PnPP-15, a Synthetic Peptide Derived from a Toxin from Phoneutria nigriventer Spider Venom, Alleviates Diabetic Neuropathic Pain and Acts Synergistically with Pregabalin in Mice.

Diabetic neuropathic pain is one of the complications that affect a wide variety of the diabetic population and is often difficult to treat. Only a small number of patients experience pain relief, which usually comes with onerous side effects and low levels of satisfaction. The search for new analgesic drugs is necessary, given the limitations that current drugs present. Combining drugs to treat neuropathic pain has been attracting interest to improve their efficacy compared to single-drug monotherapies while also reducing dose sizes to minimize side effects. The aim of our study was to verify the antinociceptive effect of a synthetic peptide, PnPP-15, alone and combined with pregabalin, in male Swiss diabetic mice using the von Frey method. PnPP-15 is a synthetic peptide derived from PnPP19, a peptide representing a discontinuous epitope of the primary structure of the toxin PnTx2-6 from the venom of the spider Phoneutria nigriventer. The antinociceptive activity of both compounds was dose-dependent and showed synergism, which was verified by isobolographic analysis. Treatment with PnPP-15 did not cause spontaneous or forced motor changes and did not cause any damage or signs of toxicity in the analyzed organs (pancreas, lung, heart, kidney, brain, or liver). In conclusion, PnPP-15 is a great candidate for an analgesic drug against neuropathic pain caused by diabetes and exerts a synergistic effect when combined with pregabalin, allowing for even more efficient treatment.

Estratégias para o treino da mastigação e deglutição em indivíduos com disfunção temporomandibular e dor orofacial: uma revisão de escopo / Strategies to train mastication and swallowing in individuals with temporomandibular disorder and orofacial pain: a scoping review

RESUMO Objetivo identificar e sintetizar evidências sobre estratégias utilizadas no treino da mastigação e deglutição em indivíduos com disfunção temporomandibular e dor orofacial. Estratégia de pesquisa revisão de escopo desenvolvida com consulta nas bases de dados MEDLINE, LILACS, BBO, IBECS, BINACIS, CUMED, SOF, DeCS, Index Psi, LIPECS e ColecionaSUS (via BVS), Scopus, CINAHL, Embase, Web of Science, Cochrane e na literatura cinzenta: Biblioteca Digital Brasileira de Teses e Dissertações (BDTD), OpenGrey e Google Acadêmico. Critérios de seleção estudos quantitativos ou qualitativos, sem limite temporal e sem restrição de idioma, que continham os seguintes descritores ou palavras-chave: Articulação Temporomandibular, Síndrome da Disfunção da Articulação Temporomandibular, Transtornos da Articulação Temporomandibular, Dor Facial, Mastigação, Deglutição, Terapêutica, Terapia Miofuncional e Fonoaudiologia. Na primeira etapa, dois revisores fizeram a triagem independente dos estudos, por meio da leitura dos títulos e resumos. Na segunda etapa, os revisores leram, independentemente, os documentos pré-selecionados na íntegra. Em caso de divergência, um terceiro pesquisador foi consultado. Resultados as 11 publicações incluídas foram publicadas entre 2000 e 2018. As estratégias mais utilizadas foram o treino da mastigação bilateral simultânea, seguido da mastigação bilateral alternada. Na deglutição, foi proposto aumento do tempo mastigatório para reduzir o alimento em partículas menores e lubrificar melhor o bolo alimentar e treinos com apoio superior de língua. Conclusão o treinamento funcional demonstrou efetividade na reabilitação dos pacientes, embora não siga uma padronização e não seja realizado de forma isolada. Os estudos encontrados apresentam baixo nível de evidência. Considera-se fundamental a realização de estudos mais abrangentes e padronizados, como ensaios clínicos randomizados.

ABSTRACT Purpose To identify and synthesize evidence on strategies used to train chewing and swallowing in individuals with temporomandibular disorder and orofacial pain. Research strategy Scoping review conducted by search in MEDLINE, LILACS, BBO, IBECS, BINACIS, CUMED, SOF, DeCS, Index Psi, LIPECS, and ColecionaSUS (via VHL), Scopus, CINAHL, Embase, Web of Science, Cochrane, and the grey literature: Brazilian Digital Theses and Dissertations Library (BDTD), OpenGrey, and Google Scholar. Selection criteria Quantitative or qualitative studies, with no restriction on time or language of publication, with the following descriptors or keywords: Temporomandibular Joint; Temporomandibular Joint Dysfunction Syndrome; Temporomandibular Joint Disorders; Facial Pain; chewing (Mastication); swallowing (Deglutition); Therapeutics; Myofunctional Therapy; Speech, Language and Hearing Sciences. In the first stage, two reviewers independently screened the studies by title and abstract reading. In the second stage, the reviewers independently read the preselected documents in full text. In case of divergences, a third researcher was consulted. Results The 11 documents included in the review were published between 2000 and 2018. The mostly used training strategies were simultaneous bilateral mastication/chewing, followed by alternating bilateral mastication. In swallowing, increased mastication time was proposed to break food into smaller bits and better lubricate the bolus; training with upper tongue support was also indicated. Conclusion Functional training proved to be effective in rehabilitation, although it was not standardized or performed alone. The studies had low levels of evidence. It is essential to conduct more encompassing and standardized studies, such as randomized clinical trials.

Polymorphisms of Nav1.6 sodium channel, Brain-derived Neurotrophic Factor, Catechol-O-methyltransferase and Guanosine Triphosphate Cyclohydrolase 1 genes in trigeminal neuralgia.

SUBJECTS: Trigeminal neuralgia is a neuropathic pain characterized by episodes of severe shock-like pain within the distribution of one or more divisions of the trigeminal nerve. Pain can be influenced by ethnicity, environment, gender, psychological traits, and genetics. Molecules Nav1.6 sodium channel, Brain-derived Neurotrophic Factor, Catechol-O-methyltransferase and Guanosine Triphosphate Cyclohydrolase 1 have been involved in mechanisms that underlie pain and neurological conditions. OBJECTIVE: The aim of this case-control study was to investigate the occurrence of genetic polymorphisms in Nav1.6 sodium channel (SCN8A/rs303810), Brain-derived Neurotrophic Factor (BDNF/rs6265/Val66Met), Catechol-O-methyltransferase (COMT/rs4680/Val158Met), and Guanosine Triphosphate Cyclohydrolase 1 (GCH1/rs8007267) genes in trigeminal neuralgia patients. METHODS: Ninety-six subjects were divided into two groups: 48 with trigeminal neuralgia diagnosis and 48 controls. Pain was evaluated by visual analog scale and genomic DNA was obtained from oral swabs and analyzed by real-time polymerase chain reaction. RESULTS: No association was observed among SCN8A, BDNF, COMT or GCH1 polymorphisms and the presence of trigeminal neuralgia. Genotype distribution and allele frequencies did not correlate to pain severity. CONCLUSIONS: Although no association of evaluated polymorphisms and trigeminal neuralgia or pain was observed, our data contributes to the knowledge of genetic susceptibility to trigeminal neuralgia, which is very scarce. Further studies may focus on other polymorphisms and mutations, as well as on epigenetics and transcriptional regulation of these genes, in order to clarify or definitively exclude the role of Nav1.6, BDNF, COMT or GCH1 in trigeminal neuralgia susceptibility and pathophysiology.

King's Parkinson's Disease Pain Scale (KPPS): Cross-cultural adaptation to Brazilian Portuguese and content validity.

Pain is one of the most common and troublesome non-motor symptoms of Parkinson's disease (PD). The King's Parkinson's Disease Pain Scale (KPPS) is the first scale of its kind to evaluate the burden and characterization of various phenotypes of pain in individuals with PD. The purpose of this study was to adapt the KPPS to Brazilian culture and to assess its content validity using the Delphi method. The process of adapting the original instrument to the Brazilian context occurred in six stages according to international standards. Following the pilot tests with individuals with PD, the pre-final version of the KPPS-Brazil was developed and submitted to judges to assess content validity. Three evaluation rounds were conducted, in which several corrections and changes suggested by the judges were accepted. The Content Validity Index (CVI) was calculated to determine the judges' degree of agreement. The results demonstrated that the KPPS-Brazil showed a quite satisfactory level of semantic, idiomatic, cultural, and conceptual equivalence. The judges' opinion showed adequate content validity for all of the KPPS-Brazil items and the scale. The use of the KPPS-Brazil will enable an adequate assessment of pain in individuals with PD, contributing to clinical practice and research.

Association of sleep quality and psychological aspects with reports of bruxism and TMD in Brazilian dentists during the COVID-19 pandemic.

BACKGROUND: Dentists are exposed to contamination by SARS-CoV-2 due to dental interventions, leading to a state of alert and potential risk of negative impact in mental health and sleep quality, associated with Temporomandibular Disorder (TMD) and bruxism. OBJECTIVE: to evaluate the psychosocial status, sleep quality, symptoms of TMD, and bruxism in Brazilian dentists (DSs) during the COVID-19 pandemic. METHODOLOGY: The sample (n=641 DSs) was divided into three groups (quarantined DSs; DSs in outpatient care; and frontline professionals), which answered an electronic form containing the TMD Pain Screening Questionnaire (Diagnostic Criteria for Temporomandibular Disorders - DC/TMD), the Pittsburgh Sleep Quality Index (PSQI), the Depression, Anxiety and Stress Scale (DASS-21), and the sleep and awake bruxism questionnaire. ANOVA test and Mann Whitney post-test were used, with Bonferroni adjustment (p<0.016) and a 95% confidence level. RESULTS: Probable TMD was found in 24.3% (n=156) of the participants, while possible sleep and awake bruxism were diagnosed in 58% (n=372) and 53.8% (n=345) of them, respectively. Among all variables evaluated, only symptoms of depression were significantly greater in the quarantined DSs group when compared to those who were working at the clinical care (p=0.002). Working DSs were significantly less likely (OR=0.630, p=0.001) to have depressive symptoms. Those who were not worried or less worried about the pandemic were less likely to experience stress (OR=0.360), anxiety (OR=0.255), and poor sleep quality (OR=0.256). Sleep had a strong positive and moderate correlation with psychological factors on frontline workers and DSs in outpatient care, respectively. CONCLUSION: The results suggest confinement may have a more negative impact on the life of DSs than the act of being actively working. The concern about Covid-19 and poor sleep quality was significantly prevalent and may negatively affect the quality of life of DSs. Thus, further research on the topic is needed.

Acupuncture for pain, mandibular function and oral health-related quality of life in patients with masticatory myofascial pain: A randomised controlled trial.

BACKGROUND: Masticatory myofascial pain is the most prevalent muscular temporomandibular disorders (TMD). It primarily affects masseter and temporal muscles. Several treatments, including acupuncture, have been recommended. However, systematic reviews have highlighted gaps in studies and absence of conclusive results. OBJECTIVES: We performed a randomised controlled clinical trial to evaluate the effectiveness of acupuncture in improving pain, mandibular function and oral health-related quality of life in women with masticatory myofascial pain. METHODS: Thirty-six patients diagnosed with masticatory myofascial pain according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were divided into the following two groups: acupuncture and control (non-penetrating acupuncture).Treatment was performed weekly for 5 weeks, and pain, mandibular function and oral health-related quality of life were evaluated one week before treatment, one week after treatment and one month after treatment. Non-parametric and parametric tests were used for comparisons between times and treatment groups (significance level of P ≤ .05). RESULTS: The acupuncture group showed a significant reduction in pain (P ≤ .01), which was not observed in the control group. Pain intensity was reduced by 61% and 84% at 1 week and 1 month after treatment, respectively. Both groups showed significant improvements in mandibular function and oral health-related quality of life over time (P ≤ .01). Statistical analysis did not show a significant difference between the groups for any other evaluated outcome (P > .05). CONCLUSION: Although acupuncture was effective in pain reduction, non-specific factors may have influenced mandibular function and oral health-related quality of life improvements in both groups, and this needs to be further addressed.

Can fatigue predict walking capacity of patients with Parkinson's disease?

Although fatigue is an expressive symptom of Parkinson's disease (PD), few studies have investigated the association between fatigue, mobility and walking capacity of these patients. OBJECTIVE: To investigate whether fatigue is an independent factor associated with mobility and the walking capacity in patients with PD. METHODS: Forty-eight patients with PD (22 with fatigue) were tested for mobility and their walking capacity: Timed Up and Go (TUG), 10-Meter Walk Test (10MWT) at usual and fastest speed, and 6-Minute Walk Test (6MWT). Fatigue was measured with Parkinson's Fatigue Scale (PFS-16). Linear regression analysis was used to investigate if fatigue is an independent factor contributing to variance in mobility and walking capacity. RESULTS: There was a positive correlation between PFS-16 and TUG (rs=0.385; p=0.007). There was a negative correlation between PFS-16 and 10MWT at comfortable (r=-0.385; p=0.007) and fast speeds (r=-0.396; p=0.005), and 6MWT (r=-0.472; p=0.001). Linear regression analysis revealed that fatigue did not explain the variance of TUG and 10MWT. PFS-16, age and section III of UPDRS explained 49.6% (adjusted R2; p<0.001) variance in the 6MWT, and fatigue was the most significant predictor (F=-32.1; p=0.022). CONCLUSIONS: Fatigue is an independent factor contributing to the distance covered during 6MWT in patients with PD. Our results highlight the importance of recognition and management of this symptom.

Can fatigue predict walking capacity of patients with Parkinson's disease? / A fadiga pode predizer a mobilidade e a capacidade de marcha em pacientes com doença de Parkinson?

ABSTRACT Although fatigue is an expressive symptom of Parkinson's disease (PD), few studies have investigated the association between fatigue, mobility and walking capacity of these patients. Objective: To investigate whether fatigue is an independent factor associated with mobility and the walking capacity in patients with PD. Methods: Forty-eight patients with PD (22 with fatigue) were tested for mobility and their walking capacity: Timed Up and Go (TUG), 10-Meter Walk Test (10MWT) at usual and fastest speed, and 6-Minute Walk Test (6MWT). Fatigue was measured with Parkinson's Fatigue Scale (PFS-16). Linear regression analysis was used to investigate if fatigue is an independent factor contributing to variance in mobility and walking capacity. Results: There was a positive correlation between PFS-16 and TUG (rs=0.385; p=0.007). There was a negative correlation between PFS-16 and 10MWT at comfortable (r=-0.385; p=0.007) and fast speeds (r=-0.396; p=0.005), and 6MWT (r=-0.472; p=0.001). Linear regression analysis revealed that fatigue did not explain the variance of TUG and 10MWT. PFS-16, age and section III of UPDRS explained 49.6% (adjusted R2; p<0.001) variance in the 6MWT, and fatigue was the most significant predictor (F=-32.1; p=0.022). Conclusions: Fatigue is an independent factor contributing to the distance covered during 6MWT in patients with PD. Our results highlight the importance of recognition and management of this symptom.

RESUMO Embora a fadiga seja um sintoma importante na doença de Parkinson (DP), poucos estudos investigaram a associação entre fadiga, mobilidade e capacidade de marcha nesses pacientes. Objetivo: Investigar se a fadiga é um fator independente associado à mobilidade e à capacidade de marcha em pacientes com DP. Métodos: Quarenta e oito pacientes com DP (22 com fadiga) foram avaliados com testes de mobilidade e capacidade de marcha: Timed Up and Go (TUG), Teste de Caminhada de 10 metros (T10m) na velocidade usual e máxima, Teste de Caminhada de Seis Minutos (TC6m). A fadiga foi medida pela Escala de Fadiga no Parkinson (PFS-16). A análise de regressão linear foi utilizada para investigar se a fadiga é um fator independente que contribui para a variação na mobilidade e capacidade de marcha. Resultados: Houve correlação positiva entre PFS-16 e TUG (rs=0,385; p=0,007). Houve correlação negativa entre PFS-16 e T10m na velocidade usual (r=-0,385; p=0,007) e máxima (r=-0,396; p=0,005) e TC6m (r=-0,472; p=0,001). Análise de regressão linear revelou que a fadiga não explicava a variância do TUG e T10m. A PFS-16, a idade e a seção III da UPDRS explicaram 49,6% (R2 ajustado, p<0,001) da variância no TC6m e a fadiga foi o preditor mais significativo (F=-32,1; p=0,022). Conclusões: A fadiga é um fator independente que contribui para a distância percorrida durante o TC6m em pacientes com DP. Nossos resultados destacam a importância do reconhecimento e manejo desse sintoma.

Mice chronically fed a high-fat diet are resistant to malaria induced by Plasmodium berghei ANKA.

C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) develop neurological symptoms and die 6--7-day post-inoculation in the absence of high parasitemia. The effects of chronic intake of a high-fat diet on this process are largely unknown. In this study, we assessed the effect of a high-fat diet on the host-parasite response to malarial infection. Mice were fed ad libitum with either standard or a high-fat diet for 8 weeks and afterwards were infected with PbA. PbA-infected mice feeding a standard diet presented blood parasitemia, hepatic and cerebral histopathological alterations, and hepatic injury with increased hemozoin deposition in the liver. By contrast, these changes were not observed in the malaria high-fat diet group. In addition, mice fed a high-fat diet did not develop the expected neurological symptoms of cerebral malaria and were resistant to death. Taken together, our results indicate that chronic ingestion of high-fat diet prevents the development of experimental malaria induced by PbA injection, suggesting a relationship between a high-fat diet and malaria, which is an interesting subject for further study in humans.

Treatment with selenium-enriched Saccharomyces cerevisiae UFMG A-905 partially ameliorates mucositis induced by 5-fluorouracil in mice.

PURPOSE: Gastrointestinal mucositis is a major problem associated with cancer therapy. To minimize these deleterious effects, simultaneous administration of antioxidant components, such as selenium, can be considered. There is a growing interest in the use of yeasts because they are able to convert inorganic selenium into selenomethionine. In the present study, oral administration of Saccharomyces cerevisiae UFMG A-905 enriched with selenium was evaluated as an alternative in minimizing the side effects of 5FU-induced mucositis in mice. METHODS: Mice body weight, food consumption, faeces consistency and the presence of blood in faeces were assessed daily during experimental mucositis induced by 5-fluorouracil (5FU). Blood was used for intestinal permeability determination, and small intestine for oxidative stress, immunological and histopathological examination. RESULTS: The increased intestinal permeability observed with mucositis induction was partially reverted by S. cerevisiae and selenium-enriched yeast. Both treatments were able to reduce myeloperoxidase activity, but only selenium-enriched yeast reduced eosinophil peroxidase activity. CXCL1/KC levels, histopathological tissue damage and oxidative stress (lipid peroxidation and nitrite production) in the small intestine were reduced by both treatments; however, this reduction was always higher when treatment with selenium-enriched yeast was evaluated. CONCLUSIONS: Results of the present study showed that the oral administration of S. cerevisiae UFMG A-905 protected mice against mucositis induced by 5-FU, and that this effect was potentiated when the yeast was enriched with selenium.

No Association of Polymorphisms in Nav1.7 or Nerve Growth Factor Receptor Genes with Trigeminal Neuralgia.

OBJECTIVE: Trigeminal neuralgia is defined as a sudden severe shock-like pain within the distribution of the trigeminal nerve. Pain is a subjective experience that is influenced by gender, culture, environment, psychological traits, and genes. Sodium channels and nerve growth factor play important roles in the transmission of nociceptive signals and pain. The aim of this study was to investigate the occurrence of Nav1.7 sodium channel and nerve growth factor receptor TrkA gene polymorphisms (SCN9A/rs6746030 and NTRK1/rs633, respectively) in trigeminal neuralgia patients. METHODS: Ninety-six subjects from pain specialty centers in the southeastern region of Brazil were divided into 2 groups: 48 with classical trigeminal neuralgia diagnosis and 48 controls. Pain was evaluated using the visual analog scale and multidimensional McGill Pain Questionnaire. Genomic DNA was obtained from oral swabs in all individuals and was analyzed by real-time polymerase chain reaction. RESULTS: No association was observed between evaluated polymorphisms and trigeminal neuralgia. For allele analyses, patients and controls had similar frequencies for both genes. Genotype distribution or allele frequencies of polymorphisms analyzed here did not correlate to pain scores. CONCLUSIONS: Although no association of evaluated polymorphisms and trigeminal neuralgia diagnosis or pain severity was observed, our data do not exclude the possibility that other genotypes affecting the expression of Nav1.7 or TrkA are associated with the disease. Further studies should investigate distinct genetic polymorphisms and epigenetic factors that may be important in expression of these molecules.

Caracterização da dor em pacientes com doença de Parkinson / Pain characterization of Parkinson's disease patients

FUNDAMENTO: A dor é um sintoma não motor frequente em indivíduos com doença de Parkinson (DP). Pode estar associada aos sinais motores ou surgir no início da doença. Os mecanismos subjacentes à dor na DP ainda não são bem elucidados e muitos fatores podem influenciá-la, como o uso de levodopa e a presença de outros sintomas não motores, como depressão. OBJETIVOS: Descrever a prevalência e caracterizar a dor em pacientes com DP de um centro terciário referência em pesquisa e assistência clínica. MÉTODOS: Foram recrutados pacientes com diagnóstico de DP idiopática a partir do ambulatório de neurologia do Centro de Especialidades Médicas (CEM) da Santa Casa de Belo Horizonte/MG. Um questionário para coleta de dados sociodemográficos e clínicos foi aplicado. A função cognitiva, gravidade dos sinais e sintomas, depressão, distúrbios de sono e fadiga foram avaliados. A dor foi mensurada por meio do Questionário de McGill e Escala Visual Numérica. RESULTADOS: Participaram do estudo 45 pacientes, sendo que 19 (42,2%) apresentavam queixa de dor e, em sua maioria, após o diagnóstico de DP (74%). Não houve diferença entre os grupos com dor e sem dor para os parâmetros clínicos avaliados, com exceção da fadiga que foi mais prevalente (p=0,036) e mais grave (p=0,031) nos pacientes com dor. CONCLUSÃO: A dor é um sintoma prevalente em pacientes com DP atendidos no CEM. A partir dos resultados obtidos pelo McGill, observou-se que a dor crônica e profunda, acometendo principalmente os membros inferiores, com importantes aspectos sensoriais e afetivos, foi comum nos pacientes avaliados.

BACKGROUND: Pain is a common non-motor symptom in Parkinson´s Disease (PD). It can be associated to motor signs or can arise in the beginning of the disease. Mechanisms of pain in PD are not completely understood. Moreover, many factors can interfere, such as use of levodopa and presence of other non-motor symptoms as depression. OBJECTIVES: The aim of this study was to describe prevalence and characterization of pain in PD patients from a research and clinical terciary care center in Belo Horizonte, Minas Gerais, Brazil. METHODS: PD patients from the Neurology Center of Santa Casa Hospital (Belo Horizonte, MG, Brazil) were recruted. Socio-demographic and clinical data were collected. Cognitive function, severity of PD signs and symptoms, depression, sleep disturbance and fatigue were evaluated. Pain was measured by McGill Pain Questionnaire and Visual Numeric Scale (VNS). RESULTS: Forty-five PD patients participated in the study and 42,2% had pain complaints, mostly (74%) after PD diagnosis. No difference between group with pain or without pain for clinical parameters was detected, except for fatigue, which was more prevalent (p=0,036) and more severe (p=0.031) in patients with pain. CONCLUSION: Pain was very prevalent in PD patients from CEM. Results obtained from McGill showed that chronic and deep pain, mostly in lower limbs, with important physical and affective features was very common in this sample of PD patients.

Effectiveness of Sequential Viscosupplementation in Temporomandibular Joint Internal Derangements and Symptomatology: A Case Series.

Viscosupplementation is a minimally invasive technique that replaces synovial fluid by intra-articular injection of hyaluronic acid (HA). Although effective in some joints, there is not conclusive evidence regarding temporomandibular disorders. This case series described the efficacy of a viscosupplementation protocol in intra-articular temporomandibular disorders. Ten patients with a diagnosis of disc displacement and/or osteoarthritis by Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were submitted to four monthly injections of low or medium molecular weight HA. Pain, mandibular function, image analysis by tomography and magnetic resonance, and quality of life were assessed at baseline and follow-ups (1 and 6 months). Pain, jaw range-of-motion, mandibular function, and quality of life improved at follow-up evaluations. Osteoarthritis changes decreased, and 20% of patients improved mandibular head excursion after treatment. Resolution of effusion and improvement in disc morphology were observed for most patients. This viscosupplementation protocol reduced pain and symptoms associated with internal derangement of temporomandibular joint, improved quality of life, and showed benefits from both low and medium molecular weight HA in alternate cycles.

Correction: Enteric Neuronal Damage, Intramuscular Denervation and Smooth Muscle Phenotype Changes as Mechanisms of Chagasic Megacolon: Evidence from a Long-Term Murine Model of Tripanosoma cruzi Infection.

[This corrects the article DOI: 10.1371/journal.pone.0153038.].

Enteric Neuronal Damage, Intramuscular Denervation and Smooth Muscle Phenotype Changes as Mechanisms of Chagasic Megacolon: Evidence from a Long-Term Murine Model of Trypanosoma cruzi Infection.

We developed a novel murine model of long-term infection with Trypanosoma cruzi with the aim to elucidate the pathogenesis of megacolon and the associated adaptive and neuromuscular intestinal disorders. Our intent was to produce a chronic stage of the disease since the early treatment should avoid 100% mortality of untreated animals at acute phase. Treatment allowed animals to be kept infected and alive in order to develop the chronic phase of infection with low parasitism as in human disease. A group of Swiss mice was infected with the Y strain of T. cruzi. At the 11th day after infection, a sub-group was euthanized (acute-phase group) and another sub-group was treated with benznidazole and euthanized 15 months after infection (chronic-phase group). Whole colon samples were harvested and used for studying the histopathology of the intestinal smooth muscle and the plasticity of the enteric nerves. In the acute phase, all animals presented inflammatory lesions associated with intense and diffuse parasitism of the muscular and submucosa layers, which were enlarged when compared with the controls. The occurrence of intense degenerative inflammatory changes and increased reticular fibers suggests inflammatory-induced necrosis of muscle cells. In the chronic phase, parasitism was insignificant; however, the architecture of Aüerbach plexuses was focally affected in the inflamed areas, and a significant decrease in the number of neurons and in the density of intramuscular nerve bundles was detected. Other changes observed included increased thickness of the colon wall, diffuse muscle cell hypertrophy, and increased collagen deposition, indicating early fibrosis in the damaged areas. Mast cell count significantly increased in the muscular layers. We propose a model for studying the long-term (15 months) pathogenesis of Chagasic megacolon in mice that mimics the human disease, which persists for several years and has not been fully elucidated. We hypothesize that the long-term inflammatory process mediates neuronal damage and intramuscular and intramural denervation, leading to phenotypic changes in smooth muscle cells associated with fibrosis. These long-term structural changes may represent the basic mechanism for the formation of the Chagasic megacolon.

Demyelination/remyelination and expression of interleukin-1ß, substance P, nerve growth factor, and glial-derived neurotrophic factor during trigeminal neuropathic pain in rats.

The etiology of trigeminal neuropathic pain is not clear, but there is evidence that demyelination, expression of cytokines, neuropeptides, and neurotrophic factors are crucial contributors. In order to elucidate mechanisms underlying trigeminal neuropathic pain, we evaluated the time course of morphological changes in myelinated and unmyelinated trigeminal nerve fibers, expression of cytokine IL-1ß, neuropeptide substance P (SP), nerve growth factor (NGF), and glial derived neurotrophic factor (GDNF) in peripheral and ganglion tissues, using a rat model of trigeminal neuropathic pain. Chronic constriction injury (CCI) of the infraorbital nerve (IoN), or a sham surgery, was performed. Mechanical allodynia was evaluated from day 3 to day 15 post-surgery. Trigeminal nerves were divided into 2 sections - distal to CCI and ganglion - for morphological analyses, immunohistochemistry (IL-1ß, SP), and protein quantification by ELISA (NGF, GDNF). At early postoperative time points, decreased mechanical responses were observed, which were associated with demyelination, glial cell proliferation, increased immunoexpression of IL-1 ß and SP, and impaired GDNF production. In the late postoperative period, mechanical allodynia was present with partial recovery of myelination, glial cell proliferation, and increased immunoreactivity of IL-1ß and SP. Our data show that demyelination/remyelination processes are related to the development of pain behavior. IL-1ß may have effects both in ganglia and nerves, while SP may be an important mediator at the nerve endings. Additionally, low levels of GDNF may produce impaired signaling, which may be involved in generation of pain.

Sequential infiltration of sodium hyaluronate in the temporomandibular joint with different molecular weights. Case report / Infiltração sequencial de hialuronato de sódio com diferentes pesos moleculares na articulação temporomandibular. Relato de caso

ABSTRACT BACKGROUND AND OBJECTIVES: Temporomandibular disorders are diseases causing pain and dysfunction in joints and muscles controlling mandibular movements. Their etiology is multifactorial and multidisciplinary approaches are needed to reach a differential diagnosis and an adequate management plan. This case report proposes a management protocol, with monthly sodium hyaluronate infiltrations, with different molecular weights, to control such changes and promote improvement of temporomandibular joint biomechanics and pain. CASE REPORT: This study describes a case of a 48-year old patient with a 10-year history of temporomandibular pain with function loss since 2001. Patient has classified her pain as 9 according to analog visual scale. In addition, history and detailed physical evaluation have shown different signs and symptoms, such as localized pain (right side), and right temporomandibular joint arthralgia with noise. Diagnosis was disc displacement with reduction and possible synovitis/ capsulitis to the right. Right temporomandibular joint osteoarthritis was also diagnosed by cone beam CT-scan. Initially, a flat upper splint with total coverage and contact with all antagonist teeth was used. In the attempt to decrease temporomandibular arthralgia, non-steroid anti-inflammatory drugs and muscle relaxants were used. Since right temporomandibular joint pain was not effectively managed, we decided to use intra-joint sodium hyaluronate injections with different molecular weights, per month, in a total of four applications. At treatment completion, clinical evaluation has shown normal function, no pain with visual analog scale = zero, in addition to adequate interincisal distance. CONCLUSION: This report has suggested that viscosupplementation cycles with sodium hyaluronate of different molecular weights may provide excellent results in the long run, to control joint temporomandibular disorder symptoms. Therapeutic benefits were maintained for four years with no need for annual maintenance cycles.

RESUMO JUSTIFICATIVA E OBJETIVOS: As disfunções temporomandibulares são um grupo de doenças que causam dor e disfunção na articulação e nos músculos que controlam os movimentos da mandíbula. Sua etiologia é multifatorial e abordagens multidisciplinares são necessárias para chegar a um diagnóstico diferencial e plano de tratamento adequado. Propõe-se um protocolo de tratamento, com infiltrações mensais, empregando hialuronato de sódio, com diferentes pesos moleculares, para controlar essas alterações e promover uma melhoria da função biomecânica da articulação temporomandibular, bem como da sua dor. RELATO DO CASO: Este estudo descreve um caso de uma paciente de 48 anos que apresentava uma história de 10 anos de dor temporomandibular com perda de função que apareceu em 2001. Ela classificou a intensidade da sua dor como grau 9 de acordo com a escala visual analógica. Além disso, anamnese e exame clínico detalhado mostraram diversos sinais e sintomas, como dor localizada miofascial (lado direito), artralgia da articulação temporomandibular direita com ruído. O diagnóstico foi de deslocamento de disco com redução e possível sinovite/capsulite à direita. Osteoartrose da articulação temporomandibular direita também foi confirmada por tomografia computadorizada de feixe cônico. Inicialmente, foi utilizada uma placa superior plana de cobertura total com contato com todos os dentes antagonistas. Numa tentativa de diminuir a artralgia temporomandibular, foram empregados anti-inflamatórios não esteroides e um relaxante muscular. Como a dor da articulação temporomandibular direita não foi efetivamente eliminada,optou-se pela utilização de uma injeção intra-articular de hialuronato de sódio, com diferentes pesos moleculares, por mês, totalizando quatro aplicações. No final do tratamento, o exame clínico mostrou normalização da função, a dor havia desaparecido, escala analógica visual=zero, além de uma distância interincisal adequada. CONCLUSÃO: O presente trabalho sugeriu que ciclos de viscossuplementação com hialuronato de sódio, de diferentes pesos moleculares, podem proporcionar excelentes resultados, em longo prazo, no controle de sinais e sintomas da disfunção temporomandibular de origem articular. Os benefícios terapêuticos foram mantidos por um período de quatro anos, sem a necessidade de ciclos anuais de manutenção.