Nociceptive and histomorphometric evaluation of the effects of ozone therapy on the rat masseter muscle in a carrageenan model of myofascial pain.

OBJECTIVE: This study evaluated the effects of intramuscular ozone therapy on nociception, inflammation, and tissue damage caused by the injection of carrageenan in the masseter muscle of rats. DESIGN: Rat masseter muscles were injected with saline or carrageenan. Seventy-seven adult male rats were divided into six groups: Sal, saline; Car, carrageenan; Ibup + Sal, ibuprofen and saline; Ibup + Car, ibuprofen and carrageenan; O3 + Sal, ozone and saline; and O3 + Car, ozone and carrageenan. The mixture of 5% ozone and 95% oxygen (20 µg/mL) was administered three times in the course of a week. Nociceptive responses in the masseter muscles were measured using a head withdrawal threshold, determined by an electronic von Frey anesthesiometer. The animals were euthanized one or eight days after the carrageenan injection, and the masseters were submitted to histological and histomorphometric analyses. RESULTS: Mechanical allodynia and inflammation levels were reduced in the Ibup + Car group compared to the other groups. Myonecrosis was similar among carrageenan-treated groups. Picrosirius red stained sections showed more collagen fibers and more regenerating myofibers in the O3 + Car group compared to the other groups. Eight days after carrageenan injection, the O3 + Car group showed neutrophils close to the regenerating myofibers. CONCLUSIONS: Intramuscular ozone therapy did not alleviate mechanical allodynia, and it did not protect the masseter muscle against the deleterious effects produced by carrageenan, probably due to the mode of administration of this therapeutic agent.

Renal functional and structural alterations induced by intramuscular injection of Bothrops leucurus venom.

Acute kidney injury (AKI) is the main cause of death from Bothrops snakebite. Although many studies have investigated the nephrotoxicity induced by other Bothrops species, no study has assessed the renal alterations induced by intramuscular (i.m.) injection of Bothrops leucurus venom. In this study, we evaluated the nephrotoxicity induced by B. leucurus venom by analyzing renal function and histology. Wistar rats were submitted to i. m. injection of B. leucurus venom or saline and divided into two groups: Control group (C), rats submitted to i. m. injections of saline, and B. leucurus group (Bl), rats submitted to i. m. injections of B. leucurus venom (1 mg/kg). After venom or saline injection, serum and urine were collected to measure creatinine, albumin, sodium, and potassium levels. The glomerular filtration rate (GFR), urinary flow urinary, creatinine/serum creatinine ratio, and albuminuria-urinary creatinine ratio were determined. All rats were euthanized 72 h following the injections, and the kidneys were removed for histology and immunohistochemical studies. B. leucurus experimental envenoming was accompanied by an increase of 236% in serum creatine kinase activity in the Bl group. The weights of the right and left kidneys were, respectively, 26 and 22% higher in rats of the Bl group than in control rats. Regarding renal function, the Bl group showed a decrease of 37% in GFR compared to control group. The rats of the Bl group also presented increased cortical (8.20 ± 1.35) and medullar (6.17 ± 2.00) tubulointerstitial lesion area when compared to control group (0.02 ± 0.00) (1.20 ± 0.73), respectively. The number of macrophages was also higher in the renal cortex (6.66 ± 0.06) and medulla (1.22 ± 0.10) of rats from the Bl group when compared to control rats (1.04 ± 0.55), (0.65 ± 0.10), respectively. Our results indicate that B. leucurus venom promoted significant histological and functional renal alterations following intramuscular inoculation, which simulates the majority of snakebites observed in the clinical practice.

Bothrops leucurus snake venom protein profile, isolation and biological characterization of its major toxin PLA2s-like.

Bothrops leucurus is considered as a snake of medical interest in the State of Bahia, Brazil. However, so far, there are no studies that provide a refined mapping of the composition of this venom. The aim of this work was to better understand the protein composition of B. leucurus snake venom and to isolate and biologically characterize the most abundant toxin, a basic PLA2-like. Shotgun proteomics approach identified 137 protein hits in B. leucurus venom subdivided into 19 protein families. The new basic PLA2-like toxin identified was denominated Bleu-PLA2-like, it and other proteoforms represents about 25% of the total proteins in the venom of B. leucurus and induces myotoxicity, inflammation and muscle damage. Immunoreactivity assays demonstrated that B. leucurus venom is moderately recognized by bothropic and crotalic antivenoms, and on the other hand, Bleu-PLA2-like and its proteoforms are poorly recognized. Our findings open doors for future studies in order to assess the systemic effects caused by this snake venom in order to better understand the toxinological implications of this envenomation and, consequently, to assist in the clinical treatment of victims.

Widow spiders in the New World: a review on Latrodectus Walckenaer, 1805 (Theridiidae) and latrodectism in the Americas.

Humankind has always been fascinated by venomous animals, as their toxic substances have transformed them into symbols of power and mystery. Over the centuries, researchers have been trying to understand animal venoms, unveiling intricate mixtures of molecules and their biological effects. Among venomous animals, Latrodectus Walckenaer, 1805 (widow spiders) have become feared in many cultures worldwide due to their extremely neurotoxic venom. The Latrodectus genus encompasses 32 species broadly spread around the globe, 14 of which occur in the Americas. Despite the high number of species found in the New World, the knowledge on these spiders is still scarce. This review covers the general knowledge on Latrodectus spp. from the Americas. We address widow spiders' taxonomy; geographical distribution and epidemiology; symptoms and treatments of envenomation (latrodectism); venom collection, experimental studies, proteome and transcriptome; and biotechnological studies on these Latrodectus spp. Moreover, we discuss the main challenges and limitations faced by researchers when trying to comprehend this neglected group of medically important spiders. We expect this review to help overcome the lack of information regarding widow spiders in the New World.

Effects of photobiomodulation therapy on the local experimental envenoming by Bothrops leucurus snake.

Bothrops leucurus is the major causative agent of snakebites in Brazil's Northeast. The systemic effects of its venom are effectively neutralized by antivenom therapy, preventing bitten patients' death. However, antivenom fails in neutralizing local effects that include intense pain, edema, bleeding, and myonecrosis. Such effects can lead to irreversible sequels, representing a clinically relevant issue for which there is no current effective treatment. Herein, the effects of photobiomodulation therapy (PBMT) were tested in the local actions induced by B. leucurus venom (BLV) in mice (n = 123 animals in 20 experimental groups). A continuous emission AlGaAs semiconductor diode laser was used in two wavelengths (660 or 780 nm). Mechanical nociceptive thresholds were assessed with the electronic von Frey apparatus. Local edema was determined by measuring the increase in paw thickness. Hemorrhage was quantified by digital measurement of the bleeding area. Myotoxicity was evaluated by serum creatine kinase (CK) activity and histopathological analysis. PBMT promoted anti-hypernociception in BLV-injected mice; irradiation with the 660 nm laser resulted in faster effect onset than the 780 nm laser. Both laser protocols reduced paw edema formation, whether irradiation was performed immediately or half an hour after venom injection. BLV-induced hemorrhage was not altered by PBMT. Laser irradiation delayed, but did not prevent myotoxicity caused by BLV, as shown by a late increase in CK activity and histopathological alterations. PBMT was effective in the control of some of the major local effects of BLV refractory to antivenom. It is a potential complementary therapy that could be used in bothropic envenoming, minimizing the morbidity of these snakebite accidents.

Widow spiders in the New World: a review on Latrodectus Walckenaer, 1805 (Theridiidae) and latrodectism in the Americas

Humankind has always been fascinated by venomous animals, as their toxic substances have transformed them into symbols of power and mystery. Over the centuries, researchers have been trying to understand animal venoms, unveiling intricate mixtures of molecules and their biological effects. Among venomous animals, Latrodectus Walckenaer, 1805 (widow spiders) have become feared in many cultures worldwide due to their extremely neurotoxic venom. The Latrodectus genus encompasses 32 species broadly spread around the globe, 14 of which occur in the Americas. Despite the high number of species found in the New World, the knowledge on these spiders is still scarce. This review covers the general knowledge on Latrodectus spp. from the Americas. We address widow spiders' taxonomy; geographical distribution and epidemiology; symptoms and treatments of envenomation (latrodectism); venom collection, experimental studies, proteome and transcriptome; and biotechnological studies on these Latrodectus spp. Moreover, we discuss the main challenges and limitations faced by researchers when trying to comprehend this neglected group of medically important spiders. We expect this review to help overcome the lack of information regarding widow spiders in the New World.(AU)

Widow spiders in the New World: a review on Latrodectus Walckenaer, 1805 (Theridiidae) and latrodectism in the Americas

Abstract Humankind has always been fascinated by venomous animals, as their toxic substances have transformed them into symbols of power and mystery. Over the centuries, researchers have been trying to understand animal venoms, unveiling intricate mixtures of molecules and their biological effects. Among venomous animals, Latrodectus Walckenaer, 1805 (widow spiders) have become feared in many cultures worldwide due to their extremely neurotoxic venom. The Latrodectus genus encompasses 32 species broadly spread around the globe, 14 of which occur in the Americas. Despite the high number of species found in the New World, the knowledge on these spiders is still scarce. This review covers the general knowledge on Latrodectus spp. from the Americas. We address widow spiders taxonomy; geographical distribution and epidemiology; symptoms and treatments of envenomation (latrodectism); venom collection, experimental studies, proteome and transcriptome; and biotechnological studies on these Latrodectus spp. Moreover, we discuss the main challenges and limitations faced by researchers when trying to comprehend this neglected group of medically important spiders. We expect this review to help overcome the lack of information regarding widow spiders in the New World.

O modelo de dor inflamatória induzida pela carragenina como estratégia para avaliar a ação de drogas sobre a dor miofascial / The carrageenan-induced inflammatory pain model as a tool to assess the action of drugs on myofascial pain

A dor miofascial orofacial vem sendo tratada com analgésicos, anti-inflamatórios, relaxantes musculares, fisioterapia, laserterapia e placas oclusais. Contudo, muitas vezes, tais condutas falham em amenizar o quadro doloroso, havendo a necessidade de testar outras estratégias de tratamento. Metodologia: Uma opção para avaliação experimental dessas terapias seria o teste de dor induzido pela carragenina, associado ao teste de avaliação do limiar nociceptivo, originalmente desenvolvido para avaliar a ação de drogas nas patas de roedores. Sendo assim, o presente estudo analisou a nocicepção causada pela carragenina em masseteres de ratos, através do teste de Von Frey, correlacionando-a com alterações teciduais produzidas por esta droga. A carragenina foi injetada no músculo masseter de ratos, enquanto o grupo controle recebeu soro fisiológico. O limiar nociceptivo foi mensurado com um analgesímetro digital antes da administração da carragenina e 5 horas, 1, 3 e 7 dias após o seu uso. Decorridos 8 dias da intervenção, os animais foram eutanasiados, sendo seus masseteres encaminhados para processamento histológico e coloração H&E. Resultados: Observou-se uma diminuição do limiar da resposta nociceptiva em todos os períodos no grupo com carragenina, quando comparado com o grupo controle, havendo diferença estatisticamente significante nas 5 horas. A análise histológica do grupo experimental mostrou a presença de espaços perimisial e endomisial alargados e preenchidos por uma matriz com alguns linfócitos, muitos macrófagos e raros mastócitos. Conclusão: Os resultados indicaram que a associação de uma droga inflamatória com o método Von Frey pode ser uma opção para o estudo do efeito de terapias de dor miofascial.

Myofascial orofacial pain has been treated with analgesics, anti-inflammatories, muscle relaxants, physiotherapy, laser therapy and occlusal plaques. However, many times, such behaviors fail to alleviate the painful condition, with the need to test other treatment strategies. Methodology: An option for experimental evaluation of these therapies would be the pain test induced by carrageenan associated with the nociceptive threshold assessment test, originally developed to assess the action of drugs on the rodents' feet. Thus, the present study analyzed the nociception caused by carrageenan in rat masseter using the Von Frey test, correlating it with tissue changes produced by this drug. Carrageenan was injected into the masseter muscle of rats, while the control group received saline. The nociceptive threshold was measured with a digital analgesometer before administration of carrageenan and 5 hours, 1, 3 and 7 days after its use. After 8 days of the intervention, the animals were euthanized, and their masseters were sent for histological processing and H&E staining. Results: There was a decrease in the nociceptive response threshold in all periods in the group treated with carrageenan when compared to the control group, with a statistically significant difference at 5 hours. Histological analysis of the experimental group showed the presence of enlarged perimisial and endomisial spaces, filled by a matrix with some lymphocytes, many macrophages and rare mast cells. Conclusion: Results indicated that the association of an inflammatory drug with the Von Frey method may be an option for studying the effect of therapies on myofascial pain.

Pain modulatory properties of Phoneutria nigriventer crude venom and derived peptides: A double-edged sword.

Phoneutria nigriventer venom (PNV) is a complex mixture of toxins exerting multiple pharmacological effects that ultimately result in severe local pain at the site of the bite. It has been proposed that the PNV-induced pain is mediated by both peripheral and central mechanisms. The nociception triggered by PNV is peripherally mediated by the activation of B2, 5-HT4, NMDA, AMPA, NK1, and NK2 receptors, as well as TTXS-Na+, ASIC, and TRPV1 channels. The activation of tachykinin, glutamate and CGRP receptors along with the production of inflammatory mediators are, at least partially, responsible for the central component of pain. Despite its well established pro-nociceptive properties, PNV contains some toxins with antinociceptive activity, which have been studied in the last few years. The toxins ω-CNTX-Pn4a, ω-CNTX-Pn2a, ω-CNTX-Pn3a, κ-CNTX-Pn1a, U7-CNTX-Pn1a, δ-CNTX-Pn1a, and Γ-CNTX-Pn1a from PNV, as well as the semi-synthetic peptide PnPP-19 have been tested in different experimental models of pain showing consistent antinociceptive properties. This review aims to discuss the pro- and antinociceptive actions of PNV and its toxins, highlighting possible mechanisms involved in these apparently dualistic properties.

Análise das habilidades pragmáticas de crianças nascidas pré-termo / Analysis of the pragmatic skills in preterm children

RESUMO Objetivo Caracterizar as habilidades pragmáticas de crianças nascidas pré-termo e investigar se existe correlação com a idade gestacional, o gênero e a faixa etária. Métodos Foram avaliadas 42 crianças nascidas pré-termo, com baixo peso ao nascer, de ambos os gêneros, na faixa etária de 2 a 4 anos. A análise do perfil comunicativo foi realizada por meio do Protocolo de Pragmática do ABFW - Teste de Linguagem Infantil nas Áreas de Fonologia, Vocabulário, Fluência e Pragmática. Resultados Quanto à iniciativa na comunicação, houve melhor desempenho das crianças pré-termo moderadas e tardias. Em relação aos atos comunicativos, as crianças não alcançaram os valores de referência propostos pelo teste. Os meios verbais foram mais utilizados, apesar de haver grande ocorrência dos meios gestuais. As funções comunicativas mais observadas foram comentário, narrativa, jogo e pedido de objeto. Conclusão As crianças pré-termo apresentaram desvios nas habilidades pragmáticas, na faixa etária investigada. As variáveis linguísticas descritas neste estudo não apresentaram correlação com idade e gênero.

ABSTRACT Purpose To characterize the pragmatic skills of preterm children and investigate whether it is correlated with gestational age, gender and age group. Methods 42 low-birth-weight preterm infants of both genders, aged 2 to 4 years, were evaluated. The analysis of the communication profile was performed through the Pragmatics Protocol of the ABFW - child language test in the fields of phonology, vocabulary, fluency and pragmatics. Results regarding the communication initiative, there was a better performance of moderate and late preterm children. Regarding the communicative acts, the children did not reach the reference values proposed by the test. The verbal means were the most used, although there was a high occurrence of the gestural means. The most observed communicative functions were commenting, narrative, game and object request. Conclusion The preterm children had deviations in pragmatic skills in the age group investigated. The linguistic variables described in this study were not correlated with age and gender.

Description of the linguistic and neurological findings of twins born preterm at two years of age / Descrição dos achados linguísticos e neurológicos de gemelares nascidos pré-termo aos dois anos de idade

INTRODUCTION: Prematurity, low birth weight and multiple births are risk factors for structural changes in the brain, as well as for motor, cognitive, social and language developmental disorders OBJECTIVE: Describe the linguistic findings and investigate the presence of neurological alterations in preterm twins at two years of age METHODS: This is a cross-sectional study based on data analysis of the medical records of six pairs of low birth weight preterm twins of both sexes, at two years of age, attended at the State Center for the Prevention and Rehabilitation of People with Disabilities - CEPRED, in Salvador-Bahia-Brazil. To this end, information regarding birth; the clinical history; the imaging exams; and the speech, neurological and interdisciplinary assessments were collected RESULTS: Preterm twins had atypical language development and neurological changes that may compromise oral language development. From the neurological point of view, abnormalities common to the premature newborn, such as peri-intraventricular hemorrhage, were observed CONCLUSION: Multiple births associated with prematurity and low birth weight may pose risks to children's language acquisition

INTRODUÇÃO: A prematuridade, o baixo peso ao nascer e os nascimentos múltiplos são fatores de risco para alterações estruturais no cérebro, assim como para desvios no desenvolvimento motor, cognitivo, social e de linguagem OBJETIVO: Descrever os achados linguísticos e investigar a presença de alterações neurológicas em gemelares nascidos pré-termo, aos dois anos de idade MÉTODO: Trata-se de um estudo do tipo corte transversal, realizado por meio da análise de dados dos prontuários de seis pares de gêmeos nascidos pré-termo, com baixo peso ao nascer, de ambos os sexos, aos dois anos de idade, atendidos no Centro Estadual de Prevenção e Reabilitação da Pessoa com Deficiência - CEPRED, em Salvador-Bahia-Brasil. Para tanto, foram coletadas as informações referentes ao nascimento; a história clínica; os exames de imagem; e as avaliações fonoaudiológica, neurológica e interdisciplinar RESULTADOS: Os gemelares nascidos pré-termo apresentaram desenvolvimento linguístico atípico e alterações neurológicas que podem comprometer o desenvolvimento da linguagem oral. Do ponto de vista neurológico, foram observadas anormalidades comuns ao recém-nascido prematuro, como a hemorragia peri-intraventricular CONCLUSÃO: Os nascimentos múltiplos associados à prematuridade e ao baixo peso ao nascer podem oferecer riscos à aquisição da linguagem da criança

The influence of prematurity on the development of phonological skills / A influência da prematuridade no desenvolvimento das habilidades fonológicas

ABSTRACT Purpose: to check the use of phonological processes in preterm infants. Methods: phonological evaluation was performed through the ABFW Child Language Test in 40 children, aged two to four years, i.e., 20 preterm and 20 full-term children, matched according to age, gender and socioeconomic level. Preterm children were evaluated at the State Center for Prevention and Rehabilitation of People with Disabilities - CEPRED; full-term children were selected and evaluated in a municipal nursery in the city of Salvador, BA, Brazil. The pertinent statistical tests were applied adopting the level of significance lower than 0.05%. Results: in the phonology test, the number of productive phonological processes not expected for the chronological age was statistically significant in the preterm group, especially syllable reduction, consonantal harmony, velar backing and liquid reduction. The high prevalence of cluster reduction and final consonant deletion, though still compatible with chronological age, shows the need to follow up the language acquisition of these children, after the age of four. Conclusion: the results evidenced the difficulty found by preterm infants in the development of phonological skills, emphasizing the importance of early diagnosis and speech-language monitoring in language acquisition.

RESUMO Objetivo: verificar o uso dos processos fonológicos em crianças nascidas pré-termo. Métodos: a avaliação da Fonologia foi realizada por meio do ABFW - Teste de Linguagem Infantil, em 40 crianças, na faixa etária de dois a quatro anos, sendo 20 crianças nascidas pré-termo e 20 crianças nascidas a termo, pareadas conforme idade, sexo e nível socioeconômico. As crianças nascidas pré-termo foram avaliadas no Centro Estadual de Prevenção e Reabilitação da Pessoa com Deficiência - CEPRED; as crianças nascidas a termo foram selecionadas e avaliadas em uma creche municipal, na cidade de Salvador-BA. Foram aplicados os testes estatísticos pertinentes adotando o nível de significância menor que 0,05%. Resultados: na prova de Fonologia, o número de processos fonológicos produtivos não esperados para a idade cronológica foi estatisticamente significante no grupo pré-termo, destacando-se os processos de redução de sílaba, harmonia consonantal, posteriorização para velar e simplificação de líquida. A alta prevalência da simplificação de encontro consonantal e da simplificação de consoante final, apesar de ainda compatíveis com a idade cronológica, alerta para a necessidade do acompanhamento da aquisição da linguagem dessas crianças, após os quatro anos de idade. Conclusão: os resultados evidenciam a dificuldade encontrada pelas crianças nascidas pré-termo no desenvolvimento das habilidades fonológicas, ressaltando a importância do diagnóstico precoce e do monitoramento fonoaudiológico na aquisição da linguagem.

Pain-like behaviors and local mechanisms involved in the nociception experimentally induced by Latrodectus curacaviensis spider venom.

The present study was undertaken to characterize the behavioral manifestations of nociception and the local mechanisms involved with the nociceptive response elicited by Latrodectus curacaviensis venom (LCV) in mice. After the intraplantar LCV inoculation, spontaneous nociception, mechanical and thermal nociceptive thresholds, motor performance, edema and cytokine levels were evaluated using von Frey filaments, hot/cold plate, rota-rod, plethismometer and ELISA, respectively. Analysis of LCV was performed by SDS-PAGE and chromatography. Intraplantar injection of LCV (1-100 ng/paw) induced intense and heat-sensitive spontaneous nociception, mediated by serotonin and bradykinin receptors, TRPV1 channels, as well as by transient local inflammation. LCV (0.1-10 ng/paw) induced mechanical allodynia, which was reduced by the local pretreatment with H1 receptor or TRPV1 antagonists. Corroborating the TRPV1 involvement, in thermal nociception assays, LCV induced a similar response to that of capsaicin, a TRPV1 agonist, facilitating the response to noxious hot stimuli and inhibiting the response to cold noxious stimulation. LCV promoted mast cell degranulation, increased IL-1ß paw levels, but did not produce a relevant edematogenic effect. Analysis of LCV components showed a predominance of high molecular weight proteins. This work provides the first mechanistic hypothesis to explain the local pain induced by LCV, the most frequent clinical symptom of human envenomation.

Neurogenic mediators contribute to local edema induced by Micrurus lemniscatus venom.

BACKGROUND/AIMS: Micrurus is one of the four snake genera of medical importance in Brazil. Coral snakes have a broad geographic distribution from the southern United States to Argentina. Micrurine envenomation is characterized by neurotoxic symptoms leading to dyspnea and death. Moreover, various local manifestations, including edema formation, have been described in patients bitten by different species of Micrurus. Thus, we investigated the ability of Micrurus lemniscatus venom (MLV) to induce local edema. We also explored mechanisms underlying this effect, focusing on participation of neuropeptides and mast cells. METHODOLOGY/PRINCIPAL FINDINGS: Intraplantar injection of MLV (1-10 µg/paw) in rats caused dose- and time-dependent edema with a peak between 15 min and 1 h after injection. MLV also induced degranulation of peritoneal mast cells (MCs). MC depletion by compound 48/80 markedly reduced MLV-induced edema. Pre-treatment (30 min) of rats with either promethazine a histamine H1 receptor antagonist or methysergide, a nonselective 5-HT receptor antagonist, reduced MLV-induced edema. However, neither thioperamide, a histamine H3/H4 receptor antagonist, nor co-injection of MLV with HOE-140, a BK2 receptor antagonist, altered the response. Depletion of neuropeptides by capsaicin or treatment of animals with NK1- and NK2-receptor antagonists (SR 140333 and SR 48968, respectively) markedly reduced MLV-induced edema. CONCLUSIONS/SIGNIFICANCE: In conclusion, MLV induces paw edema in rats by mechanisms involving activation of mast cells and substance P-releasing sensory C-fibers. Tachykinins NKA and NKB, histamine, and serotonin are major mediators of the MLV-induced edematogenic response. Targeting mast cell- and sensory C-fiber-derived mediators should be considered as potential therapeutic approaches to interrupt development of local edema induced by Micrurus venoms.

Mechanisms involved in hearing disorders of thyroid ontogeny: a literature review.

Endocochlear, retrocochlear and/or central origin hearing damage may be related to the absence of appropriate levels of thyroid hormone during morphogenesis and/or auditory system development. Hearing disorders related to the thyroid are not well studied, despite speculation on the pathophysiological mechanisms. The objective of this review was to characterize the main pathophysiological mechanisms of congenital hypothyroidism and to evaluate the relationship with central and peripheral hearing disorders. We conducted a literature review using the databases MedLine, LILACS, Cochrane Library, SciELO, Institute for Scientific Information (ISI), Embase, and Science Direct between July and September on 2016. We identified the studies that address hearing disorder mechanisms on the congenital hypothyroidism. Congenital hypothyroidism may have clinical and subclinical manifestations that affect the auditory system and may be a potential risk factor for hearing impairment. Hearing impairment can severely impact quality-of-life, which emphasizes the importance of monitoring and evaluating hearing during the clinical routine of these patients.

Mechanisms involved in hearing disorders of thyroid ontogeny: a literature review

ABSTRACT Endocochlear, retrocochlear and/or central origin hearing damage may be related to the absence of appropriate levels of thyroid hormone during morphogenesis and/or auditory system development. Hearing disorders related to the thyroid are not well studied, despite speculation on the pathophysiological mechanisms. The objective of this review was to characterize the main pathophysiological mechanisms of congenital hypothyroidism and to evaluate the relationship with central and peripheral hearing disorders. We conducted a literature review using the databases MedLine, LILACS, Cochrane Library, SciELO, Institute for Scientific Information (ISI), Embase, and Science Direct between July and September on 2016. We identified the studies that address hearing disorder mechanisms on the congenital hypothyroidism. Congenital hypothyroidism may have clinical and subclinical manifestations that affect the auditory system and may be a potential risk factor for hearing impairment. Hearing impairment can severely impact quality-of-life, which emphasizes the importance of monitoring and evaluating hearing during the clinical routine of these patients.

Neurogenic mediators contribute to local edema induced by Micrurus lemniscatus venom

Background/Aims Micrurus is one of the four snake genera of medical importance in Brazil. Coral snakes have a broad geographic distribution from the southern United States to Argentina. Micrurine envenomation is characterized by neurotoxic symptoms leading to dyspnea and death. Moreover, various local manifestations, including edema formation, have been described in patients bitten by different species of Micrurus. Thus, we investigated the ability of Micrurus lemniscatus venom (MLV) to induce local edema. We also explored mechanisms underlying this effect, focusing on participation of neuropeptides and mast cells. Methodology/Principal findings Intraplantar injection of MLV (1–10 µg/paw) in rats caused dose- and time-dependent edema with a peak between 15 min and 1 h after injection. MLV also induced degranulation of peritoneal mast cells (MCs). MC depletion by compound 48/80 markedly reduced MLV-induced edema. Pre-treatment (30 min) of rats with either promethazine a histamine H1 receptor antagonist or methysergide, a nonselective 5-HT receptor antagonist, reduced MLV-induced edema. However, neither thioperamide, a histamine H3/H4 receptor antagonist, nor co-injection of MLV with HOE-140, a BK2 receptor antagonist, altered the response. Depletion of neuropeptides by capsaicin or treatment of animals with NK1- and NK2-receptor antagonists (SR 140333 and SR 48968, respectively) markedly reduced MLV-induced edema. Conclusions/Significance In conclusion, MLV induces paw edema in rats by mechanisms involving activation of mast cells and substance P-releasing sensory C-fibers. Tachykinins NKA and NKB, histamine, and serotonin are major mediators of the MLV-induced edematogenic response. Targeting mast cell- and sensory C-fiber-derived mediators should be considered as potential therapeutic approaches to interrupt development of local edema induced by Micrurus venoms.

Influence of thyroid states on the local effects induced by Bothrops envenoming.

Bothrops leucurus venom causes significant local effects, such as necrosis, pain, hemorrhage and edema. These effects are important because of their high frequency and severity. The treatment of these local effects is not simple because of their quick triggering and a variety of components that induce these effects. Myonecrosis, dermonecrosis and edema are primarily caused by the action of hemorrhagins and myotoxins. A number of investigators have demonstrated the influence of thyroid hormones on inflammatory processes, particularly on wound healing. We investigated the edematogenic, hemorrhagic and necrotic activity of the B. leucurus venom in the hypothyroid, hyperthyroid and euthyroid of rats. The CK (creatine kinase) plasma level decreased in the animals in a hypothyroid state. The hypothyroid condition also significantly reduced the hemorrhagic and dermonecrotic area compared to the euthyroidism and hyperthyroidism states. It also mitigated the rat paw edema compared to that found in the euthyroid and hyperthyroid animals. The hyperthyroid animals showed no significant differences in the three treatments compared to the euthyroid animals. Our results suggest that the triggering of local effects induced by envenomation by B. leucurus is attenuated in hypothyroid animals, possibly by the effect of hypothyroidism on the immune system and blood flow.

Antinociceptive properties of Micrurus lemniscatus venom.

The therapeutic potential of snake venoms for pain control has been previously demonstrated. In the present study, the antinociceptive effects of Micrurus lemniscatus venom (MlV) were investigated in experimental models of pain. The antinociceptive activity of MIV was evaluated using the writhing, formalin, and tail flick tests. Mice motor performance was assessed in the rota rod and open field tests. In a screening test for new antinociceptive substances--the writhing test--oral administration of MlV (19.7-1600 µg/kg) produced significant antinociceptive effect. The venom (1600 µg/kg) also inhibited both phases of the formalin test, confirming the antinociceptive activity. The administration of MlV (1600 µg/kg) did not cause motor impairment in the rota rod and open field tests, which excluded possible non-specific muscle relaxant or sedative effects of the venom. The MIV (177-1600 µg/kg) also increases the tail flick latency response, indicating a central antinociceptive effect for the venom. In this test, the MlV-induced antinociceptive effect was long-lasting and higher than that of morphine, an analgesic considered the gold standard. In another set of experiments, the mechanisms involved in the venom-induced antinociception were investigated through the use of pharmacological antagonists. The MlV (1600 µg/kg) antinociceptive effect was prevented by naloxone (5 mg/kg), a non-selective opioid receptor antagonist, suggesting that this effect is mediated by activation of opioid receptors. In addition, the pre-treatment with the µ-opioid receptor antagonist CTOP (1 mg/kg) blocked the venom antinociceptive effect, while the k-opioid receptor antagonist nor-BNI (0.5 mg/kg) or the δ-opioid receptor antagonist naltrindole (3 mg/kg) only partially reduced the venom-induced antinociception. The present study demonstrates, for the first time, that oral administration of M. lemniscatus venom, at doses that did not induce any motor performance alteration, produced potent and long-lasting antinociceptive effect mediated by activation of opioid receptors.

Activation of cellular functions in macrophages by venom secretory Asp-49 and Lys-49 phospholipases A(2).

The in vitro effects of myotoxin III (MT-III), an Asp-49 catalytically-active phospholipase A(2), and myotoxin II (MT-II), a catalytically-inactive Lys-49 variant, isolated from Bothrops asper snake venom, on phagocytosis and production of hydrogen peroxide (H(2)O(2)) by thioglycollate-elicited macrophages were investigated. MT-II and MT-III were cytotoxic to mouse peritoneal macrophages at concentrations higher than 25 microg/ml. At non-cytotoxic concentrations, MT-II stimulated Fcgamma, complement, mannose and beta-glucan receptors-mediated phagocytosis, whereas MT-III stimulated only the mannose and beta-glucan receptors-mediated phagocytosis. Moreover, both myotoxins induced the release of H(2)O(2) by thioglycollate-elicited macrophages, MT-III being the most potent stimulator. MT-II induced the release of H(2)O(2) only at a concentration of 3.2 microg/ml (130% increment) while MT-III induced this effect at all concentrations tested (0.5-2.5 microg/ml; average of 206% increment). It is concluded that, at non-cytotoxic concentrations, MT-II and MT-III activate defense mechanisms in macrophages up regulating phagocytosis, mainly via mannose and beta-glucan receptors, and the respiratory burst.