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Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder caused by mutations of chromosome 17. The NF1 clinical diagnosis is based on pre-established criteria, including the presence of cutaneous neurofibromas, café au lait spots, and iris (Lisch) nodules. Early detection and a multidisciplinary approach are essential for the prevention of complications, including problems of function, aesthetics, and self-esteem, as well as the occurrence of malignant transformation. This study reports a case of an exuberant NF1 manifestation diagnosed by a dental surgeon, whose investigation of a family led to the diagnosis of NF1, with different expressivities, in 3 generations.

Made available in DSpace on 2019-10-06T16:46:49Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-01 Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG35-55 and the animals were injected daily with Ket from the seventh to the 17th day after disease induction. This early intervention with Ket significantly reduced disease prevalence and severity. The protective effect was concomitant with less NLRP3 inflammasome activation, rebalanced oxidative stress and also reduced T cell infiltration at the CNS. Even though Ket administration did not alter mast cell percentage at the CNS, it decreased the local CPA3 and CMA1 mRNA expression that are enzymes typically produced by these cells. Evaluation of the CNS-barrier permeability indicated that Ket clearly restored the permeability levels of this barrier. Ket also triggered an evident lymphadenomegaly due to accumulation of T cells that produced higher levels of encephalitogenic cytokines in response to in vitro stimulation with MOG. Altogether these findings reinforce the concept that mast cells are particularly relevant in MS immunopathogenesis and that Ket, a known stabilizer of their activity, has the potential to be used in MS control. Department of Microbiology and Immunology Institute of Biosciences São Paulo State University (UNESP), Rua Dr. Plinio Pinto e Silva, S/N, Distrito de Rubião Júnior Department of Chemistry and Biochemistry Institute of Biosciences São Paulo State University (UNESP) Department of Surgery Stomatology Pathology and Radiology Bauru School of Dentistry University of São Paulo (USP) Department of Microbiology and Immunology Institute of Biosciences São Paulo State University (UNESP), Rua Dr. Plinio Pinto e Silva, S/N, Distrito de Rubião Júnior Department of Chemistry and Biochemistry Institute of Biosciences São Paulo State University (UNESP)

Made available in DSpace on 2020-12-12T01:34:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-06-01 Aim: To investigate the immune response of disseminated Ryzopus oryzae infection in immunocompetent mice. Methods: C57Bl/6, BALB/c and Swiss wild-type mice were intravenously infected with R. oryzae; the parameters of infection and immune response were determined. Transcriptional signature of Th17 immune response and infection in Il17ra-/- mice were also evaluated. Results: All mouse strains showed an initial spread of R. oryzae in the target tissues; however, after 30 days, C57Bl/6 and BALB/c mice showed an effective fungal clearance associated with specific production of IL-17 and IL-2. We also observed that 60% of Il17ra-/- mice succumbed to infection within 16 days. Conclusion: This study has established an immunocompetent model for disseminated mucormycosis and highlighted the role of IL-17 signaling in immunity against R. oryzae. Universidade Estadual Paulista (Unesp) Faculdade de Ciências Universidade Estadual Paulista (Unesp) Instituto de Biociências Lauro de Souza Lima Institute Universidade de São Paulo (USP), Faculdade de Odontologia de Bauru (FOB) Universidade Federal de Mato Grosso do Sul (UFMS) Faculdade de Medicina Universidade Estadual Paulista (Unesp) Faculdade de Ciências Universidade Estadual Paulista (Unesp) Instituto de Biociências

Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.

The biological process of epithelial-to-mesenchymal transition (EMT) has been studied in oral squamous cell carcinoma (OSCC) metastasis, but it is rarely evaluated at several stages of oral carcinogenesis. This study aimed to analyze the presence of SNAIL and E-cadherin proteins, markers of EMT, in the development and progression of OSCC, evaluating excised specimens of potentially malignant lesions (oral leukoplakia with and without dysplasia-OL and OLD, respectively), tumor tissues (OSCC), metastatic lymph nodes (LN), and normal oral mucosa (NOM) by immunohistochemistry, considering subcellular localization. Additionally, SNAIL and E-cadherin transcripts were evaluated in vitro by qPCR, using SCC-9 cell line in comparison to human keratinocytes (HPEC). There was a significant increase in nuclear expression of SNAIL from NOM to OLD followed by a noticeable decrease in nuclear expression accompanied by increased cytoplasmic expression in OSCC (p0.05). The E-cadherin cytoplasmic expression was remarkable and statistically significant higher in OSCC and LN, both compared to NOM (p0.0001), OL (p0.01) and OLD (p0.0001 and p0.001, respectively). In vitro, E-cadherin and SNAIL transcripts were lower in SCC-9 compared to HPEC cells, although only the decrease of E-cadherin was statistically significant (p0.05). Regarding the association of E-cadherin and SNAIL expression with the clinical findings, the analysis revealed an association between the cytoplasmic expression of SNAIL and the invasion pattern (p=0.05) in OSCC. The increased nuclear SNAIL expression may be characteristic of OLD, and the presence of E-cadherin in cell cytoplasm a marker of transformation to malignancy of potentially malignant oral leukoplakias into OSCC.

Made available in DSpace on 2022-04-29T08:27:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-07-20 Squamous cell carcinoma (SCC) is the second most common form of skin cancer and the mechanism(s) involved in the progression of this tumor are unknown. Increases in the expression of IL-33/ST2 axis components have been demonstrated to contribute to neoplastic transformation in several tumor models and interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue. Based on these observations, we sought to determine the role of the IL-33/ST2 pathway during the development of SCC. Our findings show that ST2- deficiency led to a marked decrease in the severity of skin lesions, suggesting that ST2 signaling contributed to tumor development. An analysis of tumor lesions in wild-type and ST2KO mice revealed that a lack of ST2 was associated with specific and significant reductions in the numbers of CD4+ T cells, CD8+ T cells, dendritic cells, and macrophages. In addition, NK cells that were isolated from ST2KO mice exhibited higher cytotoxic activity than cells isolated from wild-type mice. Notably, ST2 deficiency resulted in lower IFN-γ, TNF-α, IL-10, and IL-17 production in tumor samples. Our findings indicate that the IL-33/ST2 pathway contributes to the development of SCC by affecting leukocyte migration to tumor microenvironment and impairing NK cytotoxic activity. Department of Biological Sciences Bauru School of Dentistry University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla Department of Microbiology and Immunology Institute of Biosciences of Botucatu São Paulo State University, R. Prof. Dr. Antônio Celso Wagner Zanin Department of Stomatology - Oral Pathology Bauru School of Dentistry University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla Department of Biochemistry and Immunology School of Medicine of Ribeirão Preto University of São Paulo Department of Biomedical Sciences (Research Division of Immunology) and Medicine F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Cedars-Sinai Medical Center Department of Medicine Division of Pulmonary and Critical Care Medicine Cedars-Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center Department of Microbiology and Immunology Institute of Biosciences of Botucatu São Paulo State University, R. Prof. Dr. Antônio Celso Wagner Zanin

Background Tumour metastasis has been associated with cancer stem cells, a small population with stem-like cells properties, higher rate of migration and metastatic potential compared to cells from the tumour bulk. Our aim was to evaluate the immunoexpression of the putative cancer stem cell biomarkers ALDH1 and CD44 in primary tumour and corresponding metastatic lymph nodes. Methods Tumour tissue specimens (n = 50) and corresponding metastatic lymph nodes (n = 25) were surgically obtained from 50 patients with oral squamous cell carcinoma and submitted to immunohistochemistry. CD44 and ALDH1 were semi-quantitatively scored according to the proportion and intensity of positive cells within the invasive front and metastatic lymph nodes as a whole. A combined score was obtained by multiplying both parameters and later dichotomized into a final score classified as low (≤2) or high (>2) immunoexpression. Results ALDH1 immunoexpression and CD44 immunoexpression were detected in both tumour sites, although the means of ALDH1 (P = .0985) and CD44 (P = .4220) cells were higher in metastasis compared to primary tumours. ALDH1high was positively associated (P = .0184) with angiolymphatic invasion, while CD44high was positively associated (P = .0181) with metastasis (N+). At multivariate analysis, CD44 significantly increased the odds of lymph node metastasis, regardless of T stage (OR = 8.24; 1.64-65.64, P = .0088). Conclusions CD44 immunoexpression was a significant predictor of lymph node metastasis, while ALDH1high immunostaining was associated with angiolymphatic invasion. Altogether, it suggests that immunoexpression of CD44 and ALDH1 links the cancer stem cell phenotype with oral squamous cell carcinoma invasion and metastasis.

Due to the low incidence of the Ewing's Sarcoma (ES) family tumors, the available epidemiology is likely to be unreliable, and at present, there are no standard diagnostic or clinical guidelines outlining their management. This report describes a case of peripheral primitive neuroectodermal tumor (ES/pPNET) which initially mimicked cystic lesions, and describes a comparison between ES and ES/pPNET in the jaws by the World Health Organization classification. This review addressed 63 cases published in the English literature between 1950 and 2016. The majority of cases were ES. Both ES and ES/pPNET mimicked other benign entities such as traumatic, cystic and inflammatory lesions. The patients who died of their disease had a history of metastatic tumors, and primary tumor located in the mandible and maxilla for ES and ES/pPNET, respectively. The differentiation of the ES family tumors from other small blue-cell tumors may be difficult and requires familiarity with histological and immunohistochemical features.

A 55-year-old male with leukoderma, retired, had a main complaint of having a white spot on the tongue, unknown evolution time. The patient had no systemic history and was an ex-smoker (35 years). Clinically, he had a white plaque on the right lateral border of the tongue, asymptomatic, 5.0 × 1.5 cm in diameter, resilient, smooth surface, homogeneous, and well delimited. In addition, he had whitish plaques in the eyes. Incisional biopsy revealed oral mucosa consisting of hyperplastic stratified squamous epithelium, with areas of acanthosis, and cells of the middle and superficial layers were vacuolized with clear cytoplasm (basket weave aspect). Underlying, fibrous connective tissue with an extensive area of skeletal muscle fibers interspersed with adipose cells was noted. Due to clinical and histopathologic findings, the diagnosis was hereditary benign intraepithelial dyskeratosis. The patient reported not knowing if anyone in the family showed the same lesion. The conduct was clinical preservation and periodic controls.

Purpose: Candida albicansis known to produce secreted aspartyl proteinases (SAPs) to aid adhesion, invasion, and host tissue destruction. SAPs may contribute to denture stomatitis (DS) pathogenesis. The aim of this study was to develop an in vivo experimental model for Candida-associated DS that allows the analysis of SAP2, SAP5 ,a nd SAP9 expression by C. albicans from biofilm induced on the denture surface. MaterialsandMethods: Thirty-fivemaleWistarratswere dividedintothree groups: control, denture, and denture/Candida group. The last two groups remained with dentures for 2, 4, and 6 days, with or without induced biofilm. SAP expression was concomitant with leukocyte counts as well as clinical and histological changes shown by animal palate. Results: The signs observed at 4 days in the denture/Candida group were clinically closer to the Candida-associated DS, showing a significant increase of neutrophils and decrease of lymphocytes in peripheral blood, presence of inflammation signs on the palate similar to DS Newton type I, and fungal invasion in the epithelial layer. Accordingly, the denture/Candida group at 4 days presented the highest relative expression of all SAPs studied. Conclusion: The results showed a coincidence between SAP expression and clinical, microscopic, and blood data. Finally, the molecular findings were consistent with the virulence capacities of C. albicans from biofilm formed on the denture resin, which possibly allowed epithelial invasion by the fungus.

Lipomas are very common benign slow-growing soft tissue neoplasms composed of mature adipose tissue mostly diagnosed in the fifth decade of life. These tumors rarely present in the oral cavity, representing less than approximately 5% of all benign mouth tumors. They are usually less than 2cm in size and etiology remains unclear. We report a young male patient presenting with a giant lipoma in the buccal mucosa. Histopathology revealed a large area of mature fat cells consistent with conventional lipoma and an area of the mucosal lining of the lesion suggestive of morsicatio buccarum. In the present article, we emphasize the clinicopathological features and differential diagnosis of the disease.

Nodularna leukoplakija je nehomogeni oblik oralne leukoplakije obično s bijelom bradavičastom, nodularnom, ulceriranom ili eritematoznom (crvenkastom) površinom s velikim rizikom od pretvorbe u malignu tvorbu u usporedbi s homogenim oblikom. Najčešće zahvaća komisure usnica, obraznu sluznicu i meko nepce. Često je povezana s epitelnom displazijom ili karcinomom, pa je prijeko potrebna detaljna mikroskopska procjena, a poslije redovite kontrole. Temelj za postavljanje točne dijagnoze jest odabrati pravo mjesto za biopsiju, ali i bliska suradnja liječnika dentalne medicine i oralnog patologa., Nodular leukoplakia is a non-homogeneous type of oral leukoplakia presenting a white surface with verrucous, nodular, ulcerated or erythematous features with a greater risk of malignant transformation when compared to the homogeneous type. Common sites of involvement include lip commissures, buccal mucosa and soft palate. It is often associated with epithelial dysplasia or carcinoma and requires detailed microscopic assessment and regular follow-up. The importance of a proper selection of the area to be biopsied and the close teamwork between a dentist and oral pathologist is the basis of providing an accurate final diagnosis.

Research on cancer stem cells (CSCs) has greatly increased in the field of medicine and pathology; however, some conceptual misunderstandings are still present among the public as well as within the general scientific community that is not yet familiar with the subject. The very first problem is the misinterpretation of CSCs as a synonym of their normal counterparts, the well-known stem cells (SCs). Particularly in Dentistry, another common mistake is the misinterpretation of oral CSCs as normal tooth-derived SCs. The present review aims to clarify important concepts related to normal SCs and CSCs, as well as discuss the relevance of CSCs to the development, metastasis and therapy resistance of oral squamous cell carcinoma.

Background: Antifungal agents incorporated into temporary denture resilient liners as drug carriers and delivery have been suggested as an alternative treatment for denture stomatitis. However, to test the in vivo biocompatibility of this protocol, standardization of an intraoral device for optimal drug delivery is required. Objective: Standardized criteria were produced to adjust an acrylic intraoral device (IOD) for rats feasible for denture stomatitis treatment by sustained drug-delivery based on minimal inhibitory drug concentrations (MICs) of antifungals for Candida albicans biofilm. Method: Adjustments methodological involved diet, impression technique, type of retention device to the palate and histopathological analysis. 115 Wistar rats were tested without IOD, with devices without relining or relined with temporary resilient material (Trusoft) modified or not by drugs at MICs (nystatin- 0.032g/mL; chlorhexidine diacetate-0.064g/mL; ketoconazole-0.128g/mL). The animals were sacrificed after 7 or 14 days from the IOD installation. Results: Paste diet enabled the best animal survival conditions. The IODs that most satisfactorily remained in position were those designed only to the posterior palatal mucosa and cement-retained in molars, being all obtained from impressions highly detained and individual. In both periods, Trusoft without/with drugs showed good performance. Only histological samples from hard/soft tissues were considered appropriate for region of interest-RI determination (n=12), which corresponded to the area restricted to the first molars between the palatal neurovascular bundles. Final samples of all groups allowed a standardized descriptive histopathological analysis in both periods. Conclusion: The methodological standardization of this rat model resulted in IODs for optimal antifungal delivery for denture stomatitis treatment.

Candida-associated denture stomatitis (DS) is the most frequent lesion among denture wearers, especially the elderly. DS is strongly associated with Candida albicans, as well as local and systemic factors, such as impaired immune response. Monocytes are important in the protective immune response against the fungus by the production of cytokines that recruit and activate leukocytes. There are functional changes in these cells with age, and individual alterations involving monocyte response may predispose the host to developing infections by Candida spp. In this study, our aim was to evaluate the production of TNF-α, IL-6, CXCL8, IL-1β, MCP-1 and IL-10 by monocytes from elderly denture wearers with/without DS and elderly or young non-denture wearers. We detected that monocytes from elderly denture wearers with Candida-related denture stomatitis produced lower levels of CXCL-8, IL-6 and MCP-1. This imbalance in cytokine levels was observed in spontaneous or LPS-stimulated production. Therefore, our data suggested that inherent aspects of the host, such as changes in cytokine production by monocytes, might be associated with the development and the persistence of DS irrespective of aging.

We have identified impaired neutrophils in elderly individuals which could be involved with Candida-related denture stomatitis (DS), an oral infection predominantly caused by Candida albicans, affecting especially elderly individuals using dental prosthesis. However, specific mechanisms performed by neutrophil contributing to the susceptibility of the elderly to DS are not fully understood. This study evaluated activation features of blood neutrophils from elderly and young individuals with DS. Blood neutrophils cultured with C. albicans from elderly subjects secreted decreased levels of CXCL8. However, C. albicans challenged-neutrophils from DS patients produced high IL-4 and IL-10, and low GM-CSF levels, regardless of age. Additional elastase activity of neutrophils from both elderly groups was detected after incubation with C. albicans, but only neutrophils from elderly DS demonstrated high myeloperoxidase activity. Therefore, DS patients have affected neutrophils, and the advance of age intensifies these damages. In summary, individuals with Candida-related denture stomatitis presented variation in the neutrophil phenotype and activation. Such alterations were more intense in neutrophils from infected elderly individuals.

doi: 10.1111/j.1741-2358.2011.00476.x Salivary immunity in elderly individuals presented with Candida-related denture stomatitis Objectives: Elderly individuals with Candida-related denture stomatitis (DS) present with a reduced defence against Candida albicans. This study evaluated levels of antimicrobial mediators in the elderly DS saliva and salivary neutrophils’ activation characteristics compared with elderly and young without DS. Methods: Salivary peroxidases (SPO) and elastase activities (ELA), nitric oxide (NO), transforming growth factor beta (TGF-β), IL-6 and CCL3 production were determined in saliva from elderly with or without DS, and young control individuals. TLR4, CXCR1, CD11b, CD16 and CD32 expression on salivary neutrophils were evaluated. Correlations between number and apoptosis rate of salivary neutrophils, enzymatic activities and cytokine levels were determined. Results: Elderly DS individuals exhibited the lowest SPO and ELA activities. Also, the activity of both enzymes was low in elderly without DS. Although both elderly groups showed higher salivary NO and TGF-β levels compared to young control groups, elderly DS presented the highest salivary NO, TGF-β, IL-6 and CCL3 levels. Decreased percentages of salivary TLR4+ and CD16+ neutrophils were detected in both elderly groups. Although these damages could influence the establishment and persistence of DS, the highest levels of salivary IL-6 and CCL3 in elderly DS could be preventing more serious complications.

Studies investigating the immunopathological aspects of Jorge Lobo ' s disease have shown that the infl ammatory infi ltrate consists mainly of histiocytes and multinucleated giant cells involving numerous yeast-like cells of Lacazia loboi , with the T lymphocytes more common than B lymphocytes and plasma cells. The quantifi cation of cytokines in peripheral blood mononuclear cells culture supernatant has revealed alterations in the cytokines profi le, characterized by predominance of a Th2 profi le. In view of these fi ndings and of the role of cytokines in cell interactions, the objective of the present study was to investigate the presence of the cytokines IL-10, TGF- s 1 and TNF- α , as well as iNOS enzyme in granulomas induced by L. loboi . Histological sections obtained from skin lesions of 16 patients were analyzed by immunohistochemistry for the pres- ence of these cytokines and iNOS. The results showed that TGF- s 1 was the cytokine most frequently expressed by cells present in the infl ammatory infi ltrate, followed by IL-10. There was a minimum to discrete positivity of cells expressing TNF- α and iNOS. The results suggest that the presence of immunosuppressive cytokines in skin lesions of patients with the mycosis might be responsible for the lack of containment of the patho- gen as demonstrated by the presence of numerous fungi in the granuloma.

Summary We previously showed that neutrophils from patients with Candida-related denture stomatitis exhibited damaged function, and the advance in age intensified this condition. Because such alterations had been determined in elderly people that were not denture wearers, the purpose of this study was to clarify functional and phenotypic characteristics of neutrophils from elderly denture wearers (EDW) and young denture wearers (YDW) without oral lesion. We enrolled 20 denture wearers (12 EDW and 8 YDW) and determined the positivity of Candida species on maxillary prosthesis and palate. Additionally, blood and salivary neutrophils were evaluated. Furthermore, cytokines and chemokines salivary levels were detected. YDW presented higher positivity of Candida albicans than elderly ones. However, blood neutrophils from EDW expressed less CXCR1, CD62L and CD11b and had lower C. albicans phagocytosis than YDW. Although myeloperoxidase and elastase activity was significantly higher in C. albicans-stimulated blood neutrophils from elderly, they produced high levels of IL-10 and low levels of Granulocyte macrophage-colony stimulating factor (GM-CSF). Despite apoptosis rate of salivary neutrophils was enhanced, these cells were at a high number in YDW. GM-CSF and IL10 were lower in saliva from elderly group. These data confirmed that ageing affects blood and salivary neutrophils and could predispose elderly to persistent oral infections.

Candida albicans is considered the most important Candida species able to cause oral infections in denture wearers. In recent years, Candida dubliniensis has emerged as a pathogenic yeast in humans. The close phenotypic similarities of C. albicans and C. dubliniensis have led to the misidentification of these species. In this work, our aim was to verify through PCR the presence of C. dubliniensis in palate and maxillary denture samples from 112 denture wearers presenting with or without denture-related stomatitis (DRS). C. dubliniensis was isolated at low rates from both palate (5.3 % and 10.7 %) and maxillary denture (5.3 % and 8.9 %) samples from wearers regardless of the presence of the disease. However, when C. dubliniensis was detected in individuals with DRS, it was always associated with C. albicans. In addition, our results showed that C. albicans was the most commonly identified candidal species in maxillary denture and hard palate samples from DRS patients (78.5 % and 89.2 %, respectively) as well as from controls (31.2 % and 28.5 %, respectively). In conclusion, C. dubliniensis was detected in the oral environment of denture wearers. The association of C. dubliniensis with C. albicans occurred in approximately 10 % of the DRS cases.

It is becoming accepted that multiple cell types in stromal microenvironment are involved in tumorigenesis. In this setting, mast cells (MC) display a diversity of roles that may contribute to the defense against tumors or tumor progression. Thus, the aim of this study was to evaluate density and migration of MCs in OSCC (oral squamous cell carcinoma) and pre-malignant oral hyperkeratosis (leukoplakia) as well as their relationship with clinical and microscopic parameters. The tryptase and c-kit expression was analyzed in 38 cases of OSCC, 26 cases of leukoplakia, and 12 cases of clinically healthy oral mucosa (control) by means of immunohistochemistry. The tryptase(+) cell numbers were decreased in OSCC (P=0.0003) and leukoplakia (P=0.03) compared with control. Similar numbers of tryptase(+) cells were observed in leukoplakia and OSCC (P=0.31). The density of c-kit(+) MCs was also significantly lower in OSCC and leukoplakia in relation to control resulting in a reduced c-kit(+)/tryptase(+) relationship in OSCC (19%) in comparison with leukoplakia (59%) and control (63%). No correlation was observed between MC populations with clinical and microscopic characteristics of OSCC. Our findings suggest that the decrease in MC numbers in pre-malignant and malignant oral lesions may be related to the migration failure of these cells, possibly reflecting an important modification in the microenvironment during tumor initiation and progression.

Papillary cystadenoma is a rare, benign salivary gland tumor which is well-circumscribed, containing cystic cavities with intraluminal papillary projections. Only 19 cases arising within minor salivary glands (MnSG) from the oral cavity sites have been reported in the English literature (PubMed 1958–2014). We report 11 new cases of MnSG papillary cystadenomas in conjunction with a review of the literature. Demographic information, clinical and histologic features, treatment and prognosis are compiled and discussed for all 30 cases reported in the English literature.

Background: Periapical lesions are thought to be the result of a local inflammatory response mediated by inflammatory cell infiltration and production of inflammatory mediators. Although chemokines are strongly implicated in the migration and activation of leukocytes in different inflammatory diseases and experimental models, little is known regarding the expression of chemokines and their receptors in human apical periodontitis. Objective and methods: The objective of this study was to determine the expression of chemokines and their receptors by real-time polymerase chain reaction in samples obtained from healthy gingiva, periapical granulomas, and inflammatory periradicular cysts. The inflammatory infiltrate was characterized by immunohistochemistry. Results: Comparing cysts and granulomas, an increase in CD4+ and CD8+ cells was observed in granulomas, despite the similar numbers of CD45RO-positive cells detected in both lesions. The analysis of mRNA expression revealed increased levels of CCR1, CCR2, CCR3, CCR5, CXCR1, and CXCR3 in both types of lesion compared with controls. Cysts exhibited a higher expression of CCR3, CCR5, CXCR1, and CXCR3 compared to granulomas. A significantly higher expression of RANTES, IP-10, and MCP-1 was detected in cysts compared with controls or granulomas. The expression of interleukin-8, MIP-1α, and MIP-1β was not different in the three experimental groups. Conclusions: The increase in Th1 type (CCR1, CCR5, and CXCR3) and Th2 type (CCR2 and CCR3) receptors in both periapical lesions suggests the concomitant occurrence of Th1 and Th2 responses. Furthermore, the prevalent expression of the receptors CCR3, CCR5, CXCR1, and CXCR3 and of the chemokines RANTES, IP-10, and MCP-1 in cysts may point to a role in the progression of granulomas to cysts.

To analyse age- and gender-related microscopic changes in sublingual glands obtained from human cadavers.One hundred eighty six human sublingual glands were obtained from 93 autopsies. Approximately five individuals of each gender per decade of life were allocated to three age groups: group I (0-30 years, n=26); group II (31-60 years, n=32) and group III (61-90 years, n=35). The specimens were fixed in 10% formalin and submitted to routine histological processing, and sections were stained with hematoxylin and eosin.Significant differences with increasing age were observed for the following microscopic aspects: acinar atrophy (r=0.26, p=0.0115); replacement of parenchyma by fibrous tissue (r=0.79, p0.0001) and/or adipose tissue (r=0.63, p0.0001); oncocytosis (r=0.61, p0.0001); duct-like structures (chi(2)=14.68, p=0.0006) and congested blood vessels (chi(2)=7.18, p=0.0276). The mononuclear infiltrate changed from focal to diffuse with age (H=8.47, p=0.0144). No significant differences were observed between genders.The aging process starts with acinar atrophy, followed by the presence of duct-like structures and ends with the replacement of the parenchyma by fibrous and/or adipose tissue. The mononuclear infiltrate changes from focal to diffuse. No difference in the aging of the sublingual glands is observed between men and women.

Dentin contains numerous polypeptides and signaling molecules sequestered in a mineralized matrix. The exposure and release of these molecules occur as a consequence of injury to the pulp and periodontal ligament, which may result from luxation, orthodontic movement or infections of tooth and periodontal structures. When released at these sites, dentin constituents have the potential to act on different surrounding cells, including periodontal cells, osteoblasts, osteoclasts and inflammatory cells, and to affect the course of dental disease. Experimental studies have highlighted the interactions between dentin and cells from tooth and periodontal tissues and reveal dentin to be a cell adhesive, signaling and migratory stimulus for various mesenchymal and inflammatory cells. These results support the hypothesis that dentin molecules might function as regulatory signals for the healing and resorption of dental and periodontal tissues. Data from recent and classical investigations are summarized, many open questions are discussed, and current hypotheses concerning the mechanisms of tooth resorption and periodontal healing are outlined. Many questions regarding the importance of dentin as a source of multifunctional molecules remain unanswered and provide important directions for future studies.

Cells other than macrophages and lymphocytes have recently been shown capable of producing cytokines and mediators. Among these are mast cells, a cell population now recognized for its immunoregulatory properties. Little is known about the complex interactions between cells, cytokines, and other inflammatory elements in periapical lesions. The objective of this investigation was to determine the immunohistochemical pattern of expression of mast cells tryptase in periapical lesions based on study of 20 apical granulomas and 20 periapical cysts. Microscopic analysis revealed mast cells to be present in greater numbers in periapical cysts than in apical granulomas, and in cysts were more numerous in regions of active inflammation. Mast cells tended to be more common in the peripheral regions of both periapical lesions, and were often found in close proximity to lymphocytes. These findings lead us to propose a functional relationship between these two cell populations that may facilitate elicitation of an immune response contributory to the pathogenesis of periapical lesions.

A distinctive form of paradental cyst can occur on the buccal and apical aspects of erupted mandibular molars. This cyst has peculiar clinical and radiographic features, although the microscopic findings are the same as those of odontogenic inflammatory cysts. Diagnostic and therapeutic problems can occur when this lesion is misinterpreted as a radicular cyst. The purpose of this paper is to present an additional case of a paradental cyst in the buccal and mesial aspects of a mandibular second molar involving the apical area of a mandibular first molar. The difficulty of diagnosis, treatment, and controversies regarding terminology are also discussed.

Pilomatricomas are relatively rare tumors of ectodermal origin from the outer root sheath cell of the hair follicle. They are usually asymptomatic, solitary, firm or hard, freely mobile, dermal or subcutaneous nodules. The purpose of this article is to present a case that illustrates the diagnostic difficulty encountered by oral surgeons and pathologists and to review the literature regarding pilomatricomas of the auricular region. Pilomatricomas são tumores relativamente raros de origem ectodérmica a partir das células da bainha externa do folículo piloso. Estes se apresentam geralmente como nódulos dérmicos ou subcutâneos, usualmente assintomáticos, solitários, firmes ou duros e extremamente móveis. O objetivo deste artigo é apresentar um caso que ilustra a dificuldade de diagnóstico encontrada pelos cirurgiões e patologistas bucais e apresentar uma revisão da literatura relativa aos pilomatricomas da região auricular.

The expression of the inducible nitric oxide synthase enzyme (iNOS) is a response to an inflammatory stimulus and produces a large amount of nitric oxide (NO), which may act as a cytotoxic molecule against the invading microorganism and may be related to both harmful and beneficial effects to tissues. OBJECTIVE AND MATERIAL AND METHODS: Inorder to further characterize the presence of NO in human periodontal disease, we undertook a quantitative study of iNOS positive cells in samples of clinically healthy gingival tissues, plaque-induced gingivitis and localized chronic periodontitis using immunohistochemistry. RESULTS: A significant increase in the number of iNOS+ cells mm−2 was found in the samples of the gingivitis and periodontitis compared with those of the control. In all groups most of the polymorphonuclear cells showed intense immunoreactivity for iNOS independent of the disease stage, and the percentage of iNOS+ polymorphonuclear cells increased significantly in periodontal disease when compared with the control. CONCLUSION: Our results indicate that iNOS increases in the presence of periodontal disease. In addition, our findings suggest that polymorphonuclear cells present anadditional activation pathway in periodontal disease, expressing significant iNOS and probably representing an important source of NO in human periodontal disease that has not been previously reported.

In the periapex, the interaction among inflammatory cells and microorganisms and their products results both in specific and nonspecific immune responses. Many studies have reported quantitative analysis of the immunocompetent cells in periapical lesions, but the exact ratio of these cells in cysts and granulomas remains unknown. In the present study, we undertook a quantitative analysis of CD68 + cells and CD8 + T cells in human periapical granulomas and cysts. Immunoperoxidase staining revealed that CD68 + cells were present in both lesions, with no statistically significant difference, mainly distributed in the inner portion of the lesion, where the inflammation site is more active. On the other hand, CD8 + lymphocytes were more numerous in cysts. Thus, it appears that CD8 + T cells may play a more important role in a later phase of periapical lesion progression, probably exerting regulatory or cytotoxic functions in cellular immune response, which may lead to the stabilization of these lesions. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:221-7)

This study evaluated the expression of pattern recognition receptors (PRRs) and activation factors associated with salivary and blood neutrophils from different aged patients diagnosed with Candida-related denture stomatitis (DS). Expression of neutrophil PRRs was determined by flow cytometry and immunofluorescence, and the levels of selected cytokines that influence immune activation were determined by ELISA. The salivary (but not the serum derived) neutrophils of individuals with DS were found to have an increased expression of CD69 regardless of the age of the patient compared to patients without DS. However, these salivary neutrophils had a lower expression of CD66b and CD64. Expression of TLR2 was lower on the salivary- and serum-derived neutrophils from elderly individuals compared to the neutrophils of younger subjects, regardless of whether the individual had DS. Salivary interleukin (IL)-4 was elevated in both of the elderly subject groups (with or without DS). Only elderly DS patients were observed to have increased serum IL-4 levels and reduced salivary IL-12 levels. Younger DS patients showed an increase in salivary IL-10 levels, and both the saliva and the serum levels of IFN-γ were increased in all of the younger subjects. Our data demonstrated that changes in both the oral immune cells and the protein components could be associated with DS. Furthermore, changes in the blood-derived factors were more associated with age than DS status.

Initially described by Gorlin et al. in 1962, the calcifying cystic odontogenic tumor (CCOT) may be associated with unerupted teeth, ameloblastomas, adenomatoid odontogenic tumors, and, in many cases, with odontomas. It is rare in patients in the first decade of life, particularly involving deciduous teeth. Surgery is the treatment of choice, with low recurrence rates. We present a clinical case of CCOT associated with odontoma and a missing deciduous tooth in a 3-year-old female patient. The lesion was removed under general anesthesia. The patient has been followed up for 1 year, and no recurrence was found. This appears to be the first report in such a young age.

Pleomorphic adenoma (PA), the most common salivary gland tumor, accounts for 54 to 65% of all salivary gland neoplasias and 80% of the benign salivary gland tumors. It most frequently affects the parotid gland, followed by the submandibular and the minor salivary glands. Microscopically, mucous, sebaceous, oncocytic and squamous metaplasia, sometimes with the formation of keratin pearls, may be present, but the latter rarely results in the formation of extensive keratin-filled cysts lined by squamous epithelium. Extensive squamous metaplasia can be mistaken for malignancy, including mucoepidermoid carcinoma and squamous cell carcinoma. Here, we present an unusual case of PA with extensive squamous metaplasia and keratin cyst formations in a minor salivary gland, and discuss its microscopic features, including the immunohistochemical characteristics, and differential diagnosis of this uncommon presentation.

Inhibitory signals mediated via molecules such as programmed death-1 (PD-1) play a critical role in downmodulating immune responses and maintaining peripheral tolerance. We investigated the involvement of cytokines and PD-1 engagement in mediating the T-cell unresponsiveness to bacterial and ubiquitous antigens in periodontal diseases.Gingival and peripheral blood samples from healthy individuals and patients with chronic periodontitis were collected and used for the subsequent assays. Leukocytes in the lesion site and blood were evaluated using flow cytometry. The production of interferon-gamma, interleukin-10, and transforming growth factor-beta proteins was evaluated by enzyme-linked immunosorbent assay (ELISA), and the presence of PD-1+ cells in the inflamed gingiva was confirmed by immunofluorescence confocal microscopy for CD4 and PD-1 colocalization.T cells from patients with chronic periodontitis proliferated poorly in response to Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) antigen. T-cell unresponsiveness was not associated with imbalanced cytokine production. However, T cells from patients with chronic periodontitis expressed significantly higher levels of PD-1 either upon isolation or after culture with antigens. Moreover, PD-1 blocking did not result in significant T-cell proliferation in cells cultured with phytohemagglutinin or bacterial antigens. The blockade of PD-1 resulted in the increased production of IFN-gamma. In addition, CD4+ and CD8+ T cells expressing PD-1 accumulated in lesions with chronic periodontitis.These data show that PD-1 engagement could be involved in the modulation of IFN-gamma production by T cells in patients with chronic periodontitis.

Objective The objective of this study was to determine the expression of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) during apical periodontitis development. Methods Using an experimental design of induced periapical lesions in rats and immunohistochemistry assay as investigative tool, the MMP-2 and MMP-9 expression and distribution were evaluated at 3, 7, 14, 21, 30, 60 and 90 days after coronary access and pulp exposure of the first left mandibular molar to the oral environment. Two blind observers scored the immunoreactivity. A semi-quantitative analysis was performed. Results Except at day 3, MMP-2 and MMP-9 immunostaining was observed in all experimental periods. The MMP-2 ( p = 0.004) and MMP-9 ( p = 0.005) immunostaining was higher in the period between 7 and 21 days. They were mainly observed in cells surrounding the apical foramen and adjacent periapical areas. Cells into the hypercementosis areas were strongly stained while both osteoblasts and osteoclasts presented discrete staining along of this study. No staining was observed on epithelial walls. At 30, 60 and 90 days, the subjacent connective tissue presented intense MMP-2 and MMP-9 immunostaining in mononuclear cells (suggestive of fibroblasts, macrophages, infiltrating neutrophils and lymphocytes). Conclusion The results observed in this study suggest that MMP-2 and MMP-9 play a critical role in the development of inflammatory periapical lesions, probably involved in the extracellular matrix (ECM) degradation during the initial phase of the lesion development.

Objective To investigate the expression of bone resorption regulators (receptor activator of nuclear factor kappa B [RANK], RANK ligand [RANKL], and osteoprotegerin [OPG]) in calcifying cystic odontogenic tumor (CCOT), adenomatoid odontogenic tumor (AOT), calcifying epithelial odontogenic tumor (CEOT), odontogenic myxoma (OM), and ameloblastic fibroma (AF). Study design The expression of these mediators was evaluated by means of immunohistochemistry. Results All specimens demonstrated positive immunoreactivity to RANK, RANKL, and OPG. The quantification of these mediators in epithelium revealed a similar pattern of expression for RANKL and OPG in CCOT, AOT, CEOT, and AF. With regard to stromal/mesenchymal cells, the majority of AOT and CCOT cases showed a higher content of OPG than RANKL, whereas CEOT, OM, and especially AF had a tendency to present a greater content of RANKL than OPG. Conclusion Our data indicate that the CCOT, AOT, CEOT, OM, and AF cell constituents express key regulators of bone metabolism that might locally modulate tumor-associated bone resorption.

Primary failure of eruption represents a cessation of tooth eruption before emergence not due to a physical barrier or abnormal position and has no systemic cause. This failure of tooth eruption is rare phenomenon and it has not been associated with alterations of dental follicle. This case report describes a permanent right first molar with primary failure of eruption at the inferior border of the mandible presenting microscopic, clinical and radiographic findings compatible with follicular cystic lesion. The follicular tissues of this molar showed microscopic aspects of inflammation. Thus, pericoronal tissues surrounding long-term unerupted teeth with primary failure of eruption has potential to develop into odontogenic cysts. The lesion presented herein probably arose in association with a periodontal pocket mesial to the adjacent second molar, representing an atypical inflammatory follicular cyst. This case shares etiological, radiological and microscopic features with the usual form of the inflammatory follicular cyst associated with infected primary teeth, except for the infection pathways reaching the tooth follicle. The controversies regarding the terminology for this cyst are discussed. A falha primária de erupção é caracterizada pelo não irrompimento de um dente sem que haja impedimento mecânico ou que o dente esteja em posição anormal ou devido à causas sistêmicas. É um fenômeno raro e não foi associado com alterações do folículo dentário. Este relato descreve um caso de falha primária de erupção de um primeiro molar inferior direito permanente, localizado na base da mandíbula, que apresenta achados clínicos, radiográficos e microscópicos compatíveis com cisto folicular. O folículo pericoronário deste molar apresentou aspectos microscópicos de inflamação. Assim como os tecidos pericoronários dos dentes não irrompidos, a longo prazo, os folículos pericoronários dos dentes com falha primária de irrompimento têm o potencial para desenvolver cistos odontogênicos. Esta lesão provavelmente surgiu em associação com uma bolsa periodontal na mesial do segundo molar adjacente, caracterizando um cisto folicular inflamatório atípico. Este caso apresenta características etiológicas, radiográficas e microscópicas comuns nos cistos foliculares inflamatórios associados a dentes decíduos infectados, com exceção das infecções que alcançam o folículo. São discutidas ainda as controvérsias relativas à terminologia deste cisto.

Paracoccidioidomycosis is a chronic granulomatous disease that induces a specific inflammatory and immune response. The participation of nitric oxide (NO), a product of the inducible nitric oxide synthase enzyme (iNOS), as an important fungicidal molecule against Paracoccidioides brasiliensis has been demonstrated. In order to further characterize the Oral Paracoccidioidomycosis (OP), we undertook an immunohistochemical study of iNOS+, CD45RO+, CD3+, CD8+, CD20+, CD68+ cells and mast cells. The samples were distributed in groups according to the number of viable fungi per mm². Our results showed weak immunolabeling for iNOS in the multinucleated giant cells (MNGC) and in most of the mononuclear (MN) cells, and the proportion of iNOS+ MN/MNGC cells in the OP were comparable to Control (clinically healthy oral tissues). Additionally, our analysis revealed a similarity in the number of CD4+ cells between the Control and the OP groups with higher numbers of fungi. These findings suggest that a low expression of iNOS and a decrease in the CD4+ T cells in OP may represent possible mechanisms that permit the local fungal multiplication and maintenance of active oral lesions. A paracoccidioidomicose é uma doença granulomatosa crônica que induz resposta inflamatória e imune específica. A participação do óxido nítrico (NO), produto da enzima óxido nítrico sintase induzível (iNOS), como uma importante molécula fungicida contra o fungo Paracoccidioides brasiliensis tem sido demonstrada. Com o objetivo de melhor caracterizar as lesões orais da paracoccidioidomicose (OP), propusemos estudo imunohistoquímico das células iNOS+ e das células CD45RO+, CD3+, CD8+, CD20+, CD68+ e mastócitos. As amostras foram distribuídas em grupos de acordo com o número de fungos viáveis por mm². Nossos resultados demonstraram leve imunomarcação para iNOS nas células gigantes multinucleadas (MNGC) e na maioria das células mononucleares (MN), e a proporção de células MN/MNGC iNOS+ na OP foi comparável a do grupo Controle (tecido bucal clinicamente saudável). Adicionalmente, nossa análise revelou similaridade no número de células CD4+ entre o Controle e o grupo de OP com elevado número de fungos. Estes achados sugerem que a baixa expressão de iNOS e a diminuição de células CD4+ na OP podem representar possíveis mecanismos que permitiram a multiplicação local do fungo e a manutenção das lesões bucais ativas.

OBJECTIVE AND METHODS: Among the cells involved in immune and inflammatory responses in periodontal disease, mast cells have been shown to be capable of generating a large number of biologically active substances. The present study was undertaken to identify and quantify the presence of mast cells in different stages of human periodontal disease using histochemical (toluidine blue) and immunohistochemical (tryptase-positive mast cells) techniques. RESULTS: Mast cell densities (cells per mm 2 ) were significantly increased in chronic periodontitis/gingivitis lesions compared with clinically healthy gingival tissues (Health) uniquely by immunohistochemical technique. Interestingly, mast cells were distributed specially in close apposition to mononuclear cells. CONCLUSIONS: In human periodontal disease there is an increase in the number of mast cells that may be participating either in the destructive events or in the defense mechanism of periodontal disease via secretion of cytokines, including perpetuation of the Th2 response, and cellular migration and healing processes. Oral Diseases (2005) 11, 249–254

The Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome (NBCCS), is an infrequent multisystemic disease inherited in a dominant autosomal way, which shows a high level of penetrance and variable expressiveness. It is characterized by keratocystic odontogenic tumors (KCOT) in the jaw, multiple basal cell nevi carcinomas and skeletal abnormities. This syndrome may be diagnosed early by a dentist by routine radiographic exams in the first decade of life, since the KCOTs are usually one of the first manifestations of the syndrome. This article paper reports the case of a patient, a 10-year-old boy with NBCCS, emphasizing its clinical and radiographic manifestations. This study highlights the importance of health professionals in the early diagnosis of NBCCS and in a preventive multidisciplinary approach to provide a better prognosis for the patient.

Background Ageing leads to a decline in the function of the immune system, increasing the body's susceptibility to infections through the impairment of T-cells, macrophages, neutrophils and dendritic cells Denture stomatitis is a primary oral disease affecting elderly denture wearers. The major etiologic factor involved in this pathology is the infection by Candida albicans, an opportunistic pathogen that causes local and disseminated diseases in immunosuppressed humans. Neutrophils play a critical role in the immune response against C. albicans and are continually present in the salivary fluid and in the blood. The aim of this study was to determine ageing-related changes in salivary and blood neutrophils and their potential implications in Candida-related denture stomatitis. Results Our results showed a lower number of neutrophils in the saliva from patients presenting Candida-related denture stomatitis in comparison to their matched controls. Furthermore, fewer neutrophils were isolated from the saliva of aged control individuals in comparison to matched younger subjects. CXCR1, CD62L and CD11b expression were significantly greater on systemic neutrophils from younger control individuals. Elderly individuals showed more apoptotic salivary neutrophils and lower GM-CSF levels than younger ones, regardless of the occurrence of Candida infection. On the other hand, CXCL-8 concentrations were higher in the saliva from elderly individuals. Besides, TNF-α was detected at elevated levels in the saliva from infected elderly subjects. Salivary neutrophils from elderly and young patients presented impaired phagocytic activity against C. albicans. However, just systemic neutrophils from elderly showed decreased phagocytosis when compared to the younger ones, regardless of the occurrence of infection. In addition, neutrophils from aged individuals and young patients presented low fungicidal activity. Conclusion The data suggests that the Candida related-denture stomatitis is associated to neutrophils function deficiency, and ageing drastically appears to alter important characteristics of such cells, facilitating the establishment of this infection.