Crotalphine Attenuates Pain and Neuroinflammation Induced by Experimental Autoimmune Encephalomyelitis in Mice.

Multiple sclerosis (MS) is a demyelinating disease of inflammatory and autoimmune origin, which induces sensory and progressive motor impairments, including pain. Cells of the immune system actively participate in the pathogenesis and progression of MS by inducing neuroinflammation, tissue damage, and demyelination. Crotalphine (CRO), a structural analogue to a peptide firstly identified in Crotalus durissus terrificus snake venom, induces analgesia by endogenous opioid release and type 2 cannabinoid receptor (CB2) activation. Since CB2 activation downregulates neuroinflammation and ameliorates symptoms in mice models of MS, it was presently investigated whether CRO has a beneficial effect in the experimental autoimmune encephalomyelitis (EAE). CRO was administered on the 5th day after immunization, in a single dose, or five doses starting at the peak of disease. CRO partially reverted EAE-induced mechanical hyperalgesia and decreased the severity of the clinical signs. In addition, CRO decreases the inflammatory infiltrate and glial cells activation followed by TNF-α and IL-17 downregulation in the spinal cord. Peripherally, CRO recovers the EAE-induced impairment in myelin thickness in the sciatic nerve. Therefore, CRO interferes with central and peripheral neuroinflammation, opening perspectives to MS control.

Case Report: Clinical Outcome and Image Response of Two Patients With Secondary High-Grade Glioma Treated With Chemoradiation, PCV, and Cannabidiol.

We describe two patients with a confirmed diagnosis of high-grade gliomas (grades III/IV), both presenting with O6-methylguanine-DNA methyltransferase (MGMT) methylated and isocitrate dehydrogenase (IDH-1) mutated who, after subtotal resection, were submitted to chemoradiation and followed by PCV, a multiple drug regimen (procarbazine, lomustine, and vincristine) associated with cannabidiol (CBD). Both patients presented with satisfactory clinical and imaging responses at periodic evaluations. Immediately after chemoradiation therapy, one of the patients presented with an exacerbated and precocious pseudoprogression (PSD) assessed by magnetic resonance imaging (MRI), which was resolved in a short period. The other patient presented with a marked remission of altered areas compared with the post-operative scans as assessed by MRI. Such aspects are not commonly observed in patients only treated with conventional modalities. This observation might highlight the potential effect of CBD to increase PSD or improve chemoradiation responses that impact survival. Further investigation with more patients and critical molecular analyses should be performed.

Disruption of beta3 adrenergic receptor increases susceptibility to DIO in mouse.

The brown adipose tissue (BAT) mediates adaptive changes in metabolic rate by responding to the sympathetic nervous system through ß-adrenergic receptors (AR). Here, we wished to define the role played by the ARß3 isoform in this process. This study focused on the ARß3 knockout mice (ARß3KO), including responsiveness to cold exposure, diet-induced obesity, intolerance to glucose, dyslipidaemia and lipolysis in white adipose tissue (WAT). ARß3KO mice defend core temperature during cold exposure (4°C for 5 h), with faster BAT thermal response to norepinephrine (NE) infusion when compared with wild-type (WT) mice. Despite normal BAT thermogenesis, ARß3KO mice kept on a high-fat diet (HFD; 40% fat) for 8 weeks exhibited greater susceptibility to diet-induced obesity, markedly increased epididymal adipocyte area with clear signs of inflammation. The HFD-induced glucose intolerance was similar in both groups but serum hypertriglyceridemia and hypercholesterolemia were less intense in ARß3KO animals when compared with WT controls. Isoproterenol-induced lipolysis in isolated white adipocytes as assessed by glycerol release was significantly impaired in ARß3KO animals despite normal expression of key proteins involved in lipid metabolism. In conclusion, ARß3 inactivation does not affect BAT thermogenesis but increases susceptibility to diet-induced obesity by dampening WAT lipolytic response to adrenergic stimulation.

Inactivation of the adrenergic receptor ß2 disrupts glucose homeostasis in mice.

Three types of beta adrenergic receptors (ARß1-3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse with Arß2 knockout (ARß2KO). At room temperature, ARß2KO mice have normal core temperature and, upon acute cold exposure (4 °C for 4 h), ARß2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARß2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and of Arß1, and Arß3 mRNA levels. In addition, ARß2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepatic Pepck (Pck1) mRNA levels. The animals were fed a high-fat diet (40% fat) for 6 weeks, ARß2KO mice doubled their caloric intake, accelerated energy expenditure, and induced Ucp1 expression in a manner similar to WT controls, exhibiting a similar body weight gain and increase in the size of white adipocytes to the WT controls. However, ARß2KO mice maintain fasting hyperglycemia as compared with WT controls despite very elevated insulin levels, but similar degrees of liver steatosis and hyperlipidemia. In conclusion, inactivation of the ARß2KO pathway preserves cold- and diet-induced adaptive thermogenesis but disrupts glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion. Feeding on a high-fat diet worsens the metabolic imbalance, with significant fasting hyperglycemia but similar liver structure and lipid profile to the WT controls.

ß(1) Adrenergic receptor is key to cold- and diet-induced thermogenesis in mice.

Brown adipose tissue (BAT) is predominantly regulated by the sympathetic nervous system (SNS) and the adrenergic receptor signaling pathway. Knowing that a mouse with triple ß-receptor knockout (KO) is cold intolerant and obese, we evaluated the independent role played by the ß(1) isoform in energy homeostasis. First, the 30  min i.v. infusion of norepinephrine (NE) or the ß(1) selective agonist dobutamine (DB) resulted in similar interscapular BAT (iBAT) thermal response in WT mice. Secondly, mice with targeted disruption of the ß(1) gene (KO of ß(1) adrenergic receptor (ß(1)KO)) developed hypothermia during cold exposure and exhibited decreased iBAT thermal response to NE or DB infusion. Thirdly, when placed on a high-fat diet (HFD; 40% fat) for 5 weeks, ß(1)KO mice were more susceptible to obesity than WT controls and failed to develop diet-induced thermogenesis as assessed by BAT Ucp1 mRNA levels and oxygen consumption. Furthermore, ß(1)KO mice exhibited fasting hyperglycemia and more intense glucose intolerance, hypercholesterolemia, and hypertriglyceridemia when placed on the HFD, developing marked non-alcoholic steatohepatitis. In conclusion, the ß(1) signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis.

Characteristics of muscle fibers in rats with limb movements during sleep after spinal cord injury.

BACKGROUND/AIMS: Previous studies have demonstrated that spinal cord injury (SCI) results in changes in sleep patterns through increased arousals and limb movements during sleep. Dramatic changes in muscle myosin heavy-chain isoforms have also been reported. The aim of this study was to investigate the characteristics of muscle fibers after SCI in rats with limb movements during sleep. METHODS: Forty male Wistar rats were divided into four groups: SHAM, SCI 3, 7 and 15 days. Animals were subjected to electrode insertion surgery, 24-hour baseline sleep recording, SCI, and subsequent sleep recording for 3, 7, or 15 consecutive days. In addition, the gastrocnemius muscle and spinal cord were collected for histopathological/histochemical analyses. RESULTS: Our results indicate a rapid and progressive decrease in the cross-sectional area of type I fibers in the gastrocnemius muscle (35.76-24.74 µm(2)) after SCI. Additionally, we found SCI-induced changes in sleep patterns. Following SCI, we also observed limb movements in sleeping rats, as well as significant negative moderate correlations between type I fibers and limb movement. CONCLUSION: Our study strengthened the hypothesis by correlation between changes in types of muscle fiber (decline in type I fibers) and an increase in limb movements during sleep after SCI.

[Encephalometry on the medial face of the human brain hemisphere: a necropsy study].

This study aims to evaluate the dimensions of the human brain, specifically in the frontal cortex, helping the analysis of neuroimaging. A form was made to register and describe encephalic measurements and 81 cerebral hemispheres (CH) were analyzed. Male individuals showed larger CH length; wider superior frontal gyrus in the right CH; bigger encephalic weight and corpus callosum (CC) width. The proportion of measurement from the frontal pole to the most anterior part of the CC genu, related to the CH length gets smaller with aging, whereas the average distance from the most posterior part of the splenum of the CC to the occipital pole was bigger in both male CHs and there was a tendency of decrease in this difference with aging.

Encephalometry on the medial face of the human brain hemisphere: a necropsy study

Este estudo visa avaliar as dimensões do cérebro humano, particularmente do córtex frontal, podendo colaborar para as análises de neuroimagem. Foi elaborado um formulário para registro e descrição das medidas encefálicas. A amostra foi constituída por 81 hemisférios cerebrais (HC) adultos. Os homens apresentaram maior comprimento do HC; giro frontal superior mais largo no HC direito; maior peso encefálico e largura do corpo caloso (CC). A proporção da medida do pólo frontal à parte mais anterior do joelho do CC, em relação ao comprimento do HC diminui com o avanço da idade. Já a da média da distância da parte mais posterior do esplênio do CC ao pólo occipital foi maior em ambos HC dos homens e houve tendência à diminuição desta proporção com o avanço da idade.

Um caso particular de granuloma de sílica na mucosa nasal / A particular case of silica granuloma in nasal mucosa

A silicose é uma doença granulomatosa que acomete o pulmäo de pessoas expostas a cristais de sílica, porém näo encontramos na revisäo de literatura outro caso acometendo a mucosa nasal. Trata-se de uma paciente de 46 anos que começou a apresentar queda de dorso nasal em área K e rinorréia sanguinolenta, tendo evoluindo para perfuraçäo de septo; ao exame a mucosa apresentava aspecto granuloso de onde foi colhido material para exame anátomo-patológico que revelou cristais de sílica em meio a processo inflamatório linfoplasmocitário. Näo foi encontrada a forma de exposiçäo à sílica nessa paciente, que depois de um período de 3 anos sem sintomas, sem formaçäo de crostas nasais ou alteraçäo do aspecto externo da pirâmide nasal, foi submetida à rinoplastia para correçäo do afundamento em dorso nasal. Esse caso näo deve ser considerado apenas como curiosidade, mas como uma doença cuja patogenia näo está esclarecida

Correlaçäo entre ultra-som de crânio e achados de autópsia em recém-nascidos pré-termo que evoluíram para óbito no período neonatal / Correlation between serial cranial ultrassound and findings at autopsy im prematures who evoluted to death during the first postnatal month

Objetivo: avaliar a correlaçäo entre o ultra-som de crânio seriado neonatal e achados anáyomo-patológicos em recém-nascidos pré-termo que evoluiram para óbito no período neonatal. Metodologia: foram estudados prospectivamente 22 pacientes com idade gestacional média de 30,5 semanas e peso médio de 1095 gramas no nascimento, nos quais foi realizado ultra-som de crânio de forma e a seriada e a análise cerebral macroscópica na autópsia, estabelecendo-se uma relaçäo entre o diagnóstico ultra-sonográfico e os achados anátomo-patológicos. Foi realizada a comparaçäo estatística entre estes dois fatores, por meio dos cálculos da sensibilidade, especificidade, valores preditivos positivo e negativo. Resultados: a especificidade do ultra-som foi de 88,9 por cento, a sensibilidade de 76,9 por cento, o valor preditivo positivo foi de 90,9 por cento e o valor preditivo negativo de 72,7 por cento

Schwannoma maligno de órbita / Schwannoma malignant orbital

Relatou-se um caso de tumor maligno de nervo periférico (schwannoma) na órbita e revisou-se a literatura sobre essa rara lesäo

Esclerose múltipla: estudo clínico e patológico de um caso / Multiple sclerosis: clinical and pathological study of a case

Apresentamos um caso com diagnóstico definido de esclerose múltipla confirmado pelos achados necroscópicos. Os aspectos anatompatológicos nessa doença säo bem conhecidos e têm sido referidos por vários autores. O objetivo desta apresentaçäo é a divulgaçäo do primeiro caso de esclerose múltipla autopsiado na Santa Casa de Säo Paulo, onde já foram realizadas cerca de 30500 autópsias. Os achados macro e microscópicos observados no sistema nervoso central, com placas de desmielinizaçäo em fases diferentes de atividade, säo características da doença. A detecçäo de imunoglobulinas nessas placas, pelo método de imunohistoquímica, adicionou aos achados morfológicos a hipótese patogênica de uma doença imunologicamente mediada