Innovative Pre-Clinical Data Using Peptides to Intervene in the Evolution of Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, relentless, and deadly disease. Little is known about its pathogenetic mechanisms; therefore, developing efficient pharmacological therapies is challenging. This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a chronic pulmonary fibrosis murine model. BALB/c mice were intratracheally instilled with bleomycin (BLM) and followed for 30 days. The mice were treated with the immune modulatory peptides ToAP3 and ToAP4 every three days, starting on the 5th day post-BLM instillation. ELISA, qPCR, morphology, and respiratory function analyses were performed. The treatment with both peptides delayed the inflammatory process observed in the non-treated group, which showed a fibrotic process with alterations in the production of collagen I, III, and IV that were associated with significant alterations in their ventilatory mechanics. The ToAP3 and ToAP4 treatments, by lung gene modulation patterns, indicated that distinct mechanisms determine the action of peptides. Both peptides controlled the experimental IPF, maintaining the tissue characteristics and standard function properties and regulating fibrotic-associated cytokine production. Data obtained in this work show that the immune response regulation by ToAP3 and ToAP4 can control the alterations that cause the fibrotic process after BLM instillation, making both peptides potential therapeutic alternatives and/or adjuvants for IPF.

Pathogenicity and Growth Conditions Modulate Fonsecaea Extracellular Vesicles' Ability to Interact With Macrophages.

Chromoblastomycosis (CBM) is a chronic cutaneous and subcutaneous mycosis caused by black, dimorphic, and filamentous fungi of the Herpothrichiellaceae family, such as species of the genus Fonsecaea. These fungi can switch between the saprophytic forms (conidia and hyphae) and the pathogenic form, the muriform cells (MCs), which is considered an essential mechanism for fungal virulence. Nearly all types of cells can produce membranous structures formed by a lipid bilayer that communicate extracellularly with other cells, known as "extracellular vesicles" (EVs), which may act as virulence factors, as observed for several species of pathogenic fungi. Our findings demonstrated for the first time that F. pedrosoi, F. nubica, and F. erecta produce EVs in response to nutritional conditions. The EVs varied in sterol and protein contents, size, and morphology. Moreover, the EVs induced different cytokine and nitric oxide release patterns by bone marrow-derived macrophages (BMDMs). The EVs activated IL-1ß production, possibly acting as the first signal in inflammasome activation. Unlike the pathogenic species, the EVs isolated from F. erecta did not significantly stimulate TNF and IL-10 production in general. Overall, these results demonstrated that different species of Fonsecaea produce EVs capable of modulating pro- and anti-inflammatory cytokine and nitric oxide production by BMDMs and that growth conditions affected the immunomodulatory capacities of the EVs as well as their size, content, and morphology.

Fish Oil Nanoemulsion Supplementation Attenuates Bleomycin-Induced Pulmonary Fibrosis BALB/c Mice.

Diets rich in omega-3 or -6 fatty acids will produce different profiles for cell membranes phospholipid constitutions. Omegas 3 and 6 are part of the diet and can modulate the inflammatory profile. We evaluated the effects of the oral absorption of fish oil, when associated with a lipid nanoemulsion in an experimental pulmonary inflammatory model. Pulmonary fibrosis is a disease associated with excessive extracellular matrix deposition. We determined to investigate the morphophysiological mechanisms in mice that were pretreated after induction with bleomycin (BLM). The pretreatment was for 21 days with saline solution, sunflower oil (SO), fish oil (FO), and fish oil nanoemulsion (NEW3). The animals received a daily dose of 50 mg/Kg of docosahexaenoic acid DHA and 10 mg/Kg eicosapentaenoic (EPA) (100 mg/Kg), represented by a daily dose of 40 µL of NEW3. The blank group was treated with the same amount daily (40 µL) during the 21 days of pretreatment. The animals were treated with SO and FO, 100 mg/Kg (containing 58 mg/Kg of polyunsaturated fats/higher% linoleic acid) and 100 mg/Kg (50 mg/Kg of DHA and 10 mg/Kg EPA), respectively. A single dose of 5 mg/mL (50 µL) bleomycin sulfate, by the intratracheal surgical method in BALB/cAnNTac (BALB/c). NEW3 significantly reduced fibrotic progression, which can be evidenced by the protection from loss of body mass, increase in respiratory incursions per minute, decreased spacing of alveolar septa, decreased severity of fibrosis, and changes in the respiratory system. NEW3 attenuated the inflammatory changes developed in the experimental model of pulmonary fibrosis, while group SO showed a significant increase in inflammatory changes. This concluded that the presented results demonstrated that is possible to positively modulate the immune and inflamamtory response to an external agressor, by changing the nutitional intake of specific fatty acids, such as omega-3 placed in fish oil. Moreover, these benefits can be improved by the nanoencapsulation of fish oil in lipid nanoemulsions.

Influence of Different Surface Treatments on the Bond Strength Between Composites and Resin Cement / INFLUÊNCIA DE DIFERENTES TRATAMENTOS DE SUPERFÍCIE NA RESISTÊNCIA DE UNIÃO ENTRE COMPÓSITOS E CIMENTO RESINOSO

The aim of this study was to evaluate the influence of different surface treatments on bond strength (BS) between composite and a resin cement trough microshear bond strength test. Seventy five discs (10x2 mm) of Filtek P90, Filtek Z250 and Filtek Z350 XT (3M ESPE), were divided into 5 groups according to the treatment: C= control - no treatment; sandblasting J= aluminum oxide (50µm); sandblasting JE = + 99.3% ethanol for 5 min; silica coating S = (3M-ESPE Cojet - 30 microns); SS = silica coating + silane. PVC tubes (0.5 x 0.80 mm) were attached on the composite disc, and then, inserted resin cement (3M ESPE-RelyX ARC). After 24 hours artificial saliva storage at 37oC, the specimens were tested for microshear crosshead speed of 1.0 mm/min. Data were evaluated in two-way ANOVA and Tukey's test (5%) for contrast. The results showed that sandblasting with aluminum oxide (J) was efficient in increasing the BS for composites Z350 and P90. For the Z250, there were no difference between treatments. Also, CS showed results similar to controls for all composites. SE showed the worst results for Z350 e P90. BS values were dependent on the type of composite and the surface treatment used. Sandblasting with aluminum oxide seems to be an effective surface treatment for composites and may lead to higher BS values, while the use of ethanol could be harmful.

O objetivo deste estudo foi avaliar a influência de tratamentos de superfície na resistência de união (RU) entre compósitos e um cimento resinoso. Setenta e cinco discos (10x2 mm) das resinas Filtek P90, Filtek Z250 e Filtek Z350 (3M ESPE) foram divididos em 5 grupos de acordo com o tratamento: N= sem tratamento; S= jateamento com óxido de alumínio (50µm); SE= jateamento de óxido de alumínio + 99,3% de etanol por 5 min; C= jateamento de sílica com Cojet - 30 microns (3M ESPE); CS= jateamento de sílica + silano. Tubos de PVC (0,5 x 0,80 mm) foram fixados nos discos e o cimento resinoso (RelyX ARC, 3M ESPE) foi inserido. Após 24 horas de armazenamento em saliva artificial a 37oC, os espécimes foram submetidos ao teste de microcisalhamento com velocidade de 1,0 mm/min. Os dados foram avaliados em ANOVA de dois fatores e no teste de Tukey (5%) para contraste. Os resultados mostraram que o tratamento com oxido de alumínio (J) foi eficiente no aumento da RU nos compósitos Filtek Z350 e P90. Não houve diferença entre tratamentos para a Z250. Grupo CS mostrou resultados semelhantes aos do controle para todos os compósitos. Já o SE mostrou os piores resultados de RU. Concluiu-se que os valores de RU foram dependentes do tipo de compósito e do tratamento de superfície utilizado. O jateamento com óxido de alumínio parece ser um tratamento de superfície eficaz e pode elevar os valores de RU, já o uso de etanol pode ser prejudicial

Peptides ToAP3 and ToAP4 decrease release of inflammatory cytokines through TLR-4 blocking.

Antimicrobial peptides (AMPs) are small molecules with microbicidal and immunoregulatory activities. In this study we evaluated the anti-inflammatory and antimicrobial activities of peptides ToAP3 and ToAP4, AMPs from the venom of the Brazilian scorpion Tityus obscurus. To test the peptides' activity, murine bone marrow-derived macrophages (BMDMs) or dendritic cells (BMDCs) were stimulated with peptides plus LPS to analyze their ability to modulate cytokine release as well as phenotypic markers. For antimicrobial analysis, we evaluated the indirect activity against macrophage-internalized Cryptococcus neoformans and direct activity against Mycobacterium massiliense. Our data demonstrate that they were able to reduce TNF-α and IL-1ß transcript levels and protein levels for BMDM and BMDC. Furthermore, the reduction of TNF-α secretion, before LPS- inflammatory stimuli, is associated with peptide interaction with TLR-4. ToAP4 increased MHC-II expression in BMDC, while ToAP3 decreased co-stimulatory molecules such as CD80 and CD86. Although these peptides were able to modulate the production of cytokines and molecules associated with antigen presentation, they did not increase the ability of clearance of C. neoformans by macrophages. In antimicrobial analysis, only ToAP3 showed potent action against bacteria. Altogether, these results demonstrate a promising target for the development of new immunomodulatory and anti-bacterial therapies.

Equilíbrio postural de pacientes em hemodiálise compara-dos a indivíduos sem doença renal crônica: estudo transver-sal / Postural balance in hemodialysis patients compared to individuals without chronic kidney disease: a cross-sectional study

Introdução: Pacientes com doença renal crônica (DRC) em hemodiálise (HD) apresentam fatores que contribuem para alterações no equilíbrio postural, aumentando o risco de quedas. Objetivo: Comparar o equilíbrio postural de pacientes em HD com indivíduos sem DRC, bem como verificar os fatores associados a alterações do equilíbrio postural nesses pacientes. Material e métodos: Foi realizado estudo transversal que incluiu um grupo de pacientes com DRC em Hemodiálise (GH) (n= 39, 55,1 ± 7,7 anos, 53,8% do gênero masculino) e um grupo controle (GC) com indivíduos sem DRC (n= 39, 55,3 ± 7,5 anos, 53,8% do gênero masculino). Os participantes foram submetidos a avaliações de equilíbrio postural (Mini Balance Evaluation Systems Test ­ Mini-BESTest), mobilidade funcional (Time Up and Go), velocidade de marcha (Gait Speed Measured over 4m), força muscular (preensão palmar e teste de sentar e levantar de 10 repetições) e qualidade de vida (36-Item Short Form Survey). Resultados: O GH apresentou pior equilíbrio postural avaliado pelo escore do Mini-BESTest [22 (3) vs. 24 (2); p<0,001] quando comparado ao GC. O equilíbrio postural nos pacientes em HD apresentou correlação significante com a velocidade de marcha (ρ= 0,381; p= 0,017) e a força muscular avaliada pelo teste de sentar e levantar (ρ= -0,358; p= 0,027). Na regressão linear múltipla foi observada associação do equilíbrio postural com a velocidade de marcha, sendo o coeficiente de determinação múltiplo de 0,291 e o coeficiente de determinação múltiplo ajustado de 0,231. Conclusão: Pacientes em HD apresentaram pior equilíbrio postural quando comparados a indivíduos sem DRC. O equilíbrio postural foi associado à velocidade de marcha nesses pacientes.

Introduction: Patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) show several factors that contribute to postural balance impairment and higher risk of falls. Objective: To compare postural balance between HD patients and subjects without CKD, and to evaluate the factors associated with impairment of postural balance in these patients. Material and methods: A cross-sectional study was conducted, including a group of Hemodialysis patients (HG) (n= 39, 55.1 ± 7.7 years, 53.8% males) and a control group (CG) (n= 39, 55.3 ± 7.5 years, 53.8% male). Participants were submitted to the following evaluations: postural balance (Mini Balance Evaluation Systems Test - Mini-BESTest), functional mobility (Time Up and Go), gait speed (Gait Speed Measured over 4 m), muscle strength (handgrip and sit-to-stand test), and quality of life (36-Item Short Form Survey questionnaire). Results: The HG showed worse postural balance evaluated by Mini-BESTest score [22 (3) vs. 24 (2), p<0.001) when compared to CG. Postural balance was significantly correlated with gait speed (ρ= 0.381, p= 0.017) and muscle strength evaluated by the sit-to-stand test (ρ= -0.358, p<0.027). The linear regression showed an association between the postural balance and the gait speed. The multiple R-squared was 0.291 and the adjusted R-squared was 0.231. Conclusion: In the present study, HD patients showed worse postural balance when compared to the subjects without CKD. The postural balance was associated with gait speed in these patients.

ADDUCTOR POLLICIS MUSCLE THICKNESS AND PREDICTION OF POSTOPERATIVE MORTALITY IN PATIENTS WITH STOMACH CANCER.

BACKGROUND: Malnutrition is very prevalent in patients with gastric cancer and increases the risk of morbidity and mortality. Adductor pollicis muscle thickness (APMT) appears as an important objective, quick, inexpensive and noninvasive measure to assess the muscle compartment. AIM: To compare APMT and other nutritional assessment methods and to correlate these methods with postoperative mortality. METHODS: Forty-four patients, 29 men and 15 women, mean age of 63±10.2 and ranging from 34-83 years, who underwent nine (20.5%) partial and 34 (77.3%) total gastrectomies due to stomach cancer (stage II to IIIa) were preoperatively assessed by Patient Generated Subjective Global Assessment (PG-SGA), anthropometry and laboratorial profile. RESULTS: APMT better predicted death (p<0.001) on both, dominant and non-dominant hand, and well correlated with albumin (p=0.039) and PG-SGA (p=0.007). CONCLUSION: APMT clearly allowed to determine malnutrition and to predict risk of death in patients with gastric cancer.

Adductor pollicis muscle thickness and prediction of postoperative mortality in patients with stomach cancer / Espessura do músculo adutor do polegar e predição de mortalidade pós-operatória em pacientes com câncer gástrico

ABSTRACT Background: Malnutrition is very prevalent in patients with gastric cancer and increases the risk of morbidity and mortality. Adductor pollicis muscle thickness (APMT) appears as an important objective, quick, inexpensive and noninvasive measure to assess the muscle compartment Aim: To compare APMT and other nutritional assessment methods and to correlate these methods with postoperative mortality Methods: Forty-four patients, 29 men and 15 women, mean age of 63±10.2 and ranging from 34-83 years, who underwent nine (20.5%) partial and 34 (77.3%) total gastrectomies due to stomach cancer (stage II to IIIa) were preoperatively assessed by Patient Generated Subjective Global Assessment (PG-SGA), anthropometry and laboratorial profile Results: APMT better predicted death (p<0.001) on both, dominant and non-dominant hand, and well correlated with albumin (p=0.039) and PG-SGA (p=0.007) Conclusion: APMT clearly allowed to determine malnutrition and to predict risk of death in patients with gastric cancer.

RESUMO Racional: A desnutrição é muito prevalente em pacientes com câncer gástrico e aumenta o risco de morbidade e mortalidade. A espessura do músculo adutor do polegar (APMT) aparece como uma importante medida objetiva, rápida, barata e não invasiva para avaliar o compartimento muscular. Objetivo: O objetivo deste estudo foi comparar a APMT e outros métodos de avaliação nutricional e correlacionar esses métodos com a mortalidade pós-operatória. Métodos: Quarenta e quatro pacientes, 29 homens e 15 mulheres; média (SD) de 63 anos (10,2) e variando de 34 a 83 anos, que foram submetidos a 9 (20,5%) gastrectomias parciais e 34 (77,3%) totais por câncer de estômago (Estágio II a IIIa) e avaliados no pré operatório por Avaliação Subjetiva Global Produzida Pelo Paciente (PG-SGA), antropometria e perfil laboratorial. Resultados: APMT melhor predisse morte (p<0,001) em ambas mãos, dominante e não-dominante, e se correlacionou bem com albumina (p=0,039) e PG-SGA (p=0,007). Conclusão: APMT permitiu claramente determinar a desnutrição e prever o risco de morte em pacientes com câncer gástrico.

Nutritional assessment methods as predictors of postoperative mortality in gastric cancer patients submitted to gastrectomy.

OBJECTIVES: to determine the nutritional evaluation method that best predicts mortality in 90 days of patients submitted to gastrectomy for gastric cancer. METHODS: we conducted a prospective study with 44 patients with gastric cancer, stages II to IIIa, of whom nine were submitted to partial gastrectomy, 34 to total gastrectomy, and one to esophago-gastrectomy. All patients were nutritionally evaluated through the same protocol, up to 72h after hospital admission. The parameters used were Patient-Generated Subjective Global Assessment (PGSGA), classical anthropometry, current weight and height, percentage of weight loss (%WL) and body mass index (BMI). We also measured the thickness of the thumb adductor muscle (TAM) in both hands, dominant hand (TAMD) and non-dominant hand (TAMND), as well as the calculated the prognostic nutritional index (PNI). The laboratory profile included serum levels of albumin, erythrocytes, hemoglobin, hematocrit, leukocytes, and total lymphocytes count (TLC). RESULTS: of the 44 patients studied, 29 (66%) were malnourished by the subjective method, 15 being grade A, 18 grade B and 11 grade C. Cases with PGSGA grade B and TAMD 10.2±2.9 mm were significantly associated with higher mortality. The ROC curves (95% confidence interval) of both PGSGA and TAMD thickness reliably predicted mortality at 30 and 90 days. No laboratory method allowed predicting mortality at 90 days. CONCLUSION: PGSGA and the TAMD thickness can be used as preoperative parameters for risk of death in patients undergoing gastrectomy for gastric cancer.

Nutritional assessment methods as predictors of postoperative mortality in gastric cancer patients submitted to gastrectomy / Métodos de avaliação nutricional preditores de mortalidade pós-operatória em pacientes submetidos à gastrectomia por câncer gástrico

ABSTRACT Objectives: to determine the nutritional evaluation method that best predicts mortality in 90 days of patients submitted to gastrectomy for gastric cancer. Methods: we conducted a prospective study with 44 patients with gastric cancer, stages II to IIIa, of whom nine were submitted to partial gastrectomy, 34 to total gastrectomy, and one to esophago-gastrectomy. All patients were nutritionally evaluated through the same protocol, up to 72h after hospital admission. The parameters used were Patient-Generated Subjective Global Assessment (PGSGA), classical anthropometry, current weight and height, percentage of weight loss (%WL) and body mass index (BMI). We also measured the thickness of the thumb adductor muscle (TAM) in both hands, dominant hand (TAMD) and non-dominant hand (TAMND), as well as the calculated the prognostic nutritional index (PNI). The laboratory profile included serum levels of albumin, erythrocytes, hemoglobin, hematocrit, leukocytes, and total lymphocytes count (TLC). Results: of the 44 patients studied, 29 (66%) were malnourished by the subjective method, 15 being grade A, 18 grade B and 11 grade C. Cases with PGSGA grade B and TAMD 10.2±2.9 mm were significantly associated with higher mortality. The ROC curves (95% confidence interval) of both PGSGA and TAMD thickness reliably predicted mortality at 30 and 90 days. No laboratory method allowed predicting mortality at 90 days. Conclusion: PGSGA and the TAMD thickness can be used as preoperative parameters for risk of death in patients undergoing gastrectomy for gastric cancer.

RESUMO Objetivos: determinar o método de avaliação nutricional que melhor prediz a mortalidade em 90 dias de pacientes submetidos à gastrectomia por câncer gástrico. Métodos: estudo prospectivo de 44 pacientes portadores de câncer gástrico, estágios II a IIIa, dos quais nove foram submetidos à gastrectomia parcial, 34 à gastrectomia total e um à esôfago-gastrectomia. Todos os pacientes foram avaliados nutricionalmente através do mesmo protocolo, até 72h da admissão hospitalar. Os parâmetros utilizados foram a Avaliação Subjetiva Global Produzida Pelo Paciente (ASG-PPP), antropometria clássica, incluindo peso e altura atuais, porcentagem de perda ponderal (%PP) e índice de massa corporal (IMC). A espessura do músculo adutor do polegar (MAP) em ambas mãos, mão dominante (MAPD) e mão não-dominante (MAPND) também foram realizadas, assim como o cálculo do índice nutricional prognóstico (IPN). O perfil laboratorial incluiu níveis séricos de albumina, eritrócitos, hemoglobina, hematócrito, leucócitos e contagem total de linfócitos (CTL). Resultados: dos 44 pacientes estudados, 29 (66%) eram desnutridos pelo método subjetivo, sendo 15 grau A, 18 grau B e 11 grau C. Os casos com ASG-PPP grau B e com MAPD 10,2±2,9 mm foram significativamente associados à maior mortalidade. As curvas ROC (intervalo de confiança de 95%) de ambas ASG-PPP e espessura da MAPD fidedignamente predisseram mortalidade em 30 e 90 dias. Nenhum método laboratorial permitiu prever a mortalidade em 90 dias. Conclusão: a ASG-PPP e a espessura da MAPD podem ser utilizados como parâmetros pré-operatórios para risco de morte em pacientes submetidos à gastrectomia por câncer gástrico.

Preoperative nutritional assessment and prognosis in patients with foregut tumors.

Malnourished patients with gastrointestinal tumours are at risk for postoperative complications and death. The aim of this study was to determine which nutritional assessment method better predicts outcome. Seventy-four patients, 45 men and 29 women; mean (SD) age of 63 (102) yr (range = 34 to 83), undergoing surgical resections for esophageal (n = 19) gastric (n = 43) and pancreatic (n = 12) tumors were preoperatively assessed by Patient Generated Subjective Global Assessment, anthropometry, and by laboratory sampling. Forty-three (58%) of them were unnourished; 25 Subjective Global Assessment (SGA)-A, 34 SGA-B, and 15 SGA-C cases. Mean (SD) of dominant hand adductor pollicis muscle thickness (DAPM) was 13 (3.5) mm and mean (SD) serum albumin was 3.8 (0.5) g/dL. Mean (SD) hospital staying for patients who complicated and died was 34 (29) days and 23 (13) days for survivors (not significant); SGA-B cases were significantly associated with higher mortality (n = 12, P<0.001). Patients with a mean (SD) DAPM below 10.8 (3.7) mm died more frequently than those with a mean (SD) greater than 14 (3) mm (P < 0.001). None of the methods was significantly related to hospital stay, but receiver operating characteristic curves (95% confidence interval) for PG-SGA and DAPM thickness (0.75 and 0.74) reliably predicted mortality (P<0.001) and these methods may be used as preoperative parameter.