Oxidative stress and cellular immunity in patients with recurrent aphthous ulcers

Recurrent aphthous ulcer (RAU) is an inflammatory condition of the oral mucosa characterized by painful, well-circumscribed, single or multiple round or ovoid ulcerations. The exact etiologic factor(s) of these ulcerations are not yet understood. The objective of this study was to evaluate inflammatory processes and free radical metabolism of 25 patients with RAUs compared to 25 healthy controls. The levels of malondialdehyde (MDA) and glutathione (GSH) were determined by high-performance liquid chromatography. Tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), IL-10, and IL-12 were determined by ELISA. Nitric oxide (NO), myeloperoxidase (MPO), total antioxidant status (TAS), and total oxidant status (TOS) levels were measured spectroscopically in serum. The levels of MDA, GSH, TNF-α, IL-2, IL-12, MPO, and TOS, and oxidative stress index (OSI) were higher, and the levels of NO, IL-10, and TAS were lower in patients with RAU than in controls. Statistical analysis showed that GSH, TNF-α, IL-2, IL-10, and OSI differed significantly in patients with RAU compared to controls. These parameters have important roles in oxidant/antioxidant defense.

Toll-like receptor activity in Recurrent Aphthous Ulceration

Toll-like receptors (TLR) are membrane proteins that recognize conserved molecules derived from bacterial, virus, fungal or host tissues. Activation of TLRs causes the production of cytokines that mediate inflammatory responses and drive T helper (Th) 1 and 2 cell development. As an exaggerated Th1 immune response is supposed to be involved in pathogenesis of Recurrent Aphthous Ulceration (RAU), we suggest that RAU patients may have an imbalance in TLR pathways. To study the function of TLR activation ex vivo, peripheral blood mononuclear cells (PBMCs) from RAU patients (n = 17) and controls (n = 17) were exposed to TLR2 [lipoteichoic acid (LTA), heat-killed Listeria monocytogenes (HKLM) and PamC3CSK4], TLR3 [Poly(I:C)], TLR4 [lipopolysaccharide (LPS)], TLR5 (flagellin) and TLR7 (imiquimod) ligands, and the time course of supernatant tumor necrosis factor-alpha (TNF-alpha) levels was quantified by enzyme-linked immunosorbent assay. In addition, serological and salivary TNF-alpha and soluble CD14 levels were quantified. The TNF-alpha produced by PBMCs in contact with each TLR ligand and autologous serum or saliva at the same time was also investigated. The data were analyzed by statistical multivariate tests. The control group had a higher response to LTA, whereas RAU had a higher response to HKLM. LTA and LPS interfered with the salivary stimulation of the RAU PBMC and HKLM with the stimulation of the control. Autologous serum was capable of inhibiting TLR2 responsiveness to LTA and enhancing LPS stimulation. Salivary and serological levels of sCD14 and TNF-alpha were not significantly different. Recurrent Aphthous Ulceration patients have an anomalous activity of the TLR2 pathway that probably influences the stimulation of an abnormal Th1 immune response.

Psychological stress and recurrent aphthous stomatitis

INTRODUCTION AND OBJECTIVES: Recurrent aphthous stomatitis (RAS) is the most common type of ulcerative disease of the oral mucosa. Despite its worldwide occurrence and the extensive amount of research that has been devoted to the subject, the etiology of RAS remains unclear. Nevertheless, several hereditary, nutritional, infectious and psychological factors have been associated with RAS. The aim of this case-control study was to assess the influence of psychological stress on the manifestation of RAS. METHOD: Fifty patients were enrolled in the trial. Twenty-five RAS patients constituted the study group and another 25 non-RAS patients who were similarly matched for sex, age and socioeconomic status constituted the control group. Each patient was evaluated in terms of the four domains of stress (emotional, physical, social and cognitive) using an internationally validated questionnaire, which was comprised of 59 items and measured the frequency and intensity of stress symptoms. The RAS group was interviewed during an active RAS episode. Completed questionnaires were submitted to proper analytical software and interpreted by an expert psychologist. RESULTS: There was a higher level of psychological stress among RAS group patients when compared to the control group (P < 0.05). CONCLUSION: Psychological stress may play a role in the manifestation of RAS; it may serve as a trigger or a modifying factor rather than being a cause of the disease.

Systemic treatment in severe cases of recurrent aphthous stomatitis: an open trial

PURPOSE: This study aimed to evaluate the efficacy of the systemic drugs thalidomide, dapsone, colchicine, and pentoxifylline in the treatment of severe manifestations of RAS. METHODS: An open, 4-year clinical trial was carried out for 21 consecutive patients with severe RAS. Initially, patients were given a 2-week course of prednisone to bring them to a baseline status. Simultaneously, one of the four test drugs was assigned to each patient to be taken for a period of 6 months. During the course of the trial, patients were switched to one of the other three drugs whenever side effects or a lack of satisfactory results occurred, and the 6-month limit of the treatment was then reset. RESULTS: The most efficient and best-tolerated drug was thalidomide, which was administered to a total of eight patients and resulted in complete remission in seven (87.5%). Dapsone was prescribed for a total of nine patients, of whom eight (89%) showed improvement in their symptoms, while five showed complete remission. Colchicine was administered to a total of ten patients, with benefits observed in nine (90%), of whom four showed complete remission. Pentoxyfilline was administered to a total of five patients, with benefits observed in three (60%), of whom one patient showed complete remission. CONCLUSION: The therapeutic methods used in this trial provided significant symptom relief. Patients experienced relapses of the lesions; however, this occurred after withdrawal of their medication during the follow-up period.

Aphtes récidivants: comment faire face [How to cope with recurrent aphthous stomatitis].

Recurrent aphthous stomatitis (RAS) is the most common oral mucosa ailment. This condition is frequently considered as idiopathic due to the doubts about its etiology, probably related to a minor immunological dysregulation in a context of genetic predisposition. However, ulcers that resemble recurrent aphthous stomatitis in some respects can be found in systemic disorders that must be ruled out for the differential diagnosis of SAR, particularly when they appear after adolescence and/or when associated lesions exist out of the oral cavity. SAR management lies on the elimination of predisposing factors (drugs, oral trauma, food allergies...) and if needed, topical corticosteroids are the first choice regimen. More severe cases may require systemic regimens.

CC chemokine ligand 3 and receptors 1 and 5 gene expression in recurrent aphthous stomatitis

Objective. The aim of this study was to investigate the local and systemic expression of CC-chemokine ligand 3 (CCL3) and its receptors (CCR1 and CCR5) in tissue samples and peripheral blood mononuclear cells of recurrent aphthous stomatitis (RAS) patients. Study Design. This case-control study enrolled 29 patients presenting severe RAS manifestations and 20 non-RAS patients proportionally matched by sex and age. Total RNA was extracted from biopsy specimens and peripheral blood mononuclear cells for quatitative reverse-transcription polymerase chain reaction. The data obtained by relative quantification were evaluated by the 2(-Delta Delta Ct) method, normalized by the expression of an endogenous control, and analyzed by Student t test. Results. The results demonstrated overexpression in RAS tissue samples of all of the chemokines evaluated compared with healthy oral mucosa, whereas the blood samples showed only CCR1 overexpression in RAS patients. Conclusions. These findings suggest that the increased expression of CCL3, CCR1, and CCR5 may influence the immune response in RAS by T(H)1 cytokine polarization. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:93-98)

Differential expression of toll-like receptor mRNAs in recurrent aphthous ulceration

BACKGROUND: Toll-like receptors (TLR) are membrane proteins that recognize conserved molecules derived from bacterial, viral, fungal or host tissues. They are responsible for promoting the production of cytokines and chemokines, increasing the expression of costimulatory molecules and influencing the T Helper response (Th) toward either a Th1 or Th2 profile, thereby modulating the regulatory T cell response and controlling the integrity of the epithelial barrier. The key factors responsible for increased susceptibility to recurrent aphthous ulceration (RAU) are unclear, and because TLRs are involved in both immune regulation and control of the epithelial barrier, a deficiency in TLR activity is likely to cause increased susceptibility. METHODS: We investigated the gene expression of TLRs one through 10 in tissue samples and peripheral blood mononuclear cells (PBMC) of RAU patients in comparison to healthy controls using real-time quantitative reverse transcription PCR. RESULTS: The analysis of mRNA expression levels in oral lesion showed significant (P < 0.01) overexpression of the TLR2(similar to 6-fold) gene and decreased expression of the TLR3 (similar to 5-fold) and TLR5 (similar to 6-fold) genes in comparison with healthy oral mucosa. The analysis of mRNA expression in PBMC indicated a down-regulation of TLR5 gene expression in the cells from RAU patients (P < 0.05; similar to 2-fold). CONCLUSION: Our results support the hypothesis that a subset of RAU patients has fewer TLR expression that have been tentatively implicated in antiinflammatory effects. This derangement of TLR gene expression may cause an overlay exuberant inflammation reaction in situations where normal individuals are resistant. J Oral Pathol Med (2012) 41: 8085

Gastrinoma de Localização Pilórica numa Doente com Úlcera Péptica Recorrente

Apresenta-se o caso clínico de uma mulher de 56 anos, raça branca, com úlcera duodenal e esofagite com 3 anos de evolução apesar de terapêutica mantida com bloqueadores dos receptores H2. O valor da gastrina sérica basal estava ligeiramenteacima dos limites superiores do normal. O teste de estimulação de secretina foi sugestivo de gastrinoma. Com tomografia axial computorizada e arteriografia selectiva não se localizou o tumor. Na laparotomia exploradora encontrou-se um nódulo pilórico que se demonstrou corresponder ao gastrinoma. Dezoito meses após a cirurgia a doente encontrou-se assintomática e os exames de controle são negativos.

Prevalence of Oral Lesions in Hospitalized Patients with Infectious Diseases in Northern Brazil

The aim of this study was to assess the prevalence of oral lesions in infectious-contagious diseases patients being treated in the University Hospital of the Federal University of Para, northern Brazil. One hundred seven patients with infectious diseases were clinically investigated for oral lesions at the University Hospital of Para, northern Brazil. From total sample, most patients were men (65.7%) with a mean age of 45.4 years. About prevalence of systemic diseases, tuberculosis was the most frequent illness, followed by AIDS, hepatitis types B and C, leishmaniasis, and meningitis. Analyzing oral manifestations, periodontal diseases and candidiasis were the most prevalent diseases in both genders, followed by recurrent aphthous ulcers, saburral tongue, simplex herpes, and squamous cell carcinoma. Of all 107 patients, only 10 males and 6 females did not present any oral manifestation. There was no statistical difference between genders with any systemic condition (P > 0.05). The great prevalence of oral manifestations in hospitalized patients with systemic disorder emphasizes the need of integral dental care in this context, aiming at a multidisciplinary approach of patients. Therefore, presence of some oral conditions, such as candidiasis, should be an alert to different systemic conditions, once in assistance with physicians; dentists can influence the early diagnosis and treatment.

Oral manifestations in patients with hypogammaglobulinemia

Objective. The overall objective of this study was to assess the oral manifestations and their association with immunologic status and health history, of individuals with hypogammaglobulinemia. Study Design. A case-controlled study of 100 subjects with hypogammaglobulinemia and 93 control individuals was performed. All participants were examined for dental caries, periodontal disease, mucosal lesions/infections, and general oral health problems. Decayed, missing, filled teeth and community periodontal index were recorded. Complete blood count, serum immunoglobulins, and lymphocyte immunophenotyping were measured on the same day of the oral health assessment. Results. Individuals with hypogammaglobulinemia showed higher prevalence of enamel hypoplasia and complaints of dry mouth, and lower prevalence of dental caries and periodontal disease. Conclusions. The systemic conditions associated with hypogammaglobulinemia were not associated with enhanced susceptibility to caries, gingivitis, or periodontitis; however, individuals with hypogammaglobulinemia were more likely to report more episodes of recurrent aphthous ulcers compared with control individuals. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e19-e24)

Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production.

BACKGROUND: The exact pathogenesis of the pediatric disorder periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome is unknown. OBJECTIVES: We hypothesized that PFAPA might be due to dysregulated monocyte IL-1β production linked to genetic variants in proinflammatory genes. METHODS: Fifteen patients with PFAPA syndrome were studied during and outside a febrile episode. Hematologic profile, inflammatory markers, and cytokine levels were measured in the blood. The capacity of LPS-stimulated PBMCs and monocytes to secrete IL-1β was assessed by using ELISA, and active IL-1β secretion was visualized by means of Western blotting. Real-time quantitative PCR was performed to assess cytokine gene expression. DNA was screened for variants of the MEFV, TNFRSF1A, MVK, and NLRP3 genes in a total of 57 patients with PFAPA syndrome. RESULTS: During a febrile attack, patients with PFAPA syndrome revealed significantly increased neutrophil counts, erythrocyte sedimentation rates, and C-reactive protein, serum amyloid A, myeloid-related protein 8/14, and S100A12 levels compared with those seen outside attacks. Stimulated PBMCs secreted significantly more IL-1β during an attack (during a febrile episode, 575 ± 88 pg/mL; outside a febrile episode, 235 ± 56 pg/mL; P < .001), and this was in the mature active p17 form. IL-1β secretion was inhibited by ZYVAD, a caspase inhibitor. Similar results were found for stimulated monocytes (during a febrile episode, 743 ± 183 pg/mL; outside a febrile episode, 227 ± 92 pg/mL; P < .05). Genotyping identified variants in 15 of 57 patients, with 12 NLRP3 variants, 1 TNFRSF1A variant, 4 MEFV variants, and 1 MVK variant. CONCLUSION: Our data strongly suggest that IL-1β monocyte production is dysregulated in patients with PFAPA syndrome. Approximately 20% of them were found to have NLRP3 variants, suggesting that inflammasome-related genes might be involved in this autoinflammatory syndrome.

International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients.

OBJECTIVES: The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. METHODS: We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. RESULTS: Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. CONCLUSION: We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome: a Review of the Pathogenesis.

PFAPA syndrome represents the most common cause of recurrent fever in children in European populations, and it is characterized by recurrent episodes of high fever, pharyngitis, cervical adenitis, and aphthous stomatitis. Many possible causative factors have been explored so far, including infectious agents, immunologic mechanisms and genetic predisposition, but the exact etiology remains unclear. Recent findings demonstrate a dysregulation of different components of innate immunity during PFAPA flares, such as monocytes, neutrophils, complement, and pro-inflammatory cytokines, especially IL-1β, suggesting an inflammasome-mediated innate immune system activation and supporting the hypothesis of an autoinflammatory disease. Moreover, in contrast with previous considerations, the strong familial clustering suggests a potential genetic origin rather than a sporadic disease. In addition, the presence of variants in inflammasome-related genes, mostly in NLRP3 and MEFV, suggests a possible role of inflammasome-composing genes in PFAPA pathogenesis. However, none of these variants seem to be relevant, alone, to its etiology, indicating a high genetic heterogeneity as well as an oligogenic or polygenic genetic background.

A sociodemographic, clinical study of patients with venous ulcer

Background Venous ulcer is the most serious consequence of chronic venous insufficiency and is responsible for almost 70% of chronic leg ulcers. The main purpose of this research was to describe social, demographic and clinical characteristics of patients with venous ulcers and to identify some professional repercussions of this pathology.Subjects and methods We evaluated patients with a clinical picture compatible with venous ulcer. The sociodemographic characteristics of the patients, and the clinical characteristics and professional repercussions of the pathology were studied. We used the ankle-brachial index to identify associated arterial disease. The body mass index (BMI) was used for the classification of the nutritional condition of the patients.Results A total of 120 patients were included in the study (90 females and 30 males; 80.8% White; 44.2% > 60 years old). Ninety-one per cent of the patients had been in education for less than 4 years, and 89.7% were on the poverty line. Thirty-five per cent were retired, 2.5% were receiving government help due to disease and 4.2% were unemployed. About 16% of patients were out of work due to the disease, and 49.2% presented some degree of disability in terms of work tasks. The ulcer area was less than 30 cm(2) in 69.1% of patients. The first ulcer episode occurred in 13.4 years on average, and 64.2% of patients had recurrent episodes. Females presented on average 5.65 pregnancies, and 75.4% of patients were overweight.Conclusion Venous ulcer occurred mainly in the low-income population, who presented with little formal education. Generally, the ulcers were present for a long time and were recurrent, with repercussions for the capabilities of patients to work.