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1.
Artigo em Inglês | MEDLINE | ID: mdl-39115684

RESUMO

In response to concerns regarding overprescribing of psychotropic medication in children/adolescents, this study examined trends in psychotropic medication use in Ireland by age group and gender. A retrospective, repeated, cross-sectional study of the Irish pharmacy claims database was conducted. Yearly prevalence of children/adolescents receiving dispensed psychotropic medications was analysed from January 2017 to December 2021 and compared across years, age groups (5-15 years, and stratified as 5-11 and 12-15 years) and gender. Yearly prevalence was defined as the mean number of patients in receipt of medication per month per 1000 eligible population during a given calendar year. Negative binomial regression was used to examine the association of year, age group and gender on prevalence. Prevalence ratios (PRs) per year (average change in prevalence between each year) were presented with 95% confidence intervals (CIs). The prevalence of included psychotropic medications dispensed in the 5-15 years group increased from 6.41 (95% CI: 6.22, 6.59) in 2017 to 8.46 (95% CI: 8.26, 8.68) in 2021 per 1000 eligible population (32% increase). The PR per year (adjusting for age category and gender) was 1.07 (95% CI: 1.035, 1.107; p < 0.001). An increasing trend over time was also observed for all individual drug classes. These findings suggest increased use of psychotropic medication in children/adolescents from 2017 to 2021. However, despite increased prevalence over time, comparison with the literature shows that psychotropic medication use in Ireland remains lower than international comparators.

2.
Front Reprod Health ; 6: 1355922, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39040132

RESUMO

Oestradiol withdrawal at menopause predisposes women to metabolic syndrome, a cluster of interrelated conditions including obesity, insulin resistance, dyslipidaemia and hypertension that together confer an increased risk of developing type 2 diabetes mellitus and cardiovascular disease. Hormone replacement therapies are commonly used to treat acute symptoms of the perimenopausal period, and whilst they have been associated with metabolic improvements in many studies, long-term use is considered unviable. Novel approaches are required to mitigate the risk of postmenopausal metabolic syndrome. In 2012, the exercise-inducible myokine irisin was isolated from the skeletal muscle of mice and identified to have anti-obesity and antidiabetic effects in vivo. Irisin is now recognised to exert pleiotropic action on cognitive, bone and metabolic health. There is accumulating evidence from in vitro and in vivo rodent studies that irisin can mitigate each component condition of metabolic syndrome. In postmenopausal women, independent associations have been observed between (a) exercise and plasma irisin concentration and (b) plasma irisin concentration and reduced incidence of metabolic syndrome. To date, however, no study has considered the mechanistic basis by which irisin, whether exercise-induced or exogenously administered, could reduce the incidence or severity of metabolic syndrome in postmenopausal women. This review aims to analyse the literature concerning the metabolic actions of irisin, with a focus on its therapeutic potential for metabolic syndrome driven by a state of oestradiol depletion. It evaluates the practicality of exercise as a therapy and discusses other irisin-based therapeutic strategies that may alleviate postmenopausal metabolic syndrome. Finally, it highlights areas where future research is required to advance knowledge of irisin's biological action such that it could be considered a viable candidate for clinical application.

3.
Allergy ; 79(8): 2197-2206, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38483174

RESUMO

BACKGROUND: Local allergic rhinitis (LAR) is defined by chronic nasal symptoms, absence of atopy, positive nasal allergen challenge (NAC) and a good response to subcutaneous allergen immunotherapy (SCIT). We sought to investigate SCIT capacity to induce local and systemic blocking antibodies in LAR patients. METHODS: A RDBPC study of grass SCIT was performed, with participants receiving either SCIT (Group A; n = 10) or placebo (Group B; n = 14) in the first 6 months. Both groups subsequently received SCIT for 12 months at Year 2. Nasal and serum antibodies (IgG4, IgA1 and IgA2) and their inhibitory capacity were measured at multiple timepoints. RESULTS: The allergen concentration tolerated increased significantly at 6 months (Group A; p = .047) and 24 months (Group B; p = .049) compared with baseline and persisted until the end of the study. Induction of serum sIgA1 to Phl p was seen in Groups A and B, albeit the former being induced earlier (1.71-fold, p = .027). A significant induction in sIgG4 to Phl p 1 and 5 was observed in serum of Group A (p = .047 and p = .0039) and sIgA2 to Phl p in Group B (p = .032 and p = .0098) at 18 and 24 months, respectively. Both local and systemic blocking antibodies can inhibit allergen-IgE complexes binding to CD23 on B cells, and this correlated with level of allergen tolerated intra-nasally in Group A (serum; 𝜌 = -.47, p = .0006, nasal; 𝜌 = -.38, p = .0294). CONCLUSIONS: Grass pollen SCIT induced functional systemic blocking antibodies that correlate with the concentration of allergen tolerated following NAC, highlighting their potential as a biomarker of SCIT in LAR.


Assuntos
Alérgenos , Dessensibilização Imunológica , Poaceae , Pólen , Rinite Alérgica , Humanos , Dessensibilização Imunológica/métodos , Dessensibilização Imunológica/efeitos adversos , Alérgenos/imunologia , Alérgenos/administração & dosagem , Masculino , Feminino , Pólen/imunologia , Adulto , Poaceae/imunologia , Rinite Alérgica/imunologia , Rinite Alérgica/terapia , Pessoa de Meia-Idade , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Adulto Jovem , Testes de Provocação Nasal , Administração Intranasal , Resultado do Tratamento , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/terapia , Injeções Subcutâneas
4.
J Allergy Clin Immunol ; 152(5): 1247-1260, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37460024

RESUMO

BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year. OBJECTIVE: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response. METHODS: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response. CONCLUSIONS: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.


Assuntos
Rinite Alérgica , Imunoterapia Sublingual , Humanos , Transcriptoma , Leucócitos Mononucleares , Pólen , Alérgenos , Dessensibilização Imunológica/métodos , Imunoterapia Sublingual/métodos , Phleum , Injeções Subcutâneas , Rinite Alérgica/terapia , Rinite Alérgica/tratamento farmacológico
5.
J Allergy Clin Immunol ; 151(5): 1357-1370.e9, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36649758

RESUMO

BACKGROUND: Immunologic mechanism of action of allergoids remains poorly understood. Previous models of allergenicity and immunogenicity have yielded suboptimal knowledge of these immunotherapeutic vaccine products. Novel single-cell RNA sequencing technology offers a bridge to this gap in knowledge. OBJECTIVE: We sought to identify the underpinning tolerogenic molecular and cellular mechanisms of depigmented-polymerized Phleum pratense (Phl p) extract. METHODS: The molecular mechanisms underlying native Phl p, depigmented Phl p (DPG-Phl p), and depigmented-polymerized (DPG-POL-Phl p) allergoid were investigated by single-cell RNA sequencing. Allergen-specific TH2A, T follicular helper (Tfh), and IL-10+ regulatory B cells were quantified by flow cytometry in peripheral blood mononuclear cells from 16 grass pollen-allergic and 8 nonatopic control subjects. The ability of Phl p, DPG-Phl p, and DPG-POL-Phl p to elicit FcεRI- and FcεRII-mediated IgE responses was measured by basophil activation test and IgE-facilitated allergen binding assay. RESULTS: Analysis revealed that DPG-POL-Phl p downregulated genes associated with TH2 signaling, induced functional regulatory T cells exhibiting immunosuppressive roles through CD52 and Siglec-10, modulated genes encoding immunoproteasome that dysregulate the processing and presentation of antigens to T cells and promoted a shift from IgE toward an IgA1 and IgG responses. In grass pollen-allergic subjects, DPG-POL-Phl p exhibited reduced capacity to elicit proliferation of TH2A, IL-4+ Tfh and IL-21+ Tfh cells while being the most prominent at inducing IL-10+CD19+CD5hi and IL-10+CD19+CD5hiCD38intCD24int regulatory B-cell subsets compared to Phl p (all P < .05). Furthermore, DPG-POL-Phl p demonstrated a hypoallergenic profile through basophil activation and histamine release compared to Phl p (31.54-fold, P < .001). CONCLUSIONS: Single-cell RNA sequencing provides an in-depth resolution of the mechanisms underlying the tolerogenic profile of DPG-POL-Phl p.


Assuntos
Alérgenos , Hipersensibilidade , Humanos , Poaceae , Interleucina-10 , Leucócitos Mononucleares , Imunoglobulina E , Pólen , Phleum , Alergoides , Extratos Vegetais , Análise de Sequência de RNA , Proteínas de Plantas
6.
J Psychiatr Res ; 152: 201-218, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35753240

RESUMO

Although high rates of poor adherence/persistence have been documented in ADHD, there is limited research targeting the problem. This systematic review evaluated interventions to address poor adherence/persistence to ADHD pharmacotherapy, with the aim of guiding the development of future interventions. An extensive search was conducted from January 1980 until January 2021. Thirteen studies were identified involving interventions based on psychoeducation, behavioural therapy, combined psychoeducation/behavioural therapy, technology-based interventions, written informed consent and a nursing support line. All 13 studies (including five RCTs) reported improvement in adherence/persistence and five studies (including four RCTs) also reported improvement in ADHD symptomatology. Almost all studies involved interventions utilising some form of education. Three RCTs of psychoeducation alone were included, with two of the three studies reporting adherence benefits at three and 12 months respectively. The third RCT was terminated early due to poor recruitment. A behavioural intervention RCT reported improved adherence six months post intervention (but not at 12 months), although a substantial drop-out rate was observed. A final included RCT used a Smartphone Application and reported a short term increase in adherence. The authors of the studies in this review make salient attempts at improving adherence and provide insight for future intervention development. We believe future interventions should involve combinations of strategies, have a theoretical framework and target the most common reasons for non-adherence. Interventions should also be integratable into routine care and include patient input to maximise sustainability.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Humanos
7.
J Allergy Clin Immunol ; 148(4): 1061-1071.e11, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33819508

RESUMO

INTRODUCTION: There is no detailed comparison of allergen-specific immunoglobulin responses following sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT). OBJECTIVE: We sought to compare nasal and systemic timothy grass pollen (TGP)-specific antibody responses during 2 years of SCIT and SLIT and 1 year after treatment discontinuation in a double-blind, double-dummy, placebo-controlled trial. METHODS: Nasal fluid and serum were obtained yearly (per-protocol population, n = 84). TGP-specific IgA1, IgA2, IgG4, IgG, and IgE were measured in nasal fluids by ELISA. TGP-specific IgA1, IgA2, and Phleum pratense (Phl p)1, 2, 4, 5b, 6, 7, 11, and 12 IgE and IgG4 were measured in sera by ELISA and ImmunoCAP, respectively. RESULTS: At years 2 and 3, TGP-IgA1/2 levels in nasal fluid were elevated in SLIT compared with SCIT (4.2- and 3.0-fold for IgA1, 2.0- and 1.8-fold for IgA2, respectively; all P < .01). TGP-IgA1 level in serum was elevated in SLIT compared with SCIT at years 1, 2, and 3 (4.6-, 5.1-, and 4.7-fold, respectively; all P < .001). Serum TGP-IgG level was higher in SCIT compared with SLIT (2.8-fold) at year 2. Serum TGP-IgG4 level was higher in SCIT compared with SLIT at years 1, 2, and 3 (10.4-, 27.4-, and 5.1-fold, respectively; all P < .01). Serum IgG4 levels to Phl p1, 2, 5b, and 6 were increased at years 1, 2, and 3 in SCIT and SLIT compared with placebo (Phl p1: 11.8- and 3.9-fold; Phl p2: 31.6- and 4.4-fold; Phl p5b: 135.5- and 5.3-fold; Phl p6: 145.4- and 14.7-fold, respectively, all at year 2 when levels peaked; P < .05). IgE to TGP in nasal fluid increased in the SLIT group at year 2 but not at year 3 compared with SCIT (2.8-fold; P = .04) and placebo (3.1-fold; P = .02). IgA to TGP and IgE and IgG4 to TGP components stratified participants according to treatment group and clinical response. CONCLUSIONS: The observed induction of IgA1/2 in SLIT and IgG4 in SCIT suggest key differences in the mechanisms of action.


Assuntos
Alérgenos/imunologia , Dessensibilização Imunológica , Imunoglobulinas/imunologia , Phleum/imunologia , Pólen/imunologia , Administração Sublingual , Adulto , Linfócitos B/imunologia , Método Duplo-Cego , Feminino , Humanos , Imunoglobulinas/sangue , Injeções Subcutâneas , Masculino , Mucosa Nasal/imunologia
8.
Am J Respir Crit Care Med ; 204(1): 23-33, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33651675

RESUMO

Rationale: Sensitization to Fel d 1 (Felis domesticus allergen 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy, are only moderately effective, and allergen immunotherapy has limited use because of safety concerns. Objectives: To explore the relationship among the pharmacokinetic, clinical, and immunological effects of anti-Fel d 1 monoclonal antibodies (REGN1908-1909) in patients after treatment. Methods: Patients received REGN1908-1909 (n = 36) or a placebo (n = 37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and Days 8, 29, and 85. Cytokine and chemokine concentrations in nasal fluids were measured, and REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. Measurements and Main Results: Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen-neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid and was detected in an inhibition assay. Type 2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES [regulated upon activation, normal T-cell expressed and secreted]) in nasal fluid were inhibited in REGN1908-1909-treated patients compared with placebo (P < 0.05 for all); IL-13 and IL-5 concentrations correlated with Total Nasal Symptom Score improvement. Ex vivo assays demonstrated that REGN1908 and REGN1909 combined were more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. Conclusions: A single, passive-dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients and was underscored by suppression of FcεRI-, FcεRII-, and T-helper cell type 2-mediated allergic responses. Clinical trial registered with www.clinicaltrials.gov (NCT02127801).


Assuntos
Alérgenos/efeitos adversos , Antialérgicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Gatos , Glicoproteínas/efeitos adversos , Fatores Imunológicos/uso terapêutico , Rinite Alérgica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antialérgicos/administração & dosagem , Anticorpos Monoclonais/imunologia , Método Duplo-Cego , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Imunoterapia , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Rinite Alérgica/etiologia , Rinite Alérgica/imunologia
9.
J Allergy Clin Immunol ; 147(2): 663-676, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33160969

RESUMO

BACKGROUND: Allergen-specific immunotherapy is a disease-modifying treatment that induces long-term T-cell tolerance. OBJECTIVE: We sought to evaluate the role of circulating CXCR5+PD-1+ T follicular helper (cTFH) and T follicular regulatory (TFR) cells following grass pollen subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) and the accompanying changes in their chromatin landscape. METHODS: Phenotype and function of cTFH cells were initially evaluated in the grass pollen-allergic (GPA) group (n = 28) and nonatopic healthy controls (NAC, n = 13) by mathematical algorithms developed to manage high-dimensional data and cell culture, respectively. cTFH and TFR cells were further enumerated in NAC (n = 12), GPA (n = 14), SCIT- (n = 10), and SLIT- (n = 8) treated groups. Chromatin accessibility in cTFH and TFR cells was assessed by assay for transposase-accessible chromatin sequencing (ATAC-seq) to investigate epigenetic mechanisms underlying the differences between NAC, GPA, SCIT, and SLIT groups. RESULTS: cTFH cells were shown to be distinct from TH2- and TH2A-cell subsets, capable of secreting IL-4 and IL-21. Both cytokines synergistically promoted B-cell class switching to IgE and plasma cell differentiation. Grass pollen allergen induced cTFH-cell proliferation in the GPA group but not in the NAC group (P < .05). cTFH cells were higher in the GPA group compared with the NAC group and were lower in the SCIT and SLIT groups (P < .01). Time-dependent induction of IL-4, IL-21, and IL-6 was observed in nasal mucosa following intranasal allergen challenge in the GPA group but not in SCIT and SLIT groups. TFR and IL-10+ cTFH cells were induced in SCIT and SLIT groups (all, P < .01). ATAC-seq analyses revealed differentially accessible chromatin regions in all groups. CONCLUSIONS: For the first time, we showed dysregulation of cTFH cells in the GPA group compared to NAC, SCIT, and SLIT groups and induction of TFR and IL-10+ cTFH cells following SCIT and SLIT. Changes in the chromatin landscape were observed following allergen-specific immunotherapy in cTFH and TFR cells.


Assuntos
Cromatina , Tolerância Imunológica/imunologia , Rinite Alérgica Sazonal/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Dessensibilização Imunológica/métodos , Feminino , Humanos , Injeções Subcutâneas , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Phleum/imunologia , Estudo de Prova de Conceito , Rinite Alérgica Sazonal/prevenção & controle , Imunoterapia Sublingual/métodos , Subpopulações de Linfócitos T/imunologia
10.
Ir J Psychol Med ; 37(3): 198-203, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32434603

RESUMO

Pharmacists, like psychiatrists, have modified their practices amidst COVID-19 in order to guarantee care and support to their patients. Designated an essential frontline service, community pharmacists are facing a spectrum of challenges to surmount to ensure patient care continues. These include assisting in the prevention of infection, managing supply chains, preventing stockpiling and provision of evidence-based medical information. However, disasters like COVID-19 disproportionately affect poor and vulnerable populations, and patients with mental health conditions may be among the hardest hit. Pharmacist-level, system-level and regulatory responses have sought to minimise this impact, although there is likely to be a lasting impression on the profession, both good and bad. This article reviews the pandemic-related challenges and responses by pharmacists, as well as forming recommendation for areas of professional support and role expansion, particularly in the case of mental health.


Assuntos
Betacoronavirus , Serviços Comunitários de Farmácia , Infecções por Coronavirus/psicologia , Transtornos Mentais/psicologia , Farmacêuticos/psicologia , Pneumonia Viral/psicologia , Papel Profissional/psicologia , COVID-19 , Humanos , Pandemias , Farmacêuticos/tendências , SARS-CoV-2 , Inquéritos e Questionários
12.
J Allergy Clin Immunol ; 144(3): 738-749, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30844425

RESUMO

BACKGROUND: A 3-week short-course of adjuvant-free hydrolysates of Lolium perenne peptide (LPP) immunotherapy for rhinoconjunctivitis with or without asthma over 4 physician visits is safe, well tolerated, and effective. OBJECTIVE: We sought to investigate immunologic mechanisms of LPP immunotherapy in a subset of patients who participated in a phase III, multicenter, randomized, double-blind, placebo-controlled trial (clinical.govNCT02560948). METHODS: Participants were randomized to receive LPP (n = 21) or placebo (n = 11) for 3 weeks over 4 visits. Grass pollen-induced basophil, T-cell, and B-cell responses were evaluated before treatment (visit [V] 2), at the end of treatment (V6), and after the pollen season (V8). RESULTS: Combined symptom and rescue medication scores (CSMS) were lower during the peak pollen season (-35.1%, P = .03) and throughout the pollen season (-53.7%, P = .03) in the LPP-treated group compared with those in the placebo-treated group. Proportions of CD63+ and CD203cbrightCRTH2+ basophils were decreased following LPP treatment at V6 (10 ng/mL, P < .0001) and V8 (10 ng/mL, P < .001) compared to V2. No change in the placebo-treated group was observed. Blunting of seasonal increases in levels of grass pollen-specific IgE was observed in LPP-treated but not placebo-treated group. LPP immunotherapy, but not placebo, was associated with a reduction in proportions of IL-4+ TH2 (V6, P = .02), IL-4+ (V6, P = .003; V8, P = .004), and IL-21+ (V6, P = .003; V8, P = .002) follicular helper T cells. Induction of FoxP3+, follicular regulatory T, and IL-10+ regulatory B cells were observed at V6 (all P < .05) and V8 (all P < .05) in LPP-treated group. Induction of regulatory B cells was associated with allergen-neutralizing IgG4-blocking antibodies. CONCLUSION: For the first time, we demonstrate that the immunologic mechanisms of LPP immunotherapy are underscored by immune modulation in the T- and B-cell compartments, which is necessary for its effect.


Assuntos
Alérgenos/imunologia , Asma/terapia , Conjuntivite/terapia , Lolium/imunologia , Peptídeos/uso terapêutico , Pólen/imunologia , Rinite Alérgica Sazonal/terapia , Adulto , Asma/imunologia , Linfócitos B Reguladores/imunologia , Conjuntivite/imunologia , Dessensibilização Imunológica , Método Duplo-Cego , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Masculino , Peptídeos/imunologia , Rinite Alérgica Sazonal/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto Jovem
13.
J Allergy Clin Immunol ; 143(3): 1131-1142.e4, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30053528

RESUMO

BACKGROUND: Grass pollen-specific immunotherapy involves immunomodulation of allergen-specific TH2 responses and induction of IL-10+ and/or TGF-ß+CD4+CD25+ regulatory T cells (induced Treg cells). IL-35+CD4+CD25+ forkhead box protein 3-negative T (IL-35-inducible regulatory T [iTR35]) cells have been reported as a novel subset of induced Treg cells with modulatory characteristics. OBJECTIVE: We sought to investigate mechanisms underlying the induction and maintenance of immunologic tolerance induced by IL-35 and iTR35 cells. METHODS: The biological effects of IL-35 were assessed on group 2 innate lymphoid cells (ILC2s); dendritic cells primed with thymic stromal lymphopoietin, IL-25, and IL-33; and B and TH2 cells by using flow cytometry and quantitative RT-PCR. Grass pollen-driven TH2 cell proliferation and cytokine production were measured by using tritiated thymidine and Luminex MagPix, respectively. iTR35 cells were quantified in patients with grass pollen allergy (seasonal allergic rhinitis [SAR] group, n = 16), sublingual immunotherapy (SLIT)-treated patients (SLIT group, n = 16), and nonatopic control subjects (NACs; NAC group, n = 16). RESULTS: The SAR group had increased proportions of ILC2s (P = .002) and IL-5+ cells (P = .042), IL-13+ cells (P = .042), and IL-5+IL-13+ ILC2s (P = .003) compared with NACs. IL-35 inhibited IL-5 and IL-13 production by ILC2s in the presence of IL-25 or IL-33 (P = .031) and allergen-driven TH2 cytokines by effector T cells. IL-35 inhibited CD40 ligand-, IL-4-, and IL-21-mediated IgE production by B cells (P = .015), allergen-driven T-cell proliferation (P = .001), and TH2 cytokine production mediated by primed dendritic cells. iTR35 cells suppressed TH2 cell proliferation and cytokine production. In addition, allergen-driven IL-35 levels and iTR35 cell counts were increased in patients receiving SLIT (all, P < .001) and NACs (all, P < .001) compared with patients with SAR. CONCLUSION: IL-35 and iTR35 cells are potential novel immune regulators induced by SLIT. The clinical relevance of SLIT can be underscored by restoration of protective iTR35 cells.


Assuntos
Alérgenos/imunologia , Interleucinas/imunologia , Linfócitos/imunologia , Poaceae/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/terapia , Imunoterapia Sublingual , Adulto , Feminino , Humanos , Tolerância Imunológica , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/imunologia , Adulto Jovem
14.
Am J Respir Crit Care Med ; 196(12): 1526-1534, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28915062

RESUMO

RATIONALE: Recombinant fragment of human surfactant protein D (rfhSP-D) has been shown to suppress house dust mite- and Aspergillus fumigatus-induced allergic inflammation in murine models. OBJECTIVES: We sought to elucidate the effect of rfhSP-D on high-affinity IgE receptor- and CD23-mediated, grass pollen-induced allergic inflammatory responses. METHODS: rfhSP-D, containing homotrimeric neck and lectin domains, was expressed in Escherichia coli BL21(λDE3)pLysS cells. Peripheral blood mononuclear cells and sera were obtained from individuals with grass pollen allergy (n = 27). The effect of rfhSP-D on basophil activation and histamine release was measured by flow cytometry. IgE-facilitated allergen binding and presentation were assessed by flow cytometry. T-helper cell type 2 (Th2) cytokines were measured in cell culture supernatants. The effect of rfhSP-D on IgE production by B cells when stimulated with CD40L, IL-4, and IL-21 was also determined. MEASUREMENTS AND MAIN RESULTS: rfhSP-D bound to Phleum pratense in a dose- and calcium-dependent manner. Allergen-induced basophil responsiveness and histamine release were inhibited in the presence of rfhSP-D, as measured by CD63, CD203c (P = 0.0086, P = 0.04205), and intracellularly labeled diamine oxidase (P = 0.0003, P = 0.0148). The binding of allergen-IgE complexes to B cells was reduced by 51% (P = 0.002) in the presence of rfhSP-D. This decrease was concomitant with reduction in CD23 expression on B cells (P < 0.001). rfhSP-D suppressed allergen-driven CD27-CD4+CRTh2+ T-cell proliferation (P < 0.01), IL-4, and IL-5 levels (all P < 0.01). Moreover, rfhSP-D inhibited CD40L/IL-4- and IL-21-mediated IgE production (77.12%; P = 0.02) by B cells. CONCLUSIONS: For the first time, to our knowledge, we show that rfhSP-D inhibited allergen-induced basophil responses at a single-cell level and suppressed CD23-mediated facilitated allergen presentation and Th2 cytokine production. In addition, rfhSP-D inhibited IgE synthesis by B cells, which is also a novel observation.


Assuntos
Linfócitos B/imunologia , Basófilos/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Poaceae/imunologia , Pólen/imunologia , Proteína D Associada a Surfactante Pulmonar/imunologia , Adulto , Alérgenos/sangue , Alérgenos/imunologia , Feminino , Citometria de Fluxo , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/prevenção & controle , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação/sangue , Inflamação/prevenção & controle , Masculino , Pessoa de Meia-Idade , Proteína D Associada a Surfactante Pulmonar/sangue , Receptores de IgE/sangue , Receptores de IgE/imunologia , Células Th2 , Adulto Jovem
15.
J Environ Health ; 76(5): 32-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24437047

RESUMO

The study described in this article evaluated the effects of public health workforce cuts on routine food safety inspections and the occurrence of critical violations. Routine inspection information was collected from two Louisiana databases for permanent food establishments categorized as risk category 3 or 4 in East Baton Rouge Parish, Louisiana, for the years 2005, 2007, and 2009. The length of time between routine inspections nearly quadrupled from 2005 to 2009. For risk category 4 establishments, a significant increase occurred in the proportion of inspections that resulted in a critical violation between the three years. The amount of time between routine inspections was significantly higher for inspections that resulted in a critical violation versus those that did not. Lastly, the amount of time between routine inspections, an establishment's risk category, and history of complaint were found to have significant predictive effects on the incidence of a critical violation during a routine inspection, although results varied by year. Study results indicate that decreased workforce capacity in Louisiana may negatively affect the outcomes of routine food safety inspections.


Assuntos
Inspeção de Alimentos/métodos , Mão de Obra em Saúde , Saúde Pública , Restaurantes , Inspeção de Alimentos/economia , Inspeção de Alimentos/estatística & dados numéricos , Inspeção de Alimentos/tendências , Órgãos Governamentais , Louisiana , Saúde Pública/tendências , Governo Estadual
16.
Artigo em Inglês | MEDLINE | ID: mdl-15586877

RESUMO

Concerns about adequate protection of children's health from chemicals in the environment have created a need for research to identify how children's risks differ from adults'. A systematic review of factors that affect child sensitivity throughout development may be useful for research and practice in this area. We summarized available literature and other peer-reviewed information on factors that affect pharmacokinetics and exposure in an age-based developmental framework. Biological processes related to chemical absorption (gastrointestinal, dermal, and pulmonary), distribution, metabolism, and excretion were considered, along with reference to behaviors and other factors associated with child-specific exposures. The available information was summarized in a timeline of maturation for biological processes. It indicates variability in the duration and timing of maturation for each biological function. Possible implications for understanding pediatric sensitivity to environmental chemicals are discussed in light of factors affecting exposure through development. Themes that emerge from the evidence are presented as hypothesis-generating conclusions. This approach may be useful for evaluating developmental trends of susceptibility, and for identifying time periods and/or chemical classes of particular concern and thus important to consider in risk assessment.


Assuntos
Desenvolvimento Infantil , Exposição Ambiental , Poluentes Ambientais/farmacocinética , Poluentes Ambientais/intoxicação , Xenobióticos/farmacocinética , Xenobióticos/intoxicação , Adolescente , Fatores Etários , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Medição de Risco
17.
J Expo Anal Environ Epidemiol ; 14(7): 516-23, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15316572

RESUMO

Communities and research participants increasingly feel that they have rights to be equal partners with researchers and to have access to the results of studies to which they have contributed. Concurrently, research sponsors have become aware of legal liabilities, societal repercussions, and credibility impacts of ignoring research communication responsibilities. However, issues related to research communications are rarely discussed at professional meetings or taught in academic programs. As a result, individual investigators may not be clear about their duties to communicate the results of their research. It is important to address this gap between expectations and abilities, because researchers' lack of communication fosters a climate of distrust in science and implies disinterest or disrespect for participants and communities. Ethical, legal, and professional frameworks and practices were reviewed to develop insights about principles, guidelines, and means that can be used to promote best practices. A review of general research guidance and specific requests for proposals revealed sponsors' communication priorities. While there are barriers to research communication, there is an increasing awareness among sponsors and investigators that effective and responsive communication is not a cheap or uniform add-on to a project or proposal. Communications must be tailored to the project considering all potential stakeholders, and resources need to be allocated specifically for communication activities within projects. Researchers, sponsors, professional societies and academia all have opportunities to improve principles, policies, frameworks, guidelines and strategies to foster "best practice" communication of research results.


Assuntos
Benchmarking , Comunicação , Relações Comunidade-Instituição , Guias como Assunto , Austrália , Saúde Ambiental , Europa (Continente) , Substâncias Perigosas/intoxicação , Humanos , América do Norte , Política Pública , Pesquisa/tendências , Medição de Risco
18.
Risk Anal ; 24(1): 197-208, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15028012

RESUMO

An interdisciplinary workshop was convened by the George Washington University in June 2001 to discuss how to incorporate new knowledge about susceptibility to microbial pathogens into risk assessment and management strategies. Experts from government, academic, and private sector organizations discussed definitions, methods, data needs, and issues related to susceptibility in microbial risk assessment. The participants agreed that modeling approaches need to account for the highly specific nature of host-pathogen relationships, and the wide variability of infectivity, immunity, disease transmission, and outcome rates within microbial species and strains. Concerns were raised about distinguishing between exposure and dose more clearly, interpreting experimental and outbreak data correctly, and using thresholds and possibly linearity at low doses. Recommendations were made to advance microbial risk assessment by defining specific terms and concepts more precisely, designing explicit conceptual frameworks to guide development of more complex models and data collection, addressing susceptibility in all steps of the model, measuring components of immunity to characterize susceptibility, reexamining underlying assumptions, applying default methods appropriately, obtaining more mechanistic data to improve default methods, and developing more biologically relevant and continuous risk estimators. The interrelated impacts of selecting specific subpopulations and health outcomes, and of increasing model complexity and data demands, were considered in the contexts of public policy goals and resources required. The participants stated that zero risk is unattainable, so targeted and effective risk reduction and communication strategies are essential not only to raise pubic awareness about water quality but also to protect the most susceptible members of the population.


Assuntos
Microbiologia , Medição de Risco , Fatores Epidemiológicos , Órgãos Governamentais , Humanos , Modelos Biológicos , Saúde Pública , Política Pública , Gestão de Riscos , Estados Unidos
19.
Risk Anal ; 24(1): 209-20, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15028013

RESUMO

Regional estimates of cryptosporidiosis risks from drinking water exposure were developed and validated, accounting for AIDS status and age. We constructed a model with probability distributions and point estimates representing Cryptosporidium in tap water, tap water consumed per day (exposure characterization); dose response, illness given infection, prolonged illness given illness; and three conditional probabilities describing the likelihood of case detection by active surveillance (health effects characterization). The model predictions were combined with population data to derive expected case numbers and incidence rates per 100,000 population, by age and AIDS status, borough specific and for New York City overall in 2000 (risk characterization). They were compared with same-year surveillance data to evaluate predictive ability, assumed to represent true incidence of waterborne cryptosporidiosis. The predicted mean risks, similar to previously published estimates for this region, overpredicted observed incidence-most extensively when accounting for AIDS status. The results suggest that overprediction may be due to conservative parameters applied to both non-AIDS and AIDS populations, and that biological differences for children need to be incorporated. Interpretations are limited by the unknown accuracy of available surveillance data, in addition to variability and uncertainty of model predictions. The model appears sensitive to geographical differences in AIDS prevalence. The use of surveillance data for validation and model parameters pertinent to susceptibility are discussed.


Assuntos
Criptosporidiose/etiologia , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/etiologia , Animais , Criptosporidiose/epidemiologia , Cryptosporidium/isolamento & purificação , Cryptosporidium/patogenicidade , Humanos , Modelos Biológicos , Cidade de Nova Iorque/epidemiologia , Saúde Pública , Medição de Risco , Água/parasitologia , Abastecimento de Água
20.
Environ Sci Technol ; 37(9): 1882-91, 2003 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-12775061

RESUMO

The City of Stockton, CA operates a wastewater treatment facility that discharges tertiary treated effluent during the summer and secondary treated effluent during the winter to the San Joaquin River. Investigations were carried out between 1996 and 2002 to provide insight regarding the potential public health benefit that may be provided by year-round tertiary treatment. A hydraulic model of the San Joaquin River and a dynamic disease transmission model integrated a wide array of disparate data to estimate the level of viral gastroenteritis in the population under the two treatment scenarios. The results of the investigation suggest that risk of viral gastroenteritis attributable to the treatment facility under the existing treatment scheme is several orders of magnitude below the 8-14 illnesses per 1000 recreation events considered tolerable by U.S. EPA, and winter tertiary treatment would further reduce the existing risk by approximately 15-50%. The methodologies employed herein are applicable to other watersheds where additional water treatment is being considered to address public health concerns from recreation in receiving waters.


Assuntos
Modelos Teóricos , Saúde Pública , Recreação , Eliminação de Resíduos Líquidos/métodos , Purificação da Água , Abastecimento de Água , Gastroenterite/etiologia , Gastroenterite/virologia , Humanos , Medição de Risco , Estações do Ano
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