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3.
Curr Opin Allergy Clin Immunol ; 18(5): 370-376, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30048251

RESUMO

PURPOSE OF REVIEW: The aim of the review is to describe the different clinical pictures of anaphylaxis (phenotypes), in relation to the underlying mechanisms and potential biomarkers, to describe anaphylaxis endotypes. This may aid in achieving a better understanding, management and outcomes of such severe reactions. RECENT FINDINGS: Different anaphylaxis phenotypes have been outlined, ranging from the classical type-I-like to those suggestive of cytokine-storm-like or complement-mediated reactions. Underlying mechanisms differ and biomarkers of cells and systems involved are being identified (tryptase, IL-6, bradykinin etc.) SUMMARY: Identifying specific phenotypes/endotypes will allow the application of precision medicine in patients with anaphylaxis, providing insights to the most appropriate approach in each case.

4.
N Engl J Med ; 379(4): 352-362, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30044938

RESUMO

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).


Assuntos
Angioedemas Hereditários/prevenção & controle , Inibidores Enzimáticos/administração & dosagem , Calicreína Plasmática/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
5.
United European Gastroenterol J ; 5(6): 887-897, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29026603

RESUMO

BACKGROUND AND GOAL: Diarrhoea-predominant irritable bowel syndrome (IBS-D) exhibits intestinal innate immune and mucosal mast cell (MC) activation. MC stabilisers have been shown to improve IBS symptoms but the mechanism is unclear. Our primary aim was to investigate the effect of oral disodium cromoglycate (DSCG) on jejunal MC activation and specific innate immune signalling pathways in IBS-D, and secondarily, its potential clinical benefit. STUDY: Mucosal MC activation (by ultrastructural changes, tryptase release and gene expression) and innate immune signalling (by protein and gene expression) were quantified in jejunal biopsies from healthy (HS; n = 16) and IBS-D subjects after six months of either treatment with DSCG (600 mg/day, IBS-D-DSCG group; n = 18) or without treatment (IBS-D-NT group; n = 25). All IBS-D patients recorded abdominal pain and bowel habits at baseline and in the last 10 days prior to jejunal sampling. RESULTS: IBS-D-NT exhibited significant MC activation and over-expression of immune-related genes as compared to HS, whereas in IBS-D-DSCG MC activity and gene expression were similar to HS. Furthermore, DSCG significantly reduced abdominal pain and improved stool consistency. CONCLUSION: Oral DSCG modulates mucosal immune activity and improves gut symptoms in IBS-D patients. Future placebo-controlled clinical trials are needed for confirmation of clinical benefit of DSCG for IBS-D.

6.
Front Immunol ; 8: 846, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28798744

RESUMO

Anaphylaxis is the most severe form of allergic reaction, resulting from the effect of mediators and chemotactic substances released by activated cells. Mast cells and basophils are considered key players in IgE-mediated human anaphylaxis. Beyond IgE-mediated activation of mast cells/basophils, further mechanisms are involved in the occurrence of anaphylaxis. New insights into the potential relevance of pathways other than mast cell and basophil degranulation have been unraveled, such as the activation of the contact and the coagulation systems. Mast cell heparin released upon activation provides negatively charged surfaces for factor XII (FXII) binding and auto-activation. Activated FXII, the initiating serine protease in both the contact and the intrinsic coagulation system, activates factor XI and prekallikrein, respectively. FXII-mediated bradykinin (BK) formation has been proven in the human plasma of anaphylactic patients as well as in experimental models of anaphylaxis. Moreover, the severity of anaphylaxis is correlated with the increase in plasma heparin, BK formation and the intensity of contact system activation. FXII also activates plasminogen in the fibrinolysis system. Mast cell tryptase has been shown to participate in fibrinolysis through plasmin activation and by facilitating the degradation of fibrinogen. Some usual clinical manifestations in anaphylaxis, such as angioedema or hypotension, or other less common, such as metrorrhagia, may be explained by the direct effect of the activation of the coagulation and contact system driven by mast cell mediators.

7.
Int Arch Allergy Immunol ; 173(3): 171-177, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28793302

RESUMO

BACKGROUND: The use of intramuscular adrenaline to treat anaphylaxis is suboptimal, despite being the first-line treatment recommended by national and international anaphylaxis guidelines. Fear of potentially severe side effects may be one of the underlying factors. The aim of this study was to assess the incidence and severity of adverse side effects after the use of adrenaline in anaphylaxis, as well as potential risk factors. METHODS: Observational study based on a multicenter online registry of cases of adrenaline administration for suspected anaphylaxis. RESULTS: 277 registered valid cases were included: 138 (51.49%) female, median age 29 years (12-47), and 6 children under 2 years with a median age of 9 months (1-21). Side effects occurred in 58 cases (21.64%), with tremors, palpitations, and anxiety being the most frequent. There was a significant association of developing side effects with older age, higher dose of adrenaline, or use of the intravenous route. Potentially severe adverse effects (high blood pressure, chest discomfort, or ECG alterations) occurred only in 8 cases (2.99%); in these cases, no differences were found according to age or adrenaline dose, but again, intravenous administration was associated with more severe adverse events. CONCLUSION: This study shows that side effects affect less than 1 in 5 patients who receive adrenaline for an anaphylactic reaction, and are usually mild and transient. Therefore, in an emergency situation such as anaphylaxis, restricting adrenaline administration due to potential adverse effects would, in general, not be justified.


Assuntos
Anafilaxia/tratamento farmacológico , Broncodilatadores/efeitos adversos , Epinefrina/efeitos adversos , Adolescente , Adulto , Broncodilatadores/uso terapêutico , Criança , Epinefrina/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Adulto Jovem
8.
N Engl J Med ; 376(12): 1131-1140, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28328347

RESUMO

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).


Assuntos
Proteína Inibidora do Complemento C1/administração & dosagem , Angioedema Hereditário Tipos I e II/prevenção & controle , Adulto , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Angioedema Hereditário Tipos I e II/classificação , Humanos , Injeções Subcutâneas , Masculino , Risco , Autoadministração , Índice de Gravidade de Doença
9.
Intern Emerg Med ; 10(3): 345-50, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25666515

RESUMO

No specific drugs are licensed for the treatment of ACE inhibitor (ACEI)-acquired angioedema (ACEI-AAE). Icatibant, an antagonist of the B2 receptor of bradykinin, is a potential treatment for this condition; however, its use in this setting is poorly documented. We report here clinical outcomes of 13 patients with ACEI-AAE treated with icatibant, in a real-life setting. Thirteen patients on ACEI seen in an Emergency Department (ED) with angioedema involving face, lips or the upper airways were analyzed. Angioedema due to known causes other than ACEI treatment was excluded. Initially, all patients received standard therapy (antihistamine, corticosteroids and epinephrine). Due to the lack of response and a worsening severity of symptoms, all patients received one subcutaneous injection of icatibant (30 mg/mL). Following icatibant treatment, all patients experienced improvement in the symptoms. The median time from onset of clinical symptoms to injection of icatibant was 3 h (IQR 2.5-5.5 h). Symptom relief was reported at 30 min (IQR 27.5-70 min). A complete resolution of symptoms was observed at 5 h (IQR 4-7 h). Ten patients had previously experienced angioedema attacks. The Median time to complete resolution of the previous attacks was higher (54 h; IQR 33-63 h), than after icatibant (p = 0.002) therapy. No patients required tracheal intubation or tracheotomy, and all patients were discharged within 24 h. No adverse events were reported. Before discharge, all patients were instructed to discontinue ACEI, and to take a different antihypertensive agent. This case series supports the efficacy of icatibant in improving symptoms of ACEI-AAE.


Assuntos
Angioedema/induzido quimicamente , Angioedema/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Bradicinina/uso terapêutico , Serviço Hospitalar de Emergência , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade
10.
Gut ; 64(9): 1379-88, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25209656

RESUMO

BACKGROUND AND AIMS: Altered intestinal barrier is associated with immune activation and clinical symptoms in diarrhoea-predominant IBS (IBS-D). Increased mucosal antigen load may induce specific responses; however, local antibody production and its contribution to IBS aetiopathogenesis remain undefined. This study evaluated the role of humoral activity in IBS-D. METHODS: A single mucosal jejunal biopsy, luminal content and blood were obtained from healthy volunteers (H; n=30) and IBS-D (n=49; Rome III criteria) participants. Intraepithelial lymphocytes, mast cells, B lymphocytes and plasma cells were studied by imaging techniques. Differential gene expression and pathway analysis were assessed by microarray and PCR techniques. Blood and luminal immunoglobulins (Igs) were quantified. Gastrointestinal symptoms, respiratory atopy and stress and depression were also recorded. RESULTS: Patients with IBS-D showed a higher number and activation of mucosal B lymphocytes and plasma cells (p<0.05). Mast cell density was increased in patients with IBS-D (non-atopic) and in close proximity to plasma cells (p<0.05). Microarray profiling identified differential humoral activity in IBS-D, involving proliferation and activation of B lymphocytes and Igs production (p<0.001). Mucosal humoral activity was higher in IBS-D, with upregulation of germline transcripts and Ig genes (1.3-fold-1.7-fold increase; p<0.05), and increased IgG(+) cells and luminal IgG compared with H (p<0.05), with no differences in blood. Biological markers of humoral activity correlated positively with bowel movements, stool form and depression. CONCLUSIONS: Enhanced small bowel humoral immunity is a distinctive feature of IBS-D. Mucosal Ig production contributes to local inflammation and clinical manifestations in IBS-D.


Assuntos
Imunidade Humoral/imunologia , Mucosa Intestinal/imunologia , Síndrome do Intestino Irritável/imunologia , Síndrome do Intestino Irritável/fisiopatologia , Jejuno/patologia , Adulto , Análise de Variância , Biópsia por Agulha , Estudos de Casos e Controles , Diarreia/imunologia , Diarreia/patologia , Progressão da Doença , Feminino , Imunofluorescência , Humanos , Imunoglobulinas/imunologia , Imunoglobulinas/metabolismo , Imuno-Histoquímica , Mucosa Intestinal/patologia , Jejuno/imunologia , Masculino , Microscopia Eletrônica de Transmissão/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
11.
J Allergy Clin Immunol ; 135(4): 1031-43.e6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25240785

RESUMO

BACKGROUND: Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell-derived mediators into the circulation. OBJECTIVES AND METHODS: We report here that a plasma protease cascade, the factor XII-driven contact system, critically contributes to the pathogenesis of anaphylaxis in both murine models and human subjects. RESULTS: Deficiency in or pharmacologic inhibition of factor XII, plasma kallikrein, high-molecular-weight kininogen, or the bradykinin B2 receptor, but not the B1 receptor, largely attenuated allergen/IgE-mediated mast cell hyperresponsiveness in mice. Reconstitutions of factor XII null mice with human factor XII restored susceptibility for allergen/IgE-mediated hypotension. Activated mast cells systemically released heparin, which provided a negatively charged surface for factor XII autoactivation. Activated factor XII generates plasma kallikrein, which proteolyzes kininogen, leading to the liberation of bradykinin. We evaluated the contact system in patients with anaphylaxis. In all 10 plasma samples immunoblotting revealed activation of factor XII, plasma kallikrein, and kininogen during the acute phase of anaphylaxis but not at basal conditions or in healthy control subjects. The severity of anaphylaxis was associated with mast cell degranulation, increased plasma heparin levels, the intensity of contact system activation, and bradykinin formation. CONCLUSIONS: In summary, the data collectively show a role of the contact system in patients with anaphylaxis and support the hypothesis that targeting bradykinin generation and signaling provides a novel and alternative treatment strategy for anaphylactic attacks.


Assuntos
Anafilaxia/imunologia , Anafilaxia/metabolismo , Fator XII/metabolismo , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Mastócitos/imunologia , Adulto , Idoso , Anafilaxia/complicações , Anafilaxia/genética , Animais , Biomarcadores , Bradicinina/metabolismo , Modelos Animais de Doenças , Fator XII/antagonistas & inibidores , Fator XII/genética , Feminino , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Hipotensão/etiologia , Cininogênios/metabolismo , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Transdução de Sinais , Fatores de Tempo , Adulto Jovem
12.
J Clin Immunol ; 34(5): 521-3, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24760113

RESUMO

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal-dominant and life-threatening disorder caused by mutations in SERPING1 gene. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. Here we report the case of a patient with HAE-C1INH without family history of angioedema. By sequencing the SERPING1 gene we detected a novel mutation (c.1249 + 5G > A) affecting the 5' donor splice site in intron 7. We analyzed the SERPING1 cDNA expecting a defect in splicing process but only the wild type allele was detected. SNP analysis of the cDNA sequence demonstrated that only one of the two alleles was present, indicating that the mRNA from the mutated allele was completely degraded. This study reinforces the concept of incomplete penetrance of this disorder since the patients' mother never presented any sign of angioedema despite carrying the same mutation.


Assuntos
Angioedemas Hereditários/genética , Proteínas Inativadoras do Complemento 1/genética , Haploinsuficiência , Mutação , Estabilidade de RNA , RNA Mensageiro/metabolismo , Adulto , Alelos , Angioedemas Hereditários/imunologia , Angioedemas Hereditários/patologia , Sequência de Bases , Proteínas Inativadoras do Complemento 1/deficiência , Proteínas Inativadoras do Complemento 1/imunologia , Proteína Inibidora do Complemento C1 , Feminino , Humanos , Íntrons , Dados de Sequência Molecular , Penetrância , Sítios de Splice de RNA , RNA Mensageiro/genética
13.
Clin Immunol ; 150(2): 143-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24412907

RESUMO

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal-dominant disease caused by mutations in SERPING1 gene. The main clinical feature of C1INH deficiency is the spontaneous edema of the subcutaneous and submucosal layers. More than 280 different mutations scattering the entire SERPING1 gene have been reported. We identified and characterized a new mutation in SERPING1 gene in a Spanish family with hereditary angioedema. The mutation (c.685 + 2 T > A) disrupts the donor splice site of intron 4 leading to the loss of exon 4 in mutant mRNA. We demonstrated that mutant mRNA is mostly degraded, probably by the surveillance pathway no-go mRNA decay. Bioinformatic analysis showed that the mutant protein, if produced, would be non-functional since the protein lacks a stretch of 45 amino acids affecting the functional RCL loop. Finally, we found a reduction of the wild-type mRNA expression in c.685 + 2 T > A carriers.


Assuntos
Angioedemas Hereditários/genética , Proteínas Inativadoras do Complemento 1/genética , Mutação , Sítios de Splice de RNA , Adulto , Angioedemas Hereditários/diagnóstico , Criança , Proteínas Inativadoras do Complemento 1/química , Proteína Inibidora do Complemento C1 , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Modelos Moleculares , Conformação de Ácido Nucleico , Linhagem , Conformação Proteica , RNA Mensageiro/química , RNA Mensageiro/genética , Análise de Sequência de DNA , Espanha
14.
Health Econ Rev ; 3(1): 2, 2013 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-23398817

RESUMO

BACKGROUND: Icatibant is the only subcutaneous treatment for acute Type I and Type II hereditary angioedema with C1-esterase inhibitor deficiency (HAE-C1-INH) licensed for self-administration in Europe. AIM: To compare the economic impact of two icatibant administration strategies: health professional-administration only (strategy 1) versus including the patient self-administration option (strategy 2). METHODS: Economic evaluation model based on the building of a decision tree. Both strategies are assumed to have equivalent effectiveness. The payer (Spanish National Health System) and the social perspectives were considered. All relevant cost-generating factors were taken into account. The time horizon was one year. Sources of information included scientific evidence, official data and experts' opinion. A deterministic sensitivity analysis was carried out to quantify the underlying uncertainty in the model. RESULTS: From the social perspective, which considers both direct (health care costs) and indirect costs (productivity losses), strategy 2 would result into average savings of €121.30 per acute attack compared to strategy 1. For Spain, this would achieve in an annual savings of €551,371. The reduction in direct costs accounts for 74% of the savings and lower indirect costs account for the remaining 26%. Savings per acute attack may range from €79.50 to €169.80; accordingly, the annual savings in Spain may vary between €90,319 and €2,315,360. CONCLUSION: Costs related to the management of acute HAE attacks with C1 inhibitor deficiency may be substantially reduced through interventions targeting home treatment by training patients to self-administer icatibant.

15.
Gut ; 62(8): 1160-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22637702

RESUMO

OBJECTIVE: Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. DESIGN: A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117(+) cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. RESULTS: Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. CONCLUSION: The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.


Assuntos
Diarreia/patologia , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/patologia , Jejuno/patologia , Adolescente , Adulto , Biópsia , Diarreia/etiologia , Diarreia/metabolismo , Feminino , Humanos , Junções Intercelulares/ultraestrutura , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestrutura , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/metabolismo , Jejuno/metabolismo , Jejuno/ultraestrutura , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Cadeias Leves de Miosina/metabolismo , Fosforilação , Estudos Prospectivos , Fatores Sexuais , Estresse Psicológico/complicações , Proteínas de Junções Íntimas/metabolismo , Adulto Jovem
16.
Int Arch Allergy Immunol ; 160(2): 192-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23018683

RESUMO

BACKGROUND: The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis. OBJECTIVE: It was the aim of this study to determine sequential serum tryptase concentrations during anaphylaxis and to evaluate its potential as a diagnostic marker. METHODS: We performed a prospective study including patients with acute anaphylaxis (according to the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria) attending the emergency department. Demographic characteristics, anaphylactic triggers, specific risk factors, clinical characteristics and management of anaphylaxis were recorded. Serum tryptase was measured at 1-2 h (T1), 4-6 h (T2) and 12-24 h (T3) following onset of the episode and at basal conditions (TB). RESULTS: A total of 102 patients were included (63 females, mean age 47.4 ± 19.1 years). Tryptase concentration at T1 (19.3 ± 15.4 µg/l) was significantly higher than at T2, T3 and TB (all <11.4 µg/l; p < 0.0001). Importantly, tryptase was not raised in 36.3% of cases; furthermore, in 60.6% of these patients, no changes were observed in tryptase levels comparing T1 and TB (ΔT1-TB = 0). Tryptase was more frequently elevated in more severe anaphylaxis (p < 0.0001) and positively correlated with the grades of severity (p < 0.001, r = 0.49). Anaphylaxis was more severe and tryptase concentration higher when the causative agent was a drug compared to food, both at T1 (p = 0.045) and at TB (p = 0.019). Age and coronary risk factors were associated with more severe anaphylaxis (p = 0.001). CONCLUSION: Tryptase is a biomarker related to the severity of anaphylaxis. However, since its concentration remains unaltered in a considerable number of patients during acute anaphylaxis, there is a need for more reliable diagnostic biological tests.


Assuntos
Anafilaxia/sangue , Anafilaxia/diagnóstico , Triptases/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Health Qual Life Outcomes ; 10: 82, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22817696

RESUMO

BACKGROUND: There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. METHODS/DESIGN: Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. DISCUSSION: To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version.


Assuntos
Angioedemas Hereditários/psicologia , Proteínas Inativadoras do Complemento 1/deficiência , Psicometria/métodos , Qualidade de Vida , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Medicina Baseada em Evidências , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pesquisa Qualitativa , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Espanha
20.
Am J Gastroenterol ; 107(5): 736-46, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22415197

RESUMO

OBJECTIVES: Diarrhea-predominant irritable bowel syndrome (IBS-D) patients show altered epithelial permeability and mucosal micro-inflammation in both proximal and distal regions of the intestine. The objective of this study was to determine the molecular events and mechanisms and the clinical role of upper small intestinal alterations. METHODS: Clinical assessment and a jejunal biopsy was obtained in IBS-D patients and healthy subjects. Routine histology and immunohistochemistry was performed in all participants to assess the number of mast cells (MCs) and intraepithelial lymphocytes. RNA in tissue samples was isolated to identify genes showing consistent differential expression by microarray analysis followed by pathway and network analysis in order to identify the biological functions of the differentially expressed genes in IBS-D. Gene and protein expression of tight junction (TJ) components was also assessed by quantitative real-time polymerase chain reaction and confocal microscopy to evaluate the pathways identified by gene expression analysis. RESULTS: The analysis reveals a strong association between the transcript signature of the jejunal mucosa of IBS-D and intestinal permeability, MC biology, and TJ signaling. The expression of zonula occludens 1 (ZO-1) was reduced in IBS-D at both gene and protein level, with protein redistribution from the TJ to the cytoplasm. Remarkably, our analysis disclosed significant correlation between ZO proteins, MC activation, and clinical symptoms. CONCLUSIONS: IBS-D manifestations are linked to molecular alterations involving MC-related dysregulation of TJ functioning in the jejunal mucosa.


Assuntos
Diarreia/complicações , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/genética , Síndrome do Intestino Irritável/metabolismo , Jejuno/metabolismo , Transdução de Sinais , Junções Íntimas/metabolismo , Adulto , Feminino , Expressão Gênica , Humanos , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/patologia , Jejuno/patologia , Linfócitos/patologia , Masculino , Mastócitos/patologia , Análise em Microsséries , Pessoa de Meia-Idade , Permeabilidade , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
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