Abnormalities in Inflammatory Cytokines Confer Susceptible to Chronic Neuropathic Pain-related Anhedonia in a Rat Model of Spared Nerve Injury

OBJECTIVE: Patients with chronic neuropathic pain (CNP) have a higher incidence to develop depression. However, its pathogenesis has not yet been fully elucidated. Here we aimed to investigate the role of inflammatory cytokines in CNP-related anhedonia, which is a core symptom of depression, and to explore the effects of ketamine and parecoxib on pain and anhedonia. METHODS: A rat model of spared nerve injury (SNI) was constructed to mimic CNP. Hierarchical cluster analysis of sucrose preference test (SPT) was applied to classify the SNI rats into anhedonia susceptible and unsusceptible. Inflammatory cytokines in medial prefrontal cortex (mPFC) of brain, serum and L2–5 spinal cord were measured. Moreover, effects of ketamine or parecoxib on mechanical withdrawal test (MWT) and SPT in anhedonia susceptible rats were detected. RESULTS: Tumor necrosis factor (TNF)-α was increased in mPFC, serum and and spinal cord of anhedonia susceptible rats. Furthermore, anhedonia susceptible and unsusceptible rats both increased the interleukin (IL)-1β level in mPFC, serum and spinal cord. IL-6 was altered in serum and spinal cord, but not in mPFC. IL-10 was significantly altered in mPFC and serum, but not in spinal cord. Additionally, ketamine treatment significantly attenuated the decreased results of MWT and SPT in anhedonia susceptible rats, and that parecoxib significantly improved the MWT score, but failed to alter the result of SPT. CONCLUSION: These findings suggest that abnormalities in inflammatory cytokines confer susceptible to anhedonia in a rat model of SNI. Ketamine, a fast-acting antidepressant, has pharmacological benefits to alleviate pain and anhedonia symptoms.

Etiopatogenia de la hemorragia digestiva alta no variceal, respuesta inflamatoria y Helicobacterpylori / Etiopathogeny of the non-variceal high digestive hemorrhage, inflammatory answer and Helicobacter pylori

RESUMEN La infección por la bacteria Helicobacter pylori ocurre a nivel mundial, aunque es más frecuente en países en vías de desarrollo y en comunidades en condiciones socioeconómicas pobres, donde existe hacinamiento o migración de regiones de prevalencia alta. La infección ocurre principalmente durante la infancia y se incrementa con la edad. Se realizó una revisión exhaustiva donde se explican de manera explícita los mecanismos que desencadenan la respuesta inflamatoria una vez que la bacteria coloniza el estómago, que incluye dos etapas: la primera caracterizada por la llegada y penetración del microorganismo al moco gástrico, donde se asienta y se multiplica y la segunda etapa caracterizada por una amplificación de esta respuesta inflamatoria. El conocimiento de estos mecanismos etiopatogénicos no sólo ayuda a la erradicación de la bacteria, sino que contribuye a la regulación del sistema neuroinmune antes, durante y después del daño tisular, para lograr una regeneración tisular adecuada, mejorar la capacidad funcional del órgano sangrante e impedir la evolución tórpida de la enfermedad (AU).

ABSTRACT The infection by Helicobacter pylori occurs worldwide, although it is more frequent in developing countries and in communities with poor socioeconomic conditions, where there is overcrowding or migration from regions of high prevalence. The infection occurs mainly during the childhood and increases with age. An exhaustive review was carried out where the mechanisms unchaining the inflammatory answer after the bacteria colonizes the stomach are explained in an explicit way. It has two stages: the first one is characterized by the microorganism arrival and penetration to the gastric mucus, where it settles and multiplies, and the second stage characterized by an amplification of the inflammatory answer. The knowledge of these etiopathogenic mechanisms does not only help the eradication of the bacteria but also contributes to the regulation of the neuroimmune system before, during and after tissue damage, for reaching an adequate tissue regeneration, improving the functional capacity of the bleeding organ, and preventing the disease torpid evolution (AU).

Inflammatory Changes in Paravertebral Sympathetic Ganglia in Two Rat Pain Models / 神经科学通报·英文版

Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.

Toluene diisocyanate exposure induces airway inflammation of bronchial epithelial cells via the activation of transient receptor potential melastatin 8

Toluene diisocyanate (TDI) is the most important cause of occupational asthma (OA), and various pathogenic mechanisms have been suggested. Of these mechanisms, neurogenic inflammation is an important inducer of airway inflammation. Transient receptor potential melastatin 8 (TRPM8) is a well-established cold-sensing cation channel that is expressed in both neuronal cells and bronchial epithelial cells. A recent genome-wide association study of TDI-exposed workers found a significant association between the phenotype of TDI-induced OA and the single-nucleotide polymorphism rs10803666, which has been mapped to the TRPM8 gene. We hypothesized that TRPM8 located in airway epithelial cells may be involved in the pathogenic mechanisms of TDI-induced OA and investigated its role. Bronchial epithelial cells were treated with TDI in a dose- and time-dependent manner. The expression levels of TRPM8 mRNA and protein were determined by quantitative real-time polymerase chain reaction and western blotting. TDI-induced morphological changes in the cells were evaluated by immunocytochemistry. Alterations in the transcripts of inflammatory cytokines were examined in accordance with TRPM8 activation by TDI. TRPM8 expression at both the mRNA and protein levels was enhanced by TDI in airway epithelial cells. TRPM8 activation by TDI led to significant increases in the mRNA of interleukin (IL)-4, IL-13, IL-25 and IL-33. The increased expression of the cytokine genes by TDI was partly attenuated after treatment with a TRPM8 antagonist. TDI exposure induces increased expression of TRPM8 mRNA in airway epithelial cells coupled with enhanced expression of inflammatory cytokines, suggesting a novel role of TRPM8 in the pathogenesis of TDI-induced OA.

A proposal of injection points of botulinum toxin into temporal region for chronic migraine

Botulinum toxin (BoNT) injections have been used not only in the field of cosmetic surgery such as forehead and eye wrinkle treatment but also in the treatment of chronic migraine, dystonia, spasticity, temporomandibular disorders (TMD). BoNT injections are the only approved therapies to date for prophylactic treatment of chronic migraine patients. Unlike the previously known paralysis of motor neurons, the mechanism of action for migraine is to block the release of non-cholinergic neurotransmitters such as substance P, CGRP, and glutamate, which are associated with peripheral sensitization and neurogenic inflammation in the sensory nerve, it is hypothesized that the signal is blocked. This review focuses on the analgesic effects of BoNT and suggests the direction for the development of injection methods for chronic migraine patients.

Complex Regional Pain Syndrome Type I after Stroke

Complex regional pain syndrome (CRPS) is a chronic painful, limb-confined condition with autonomic and inflammatory characteristics. Although the exact cause is still poorly understood, facilitated neurogenic inflammation, pathologic sympathetic-afferent coupling, and maladaptive neuroplasticity of CNS are suggested as major pathophysiology of CRPS. While acute CRPS may resolve with good prognosis, chronic CRPS is likely to continue painful condition, thus it is recommended to start early management with comprehensive, multidisciplinary intervention including physical and occupational therapy. It still lacks of studies regarding CRPS after stroke which applied new diagnostic criteria, although it was established in the year of 2004. Therefore, further researches are needed regarding the CRPS after stroke using new diagnostic criteria.

Pathomechanism of Interstitial Cystitis/Bladder Pain Syndrome and Mapping the Heterogeneity of Disease / 대한배뇨장애요실금학회지

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous syndrome which is usually characterized by urinary frequency, nocturia, and bladder pain. Several pathomechanisms have been proposed, including uroepithelial dysfunction, mast cell activation, neurogenic inflammation, autoimmunity, and occult urinary tract infections. It is possible that an inflammatory process alters regulation of urothelial homeostasis and results in dysfunction of the bladder epithelium. Different phenotypes of IC/BPS have been explored including Hunner and non-Hunner type IC, hypersensitive bladder, and bladder pain both with and without functional somatic syndrome. Different gene expressions have also been found in different IC phenotypes. Abnormal expressions of uroplakin, chondroitin sulfate and adhesive protein E-cadherin, tight junction protein zonula occludens-1 in IC/BPS bladder suggest abnormal epithelial differentiation in this bladder disease. Analysis of inflammatory proteins, or cytokines in the urine or serum provides another diagnostic foundation forIC/BPS subtypes. The involvement of IC/BPS in systemic functional somatic syndrome and other pelvic organ diseases might also subdivide subtypes of IC/BPS. Chronic inflammation, increased urothelial apoptosis, and abnormal urothelial function are closely associated in IC bladders. This article reviews recent research on the pathomechanisms of IC, which might help us in mapping the heterogeneity of the disease.

Does dexamethasone act in neuropeptides SP and CGRP in neurogenic inflammation of the skin? An experimental study

PURPOSE: To investigate the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) after subcutaneous injection of dexamethasone prior to skin incision in rats.METHODS:Twenty seven Wistar-EPM-1 rats were randomly divided into three groups. The sham group (SG) of rats was injected with 0.9 % saline. The second group (Dexa) was injected with 1.0 mg/kg dexamethasone, and the third group (Dexa+) was injected with 10.0 mg/kg dexamethasone. In all groups, the three subcutaneous injections were performed 30 minutes prior to the surgical skin incision and tissue collection. SP and CGRP (15 kDa pro-CGRP and 5 kDa CGRP) were quantified by Western Blotting.RESULTS: No statistically significant differences (p>0.05) were found in pro-CGRP, CGRP and SP values in all three groups.CONCLUSION:The anti-inflammatory effect of dexamethasone did not occur when the substance P and calcitonin gene-related peptide levels were altered during the neurogenic inflammation process of skin wound healing in rats.

Efeito da toxina botulínica tipo A sobre a expressão de neuropeptídeos e o transporte mucociliar nasal em coelhos / Effect of botulinum toxin type A on nasal neuropeptides and mucociliary clearance in rabbits

INTRODUÇÃO: A toxina botulínica tipo A (TXB-A) tem sido testada no tratamento da rinite, principalmente nos casos de rinite idiopática. Sugere-se que um estado de hiper-reatividade do nervo trigêmeo esteja envolvido na fisiopatologia da rinite idiopática. O nervo trigêmeo possui fibras sensitivas não mielinizadas tipo C (FSNMT-C) que contém os neuropeptídeos substância P (SP) e peptídeo relacionado ao gene da calcitonina (CGRP). O óxido nítrico (NO) produzido pelas enzimas óxido nítrico sintase (NOS) também está envolvido nesse processo de neurorregulação nasal. O transporte mucociliar, mecanismo primário de defesa do sistema respiratório, é formado pelo batimento ciliar e muco nasal, e esses componentes podem ser influenciados por diferentes neuropeptídeos e neurotransmissores presentes na mucosa nasal. OBJETIVO: O objetivo deste estudo foi avaliar o efeito da TXB-A sobre a expressão da SP, CGRP e óxido nítrico sintase neural (nNOS), além de sua influência sobre o transporte mucociliar nasal em coelhos. MÉTODOS: Coelhos machos saudáveis da linhagem Nova Zelândia foram divididos em dois grupos: o grupo tratamento recebeu TXB-A (25UI) na concha nasomaxilar (CNM) do lado direito e soro fisiológico a 0,9% (SF0,9%) na CNM esquerda. O grupo controle recebeu SF0,9% na CNM direita e nenhuma intervenção na CNM esquerda. Foram investigados os efeitos da TXB-A sobre a expressão da SP, CGRP e nNOS no tecido de CNM por meio da imuno-histoquímica. Para esta análise, dividiu-se o tecido em camada externa (CE, acima da membrana basal) e camada interna (CI, abaixo da membrana basal). Avaliou-se também a presença de apoptose celular, a frequência de batimento ciliar (FBC), o perfil histoquímico do muco nasal (glicoproteínas ácidas e neutras) e a espessura do epitélio (ESP-CE). RESULTADOS: Foi observado um aumento significativo na quantidade de células apoptóticas na CNM do grupo tratamento que recebeu TXB-A em comparação aos controles (p <= 0,001). A CNM do grupo tratamento...(au)

INTRODUCTION: Botulinum toxin type A (BoNT-A) has been assessed in the treatment of rhinitis, especially in cases of idiopathic rhinitis. Trigeminal hyper-responsiveness appears to be involved in the pathological process of idiopathic rhinitis. Trigeminal nociceptive type C unmyelinated sensory fibers contain the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). Nitric oxide (NO) produced by the enzyme nitric oxide synthase (NOS) are also involved in this nasal neurorregulation process. The mucociliary clearance, primary defense system of the respiratory system, is composed by the ciliary beat and nasal mucus. These components can be influenced by different nasal neuropeptides and neurotransmitters. OBJECTIVE: The aim of this study was to evaluate the effect of BoNT-A on the expression of SP, CGRP and neural nitric oxide synthase (nNOS), and its influence on nasal mucociliary clearance in rabbits. METHODS: Healthy New Zealand male rabbits were divided into two groups: the treatment group was challenged with BoNT-A (25UI) in the right nasomaxillary turbinate (NMT) and saline (SF0.9%) in the left NMT. The control group received SF0.9% in the right NMT and no-intervention in the left NMT. We investigated the effects of BoNT-A on SP, CGRP and nNOS expression in the NMT tissue by immunohistochemistry. Each area of interest was subdivided into an internal layer (IL: below the basement membrane) and outer layer (OL: above the basement membrane) for analysis. It was also assessed signs of cellular apoptosis, ciliary beat frequency (CBF), mucus histochemical profile (acidic and neutral glycoproteins) and epithelial thickness (EP-TH). RESULTS: It was observed a significant increase in the amount of apoptotic cells in the BoNT-A-challanged NMT compared with controls (p <= 0.001). The NMT of treatment group which received only SF0.9% showed an increase in the amount of apoptotic cells in the IL compared with controls (NMT SF0.9%, p = 0.035)...

Papel da Lipoxina A4 na fisiologia do sistema nervoso central e no dano cognitivo associado à neuroinflamação / Lipoxin A4 paper of the central nervous system physiology and cognitive impairment associated with neuroinflammation

O papel da lipoxina A4 (LXA4) no sistema imunológico é bem estudado, mas o papeldessa molécula na fisiologia do sistema nervoso central (SNC) só foi abordado recentemente.Como um modulador alostérico positivo, a LXA4 produz efeitos canabimiméticos e pode, dessaforma, estar envolvida em vßrios aspectos de funções fisiológicas reguladas pelo sistemaendocanabinóide (eCB). Nós investigamos essa hipótese analisando o comportamento decamundongos knockout (5-LO-/-) para a enzima 5-lipoxigenase (5-LO), que participa da síntesede LXA4. Ansiedade, consumo de ßgua e alimento, locomoção, nocicepção e memórias aversivassão comportamentos reconhecidos como sob controle do sistema eCB e foram avaliados nesteestudo. Nenhuma alteração foi observada no comportamento de 5-LO-/-em relação ao consumode ßgua e alimento e locomoção no teste de campo aberto. No entanto, o tratamento com LXA4produziu efeito ansiolítico no labirinto em cruz elevada. Além disso, inibição farmacológica da 5-LO demonstrou um efeito ansiogênico em animais idosos, mas não em adultos jovens, indicandoque a LXA4 endógena exerce um efeito regulatório sobre ansiedade de forma idade-dependente.Os animais 5-LO-/-apresentaram um aumento na sensibilidade e redução na tolerância à dor noteste de sensibilidade ao choque. Ainda, uma disfunção em memória de curto prazo e extinção dememória no teste de esquiva inibitória foi observada nos animais 5-LO-/-, indicando que a LXA4pode agir na facilitação do aprendizado...

The role of lipoxin A4 (LXA4) in the immune system is well studied, however the part thismolecule plays in central nervous system (CNS) physiology has only recently been addressed.LXA4, as a CB1 allosteric enhancer, has a cannabimimetic effect and may therefore be involvedin various aspects of endocannabinoid system (eCB) physiological functions. We investigatedthis reasoning by analyzing the behavior of 5-lipoxygenase (5-LO) knockout mice (5-LO-/-).Anxiety-like behavior, appetitive behavior, locomotion, nociception and learning and memory areall known to be under control of the eCB system and were assessed in this study. No alterationwas observed in the behavior of 5-LO knockout mice regarding appetitive behavior, measured byfood and water intake, or locomotion in the open field test. However, treatment with LXA4produced an anxiolytic-like effect on the elevated plus maze. Further, pharmacological inhibitionof 5-LO showed an anxiogenic-like effect in aged, but not adult mice, indicating that endogenousLXA4 has an age-dependent effect on the modulation of anxiety-like behavior. 5-LO-/- micepresented an increase in pain sensitivity and a decrease in pain tolerance in the foot shocksensitivity test. Interestingly, the animals also presented impairment in short-term memory andextinction learning in the step-down inhibitory avoidance task, pointing out that LXA4 may act inthe facilitation of fear learning. These data are of great importance to the possible use of LXA4 astreatment to neuroinflammation induced cognitive impairment.The study of sepsis reveals that an inflammatory stimulus can induce the exacerbatedproduction of pro-inflammatory cytokines in the CNS, which causes neuroinflammation andcognitive impairment...

Estudo da substância P e do peptídeo relacionado ao gene da calcitonina em amostras do couro cabeludo e séricas de pacientes com líquen plano pilar e alopecia frontal fibrosante / Study of the neuropeptides substance P and calcitonin gene-related peptide in the scalp and serum samples from patients with lichen planopilaris and frontal fibrosing alopecia

INTRODUÇÃO: Líquen plano pilar (LPP) e alopecia frontal fibrosante (AFF) são alopecias cicatriciais linfocíticas crônicas, caracterizadas pela destruição permanente da unidade pilossebácea. Neuropeptídeos como a substância P (SP) e o peptídeo relacionado ao gene da calcitonina (CGRP) têm sido implicados no metabolismo lipídico das glândulas sebáceas e na manutenção do estado inflamatório de diversas doenças. OBJETIVOS: 1. Quantificar e comparar a expressão dos neuropeptídeos SP e CGRP em amostras do couro cabeludo (áreas afetadas e aparentemente não afetadas) e séricas de pacientes com LPP e AFF, em relação a indivíduos sadios, utilizando a técnica de ELISA. 2. Analisar áreas afetadas e aparentemente não afetadas de pacientes com LPP e AFF através da imunofluorescência direta (IFD). MÉTODO: 20 pacientes (10 com LPP e 10 com AFF) e 11 indivíduos sadios foram submetidos a biópsias com punch de 4mm do couro cabeludo e coleta de amostras sanguíneas. Pacientes foram submetidos a biópsias das áreas afetadas e aparentemente não afetadas do couro cabeludo, as quais foram pareadas com amostras da região anterior e posterior do couro cabeludo dos indivíduos-controle. As amostras dos pacientes foram enviadas para análise histopatológica, IFD e teste de ELISA para SP e CGRP. As amostras dos controles foram submetidas à análise histopatológica e aos mesmos testes de ELISA. Sintomas (dor, prurido, queimação e formigamento) e sinais inflamatórios (eritema difuso, eritema peripilar e descamação peripilar) na região afetada dos pacientes também foram avaliados. Este estudo foi realizado nas Universidades de São Paulo (BRA) e de Minnesota (EUA), entre os anos de 2012 e 2014. RESULTADOS: A análise histopatológica evidenciou infiltrado perifolicular linfocítico típico em 70% das áreas aparentemente não afetadas do couro cabeludo de pacientes com LPP e AFF, além de fibrose e depósitos de mucina perifoliculares. Em relação à IFD, o resultado se mostrou positivo em 50%...

INTRODUCTION: Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary lymphocytic cicatricial alopecias characterized by permanent destruction of the pilossebaceous unit. Neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) are related to lipid metabolism in sebaceous glands and to the maintenance of many inflammatory chronic disorders. OBJECTIVES: 1. Quantify SP and CGRP expression in affected and in normal-appearing scalp areas and serum samples from patients with LPP and FFA, and compare to healthy controls using ELISA technique. 2. Compare affected and normal-appearing areas from patients with LPP and FFA, using direct immunofluoresce (DIF) technique. METHODS: Twenty patients (10 with LPP and 10 with FFA) and eleven healthy controls underwent 4mm-punch biopsies and blood extraction. Patients collected samples from affected and normal-appearing scalp areas, and controls collected from anterior and posterior scalp areas. Patients samples were sent to histopathologic examination, DIF and ELISA tests for SP and CGRP detection. Control samples were sent to histopathologic examination and to the same ELISA tests. Symptoms (pain, burning, itching and tingling) and signs of inflammation (diffuse erythema, perifollicular erythema and perifollicular scale) were also assessed. This study was done at the Universities of São Paulo (Brazil) and Minnesota (USA), between 2012 and 2014. RESULTS: Normal-appearing scalp areas from patients with LPP and FFA showed lymphocytic perifollicular typical inflammation in 70% of the cases, as well as perifollicular fibrosis and mucin deposits. DIF test was positive in 50% of the affected areas and in 40% of normalappearing areas from patients with LPP, comparing to 40% and 20% in the FFA group, respectively. In SP ELISA test, affected areas from patients with LPP that had histopathologic moderate or intense infiltrate showed more expression of SP in the affected scalp,...

Efeitos neuroinflamatórios do uso de medicações anestésicas e sedativas na sepse / Neuroinflammatory effects of the use of medications anesthetic and sedative in sepsis

A sepse constitui importante problema de saúde pública. A incidência de sepse grave vem aumentando nas unidades de Terapia Intensiva, estando associada à alta morbimortalidade. Muitos pacientes evoluem para prótese ventilatória, precisando de drogas sedativas e analgésicas (como o midazolam e a morfina). Os sobreviventes podem apresentar disfunções cognitivas e comportamentais tardias. Estes déficits podem se dar tanto pelas alterações inflamatórias encontradas na sepse, como também por efeitos imunológicos e neurológicos de medicações utilizadas. Tentamos mimetizar este cenário clínico, usando o modelo experimental de Ligadura do Ceco e Perfuração (CLP de 2 furos e 4 furos) em camundongos suíços anestesiados com isoflurano inalatório. Após 5 h da cirurgia, eles receberam tratamento com salina 0,5 ml, midazolam 40 mg/kg ou morfina 80 mg/kg IP. Avaliamos escores de sedação, sinais clínicos de sepse, sobrevida (7-15 dias) e parâmetros neuro-inflamatórios 24 h após o CLP. Encontramos melhora dos índices de sobrevida nos grupos tratados com morfina, sobretudo no modelo de CLP de 4 furos (p<0,05)Observamos melhora dos escores clínicos de 24 h nos animais tratados com morfina e submetidos ao CLP de 4 furos (p<0,05). Houve tendência de diminuição das citocinas inflamatórias IL-1 beta, IL-6 e de MCP-1 no lavado peritoneal, medidas por ELISA, nos grupos CLP 2 furos tratados com midazolam e morfina.

Esta redução também foi verificada no córtex cerebral retirado pós perfusão. A redução de IL-6 foi significativa nos 2 grupos CLP tratados e de MCP-1, no grupo CLP tratado com midazolam (p<0,05). Esses resultados foram acompanhados pelo aumento da proteína pós-sináptica PSD95, no hipocampo dos animais dos grupos CLP tratados. Tais efeitos poderiam indicar um benefício antiinflamatório no uso de midazolam e da morfina, nas fases iniciais de sepse. Apesar dos indícios de melhorias neuroinflamatórias, ainda são necessários mais estudos para relacionarmos estas alterações a possíveis repercussões clínicas.

Sepsis is a main problem in Public Health. The incidence of severe sepsis isrising and is associated with high morbimortality indices. Many patients will need anykind of ventilatory assistance, sedative and analgesic drugs (e.g. midazolam andmorphine). Survivals may present late cognitive and neurocomportamentaldysfunctions. Sepsis inflammatory alterations, as well as neurologic andimmunomodulatory effects mediated by these drugs may cause the deficits. We triedto simulate this clinical setting using the animal model of Cecal Ligature andPuncture (CLP), with 2 and 4 perforations. Swiss mice were submitted to inalatoryanesthesia with isoflurane for the surgery. After 5 h, they received saline 0,5 ml,midazolam 40 mg/kg or morphine 80 mg/kg IP. We quantified sedation score, sepsisscore, survival (7-15 days) and inflammatory parameters in 24 h after CLP. We foundbetter survival taxes in the CLP group treated with morphine, especially in CLP with 4perforations (p<0,05). There were also better sepsis clinical scores 24 h and 48 hafter CLP with 4 perforations, treated with morphine (p<0,05). The inflammatorycytokines IL-1 beta, IL-6 and MCP-1 were lower in peritoneal lavage of CLP with 2perforations treated with morphine and midazolam, measured by ELISA. Thisreduction was also found in cerebral cortex, dissected after perfusion. IL-6 reductionin cortex was important in both treated groups (CLP+Morphine and CLP+Midazolam)and MCP-1 reduction in CLP+Midazolam group (p<0,05). Postsynaptic proteinPSD95 was augmented in hippocampal of CLP treated group. The results may pointto anti-inflammatory benefits in using midazolam and morphine in initial phases ofsepsis. Nevertheless, more studies are necessary to relate the potentialneuroinflammatory benefits of these drugs with clinical repercussions.

Teoría de la compuerta (Ronald Melzack y Patrick D. Wall, 1965) / Gate Control Theory (Ronald Melzack and Patrick D. Wall, 1965)

El conocimiento del dolor ha tenido momentos cruciales en los que el curso evolutivose modificó y que cambiaron los conceptos aceptados y abrieron nuevos horizontesde investigación, entendimiento y tratamiento. Cuando Melzack y Wall desarrollaronla teoría de la compuerta aclararon fenómenos básicos del entendimiento del dolor ysustentaron múltiples tratamientos, que son la base de procedimientos actuales. Soncincuenta años que se cumplen de la publicación de aquel artículo en la revista Science(“Pain Mechanism: A New Theory. A Gate Control System Modulates Sensory Inputfrom the Skin before it Evoques Pain Perception and Response”). Este se escribió en uncontexto científico particular y a la luz de dos vidas diferentes que ilustran un procesoejemplar de desarrollo de la ciencia. El análisis, aquí presentado, es no solo científico,sino humano de lo que ha sido este artículo para el entendimiento de las ciencias del dolor...

The quest to acquire knowledge and understanding of pain has had crucial momentsin which evolution of the process has been dramatically changed, and have openednew horizons of research, understanding and treatment. When Melzack and Walldescribed what would come to be known as the Gate Control Theory they clarifybasic aspects of pain development but to lead the way to further basic and clinicalresearch studies. It has been fifty years since the original article was published inScience magazine (“Pain Mechanism: a new theory. A gate control system modulatessensory input from the skin before it evokes pain perception and response”) The paper was written during a very particularmoment in scientific history and the context oftwo very different lives, which illustrates the incredibleprocess that leads to scientific development.This analysis symbolize to pain sciencemust be done not only from a purely scientificview point but from a human one as well...

Vital tooth with periapical lesion: spontaneous healing after conservative treatment

It is often presumed that apical periodontitis follows total pulp necrosis, and consequently root canal treatment is commonly performed. Periapical lesion development is usually caused by bacteria and its byproduct which irritate pulp, develop pulpitis, and result in necrosis through an irreversible process. Afterwards, apical periodontitis occurs. This phenomenon is observed as an apical radiolucency in radiographic view. However, this unusual case presents a spontaneous healing of periapical lesion, which has developed without pulp necrosis in a vital tooth, through conservative treatment.

Síndrome da dor vesical/cistite intersticial: aspectos atuais / Bladder pain syndrome/interstitial cystitis: current aspects

Síndrome da dor vesical é a nomenclatura proposta para substituir o termo antigamente conhecido como cistite intersticial. Deve ser diagnosticada com base nas queixas de dor, pressão ou desconforto pélvico crônico, relacionados à bexiga acompanhados por pelo menos outro sintoma urinário como urgência ou aumento de frequência. A prevalência estimada é de 300 por 100.000 mulheres. A etiologia e a fisiopatologia ainda não foram elucidadas, mas mecanismos neurológicos centrais, fatores genéticos, imunológicos e infecciosos parecem estar envolvidos. O diagnóstico é de exclusão e deve ser baseado nos sintomas. O teste com cloridrato de potássio intravesical não deve ser usado como ferramenta diagnóstica. A cistoscopia com hidrodistensão e biópsia auxilia na documentação e classificação da doença. O tratamento deverá ser multidisciplinar e multimodal, associando-se medicações orais com intravesicais, modificações na dieta e no estilo de vida e medidas não farmacológicas

Bladder pain syndrome is the nomenclature proposed to replace the term formerly known as interstitial cystitis. It should be diagnosed based on complaints of pain, chronic pelvic pressure or discomfort related to bladder accompanied by at least one other urinary symptom, such as urgency or increased frequency. The estimated prevalence is 300 per 100,000 women. The etiology and pathophysiology have not been elucidated, but central neurologic mechanisms, genetic, immunological and infectious factors seem to be involved. The diagnosis is by exclusion and should be based on symptoms. The test with intravesical potassium chloride should not be used as a diagnostic tool. Cystoscopy with hydrodistenstion and biopsy assist in the documentation and classification of the disease. Treatment should be multidisciplinary and multimodal, associating intravesical and oral medications, changes in diet and in lifestyle and nonpharmacological measures

El futuro de la depresión: una enfermedad sistémica neuroendócrina, inflamatoria y neurodegenerativa compleja / The future of depression: a complex neuroendocrine, inflammatory and neurodegenerative systemic illness

Los modelos neurobiológicos de la depresión han evolucionado más allá de la teoría monoaminérgica, que fue construida luego del advenimiento de las drogas antidepresivas en la década de 1950. Actualmente se considera que la depresión implica una amplia gama de neurotransmisores, incluyendo a la dopamina y el glutamato, y a prácticamente la totalidad del sistema nervioso central. La evidencia emergente está redefiniendo la depresión como una enfermedad crónica y sistémica que puede deteriorar la función neuroendocrina, los ritmos biológicos y las respuestas inmunes, y como una enfermedad que, de no ser tratada, puede conducir a la demencia. Diferentes abordajes de investigación, desde la biología molecular hasta los estudios clínicos, han ofrecido tanto nuevos conocimientos acerca de los mecanismos fisiológicos implicados como también indicios para desarrollar terapias antidepresivas efectivas en respuesta a los mismos. Además de los métodos ya bien establecidos, como los inhibidores de la recaptación de monoaminas y la terapia cognitivo-conductual, estos pueden incluir drogas anti-inflamatorias no esteroides, prescripción de ejercicio físico, tratamientos somáticos y toda una nueva generación de drogas antidepresivas dotadas de modos de acción originales. A medida que el manejo de la depresión se torna cada vez más multifacético, los médicos serán capaces de optimizar los resultados clínicos para sus pacientes integrando sinérgicamente las múltiples opciones terapéuticas disponibles.

Neurobiological models of depression have evolved far beyond the monoamine theory that was construed following the advent of antidepressant drugs in the 1950s. Depression is now seen to implicate a wide range of neurotransmitters, including dopamine and glutamate, and virtually the entire central nervous system. Emerging evidence is redefining depression as a chronic and systemic illness that may impair neuroendocrine function, biological rhythms and immune responses, and one which may lead to dementia if left untreated. Different research approaches, from molecular biology to clinical studies, have offered new insights into the physiological mechanisms involved as well as indications of how effective antidepressant therapies may develop in response to these. In addition to well-established methods, like monoamine reuptake inhibitors and cognitive behavioral therapy, these may include non-steroid anti-inflammatory drugs, prescription of physical exercise, somatic treatments and a whole new generation of antidepressant drugs endowed with original modes of action. As the management of depression becomes increasingly multifaceted, clinicians will be able to optimize clinical outcomes for their patients by synergistically integrating the multiple therapeutic options available.

To explore the mechanisms of neurogenic inflammation and airway hyperresponsiveness of rat by inhaled sulfur / 中国应用生理学杂志

<p><b>AIM</b>To explore the physiopathological mechanisms of airway injury and the effect on the airway responsiveness of rat by inhaled sulfur dioxide(SO2).</p><p><b>METHODS</b>Sixteen SD male rats were divided randomly into 2 groups (n = 8): the control group and SO2 group. The control group was exposed o pure air. SO2 group was exposed to SO2 of the content 1.0 mg/(m(3) x h) 6h daily for consecutive 3 d. At 4th day, we determined the airway responsiveness, collected the bronchoalveolar lavage fluid (BALF), plasma and lung tissue. Then we counted the total cellular score in BALF, measured the plasma SP content and made the immunohistochemistry staining on the lung tissue (HE and SP methods).</p><p><b>RESULTS</b>Compared with the control group, the total cellular score in BALF and plasma SP content in SO2 group's increased significantly ( P < 0.01). HE staining showed there were a great deal of inflammatory cells infiltration under the tunica mucosa bronchiorum; and SP immunohistochemistry staining indicated there were significant changes in numbers of SP-IR positive fibers of SO2group.</p><p><b>CONCLUSION</b>Exposure to low concentration of SO2 would injure healthy rat's airway, and induce airway hyperresponsiveness, neurogenic inflammation is one of its critical pathophysiological mechanisms.</p>

The Present and Future of Prostatitis / 대한비뇨기과학회지

Prostatitis is a common disease that is confusing and frustrating for urologists. Chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS) is the most common form of prostatitis. The etiology of CP/CPPS is unknown, but possibilities include infectious, autoimmune, neurological, endocrine and psychological causes. Clinical evaluation can aid in diagnosis and follow-up of the patient's response to therapy. Treatment for CP/CPPS is empiric and limited by a lack of randomized, placebo- controlled clinical trials. Antimicrobials are commonly used to treat patients with prostatitis. Other commonly used drugs include alpha-adrenoceptor antagonists, anti-inflammatory drugs, tricyclic antidepressants, and anticholinergic agents. Also, minimally invasive procedures are considered in patients with CP/CPPS and It is possible to treat intractable patients with invasive treatment. Although much progress has been made in therapy, there is no distinct treatment for patients with CP/CPPS. If the concept of neurogenic inflammation with pain is solved, it is possible to treat patients with CP/CPPS at future.