Chronic ulcers are an important and costly medical issue, causing their sufferers a large amount of pain, immobility and decreased quality of life. The common pathology in these chronic wounds is often characterised by excessive proteolytic activity, leading to the degradation of both the extracellular matrix, as well as key factors critical to the ulcer's ability to heal. As matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, have been shown to have increased activity in chronic wound fluid (CWF), it was hypothesised that this specific proteolytic activity was directly related to an ulcer's chronic nature. Although previous studies have identified elevated proteases in CWF, many have reported contradictory results and therefore the precise levels and species of MMPs in CWF are poorly understood. The studies reported herein demonstrate that MMP activity is significantly elevated in CWF compared with acute wound fluid (AWF). In particular, these studies demonstrate that this proteolytic activity can be specifically attributed to MMPs and not another class of proteases present in wound healing. Furthermore, it is shown that MMP-9 is the predominant protease responsible for matrix degradation by CWF and is an indicator of the clinical status of the wound itself. Moreover, MMP-9 can be inhibited with the bisphosphonate alendronate, in the form of a sodium salt, a functionalised analogue, and also tethered to a synthetic biocompatible hydrogel compromised of aqueous poly (2-hydroxy methacrylate) PHEMA synthesised in the presence of poly(ethylene glycol) (PEG). Together, these results highlight the potential use of a tethered MMP inhibitor as an improved ulcer treatment to inhibit protease activity in the wound fluid, while still allowing MMPs to remain active in the wound bed where they perform vital roles in the activation of growth-promoting agents and immune system regulation.

Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 153-217.

This study examined the efficacy of continuous nicotinamide (NAM) administration on recovery of function in rats following traumatic brain injury (TBI). TBI was induced via controlled cortical impact (CCI) bilaterally in the prefrontal cortex (+1.5, 0.0 relative to bregma) or sham surgeries were performed. Rats were then treated with either NAM (150 mg/kg/day) or vehicle (saline). Rats were tested behaviorally on the bilateral tactile adhesive removal task, locomotor placing task, novel exploratory behavior and the Morris water maze (MWM). Rats were also assessed histologically by looking at lesion size, GFAP expression (as a measure of active astroctyes) and MMP-9 expression (as a measure of inflammatory response) at time points of 24 and 48 hours and 30 days. The behavioral assessments showed significant improvements in the NAM-treated animals on the bilateral tactile adhesive removal, locomotor placing and MWM. The histological assessments showed significant lesion reduction at 30 days in the NAM-treated group. There were no differences between NAM-treated and vehicle groups on either GFAP or MMP-9 expression. These results indicate that NAM treatment after TBI can significantly improve recovery of function in rats.

Introdução: Níveis de fator de necrose tumoral–alfa (TNF-α), N-peptídeo do pró-colágeno III (PIIINP) e metaloproteinase de matriz –1 (MMP-1), marcadores biológicos de remodelamento ventricular, estão elevados em pacientes com insuficiência cardíaca (IC), talvez refletindo elevadas pressões de enchimento. A correlação destes marcadores com variáveis clínicas e hemodinâmicas permanece pouco compreendida, particularmente no contexto ambulatorial da IC. Objetivo: Avaliar níveis séricos de marcadores biológicos de remodelamento ventricular em pacientes com IC, comparando tratamento guiado por ecocardiografia (ECO), buscando redução de pressões de enchimento, versus tratamento convencional (CLÍNICO), baseado em sinais e sintomas. Métodos: Ensaio clínico randomizado. Pacientes estáveis com IC e fração de ejeção menor do que 40% foram alocados entre os grupos de tratamento e submetidos a ecocardiograma e coletas de sangue no início do estudo e em 180 dias. TNF-α e MMP- 1 foram medidos por ELISA, e PIIINP, por radioimunoensaio. Resultados: Incluiu-se 80 pacientes, com 59 ± 15 anos e fração de ejeção de 26 ± 7%; 25% isquêmicos e 52% masculinos. Houve redução dos marcadores biológicos intragrupos, não havendo diferença entre os tratamentos. No grupo CLÍNICO, os níveis de TNF-α, MMP-1 e PIIINP apresentaram diferenças estatisticamente significativas entre os momentos basal e final (respectivamente, 3,11 ± 2,90 versus 1,24 ± 0,60 pg/mL p < 0,0003; 2,66 ± 1,00 versus 1,16 ± 0,40 ng/mL p < 0,0001; 6,12 ± 2,60 versus 3,89 ± 1,60 μg/L p < 0,0001). De maneira semelhante, tal diferença também foi observada no grupo ECO para os três marcadores (respectivamente, 3,90 ± 4,90 versus 1,40 ± 1,30 pg/mL p < 0,0001; 2,50 ± 0,90 versus 1,09 ± 0,40 ng/mL p < 0,0001; 6,09 ± 2,60 versus 3,50 ± 1,30 μg/L p<0,0001). Ao final da intervenção, no entanto, não foi observada diferença significativa dos valores de TNF-α , MMP-1 e PIIINP entre os dois grupos de tratamento (p = 0,7; p = 0,8; e p = 0,2; respectivamente). A combinação dos valores basais das variáveis biológicas gerou um escore que se associou significativamente com o comportamento final das pressões atrial direita e sistólica da artéria pulmonar. Pacientes com marcadores biológicos basais no quartil 75% mantiveram níveis superiores de pressões atrial direita (13 mmHg; p = 0,034) e sistólica de artéria pulmonar (60 mmHg; p = 0,007) ao final do seguimento. Conclusão: Independente do tratamento alocado, houve redução dos níveis de marcadores biológicos ao final do seguimento; no entanto, níveis basais mais elevados destes marcadores foram preditores de menor redução das pressões em átrio direito e sistólica da artéria pulmonar. Os dados sugerem que indicativos de intenso processo de remodelamento ventricular se associam à progressão da IC e a pressões de enchimento elevadas. / Introduction: Levels of tumor necrosis factor-alpha (TNF-α), N-terminal propeptide of type III collagen (PIIINP) and type 1 matrix metalloproteinase (MMP-1), biological markers of ventricular remodeling, are elevated in heart failure (HF) patients, perhaps reflecting elevated filling pressures. The correlation of these markers with clinical and hemodynamic variables remains poorly understood, particularly in the outpatient setting. Objective: To evaluate serum levels of ventricular remodeling biological markers in patients with HF, comparing a conventional clinically-oriented treatment (Conventional Therapy), based on clinical signs and symptoms, to an echocardiography-guided treatment (Echo-guided Therapy), aiming at a reduction in filling pressure levels. Methods: Randomized trial. Stable patients with HF and ejection fraction lower than 40% were allocated to the treatment groups and submitted to echocardiography and blood sampling at the beginning of the study and after 180 days. TNF-α and MMP-1 were measured by ELISA, and PIIINP, by radioimmunoassay. Results: Eighty patients at 59 ± 15 years and a mean ejection fraction of 26 ± 7% were included; 25% were ischemic and 52%, males. There was a reduction in intragroup biological markers, without difference between treatments. TNF-α, MMP-1 and PIIINP levels were statistically different between baseline and final in patients allocated to Conventional Therapy (respectively, 3.11 ± 2.90 versus 1.24 ± 0.60 pg/mL p < 0.0003; 2.66 ± 1.00 versus 1.16 ± 0.40 ng/mL p < 0.0001; 6.12 ± 2.60 versus 3.89 ± 1.60 μg/L, p < 0.0001). Similarly, such a difference was also observed in the Echo-guided Therapy for the 3 markers (respectively, 3.90 ± 4.90 versus 1.40 ± 1.30 pg/mL p < 0.0001; 2.50 ± 0.90 versus 1.09 ± 0.40 ng/mL p < 0.0001; 6.09 ± 2.60 versus 3.50 ± 1.30 mg/L p<0.0001). By the completion of the intervention, however, no significant difference was observed in the values of TNF-α, MMP- 1 and PIIINP between the 2 treatment groups (p = 0.7; p = 0.8; and p = 0.2; respectively). A composite score incorporating baseline biological marker levels was statistically associated to final right-sided pressure levels (right atrial pressure and pulmonary artery systolic pressure). Patients with baseline biological marker levels over percentile 75 maintained higher right atrial (13 mmHg; p = 0.034) and pulmonary artery systolic pressures (60 mmHg; p = 0.007) at the end of protocol. Conclusion: Regardless of allocated treatment group, biological marker levels were lower at the end of the follow-up; however, higher baseline levels of these markers were predictive of lower reductions in right atrial pressure and pulmonary artery systolic pressure. The data obtained suggest that indicators of an intense remodeling process are associated with elevated filling pressures and progression of HF.

Submitted by LETÍCIA CARVALHO COUTINHO COSTA PEROTE (leticiaccc@gmail.com) on 2016-04-08T17:53:49Z No. of bitstreams: 1 Tese biblioteca finalizada.pdf: 4785988 bytes, checksum: 99777155681f63934c41a2cacd0892f3 (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-04-11T17:17:19Z (GMT) No. of bitstreams: 1 perote_lccc_dr_sjc.pdf: 4785988 bytes, checksum: 99777155681f63934c41a2cacd0892f3 (MD5) / Made available in DSpace on 2016-04-11T17:17:20Z (GMT). No. of bitstreams: 1 perote_lccc_dr_sjc.pdf: 4785988 bytes, checksum: 99777155681f63934c41a2cacd0892f3 (MD5) Previous issue date: 2016-02-17 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo deste estudo foi avaliar a influência de soluções de clorexidina e de própolis e da simulação de pressão pulpar na resistência de união entre resina e dentina. Para isto, foram obtidos segmentos coronários de 120 dentes humanos. Metade das amostras foram conectadas a um dispositivo de simulação de pressão pulpar, cuja altura foi ajustada para 15 cm de água. Foi realizado condicionamento com ácido fosfórico 37% por 15 s, lavagem e secagem com papel absorvente. Em seguida, foram divididas em 3 grupos, de acordo com a solução aplicada por 30 s: GC(Grupo Controle – nenhuma solução), CLX (Digluconato de Clorexidina 0,2%), PA (Extrato de própolis aquoso). Aplicou-se o adesivo (Single Bond Universal) e resina composta (Filtek Z250) em todos as amostras. Os grupos foram subdivididos de acordo com o tipo de envelhecimento: I (Corte Imediato), C (15000 ciclos térmicos). As amostras foram cortadas em palitos e submetidas ao teste de microtração. Os dados obtidos de resistência de união (MPa) foram submetidos ao teste de ANOVA 3 fatores. Para o fator Solução, não foi encontrada diferença estatisticamente significante entre os grupos (p=0,46), mas sim para os fatores Pressão Pulpar (p=0,00) e Envelhecimento (p=0,00), além das interações entre os fatores Solução e Pressão Pulpar (p= 0,00), Pressão Pulpar e Envelhecimento (p=0,00) e entre os três fatores (p=0,03). Os resultados do teste de Tukey para o fator Pressão Pulpar foram: CPP (com pressão pulpar): 29,19a, SPP (sem pressão pulpar): 32,98b; e para o fator Envelhecimento foram: C (ciclados): 28,12a, I (imediato): 34,05b. Concluiu-se que as soluções de clorexidina e de própolis não interferiram na resistência de união; e que a simulação de pressão pulpar e a termociclagem diminuíram os valores de resistência de união da resina à dentina. / This study aimed to assess the influence of chlorhexidine and propolis solutions and simulated pulpal pressure on the bond strength between resin and dentin. To do so, crown segments of 120 human teeth were obtained. Half of the samples were connected to a pulp pressure simulation device, adjusted to 15 cm H2O. Conditioning was accomplished with 37% phosphoric acid for 15 seconds, washing and drying with absorbing paper. Then, samples were split into 3 groups, according to the solution applied for 30 s: GC (Control group – no solution), CLX (Chlorhexidine digluconate 0.2%), PA (Aqueous propolis extract). Single Bond Universal adhesive and composite resin (Filtek Z250) were applied in all samples. Groups were subdivided according to the aging process: I (Immediate cut) and T (15000 thermal cycles). Samples were cut into beams and went through microtensile bonding tests. Bond strength data (MPa) were analyzed by three-way ANOVA. For the factor Solution, there was no statistically significant difference among the groups (p = 0.46), but was found difference for the factors Pulpal Pressure (p=0.00), Aging (p=0.00), and interaction between Solution and Pulpal Pressure (p=0.00), Pulpal Pressure and Aging (p=0.00) and between the 3 factors (p=0.03). The results from Tukey’s test for Pulpal Pressure factor were: SPP (simulated pulpal pressure): 29,19a, NPP (no pulpal pressure): 32,98b; and for the factor Aging were: T (thermal cycling): 28,12a, I (immediate): 34,05b. It was concluded that chlorhexidine and propolis solutions have not interfered in the bond strength; but simulated pulpal pressure and termal cycling reduced the dentin bond strength.

Made available in DSpace on 2014-06-11T19:33:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-12-15Bitstream added on 2014-06-13T19:03:54Z : No. of bitstreams: 1 elias_gp_dr_araca.pdf: 1560641 bytes, checksum: 3dad8c2298005cfeb8d0a078880f5e66 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo deste trabalho foi avaliar a atividade das glândulas salivares, a mineralização dental e a participação da metaloproteinase de matriz (MMP-9) nesta mineralização em filhotes de ratas espontaneamente hipertensas (SHR) tratadas ou não com atenolol. Ratas SHR e normotensas Wistar foram tratadas com atenolol (100mg/Kg/dia, via oral) durante os períodos de prenhez e lactação. Os grupos controle receberam o mesmo volume de água sem atenolol. O fluxo salivar, induzido por nitrato de pilocarpina, a concentração de proteínas (método de Lowry), a atividade da amilase (método cinético a 405 nm), o peso das glândulas salivares (parótidas, submandibulares e sublinguais), a microdureza do esmalte e da dentina de incisivos e molares e a expressão da MMP-9 (imonuperoxidase) no tecido dental foram comparados entre filhotes de ratas SHR e Wistar tratadas ou não com atenolol. Os resultados obtidos foram submetidos ao teste estatístico mais adequado, paramétrico (ANOVA ou test t de Student’s) ou não paramétrico (Kruskal-Wallis), sendo consideradas significativas as diferenças quando p<0,05. Filhotes SHR apresentaram menor fluxo salivar e concentração de proteínas do que filhotes Wistar, mas a atividade da amilase não foi diferente entre os grupos. O peso das glândulas salivares foi semelhante entre filhotes SHR e Wistar... / The objective of the present study was analyzed the salivary activity, the dental mineralization and the role of matrix metalloproteinase-9 (MMP-9) on this mineralization, in pups (30 days) of spontaneously hypertensive rats (SHR) treated, or not treated, with atenolol. Female SHR and normotensive Wistar rats were treated during pregnancy and lactation periods with Atenolol 100mg/Kg/day by oral administration. For the control group, the animals received the same water volume without the drug. The salivary flow rate (stimulated by pilocarpine injection), the protein concentration (Lowry method), salivary amylase activity (kinetic method at 405 nm), the weight of salivary glands (parotid, submandibular and sublingual), the enamel and dentin microhardness of incisors and molars teeth and the matrix metalloproteinase-9 (MMP-9, gelatinase B) localization (imunoperoxidase) in dental tissue were compared between SHR and Wistar pups of female rats treated or not with atenolol. The results were analyzed by parametric (ANOVA or Student s tests) or non-parametric (Kruskal-Wallis) tests (p<0,05). The salivary flow rate and salivary protein concentration were reduced in SHR pups. There was no alteration in amylase activity between groups. The salivary glands weight was not different between SHR and Wistar pups either. Decreased enamel and dentin microhardness were observed in incisors and molar teeth of SHR pups. No alterations in MMP-9 positive staining were observed in predentin and odontoblasts of both groups, however the density of stained ameloblasts cells and external enamel surface were higher in incisors teeth of SHR pups. Atenolol-treated SHR and Wistar rats pups showed decrease in submandibular gland weight, in saliva s flow rate and protein concentration, but no alteration in amylase activity. Atenolol increased enamel and dentin microhardness of incisors teeth of SHR and...(Complete abstract, click electronic address below)

Introdução: Níveis de fator de necrose tumoral–alfa (TNF-α), N-peptídeo do pró-colágeno III (PIIINP) e metaloproteinase de matriz –1 (MMP-1), marcadores biológicos de remodelamento ventricular, estão elevados em pacientes com insuficiência cardíaca (IC), talvez refletindo elevadas pressões de enchimento. A correlação destes marcadores com variáveis clínicas e hemodinâmicas permanece pouco compreendida, particularmente no contexto ambulatorial da IC. Objetivo: Avaliar níveis séricos de marcadores biológicos de remodelamento ventricular em pacientes com IC, comparando tratamento guiado por ecocardiografia (ECO), buscando redução de pressões de enchimento, versus tratamento convencional (CLÍNICO), baseado em sinais e sintomas. Métodos: Ensaio clínico randomizado. Pacientes estáveis com IC e fração de ejeção menor do que 40% foram alocados entre os grupos de tratamento e submetidos a ecocardiograma e coletas de sangue no início do estudo e em 180 dias. TNF-α e MMP- 1 foram medidos por ELISA, e PIIINP, por radioimunoensaio. Resultados: Incluiu-se 80 pacientes, com 59 ± 15 anos e fração de ejeção de 26 ± 7%; 25% isquêmicos e 52% masculinos. Houve redução dos marcadores biológicos intragrupos, não havendo diferença entre os tratamentos. No grupo CLÍNICO, os níveis de TNF-α, MMP-1 e PIIINP apresentaram diferenças estatisticamente significativas entre os momentos basal e final (respectivamente, 3,11 ± 2,90 versus 1,24 ± 0,60 pg/mL p < 0,0003; 2,66 ± 1,00 versus 1,16 ± 0,40 ng/mL p < 0,0001; 6,12 ± 2,60 versus 3,89 ± 1,60 μg/L p < 0,0001). De maneira semelhante, tal diferença também foi observada no grupo ECO para os três marcadores (respectivamente, 3,90 ± 4,90 versus 1,40 ± 1,30 pg/mL p < 0,0001; 2,50 ± 0,90 versus 1,09 ± 0,40 ng/mL p < 0,0001; 6,09 ± 2,60 versus 3,50 ± 1,30 μg/L p<0,0001). Ao final da intervenção, no entanto, não foi observada diferença significativa dos valores de TNF-α , MMP-1 e PIIINP entre os dois grupos de tratamento (p = 0,7; p = 0,8; e p = 0,2; respectivamente). A combinação dos valores basais das variáveis biológicas gerou um escore que se associou significativamente com o comportamento final das pressões atrial direita e sistólica da artéria pulmonar. Pacientes com marcadores biológicos basais no quartil 75% mantiveram níveis superiores de pressões atrial direita (13 mmHg; p = 0,034) e sistólica de artéria pulmonar (60 mmHg; p = 0,007) ao final do seguimento. Conclusão: Independente do tratamento alocado, houve redução dos níveis de marcadores biológicos ao final do seguimento; no entanto, níveis basais mais elevados destes marcadores foram preditores de menor redução das pressões em átrio direito e sistólica da artéria pulmonar. Os dados sugerem que indicativos de intenso processo de remodelamento ventricular se associam à progressão da IC e a pressões de enchimento elevadas. / Introduction: Levels of tumor necrosis factor-alpha (TNF-α), N-terminal propeptide of type III collagen (PIIINP) and type 1 matrix metalloproteinase (MMP-1), biological markers of ventricular remodeling, are elevated in heart failure (HF) patients, perhaps reflecting elevated filling pressures. The correlation of these markers with clinical and hemodynamic variables remains poorly understood, particularly in the outpatient setting. Objective: To evaluate serum levels of ventricular remodeling biological markers in patients with HF, comparing a conventional clinically-oriented treatment (Conventional Therapy), based on clinical signs and symptoms, to an echocardiography-guided treatment (Echo-guided Therapy), aiming at a reduction in filling pressure levels. Methods: Randomized trial. Stable patients with HF and ejection fraction lower than 40% were allocated to the treatment groups and submitted to echocardiography and blood sampling at the beginning of the study and after 180 days. TNF-α and MMP-1 were measured by ELISA, and PIIINP, by radioimmunoassay. Results: Eighty patients at 59 ± 15 years and a mean ejection fraction of 26 ± 7% were included; 25% were ischemic and 52%, males. There was a reduction in intragroup biological markers, without difference between treatments. TNF-α, MMP-1 and PIIINP levels were statistically different between baseline and final in patients allocated to Conventional Therapy (respectively, 3.11 ± 2.90 versus 1.24 ± 0.60 pg/mL p < 0.0003; 2.66 ± 1.00 versus 1.16 ± 0.40 ng/mL p < 0.0001; 6.12 ± 2.60 versus 3.89 ± 1.60 μg/L, p < 0.0001). Similarly, such a difference was also observed in the Echo-guided Therapy for the 3 markers (respectively, 3.90 ± 4.90 versus 1.40 ± 1.30 pg/mL p < 0.0001; 2.50 ± 0.90 versus 1.09 ± 0.40 ng/mL p < 0.0001; 6.09 ± 2.60 versus 3.50 ± 1.30 mg/L p<0.0001). By the completion of the intervention, however, no significant difference was observed in the values of TNF-α, MMP- 1 and PIIINP between the 2 treatment groups (p = 0.7; p = 0.8; and p = 0.2; respectively). A composite score incorporating baseline biological marker levels was statistically associated to final right-sided pressure levels (right atrial pressure and pulmonary artery systolic pressure). Patients with baseline biological marker levels over percentile 75 maintained higher right atrial (13 mmHg; p = 0.034) and pulmonary artery systolic pressures (60 mmHg; p = 0.007) at the end of protocol. Conclusion: Regardless of allocated treatment group, biological marker levels were lower at the end of the follow-up; however, higher baseline levels of these markers were predictive of lower reductions in right atrial pressure and pulmonary artery systolic pressure. The data obtained suggest that indicators of an intense remodeling process are associated with elevated filling pressures and progression of HF.

Submitted by Alison Vanceto (alison-vanceto@hotmail.com) on 2017-02-07T10:16:30Z No. of bitstreams: 1 DissNSMS.pdf: 2315984 bytes, checksum: 1245c9af0e2575904b71a6d6569edf15 (MD5) / Approved for entry into archive by Camila Passos (camilapassos@ufscar.br) on 2017-02-08T12:04:02Z (GMT) No. of bitstreams: 1 DissNSMS.pdf: 2315984 bytes, checksum: 1245c9af0e2575904b71a6d6569edf15 (MD5) / Approved for entry into archive by Camila Passos (camilapassos@ufscar.br) on 2017-02-08T12:08:17Z (GMT) No. of bitstreams: 1 DissNSMS.pdf: 2315984 bytes, checksum: 1245c9af0e2575904b71a6d6569edf15 (MD5) / Made available in DSpace on 2017-02-08T12:09:35Z (GMT). No. of bitstreams: 1 DissNSMS.pdf: 2315984 bytes, checksum: 1245c9af0e2575904b71a6d6569edf15 (MD5) Previous issue date: 2016-04-20 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Cervical cancer is the second largest cause of deaths from malignant cancer among women worldwide. Many studies show the importance of the HPV virus in the onset of cervical cancer, but because of the monoclonal nature of this cancer, it is suspected that HPV infection may not be considered the only causal factor responsible for the development of cervical carcinoma. Studies have indicated that EBV may have a role in cooperation with the HPV16 tumor development. Such cooperation could influence the tumor microenvironment by creating a favorable niche for its progression. Cancer cells secrete enzymes that degrade the extracellular matrix (ECM). Such enzymes such as matrix metalloproteinases (MMPs) facilitate cell movement in tissues and induce the activity of growth factors that promote angiogenesis. Among the group of MMPs, MMP-7 seems to have a crucial role in the development of carcinogenesis, since its action has been associated with the cleavage and release of adhesion molecules important. In this sense, this study was performed to establish the relationship between the HPV coinfection / EBV and expression of MMP-7. They were examined immunohistochemically histological slides of cervical lesions biopsies of 60 patients aged 35 to 65 years. The samples were divided into high grade lesion and low grade and evaluated semiquantitatively by scoring system ranging from 0 to +++. Histopathological indexes the degree of injury were established. It observed a statistically significant association between high-grade lesion, the expression of MMP-7 and the presence of the HPV virus, with p = 0.007 at the junction portion squamocolumnar and p = 0.023 in the portion of the ectocervix. This correlation / O câncer cervical é responsável pela segunda maior causa de mortes por neoplasia malignas entre as mulheres no mundo. Muitos estudos comprovam a importância do vírus HPV no surgimento do câncer cervical, porém devido à natureza monoclonal desta neoplasia, suspeita-se que a infecção pelo HPV não possa ser considerada o único fator causal responsável pelo desenvolvimento do carcinoma de colo de útero. Estudos já apontaram que o EBV pode ter um papel de cooperação com o HPV16 no desenvolvimento tumoral. Tal cooperação poderia influenciar o microambiente tumoral criando um nicho favorável para a sua progressão. Células de câncer secretam enzimas que degradam a matriz extracelular (MEC). Tais enzimas, como as metaloproteinases de matriz (MMPs) facilitam a movimentação celular nos tecidos e induzem a atividade de fatores de crescimento que promovem a angiogênese. Dentre o grupo das MMPs, a MMP-7 parece ter papel crucial no desenvolvimento da carcinogênese, pois sua ação já foi associada com a clivagem e a liberação de importantes moléculas de adesão. Neste sentido, foi realizado este estudo para estabelecer a relação entre a co-infecção HPV/EBV e a expressão da MMP-7. Foram examinadas imunohistoquimicamente lâminas histológicas de biópsias de lesões de colo uterino de 60 pacientes com idades entre 35 e 65 anos. As amostras foram divididas em lesão de alto grau e de baixo grau e avaliados semiquantitativamente através de um sistema de escore variando de 0 à +++. Índices histopatológicos quanto ao grau das lesões foram estabelecidos. Foi observada uma associação estatisticamente significante entre a lesão de alto grau, a expressão da MMP-7 e a presença do vírus HPV, com p=0,007 na porção da junção escamocolunar e p=0,023 na porção da ectocérvice.

Made available in DSpace on 2014-12-17T15:32:32Z (GMT). No. of bitstreams: 1 FernandoJON_TESE.pdf: 1862708 bytes, checksum: c0bcb5ceb1bfbf2e1312b265a0c10350 (MD5) Previous issue date: 2013-09-13 / Periodontal disease is an infectious disease resulting from the immunoinflammatory response of the host to microorganisms present in the dental biofilm which causes tissue destruction. The objective of this study was to evaluate the immunohistochemical expression of cyclophilin A (CYPA), extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase 7 (MMP-7) in human specimens of clinically healthy gingiva (n=32), biofilm-induced gingivitis (n=28), and chronic periodontitis (n=30). Immunopositivity for CYPA, EMMPRIN and MMP-7 differed significantly between the three groups, with higher percentages of staining in chronic periodontitis specimens, followed by chronic gingivitis and healthy gingiva specimens (p < 0.001). Immunoexpression of CYPA and MMP-7 was higher in the intense inflammatory infiltrate observed mainly in cases of periodontitis. Analysis of possible correlations between the immunoexpression of EMMPRIN, MMP-7 and CYPA and between the expression of these proteins and clinical parameters (probing depth and clinical attachment loss) showed a positive correlation of CYPA expression with MMP-7 (r = 0.831; p < 0.001) and EMMPRIN (r = 0.289; p = 0.006). In addition, there was a significant positive correlation between probing depth and expression of MMP-7 (r = 0.726; p < 0.001), EMMPRIN (r = 0.345; p = 0.001), and CYPA (r = 0.803; p < 0.001). These results suggest that CYPA, EMMPRIN and MMP-7 are associated with the pathogenesis and progression of periodontal disease / A doen?a periodontal ? uma entidade infecciosa que resulta da resposta imuno-inflamat?ria do hospedeiro aos microrganismos presentes no biofilme dent?rio, levando ? destrui??o tecidual. O prop?sito do presente estudo foi avaliar a express?o imuno-histoqu?mica da ciclofilina A (CYPA), do indutor de metaloproteinases da matriz extracelular (EMMPRIN) e da metaloproteinase da matriz 7 (MMP-7) em esp?cimes humanos de gengiva clinicamente saud?vel (n=32), gengivite induzida por biofilme dent?rio (n=28) e periodontite cr?nica (n=30). Foram realizadas bi?psias das tr?s condi??es cl?nicas e feita a an?lise imuno-histoqu?mica atrav?s da contagem total do n?mero de c?lulas positivas, correlacionando-a com par?metros cl?nicos. A imunopositividade da CYPA, do EMMPRIN e da MMP-7 revelou diferen?a estatisticamente significativa entre os tr?s grupos, com maiores percentuais de positividade nos esp?cimes de periodontite cr?nica, seguidos pelos esp?cimes de gengivite cr?nica e de gengiva saud?vel (p < 0,001). Foi evidenciada maior express?o de CYPA e MMP-7 nos grupos que tinham infiltrado inflamat?rio mais intenso. Foram observadas correla??es das imunoexpress?es de EMMPRIN, MMP-7 e CYPA, tanto entre si como com par?metros cl?nicos (profundidade de sondagem e perda de inser??o cl?nica). Foram verificadas correla??es positivas entre a express?o de CYPA e as express?es da MMP-7 (r = 0,831; p < 0,001) e do EMMPRIN (r = 0,289; p = 0,006). Al?m disso, a profundidade de sondagem revelou correla??o positiva, estatisticamente significativa, com as express?es de MMP-7 (r = 0,726; p < 0,001), EMMPRIN (r = 0,345; p = 0,001) e CYPA (r = 0,803; p < 0,001). Esses resultados evidenciam que a CYPA, o EMMPRIN e a MMP-7 podem estar associadas ? patog?nese e progress?o da doen?a periodontal

Introdução: Níveis de fator de necrose tumoral–alfa (TNF-α), N-peptídeo do pró-colágeno III (PIIINP) e metaloproteinase de matriz –1 (MMP-1), marcadores biológicos de remodelamento ventricular, estão elevados em pacientes com insuficiência cardíaca (IC), talvez refletindo elevadas pressões de enchimento. A correlação destes marcadores com variáveis clínicas e hemodinâmicas permanece pouco compreendida, particularmente no contexto ambulatorial da IC. Objetivo: Avaliar níveis séricos de marcadores biológicos de remodelamento ventricular em pacientes com IC, comparando tratamento guiado por ecocardiografia (ECO), buscando redução de pressões de enchimento, versus tratamento convencional (CLÍNICO), baseado em sinais e sintomas. Métodos: Ensaio clínico randomizado. Pacientes estáveis com IC e fração de ejeção menor do que 40% foram alocados entre os grupos de tratamento e submetidos a ecocardiograma e coletas de sangue no início do estudo e em 180 dias. TNF-α e MMP- 1 foram medidos por ELISA, e PIIINP, por radioimunoensaio. Resultados: Incluiu-se 80 pacientes, com 59 ± 15 anos e fração de ejeção de 26 ± 7%; 25% isquêmicos e 52% masculinos. Houve redução dos marcadores biológicos intragrupos, não havendo diferença entre os tratamentos. No grupo CLÍNICO, os níveis de TNF-α, MMP-1 e PIIINP apresentaram diferenças estatisticamente significativas entre os momentos basal e final (respectivamente, 3,11 ± 2,90 versus 1,24 ± 0,60 pg/mL p < 0,0003; 2,66 ± 1,00 versus 1,16 ± 0,40 ng/mL p < 0,0001; 6,12 ± 2,60 versus 3,89 ± 1,60 μg/L p < 0,0001). De maneira semelhante, tal diferença também foi observada no grupo ECO para os três marcadores (respectivamente, 3,90 ± 4,90 versus 1,40 ± 1,30 pg/mL p < 0,0001; 2,50 ± 0,90 versus 1,09 ± 0,40 ng/mL p < 0,0001; 6,09 ± 2,60 versus 3,50 ± 1,30 μg/L p<0,0001). Ao final da intervenção, no entanto, não foi observada diferença significativa dos valores de TNF-α , MMP-1 e PIIINP entre os dois grupos de tratamento (p = 0,7; p = 0,8; e p = 0,2; respectivamente). A combinação dos valores basais das variáveis biológicas gerou um escore que se associou significativamente com o comportamento final das pressões atrial direita e sistólica da artéria pulmonar. Pacientes com marcadores biológicos basais no quartil 75% mantiveram níveis superiores de pressões atrial direita (13 mmHg; p = 0,034) e sistólica de artéria pulmonar (60 mmHg; p = 0,007) ao final do seguimento. Conclusão: Independente do tratamento alocado, houve redução dos níveis de marcadores biológicos ao final do seguimento; no entanto, níveis basais mais elevados destes marcadores foram preditores de menor redução das pressões em átrio direito e sistólica da artéria pulmonar. Os dados sugerem que indicativos de intenso processo de remodelamento ventricular se associam à progressão da IC e a pressões de enchimento elevadas. / Introduction: Levels of tumor necrosis factor-alpha (TNF-α), N-terminal propeptide of type III collagen (PIIINP) and type 1 matrix metalloproteinase (MMP-1), biological markers of ventricular remodeling, are elevated in heart failure (HF) patients, perhaps reflecting elevated filling pressures. The correlation of these markers with clinical and hemodynamic variables remains poorly understood, particularly in the outpatient setting. Objective: To evaluate serum levels of ventricular remodeling biological markers in patients with HF, comparing a conventional clinically-oriented treatment (Conventional Therapy), based on clinical signs and symptoms, to an echocardiography-guided treatment (Echo-guided Therapy), aiming at a reduction in filling pressure levels. Methods: Randomized trial. Stable patients with HF and ejection fraction lower than 40% were allocated to the treatment groups and submitted to echocardiography and blood sampling at the beginning of the study and after 180 days. TNF-α and MMP-1 were measured by ELISA, and PIIINP, by radioimmunoassay. Results: Eighty patients at 59 ± 15 years and a mean ejection fraction of 26 ± 7% were included; 25% were ischemic and 52%, males. There was a reduction in intragroup biological markers, without difference between treatments. TNF-α, MMP-1 and PIIINP levels were statistically different between baseline and final in patients allocated to Conventional Therapy (respectively, 3.11 ± 2.90 versus 1.24 ± 0.60 pg/mL p < 0.0003; 2.66 ± 1.00 versus 1.16 ± 0.40 ng/mL p < 0.0001; 6.12 ± 2.60 versus 3.89 ± 1.60 μg/L, p < 0.0001). Similarly, such a difference was also observed in the Echo-guided Therapy for the 3 markers (respectively, 3.90 ± 4.90 versus 1.40 ± 1.30 pg/mL p < 0.0001; 2.50 ± 0.90 versus 1.09 ± 0.40 ng/mL p < 0.0001; 6.09 ± 2.60 versus 3.50 ± 1.30 mg/L p<0.0001). By the completion of the intervention, however, no significant difference was observed in the values of TNF-α, MMP- 1 and PIIINP between the 2 treatment groups (p = 0.7; p = 0.8; and p = 0.2; respectively). A composite score incorporating baseline biological marker levels was statistically associated to final right-sided pressure levels (right atrial pressure and pulmonary artery systolic pressure). Patients with baseline biological marker levels over percentile 75 maintained higher right atrial (13 mmHg; p = 0.034) and pulmonary artery systolic pressures (60 mmHg; p = 0.007) at the end of protocol. Conclusion: Regardless of allocated treatment group, biological marker levels were lower at the end of the follow-up; however, higher baseline levels of these markers were predictive of lower reductions in right atrial pressure and pulmonary artery systolic pressure. The data obtained suggest that indicators of an intense remodeling process are associated with elevated filling pressures and progression of HF.