Blockage of the fractalkine pathway reduces hyperalgesia and prevents morphological glial alterations-Comparison between inflammatory and neuropathic orofacial pain in male rats.

This study aimed to evaluate the effects of inhibitors of the fractalkine pathway in hyperalgesia in inflammatory and neuropathic orofacial pain in male rats and the morphological changes in microglia and satellite glial cells (SGCs). Rats were submitted to zymosan-induced arthritis of the temporomandibular joint or infraorbital nerve constriction, and treated intrathecally with a P2 X7 antagonist, a cathepsin S inhibitor or a p-38 mitogen-activated protein kinase (MAPK) inhibitor. Mechanical hyperalgesia was evaluated 4 and 6 h following arthritis induction or 7 and 14 days following nerve ligation. The expression of the receptor CX3 CR1 , phospho-p-38 MAPK, ionized calcium-binding adapter molecule-1 (Iba-1), and glutamine synthetase and the morphological changes in microglia and SGCs were evaluated by confocal microscopy. In both inflammatory and neuropathic models, untreated animals presented a higher expression of CX3 CR1 and developed hyperalgesia and up-regulation of phospho-p-38 MAPK, which was prevented by all drugs (p < .05). The number of microglial processes endpoints and the total branch length were lower in the untreated animals, but the overall immunolabeling of Iba-1 was altered only in neuropathic rats (p < .05). The mean area of SGCs per neuron was significantly altered only in the inflammatory model (p < .05). All morphological alterations were reverted by modulating the fractalkine pathway (p < .05). In conclusion, the blockage of the fractalkine pathway seemed to be a possible therapeutic strategy for inflammatory and neuropathic orofacial pain, reducing mechanical hyperalgesia by impairing the phosphorylation of p-38 MAPK and reverting morphological alterations in microglia and SGCs.

Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors.

Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.

Electroacupuncture Reduces Inflammation but Not Bone Loss on Periodontitis in Arthritic Rats.

Periodontitis and rheumatoid arthritis (RA) are inflammatory diseases characterized by chronic inflammation and bone erosion. Electroacupuncture (EA) shows anti-inflammatory and anti-resorptive effects in experimental periodontitis (EP) and in RA. It is important to investigate whether EA shows these effects in periodontal tissues in the presence of these two inflammatory diseases or not. For this, Wistar rats were divided into six groups: control (C); experimental rheumatoid arthritis (RA; bovine type II collagen-induced (CII)); experimental periodontitis (EP); RA/EP (RA + EP); EP/EA (EP treated with EA); RA/EP/EA (RA + EP treated with EA). EP was induced 21 days after RA induction and EA was performed previously and during the EP induction period, every 3 days until the 36th experimental day. The rats were euthanized on day 39. RA was evaluated by edema and the withdrawal threshold of hind paws. The maxillae were removed, and alveolar bone loss (ABL) and bone radiographic density (BRD) were evaluated. Immunohistochemical analyses for interleukins (IL)-6 and -17 and nuclear factor (NF)-κB were performed. Our results showed that EA reduced only the pain intensity in arthritic rats. Histomorphometric, macroscopic, and radiographic analyses did not show differences between the control and EP/EA groups. EA caused a reduction in ABL and BRD only in the presence of EP. EA caused a reduction in IL-6 and -17 in all groups, but NF-κB was only reduced in the arthritic rats with EP. In conclusion, EA reduced the inflammation related to periodontitis in arthritic rats but did not prevent ABL.

FLOX (5-fluorouracil + leucovorin + oxaliplatin) chemotherapy for colorectal cancer leads to long-term orofacial neurotoxicity: a STROBE-guided longitudinal prospective study.

BACKGROUND: Colorectal carcinoma (CRC) is widely treated by chemotherapy based on an intensely neurotoxic drug: oxaliplatin (OXL). We objective to evaluate prospectively the orofacial neurotoxicity during FLOX (fluorouracil + leucovorin + OXL) chemotherapy. METHODS: So, 46 patients with CRC were prospectively evaluated during FLOX chemotherapy by 3 cycles (C) of 6 weeks (W) each. We weekly applied the orofacial section of the Acute and Chronic Neuropathy Questionnaire of Common Toxicity Criteria for Adverse Events of the National Cancer Institute of the United States of America (Oxaliplatin-specific neurotoxicity scale). Patients were asked the following concerning the severity (scores 0-5) of orofacial symptoms: jaw pain, eyelids drooping, throat discomfort, ear pain, tingling in mouth, difficulty with speech, burning or discomfort of the eyes, loss of any vision, feeling shock/pain down back and problems breathing. We summed the scores (0-50) and evaluated the clinicopathological data. Friedman/Dunn, Chi square and multinomial regression logistic tests were used (SPSS 20.0, p < 0.05). RESULTS: There was a significant increase in sum of orofacial neurotoxicity from baseline to C1.W3, C2.W1 and C3.W5 (p < 0.001) due increase in scores of jaw pain (p < 0.001), eyelids drooping (p = 0.034), throat discomfort (p < 0.001), ear pain (p = 0.034), tingling in mouth (p = 0.015), burning/discomfort of your eyes (p < 0.001), loss of any vision (p < 0.001), feeling shock/pain down back (p < 0.001), problems with breathing (p = 0.045), but not difficulty with speech (p = 0.087). Women (p = 0.021) and young patients (p = 0.027) had significant higher prevalence of orofacial neurotoxicity. CONCLUSIONS: FLOX-related orofacial neurotoxicity begins acutely and remains long term with increased incidence in women and younger patients.

Involvement of Endothelin Receptors in Peripheral Sensory Neuropathy Induced by Oxaliplatin in Mice.

The aim of this study was to evaluate the participation of the endothelin ETA and ETB receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult male Swiss mice received 1 mg/kg of oxaliplatin intravenously, twice a week for 5 weeks. Dorsal root ganglia (DRG) and spinal cords were removed for evaluation of the endothelin ETA and ETB receptor expression. Afterwards, selective (BQ-123 and BQ-788; 10 nmol in 30 µL, intraplantarly) and non-selective (bosentan, 100 mg/kg, orally) antagonists were administered in order to evaluate the involvement of the endothelin receptors in OIN. Mechanical and thermal nociception tests were performed once a week for 56 days. Oxaliplatin induced mechanical and thermal hypersensitivity and increased the endothelin ETA receptor expression in both the DRG and spinal cord (P < 0.05). Endothelin ETB receptor expression was increased in the DRG (P < 0.05) but not in the spinal cord. Both endothelin ETA and ETB receptor selective antagonists partially prevented mechanical hyperalgesia in mice with OIN (P < 0.05). Moreover, bosentan prevented mechanical and thermal hypersensitivity in oxaliplatin-treated mice (P < 0.05). In conclusion, both endothelin ETA and ETB receptors seem to be involved in the OIN in mice and they should be considered possible targets for the management of this clinical feature.

Electroacupuncture increases immunoexpression of CB1 and CB2 receptors in experimental model of inflammatory bone loss.

This study evaluated the participation of CB1 and CB2 receptors in the antiresorptive effect of electroacupuncture (EA) on an experimental model of inflammatory bone loss in rats. 30 rats were divided into five groups: C (control); EP (experimental periodontitis); EA (C+ EA); EP-EA (EP+ EA in the acupoints LI4, LG11, ST36, ST44); EP - EA-sham (EP+ EA in sham acupoints). For the EP groups, a ligature was placed around the right mandibular first molars at day 1. Sessions of EA or EA-sham were assigned every other day. Animals were euthanized at day 11. Histometric analysis was performed to evaluate the percentage of bone area in the furcation area. Immunolabeling patterns in the periodontal tissues and immunofluorescent staining in the trigeminal ganglia and in the trigeminal spinal tract for CB1 and CB2 receptors were performed. It was observed increased bone loss in the furcation in the EP and EP-EA-sham groups, in comparison to the other groups (p < 0.05). Enhanced CB2 immunolabeling was observed in the periodontal tissues in the EP-EA group, when compared to the EP and EP-EA-sham groups (p < 0.05). Increased CB1 immunofluorescent staining was observed in the neural tissues in the EA treated group in comparison with the other groups (p < 0.05), while no expression of CB2 was observed in those regions. Our study showed that in the presence of inflammatory bone disease, EA treatment reduced bone erosion and increased the immunoexpression of CB1 in the neural tissues and CB2 in the periodontal tissues.

Neurotoxic effect of oxaliplatin: Comparison with its oxalate-free analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice.

Studies suggest that oxalate is involved in the development oxaliplatin-induced peripheral sensory neuropathy (OPSN). This study aimed to compare the neurotoxic effects of oxaliplatin with its oxalate-free cytotoxic analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice. Oxaliplatin and LLC-1402 were intravenously injected in male Swiss mice with a total of nine injections. Oxalate was intraperitoneally injected in other animals. The development of OPSN was evaluated using mechanical and thermal sensitivity tests. Dorsal root ganglia of the mice were removed to evaluate c-Fos, ATF3 and iNOS expression and a sample of blood was collected for leukocyte count and hepatic and renal biochemical function tests. Oxaliplatin and LLC-1402 decreased the mechanical and thermal nociceptive threshold, whilst oxalate lead to a partial and later increase in the mechanical sensitivity (P<0.05). c-Fos, ATF3 and iNOS expressions were increased in neuronal cells during and after the end of the injections in animals treated with oxaliplatin and LLC-1402 (P<0.05), even though oxaliplatin lead to an earlier increase. Only c-Fos expression was elevated during the period of injections in the oxalate group (P<0.05), but this expression reduced after the end of the treatment. c-Fos expression was also shown in glial satellite cells only in the oxaliplatin-treated animals. Oxaliplatin and LLC-1402 reduced leukocyte count (P<0.05), but did not change renal and liver functions. In conclusion, oxalate may contribute to an earlier development of peripheral sensory neuropathy. However, the antitumor cytotoxic mechanism of oxaliplatin seems to be the main responsible by its neurotoxic effect.

Anti-inflammatory and antiresorptive effects of Calendula officinalis on inflammatory bone loss in rats.

OBJECTIVE: The aim of this work was to evaluate the anti-inflammatory and antiresorptive effects of Calendula officinalis (CLO) on alveolar bone loss (ABL) in rats. MATERIAL AND METHODS: Male Wistar rats were subjected to ABL by ligature with nylon thread around the second upper left molar. The contralateral hemimaxillae were used as control. Rats received saline solution (SAL) or CLO (10, 30, or 90 mg/kg) 30 min before ligature and daily until the 11th day. The maxillae were removed and prepared for macroscopic, radiographic, micro-tomographic, histopathologic, histometric analysis, and immunohistochemical localization of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG). The gingival tissues were used to quantify the myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-α), and interleukin-1ß (IL-1ß) concentrations by ELISA. Blood samples were collected for leukogram and to evaluate the bone-specific alkaline phosphatase (BALP) activity and serum levels of aspartate and alanine transaminases (AST/ALT). RESULTS: The bone loss induced by 11 days of ligature induced bone loss, reduced levels of BALP, leukocyte infiltration, increased MPO activity, gingival concentrations of TNF-α and IL-1ß, and RANKL while reduced OPG immunoexpressions in the periodontal tissue and leukocytosis. Of the CLO, 90 mg/kg reduced bone loss, neutrophilia, the levels of pro-inflammatory mediators, and RANKL expression, while it increased OPG immunopositive cells and BALP serum levels, when compared to SAL. CLO did not affect either kidney or liver function, indicated by serum AST/ALT levels. CONCLUSION: The present data suggests that CLO reduced inflammatory bone resorption in experimental periodontitis, which may be mediated by its anti-inflammatory properties and its effects on bone metabolism. CLINICAL RELEVANCE: CLO can be a potential therapeutical adjuvant in the treatment of periodontitis.

Inflammatory pain assessment in the arthritis of the temporomandibular joint in rats: A comparison between two phlogistic agents.

Temporomandibular joint (TMJ) disorders are a group of conditions that result in TMJ pain, which frequently limits basic daily activities. Experimental models that allow the study of the mechanisms underlying these inflammatory and pain conditions are of great clinical relevance. The aim of this study was to evaluate nociception, inflammation and participation of the macrophage/microglia cells in the arthritis of the TMJ induced by two phlogistic agents. 84 rats were divided into 2 groups: Zy, which received zymosan intra-articularly, or Cg, which received carrageenan intra-articularly. Mechanical nociception, total leukocyte influx to the synovial fluid and histopathological analyses were evaluated in the TMJ. The participation of macrophage/microglia located in trigeminal ganglia (TG) and in the subnucleus caudalis (V-SnC) was assessed immunohistochemically. Both agents induced mechanical hyperalgesia 6h after the induction, but a more persistent algesic state was perceived in the Cg group, which lasted for 120h. Even though both groups presented increased leukocyte influx, the Zy-group presented a more intense influx. Zymosan recruited resident macrophage in the trigeminal ganglia 24h after the injection. In the V-SnC, the group Cg presented a more prolonged immunolabeling pattern in comparison with the group Zy. It can be concluded that zymosan induced a more intense infiltrate and peripheral nervous changes, while Cg lead to a moderate TMJ inflammation with prominent changes in the V-SnC.

Avaliação dos efeitos da eletroacupuntura na periodontite induzida por ligadura em ratos

Tem sido relatado que a acupuntura é capaz de modular a resposta imunoinflamatória dohospedeiro. O objetivo deste estudo foi a avaliar os efeitos da eletroacupuntura (EA) naperiodontite induzida por ligadura em ratos. Trinta e dois animais foram divididos nos gruposC (controle), PE (periodontite experimental), PE/EA-sham e PE/EA. Nos grupos PE, umaligadura foi posicionada ao redor dos 1os molares inferiores direitos. Cinco sessões de EA ouEA-sham foram realizadas a cada dois dias, iniciando-se no dia seguinte à colocação daligadura. Para o tratamento com EA, os acupontos IG4, IG11, E36 e E44 foram utilizados. AEA-sham foi realizada em pontos localizados fora de meridianos. Os animais foramsubmetidos à eutanásia 11 dias após a indução da periodontite. Análises histomorfométrica emicrotomográfica foram realizadas. Expressões dos RNAm de interleucina (IL)-1β,metaloproteinase de matriz (MMP)-8, IL-6, fator de necrose tumoral (TNF)-α e ciclooxigenase(COX)-2 foram avaliadas por meio da reação em cadeia da polimerase datranscrição reversa em tempo real (qRT-PCR). Os dados foram estatisticamente analisados(ANOVA, p0,05). Dentro dos limites do presente estudo, podeser concluído que a EA reduz a destruição tecidual periodontal e a expressão de algunsmediadores pró-inflamatórios na PE em ratos.

Acupuncture has been reported as capable of modulating the host’s immuno-inflammatory response. The purpose of this study was to evaluate the effects of electroacupuncture (EA) on ligature-induced periodontitis in rats.Thirty-two animals were divided into groups C (control), EP (experimental periodontitis), EP/EA-sham and EP/EA. On EP groups, a ligature was placed around right mandibular 1st molars. Five sessions of EA or EA/sham were assigned every other day, starting one day after ligature placement. For EA treatment, acupoints LI4, LI11, ST36 and ST44 were used. EA-sham was performed in off-meridian points.Animals were euthanized 11 days after the induction of periodontitis. Histomorphometric and microtomographic analyses were performed. Expressions of interleukin (IL)-1β, matrix metalloproteinase (MMP)-8, IL-6, tumor necrosis factor (TNF)-αand cyclooxygenase (COX)-2 mRNA were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Data were statistically analyzed (ANOVA, p0.05). Within the limits of the present study, it can be concluded that EA reduces periodontal tissue destruction and the expression of some pro-inflammatory mediators in EP in rats.

Pleiotropic effects of statins on the treatment of chronic periodontitis--a systematic review.

AIM: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss. METHODS: In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected. RESULTS: Statins have important anti-inflammatory and immune effects, reducing levels of C-reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-α, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts. CONCLUSION: Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis.

Avaliação do ganho ósseo em espessura com utilização de enxertos ósseos alógenos congelados / Evaluation of width bone gain after using fresh-frozen bone allograft

O osso humano é um tecido de alta mutabilidade. Quando a reabsorção ósseo-alveolar apresenta um nível elevado, a reabilitação oral é prejudicada, principalmente no caso das reabilitações por implantes osseointegrados. Nesse sentido, os enxertos ósseos em bloco passaram a ser utilizados na reconstrução óssea, podendo esses ser autógenos, alógenos, xenógenos ou aloplásticos. Apesar de osso autógeno ser considerado padrão-ouro, uma série de contratempos, como presença de segundo leito cirúrgico e maior dor pós-operatória, levou a busca de uma alternativa nos enxertos alógenos. O objetivo desse estudo foi avaliar o ganho ósseo (GO) e a reabsorção do bloco enxertado (RB) após a utilização de enxertos homógenos para reconstrução óssea maxilar, bem como a relação destes com idade, tipo de tecido enxertado (TE) e espessura inicial de rebordo (EI). Utilizou-se 34 enxertos ósseos homógenos para reconstrução óssea em 24 pacientes, de modo que, na tomografia do pós-operatório de seis meses, foram analisadas as medidas de EI, GO, espessura óssea final (EF) e RB. Não se observou nenhuma reabsorção ou incorporação total dos blocos. O valor médio de GO foi 4,42 ± 1,43 mm e o de RB foi 2,04 ± 1,48 mm. Dos 34 blocos, somente dois apresentaram EF menor que 5 mm. Os valores médios de GO e RB não mostraram diferença estatística quando relacionados à idade, TE ou EI. Concluiu-se que os enxertos ósseos alógenos são uma alternativa de alta previsibilidade para aumento de volume ósseo maxilar, não parecendo ter relação com EI, TE ou idade

The human bone is a tissue that presents high mutability. When the resorption of alveolar bone shows itself in high levels, oral rehabilitation becomes difficult, mainly in cases of rehabilitations with dental implants. For this purpose, bone blocks started to be used in bone reconstruction for rehabilitation. These blocks can be classified as autograft, allograft, xenograft or alloplastic. Even though bone autograft is considered gold-standard, some side effects, like necessity of a secondary surgery and higher level of post-operative pain, led to an alternative found in bone allografts. The aim of this study was to evaluate the bone gain (GO) and the resorption of the grafted block (RB) after grafting allograft bone for maxillary reconstruction, as well as their relation with age, type of grafted tissue (TE) and initial bone width (EI). Thirty-four allograft bones were grafted in 24 patients’ maxilla and, in the six months post-operative tomography, the values of EI, GO, final width of alveolar bone (EF) and RB were analyzed. Neither total resorption nor total incorporation of the blocks was observed. The mean value for GO was 4,42 ± 1,43 mm and the one for RB was 2.04 ± 1.48 mm. Out of the 34 allografts, only 2 showed EF lower than 5 mm. No significant difference was observed when the mean values for GO and RB were related to age, TE or EI. In conclusion, allografts are a highly predicable alternative for enhancing alveolar bone volume, and did not present relation with TE, EI or age

Abordagens motivacionais em periodontia / Motivational approaches in periodontology

As doenças periodontais são processos multifatoriais, necessitando da interação entre o biofilme aderido aos dentes e o hospedeiro para ocorrerem. A participação ativa do indivíduo nas práticas regulares de higiene bucal que desorganizam esse biofilme e a motivação do paciente em executá-las tornam-se importantes para a prevenção, o tratamento e a manutenção dos resultados obtidos com a terapia periodontal. O intuito deste trabalho foi analisar a literatura, verificando as discussões sobre os métodos mais eficazes de motivação e a influência do paciente motivado no tratamento periodontal. Pôde-se concluir que a motivação é algo inerente a cada indivíduo, mas cabe ao cirurgião-dentista estimular seu paciente com os recursos disponíveis. Das diversas formas existentes para estimular o indivíduo, a combinação de abordagens diretas e indiretas associadas a consultas frequentes para reinstruções parece ser a melhor alternativa, obtendo do paciente motivação e cooperação necessárias para o sucesso do tratamento.

Manifestações orais em pacientes diabéticos / Oral manifestations in diabetic: a literature review

0 diabetes mellitus é uma doença metabólica relativamente frequente, que tem como consequência uma alteração do nível metabólico de glicose, o que gera graves consequências sistêmicas e orais. Dentre as principais manifestações orais podem ser citadas periodontite associada ao diabetes, que acontece em consequência de alterações vasculares, sanguíneas e no tecido conjuntivo, alterando a recuperação tecidual; a hipossalivação, que gera problemas na fonação e na mastigação, além de ulcerações na mucosa; aumento do risco a cáries, em consequência da hipossalivação e do aumento da concentração de glicose na saliva; halitose, advinda da liberação de corpos cetônicos via pulmonar; aumento do grau de Infecções fúngicas, consequente da diminuição da resposta à infecção, da hiperglicemia e da cetoacidose sanguíneas, alterando a resposta imune. Além das alterações citadas, outras manifestações menos comuns podem ocorrer, como ulcerações e glossite, além de reações liquenoides ou leucoplasias. Para evitar e controlar essas alterações, este paciente deve ser tratado e acompanhado por uma equipe multidisciplinar em ordem de prevenir e tratar qualquer manifestação consequente do diabetes.