive cells and B cells were infrequent, 3.7 ± 3.0% and 2.3 ± 3.1%, respectively. When the rela tionship between the age of the lesion at biopsy and the cellular phenotype was examined, it was noted that the percentage of positive cells remained fixed for all cell types except for that of-y3 cells, which decreased with time. It is likely that @ T cells are important in the early phase of the immune response to L braziliensis and may, in general, be important in the early immune response of granulomatous diseases. TIME COURSE OF IMMUNE RESPONSE IN LEISHMANIASIS
ABSTRACT Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropods sal... more ABSTRACT Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropods salivary components. They vary in intensity and quality dependent upon the arthropod species and the individual immune response to specific proteins of the insect’s saliva. Individuals who were not previously exposed show mild localized reactions not beyond those expected by pharmacological substances present in arthropods’ saliva. Allergic reactions are immunological in their nature and the diversity derived from hypersensitivity reactions with different levels of participation of the immune system components. Some are mainly derived from a humoral immune response, and others are based predominantly on T-lymphocyte-mediated. The majority of these undesired biological answers are self-limited, and few may cause a systemic reaction. This article intends to discuss the immunological ingredients of this evolutionary interaction.
Background Granzyme K (GzmK) is a serine protease with minimal presence in healthy tissues while... more Background Granzyme K (GzmK) is a serine protease with minimal presence in healthy tissues while abundant in inflamed tissues. Initially thought to play an exclusive role in immune-mediated cell death, extracellular GzmK can also promote inflammation. Objectives To evaluate the role of GzmK in the pathogenesis of atopic dermatitis (AD), the most common inflammatory skin disease. Methods A panel of human AD and control samples was analysed to determine if GzmK is elevated. Next, to determine a pathological role for GzmK in AD-like skin inflammation, oxazolone-induced dermatitis was induced in GzmK−/− and wild-type (WT) mice. Results In human lesional AD samples, there was an increase in the number of GzmK+ cells compared with healthy controls. GzmK−/− mice exhibited reduced overall disease severity characterized by reductions in scaling, erosions and erythema. Surprisingly, the presence of GzmK did not notably increase the overall pro-inflammatory response or epidermal barrier permeability in WT mice; rather, GzmK impaired angiogenesis, increased microvascular damage and microhaemorrhage. Mechanistically, GzmK contributed to vessel damage through cleavage of syndecan-1, a key structural component of the glycocalyx, which coats the luminal surface of vascular endothelia. Conclusions GzmK may provide a potential therapeutic target for skin conditions associated with persistent inflammation, vasculitis and pathological angiogenesis.
Annals of Allergy Asthma & Immunology, Jun 1, 2009
Background: Nonsedating antihistamines (nsAHs) are recommended as first-line therapeutics for the... more Background: Nonsedating antihistamines (nsAHs) are recommended as first-line therapeutics for the treatment of mast cell-driven disorders, including allergic rhinitis and urticaria. However, their superiority over first-generation AHs (fgAHs) has recently been called into question, mainly because of the lack of supporting head-to-head therapeutic studies. Objective: To compare the effects of 3 modern nsAHs with those of the fgAH hydroxyzine on histamine-and allergen-induced skin reactions in a controlled, double-blind, clinical trial. Methods: Skin prick tests with histamine and Dermatophagoides pteronyssinus extract were performed before and 4 hours after treatment with hydroxyzine, 25 mg; desloratadine, 5 mg; epinastine, 20 mg; fexofenadine, 120 mg; or placebo. Wheal and erythema development was evaluated by digital photography and planimetric analyses. Results: The nsAHs prevented the development of positive reactions to histamine in only 10% to 20% of all individuals tested (n ϭ 75). In contrast, more than 50% of all hydroxyzine-treated individuals showed negative test reactions to histamine (ie, wheals Ͻ7 mm 2 in area or Ͻ3 mm in diameter). Similar differences, although less pronounced, were detected when comparing the effects of nsAHs with hydroxyzine on D pteronyssinus prick testing in a limited number of D pteronyssinus-sensitized individuals. Conclusions: These results indicate that hydroxyzine is more effective than nsAHs when given as recommended in suppressing histamine-induced or allergic skin reactions. Our results suggest that higher doses of nsAHs than those currently recommended are required for the treatment of skin responses to obtain antihistaminic and antiallergic effects that are equivalent to those of fgAHs.
The Journal of Allergy and Clinical Immunology, Feb 1, 2018
RATIONALE: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with itch as its most d... more RATIONALE: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with itch as its most debilitating symptom. Blockade of the type 2 cytokines IL-4 and IL-13 with dupilumab, an anti-IL-4Ra antibody, has demonstrated unprecedented efficacy in treating AD including rapid improvements of itch. However, how disrupting type 2 cytokine signaling improves itch remains unknown. Given the remarkable effects of IL-4Ra blockade on itch, we hypothesized that, in addition to their known proinflammatory functions, IL-4 and IL-13 directly stimulate sensory neurons to mediate chronic itch. METHODS: We investigated the contributions of neuronal IL-4 and IL-13 signaling to chronic itch using sensory neuron-specific genetic deletion of type 2 cytokine signaling components and pharmacologic blockade with JAK inhibitors in a mouse model of AD. We also performed observational studies to explore the anti-itch properties of JAK inhibitors in patients. RESULTS: We found that IL-4 and IL-13 directly activate itch-sensory neurons in mice. Strikingly, we observed that IL-4 also activates human sensory neurons, suggesting that neuronal type 2 cytokine signaling promotes itch across species. Using conditional deletion of IL-4Ra from sensory neurons, we discovered that neuronal IL-4Ra critically mediates AD-associated itch. Additionally, we found that type 2 cytokine responses in neurons were dependent on JAK1, and disruption of neuronal JAK1 signaling reduced chronic itch. Finally, in translational studies, we found that JAK inhibitors markedly improved itch symptoms in chronic itch patients. CONCLUSIONS: The classical immune signaling molecules IL-4Ra and JAK1 represent new targets within the sensory nervous system to treat itch in AD and other chronic itch disorders.
Urticaria or hives is a common skin condition, which can have a significant impact on the individ... more Urticaria or hives is a common skin condition, which can have a significant impact on the individual's quality of life (QOL) and be challenging to treat. Urticaria is divided into acute and chronic, depending on the duration of symptoms. Though urticaria is associated with many different disorders, routine investigations should be limited and guided by history and physical examination. New advances have been made in the classification of chronic urticaria (CU), monitoring of disease activity, QOL, and treatment. An evidence-based approach should be used in the management of these patients.
The Journal of Allergy and Clinical Immunology: In Practice, Jun 1, 2021
Chronic spontaneous urticaria and chronic inducible urticaria are characterized by wheals, angioe... more Chronic spontaneous urticaria and chronic inducible urticaria are characterized by wheals, angioedema, or both, whereas other conditions such as hereditary angioedema present only with angioedema. The unpredictability of outbreaks, disfigurement, pruritus, and associated sleep and work disturbance can cause a significant impact on quality of life (QoL). Significant breakthroughs in the understanding of these conditions in recent years have led to the development of novel therapies. Assessment of patients with these conditions not only focuses on the clinical activity of the condition, but also on the impact on QoL and disease control with treatment. Patient-reported outcome measures, especially if sufficiently validated, give due prominence to the patient's perspective regarding disease impact and treatment outcomes. This article will review the tools readily available to assess activity, impact, and control in patients with recurrent wheals, angioedema, or both.
The objective of the present study was to establish a polymerase chain reaction (PCR) technique f... more The objective of the present study was to establish a polymerase chain reaction (PCR) technique for the diagnosis of cutaneous and mucocutaneous leishmaniosis from autochthonous cases in the state of Paraná in southern Brazil as well as imported cases. We sought to determine its utility and accuracy compared with smears and present culture methods. To standardize PCR samples, skin and mucosal punch biopsies from human lesions were performed on patients living in different regions of the Paraná state (76 cases) and other endemic areas of Brazil and Argentina (7 cases). For PCR standardization, two pairs of primers (MP1L ⁄ MP3H and B1 ⁄ B2) were utilized for amplification of the conserved sequences in the minicircle of kinetoplast DNA (kDNA) for the Leishmania braziliensis complex. Two other primer pairs (b1 ⁄ b2 and a1 ⁄ a2) were species-specific for L. (V.) braziliensis and L. (V.) amazonensis, respectively. After differential diagnosis, eight patients had clinical diagnosis of the cutaneous ulcer changed to others pathologies such as syphilis, baso-cellular carcinoma, varicose ulcer, ecthyma and paracoccidioidomycosis. Of the 75 patients with cutaneous (CL) and mucocutaneous (MCL) lesions who provided samples, 47 (46 CL + 1 MCL) were diagnosed with leishmaniosis by smear and 57 (52 LC + 5 MCL) were diagnosed by culture methods. In contrast, our PCR technique presented higher accuracy when compared to the direct examination and culture of parasites. PCR is applicable both for CL where all 61 lesions were diagnosed, and MCL where 12 of 14 lesions were diagnosed. This molecular biology technique is also a faster and more specific diagnostic method compared with present parasitological procedures.
Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropod salivary comp... more Allergies to hematophagous arthropod bites are inflammatory reactivity to arthropod salivary components. They vary in intensity and quality dependent upon the arthropod specie and the individual immune response to specific proteins of the insect’s saliva. Individuals who were not previously exposed show mild localized reactions not beyond those expected by pharmacological substances present in arthropods’ saliva. Allergic reactions are immunological in their nature and the diversity derived from hypersensitivity reactions with different levels of participation of the immune system components. Some are mainly derived from a humoral immune response, and others are based predominantly on T-lymphocyte-mediated hypersensitivities. The majority of these undesired biological answers are self-limited, and few may cause a systemic reaction. This article intends to discuss the immunological ingredients of this evolutionary interaction.
Background: Allergic rhinitis is a major risk factor for asthma development. Lower airway inflamm... more Background: Allergic rhinitis is a major risk factor for asthma development. Lower airway inflammation and remodeling have been observed in allergic rhinitis subjects without asthma. Tissue repair processes involve the production of extracellular matrix, in which fibroblasts play a major role. These cells originate from bone marrow progenitors called fibrocytes. The number of fibrocytes is increased in asthmatics following allergen exposure. In allergic rhinitis, allergen-induced inflammation has been widely observed, but studies on allergen-induced lower airway remodeling are still limited. The aim of this study is to determine the effect of seasonal allergen exposure on the profile of fibrocytes isolated from blood of allergic rhinitis subjects without asthma. Methods: Non asthmatic subjects with seasonal allergic rhinitis were recruited. At baseline (out of the pollen season), medical history, skin prick tests, spirometry, methacholine bronchoprovocation, blood sampling and sputum induction were performed. At the peak of rhinitis symptoms, the tests were repeated. Fibrocytes number and level of activation were determined in whole blood. Cells were stained for fibrocyte markers (CD34, CD45, CXCR4, collagen I) and analyzed by flow cytometry. Results: Thirty subjects (18F:12M) aged 28 ± 8 years were recruited. Among the 12 subjects that completed the study yet, there were 12.2 ± 7.9 % of fibrocytes at baseline, whereas there were 7.1 ± 3.6 % of fibrocytes during the pollen season. Mean fluorescence of CXCR4 was 1614 ± 646 (arbitrary units) at baseline and 1805 ± 770 during the pollen season. Conclusion: The observed decrease in fibrocytes during allergy season may indicate an active migration of these cells from the periphery to the airways. A change in the number and profile of fibrocytes during natural seasonal exposure in non-asthmatic rhinitic subjects may help direct further studies looking at future outcome of these patients to develop a predictor of asthma onset.
Introduction: Dupilumab was initially approved in 2017 as the first biologic therapy for atopic d... more Introduction: Dupilumab was initially approved in 2017 as the first biologic therapy for atopic dermatitis (AD). We characterized adults with AD initiating dupilumab in a realworld setting in the USA/Canada. Methods: PROSE is an ongoing, longitudinal, prospective, observational, multicenter registry of patients with AD initiating dupilumab per country-specific prescribing information. We report baseline data (day of first dupilumab injection) for patients enrolled from April 2018 through July 2019. Results: Among 315 patients (mean age 42.5 years, 55.2% female), the median AD duration was 17.0 years; 65.4% reported a history of type 2 inflammatory comorbidities (e.g., allergic rhinitis, asthma), and 93.3% reported treatment(s) for AD in the previous year, including topical corticosteroids (90.8%), systemic corticosteroids (36.2%), and nonsteroidal systemic therapies (14.0%). In total, 89.2% had an Overall Disease Severity score of 3 (moderate) or 4 (severe). Other mean disease severity scores included the following: Eczema Area and Severity Index 16.9 (range 0-72), body surface area affected 26.8%, Patient-Oriented Eczema
Revista de Pesquisa: Cuidado é Fundamental Online, 2014
PESQUISA Aspectos clínicos e epidemiológicos da leishmaniose visceral em crianças Clinical and ep... more PESQUISA Aspectos clínicos e epidemiológicos da leishmaniose visceral em crianças Clinical and epidemiological aspects of visceral leishmaniasis in children Aspectos clínicos y epidemiológicos de la leischmaniasis visceral en niños
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