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No description available.

Neurólises de plexos simpáticos têm sido utilizadas no tratamento da dor oncológica, mostrando ser um recurso terapêutico bastante eficaz e seguro. Alguns estudos apontam a utilização da neurólise de plexos simpáticos em estágios iniciais da doença por prevenir a dor e melhorar a qualidade de vida, contrariando a OMS que preconiza o uso de métodos invasivos em última instância. Em estudo prospectivo, randomizado e controlado, neurólise de plexos simpáticos realizada em estágios diferentes do tratamento da dor oncológica foi comparada com o tratamento farmacológico. Foram selecionados 60 pacientes com câncer abdominal ou pélvico e alocados em três grupos. No grupo I (precoce) os pacientes estavam em uso de AINEs e opióides fracos ou fortes (dose inferior a 90mg/dia de morfina) e reportavam dor (VAS  4) quando foram submetidos a neurólise plexo celíaco (NPC), neurólise do plexo hipogástrico superior (NPHS) ou neurólise plexo simpático lombar (NPSL) de acordo com o sítio de dor. No grupo II (tardio) a neurólise foi realizada quando a utilização de AINEs e morfina foram iguais ou superiores a 90mg/dia de morfina e VAS>4. No grupo III (controle) os pacientes fizeram uso somente de medicação analgésica. Os pacientes foram observados durante 8 semanas e avaliados quanto à intensidade da dor (VAS), consumo de opióides e qualidade de vida. Imediatamente após as neurólises e durante todo o tempo de observação, os pacientes dos grupos precoce e tardio apresentaram redução da intensidade da dor e do consumo de opióides, além disso melhora da qualidade de vida quando comparados com o grupo controle. Não houve diferenças entre os grupos precoce e tardio nestes aspectos. Efeitos adversos correlacionados com o uso de opióide, como náuseas e/ou vômitos, perda do apetite e constipação foram significativamente maiores no grupo controle. Complicações relacionadas às neurólises, tais como hipotensão e diarréia, foram transitórias e não deferiram significativamente do grupo controle. Não foram encontradas complicações sérias em nenhum dos grupos experimentais. A neurólise de plexos simpáticos foi efetiva na redução da intensidade da dor e do consumo de analgésicos e dos efeitos adversos relacionados com a administração de drogas, e na melhora da qualidade de vida dos pacientes. Embora não havendo diferenças entre os grupos precoce e tardio, os resultados apontam a necessidade de utilizar esta técnica como recurso não somente em fase terminal da doença. / Neurolytic sympathetic plexus blocks (NSPB) have been used as a quite effective and safe therapeutic resource for the treatment of cancer pain. Studies point to the use of NSPB in the early phases of the disease to prevent pain and to improve the life quality, contradicting WHO that extols the use of invasive methods ultimately. We compared the use of neurolytic plexus block in two different phases of the treatment of oncology pain with the pharmacological therapy. In prospective study, randomized and controlled, sixty patients with abdominal or pelvic oncology pain were allocated to tree groups. In group I (early block) the patients using NSAID and weak opioid or oral morphine at a dose of less than 90 mg/day and reporting pain (VAS  4) were submitted to a neurolytic celiac plexus block (NCPB), superior hypogastric plexus block (SHPB) or lumbar sympathetic ganglionic chain (LSGCB), in accordance to the site of pain. In group 2 (late block) the patients were submitted neurolysis when using NSAID and oral morphine at a dose equals to or more than 90 mg/day and VAS  4. In group 3 (control), patients were treated with pharmacological therapy only. The patients were observed for 8 weeks and appraised for the intensity of the pain (VAS), opioid consumption and quality of live. The patients of groups I and II had reduction of the intensity of the pain, opioid consumption and get better quality of live immediately after to the neurolytic and during the whole time of observation when compared with the group control. There were no significant differences between groups I and II with these aspects. Adverse effects correlated with the use of opioids, as nauseas and/or vomits, loss of the appetite and constipation were significantly larger in the group control. Neurolysis related complications such as hypotension and diarrhea, were transitory and statistically similar to these found in the control group. They were not found serious complications. The neurolysis of sympathetic plexus was shown to be effective to reduce the intensity of pain, analgesic consumption and adverse effects related to the use of opioids, and in the improvement of the quality of life. The results point to the usefulness of indicating neurolytic procedure for the management of cancer pain not only in terminal phase of the disease.

É hipótese que (treinamento) T iniciado na fase pré-hipertensiva possa reduzir a atividade simpática e aumentar a vagal ao coração, melhorando a regulação autonômica nos SHR. Investigamos em SHR e WKY jovens (29 dias) os efeitos do T sobre parâmetros hemodinâmicos, funcionamento dos barorreceptores arteriais, tônus simpático e vagal ao coração e variabilidades, e expressão de neurônios pré-ganglionares vagais (Colina Acetil Transferase, ChAT) nos núcleos dorsal motor do vago (DMV) e ambíguo (NA). Ratos T ou sedentários (S) foram canulados nas semanas 0, 1, 2, 4 e 8, para registros funcionais e remoção dos encéfalos para a quantificação (peroxidade e estereologia). A participação dos aferentes periféricos na modulação dos efeitos do T foi avaliada com a desnervação sinoaórtica (SAD). Os efeitos do T são modulados por baro- e quimiorreceptores. O T precoce corrige a disfunção baroreflexa, reduz a hipertonia simpática, mantém parcialmente a tonicidade de neurônios colinérgicos, aumentando a modulação vagal ao coração e melhorando controle autonômico da circulação. / We hypothesized that aerobic training (T) starting at the pre-hypertensive phase reduces not only the sympathetic activity, but increases vagal outflow to the heart, thus improving autonomic cardiovascular control. We investigated in young SHR and WKY the T-induced effects on hemodynamic parameters, activation of arterial baroreceptor, sympathetic and vagal tone to the heart, and the expression of pre-ganglionic parasympathetic neurons (Choline acetyl transferase, ChAT) in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguous (NA). Rats (29 days) were T or sedentary (S) and cannulated at weeks 0, 1, 2, 4 and 8. After functional recordings, brains were harvested for quantification of neurons (peroxidase and stereology). The peripheral afferents was evaluated in sinoaortic denervation (SAD). SAD abrogated the improvement of baroreflex control and resting bradycardia in intact SHR-T. T-induced effects were modulated by arterial baro- and chemoreceptors. When started at the pre-hypertensive phase, T corrects baroreflex dysfunction, reduces sympathetic hyperactivity, maintain the tonicity of pre-ganglionic cholinergic neurons thus increasing vagal outflow to the heart and allowing a better autonomic control of the circulation.

Neurólises de plexos simpáticos têm sido utilizadas no tratamento da dor oncológica, mostrando ser um recurso terapêutico bastante eficaz e seguro. Alguns estudos apontam a utilização da neurólise de plexos simpáticos em estágios iniciais da doença por prevenir a dor e melhorar a qualidade de vida, contrariando a OMS que preconiza o uso de métodos invasivos em última instância. Em estudo prospectivo, randomizado e controlado, neurólise de plexos simpáticos realizada em estágios diferentes do tratamento da dor oncológica foi comparada com o tratamento farmacológico. Foram selecionados 60 pacientes com câncer abdominal ou pélvico e alocados em três grupos. No grupo I (precoce) os pacientes estavam em uso de AINEs e opióides fracos ou fortes (dose inferior a 90mg/dia de morfina) e reportavam dor (VAS  4) quando foram submetidos a neurólise plexo celíaco (NPC), neurólise do plexo hipogástrico superior (NPHS) ou neurólise plexo simpático lombar (NPSL) de acordo com o sítio de dor. No grupo II (tardio) a neurólise foi realizada quando a utilização de AINEs e morfina foram iguais ou superiores a 90mg/dia de morfina e VAS>4. No grupo III (controle) os pacientes fizeram uso somente de medicação analgésica. Os pacientes foram observados durante 8 semanas e avaliados quanto à intensidade da dor (VAS), consumo de opióides e qualidade de vida. Imediatamente após as neurólises e durante todo o tempo de observação, os pacientes dos grupos precoce e tardio apresentaram redução da intensidade da dor e do consumo de opióides, além disso melhora da qualidade de vida quando comparados com o grupo controle. Não houve diferenças entre os grupos precoce e tardio nestes aspectos. Efeitos adversos correlacionados com o uso de opióide, como náuseas e/ou vômitos, perda do apetite e constipação foram significativamente maiores no grupo controle. Complicações relacionadas às neurólises, tais como hipotensão e diarréia, foram transitórias e não deferiram significativamente do grupo controle. Não foram encontradas complicações sérias em nenhum dos grupos experimentais. A neurólise de plexos simpáticos foi efetiva na redução da intensidade da dor e do consumo de analgésicos e dos efeitos adversos relacionados com a administração de drogas, e na melhora da qualidade de vida dos pacientes. Embora não havendo diferenças entre os grupos precoce e tardio, os resultados apontam a necessidade de utilizar esta técnica como recurso não somente em fase terminal da doença. / Neurolytic sympathetic plexus blocks (NSPB) have been used as a quite effective and safe therapeutic resource for the treatment of cancer pain. Studies point to the use of NSPB in the early phases of the disease to prevent pain and to improve the life quality, contradicting WHO that extols the use of invasive methods ultimately. We compared the use of neurolytic plexus block in two different phases of the treatment of oncology pain with the pharmacological therapy. In prospective study, randomized and controlled, sixty patients with abdominal or pelvic oncology pain were allocated to tree groups. In group I (early block) the patients using NSAID and weak opioid or oral morphine at a dose of less than 90 mg/day and reporting pain (VAS  4) were submitted to a neurolytic celiac plexus block (NCPB), superior hypogastric plexus block (SHPB) or lumbar sympathetic ganglionic chain (LSGCB), in accordance to the site of pain. In group 2 (late block) the patients were submitted neurolysis when using NSAID and oral morphine at a dose equals to or more than 90 mg/day and VAS  4. In group 3 (control), patients were treated with pharmacological therapy only. The patients were observed for 8 weeks and appraised for the intensity of the pain (VAS), opioid consumption and quality of live. The patients of groups I and II had reduction of the intensity of the pain, opioid consumption and get better quality of live immediately after to the neurolytic and during the whole time of observation when compared with the group control. There were no significant differences between groups I and II with these aspects. Adverse effects correlated with the use of opioids, as nauseas and/or vomits, loss of the appetite and constipation were significantly larger in the group control. Neurolysis related complications such as hypotension and diarrhea, were transitory and statistically similar to these found in the control group. They were not found serious complications. The neurolysis of sympathetic plexus was shown to be effective to reduce the intensity of pain, analgesic consumption and adverse effects related to the use of opioids, and in the improvement of the quality of life. The results point to the usefulness of indicating neurolytic procedure for the management of cancer pain not only in terminal phase of the disease.

Komplette pharmakologische Unterbrechung des Baroreflexes mittels eines Ganglienblockers führt zu einer starken Zunahme der Wirkung vasoaktiver Substanzen auf den Blutdruck. Eine ähnliche Überempfindlichkeit gegenüber vasoaktiven Substanzen ist auch bei Erkrankungen zu beobachten, die mit Schädigungen des afferenten oder des efferenten Schenkels des Baroreflexes einhergehen. Variabilität der Baroreflexfunktion innerhalb der Population trägt somit in erheblichem Umfang zur Variabilität des Ansprechens auf vasoaktive Substanzen bei. Durch Vergleich der Wirkung kreislaufwirksamer Substanzen oder physiologischer Interventionen vor und während Ganglienblockade können zentrale und periphere Effekte voneinander unterschieden werden. Mit dieser Methode können Änderungen der vaskulären Sensitivität und der Pufferfunktion des Baroreflexes bei Krankheitszuständen charakterisiert werden. / Complete pharmacological interruption of the baroreflex using ganglionic blockade is associated with a profound increase in the blood pressure response to vasoactive substances. Similar hypersensitivity to vasoactive substances can be observed in disorders that involve the afferent arc or the efferent arc of the baroreflex. Therefore, interindividual variability in baroreflex function contributes substantially to the variability in the responsiveness to vasoactive substances. Comparison of the response to cardiovascular medications before and during ganglionic blockade can be used to dissect central and peripheral effects. This approach is also useful to characterize changes in vascular sensitivity and in baroreflex buffering function in diseases.

Indiana University-Purdue University Indianapolis (IUPUI) / Streptococcus mutans is a key contributor to dental caries. Smokers have increased caries, but the association between tobacco, nicotine, caries and S. mutans growth is little investigated. In the first section, seven S. mutans strains were used for screening. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum biofilm inhibitory concentration (MBIC) were 16 mg/ml (0.1 M), 32 mg/ml (0.2 M), and 16 mg/ml (0.1 M), respectively, for most of the S. mutans strains. Growth of planktonic S. mutans cells was significantly repressed by 2.0-8.0 mg/ml nicotine concentrations. Biofilm formation and metabolic activity of S. mutans was increased in a nicotine-dependent manner up to 16.0 mg/ml. Scanning electron microscopy (SEM) revealed higher nicotine-treated S. mutans had thicker biofilm and more spherical bacterial cells than lower concentrations of nicotine. In the second section, confocal laser scanning microscopy (CLSM) results demonstrated that both biofilm bacterial cell numbers and extracellular polysaccharide (EPS) synthesis were increased by nicotine. Glucosyltransferase (Gtf) and glucan binding protein A (GbpA) protein expression of S. mutans planktonic cells were upregulated, while GbpB protein expression of biofilm cells were downregulated by nicotine. The mRNA expression of those genes were mostly consistent with their protein results. Nicotine was not directly involved in S. mutans LDH activity. However, since it increased the total number of bacterial cells in biofilm; total LDH activity of S. mutans biofilm was increased. In the third section, a PCR-based multiple species cell counting (PCR-MSCC) method was designed to investigate the effect of nicotine on S. mutans in a ten mixed species culture. The absolute S. mutans number in mixed biofilm culture was increased but the percentage of S. mutans in the total number of bacterial cells was not changed. In conclusion, nicotine enhanced biofilm formation and biofilm metabolism of S. mutans, through stimulating S. mutans planktonic cell Gtfs and Gbps expression. This leads to more planktonic cells attaching to dental biofilm. Increased S. mutans cell numbers, in biofilms of single species or ten mixed species, resulted in higher overall LDH activity. More lactic acid may be generated and contribute to caries development in smokers.

Le gène SYNGAP1 code pour la protéine Synaptic Ras GTPase-Activating protein 1 et est essentiel pour le développement normal de la fonction synaptique et de la cognition. Les mutations dans le gène SYNGAP1 qui provoquent la perte d'une seule copie du gène (haplo-insuffisance) sont associées à un handicap intellectuel, comorbide avec un trouble du spectre autistique et l'épilepsie. Les individus présentant des mutations SYNGAP1 montrent un large éventail de caractéristiques phénotypiques telles que l'encéphalopathie épileptique, des déficits moteurs, des déficits sensoriels et d'autres anomalies comportementales et cognitives. De manière intéressante, les modèles de souris transgéniques Syngap1 haplo-insuffisantes reproduisent les déficits comportementaux et cognitifs observés chez les individus SYNGAP1. Plusieurs études se sont concentrées sur le rôle de Syngap1 dans les synapses glutamatergiques, révélant qu'il est un régulateur négatif de Ras, impliqué dans le trafic des récepteurs AMPA au niveau de la membrane postsynaptique des neurones excitateurs. Syngap1 est fortement impliqué dans la maturation des épines dendritiques et dans la régulation de la plasticité synaptique et de l'homéostasie neuronale. Toutefois, le rôle de Syngap1 dans les neurones GABAergiques est moins bien exploré. Les interneurones GABAergiques forment une population hétérogène, les sous-types dominants étant les interneurones exprimant la Parvalbumine (PV) et la Somatostatine (SST) dérivés de l'éminence ganglionnaire médiane (MGE). Des études récentes ont révélé le rôle multifacette de Syngap1 dans les interneurones GABAergiques, notamment son implication dans la migration des interneurones, le branchement axonal des cellules PV et la régulation des synapses inhibitrices sur les somas postsynaptiques. Cependant, si et comment Syngap1 affecte les types cellulaires spécifiques d’interneurones dérivés de MGE tels que les interneurones PV et/ou SST n’est pas connu, et cela est exploré dans ma thèse. De plus, nous avons exploré si et comment l'haplo-insuffisance de Syngap1 induite pré- ou post-natalement spécifiquement dans les sous-types d'interneurones PV et SST contribue aux modalités comportementales, cognitives et sensorielles chez les souris adultes. Des stratégies génétiques ont été utilisées pour induire l'haplo-insuffisance de Syngap1, 1. pré-natalement dans les cellules PV et SST en utilisant la lignée de souris Nkx2.1_Cre, 2. pré-natalement dans les cellules SST en utilisant la ligne de souris SST_Cre et 3. post-natalement dans les cellules PV en utilisant la lignée de souris PV_Cre. Nous avons constaté que la réduction de Syngap1 pré-natalement dans les cellules PV et SST (en utilisant le promoteur Nkx2.1 pour cibler les interneurones dérivés de MGE) influence le traitement sensoriel auditif, en augmentant notamment les oscillations gamma de base, en affectant l'entraînement auditif et en échouant à s'habituer aux sons répétitifs. De plus, ces souris présentent des déficits de comportement social et une flexibilité cognitive altérée dans le comportement d'extinction de la peur. De telles altérations du traitement sensoriel, ainsi que des déficits comportementaux et cognitifs, n'ont pas été observés observés lorsque Syngap1 a été supprimé dans les cellules SST prénatales (en utilisant le promoteur SST). La suppression postnatale de Syngap1 dans les cellules PV montre quant à elle une habituation auditive accrue. Cependant, ces souris transgéniques ne présentent aucun déficit de comportement social ou d'extinction de la peur. Ces résultats suggèrent que les cellules PV pré- et/ou péri-natales sont particulièrement vulnérables à l'haplo-insuffisance de Syngap1 pendant une fenêtre temporelle sensible précoce lors du développement cérébral chez la souris. Alors que des modèles de souris conditionnelles spécifiques aident à comprendre la fonction biologique fondamentale de Syngap1, ils n'englobent pas la complexité du trouble génétique causé par SYNGAP1-ID. Nous avons donc étendu notre étude pour comprendre si les cellules PV sont altérées dans un modèle murin d'haplo-insuffisance germinale de Syngap1. En raison de leur innervation unique du soma et des dendrites proximales de leurs cibles postsynaptiques, les cellules PV influencent fortement l'activité du réseau et sont impliquées dans des fonctions cognitives supérieures telles que l'attention sélective, la mémoire de travail et la flexibilité cognitive, en particulier dans le cortex préfrontal (PFC). Nous avons étudié la connectivité synaptique des cellules PV et avons constaté qu'elles reçoivent des entrées excitatrices réduites dans les cortex préfrontal et auditif adultes. En parallèle, nous avons montré une connectivité réduite des cellules PV sur les cellules excitatrices avec moins de recrutement dans le PFC des souris adultes. Les souris transgéniques germinales présentent également des déficits de flexibilité cognitive (comme dans le comportement d'extinction de la peur) et dans l'apprentissage de la peur contextuelle. Ces résultats suggèrent un déséquilibre global entre l'excitation et l'inhibition dû à des altérations dans la connectivité des cellules PV. Nos études explorent donc le rôle de Syngap1 dans des lignées transgéniques haplo-insuffisantes conditionnelles et germinales en se concentrant sur des types cellulaires GABAergiques distincts (cellules PV et/ou SST), et montrent que les déficits des cellules PV, pendant une fenêtre de développement précoce, sont un facteur prédominant contribuant à la physiopathologie sous-jacente des mutations de Syngap1. Une meilleure compréhension du rôle de Syngap1 dans différents types cellulaires et stades de développement aidera à concevoir des stratégies d'intervention thérapeutique optimales. / SYNGAP1 gene encodes for the Synaptic Ras GTPase-Activating protein 1, and is critical for the normal development of synaptic function and cognition. Mutations in SYNGAP1 gene that cause loss of single copy of the gene (haploinsufficiency) are associated with intellectual disability, comorbid with autism spectrum disorder and epilepsy. Individuals with SYNGAP1 mutations show a broad spectrum of phenotypic features such as epileptic encephalopathy, motor deficits, sensory deficits and other behavioral and cognitive abnormalities. Interestingly, transgenic Syngap1 haploinsufficient mouse models phenocopy the behavioral and cognitive deficits as in SYNGAP1 individuals. Several studies have focused on the role of Syngap1 in glutamatergic synapses and revealed it to be a negative regulator of Ras, involved in the trafficking of AMPA receptors at the postsynaptic membrane of excitatory neurons. Syngap1 is strongly implicated in dendritic spine maturation and in regulating synaptic plasticity and neuronal homeostasis. The role of Syngap1 in GABAergic neurons however is less well explored. GABAergic interneurons form a heterogenous population, the dominant subtypes being the Parvalbumin (PV) and Somatostatin (SST) expressing interneurons derived from Medial Ganglionic Eminence (MGE). Recent studies have divulged the multi-faceted role of Syngap1 in GABAergic interneurons such as its involvement with interneuron migration, PV cell axonal branching, and regulation of inhibitory synapses onto postsynaptic somata. However, whether and how Syngap1 affects specific MGE-derived interneuron cell types such as PV and/or SST interneurons is unknown and explored in my thesis. Further, we explored whether and how Syngap1 haploinsufficiency induced either pre- or postnatally specifically in PV and SST interneuron subtypes, contributes to behavioral, cognitive and sensory related modalities in adult mice. Genetic strategies were used to induce Syngap1 haploinsufficiency, 1. prenatally in PV and SST cells using the Nkx2.1_Cre driver line, 2. prenatally in SST cells using SST_Cre driver line and 3. postnatally in PV cells using the PV_Cre driver line. We found that reduction of Syngap1 prenatally in both PV and SST cells (using the Nkx2.1 promoter to target MGE-derived interneurons) influences auditory sensory processing, in particular increasing the baseline gamma oscillations, affecting auditory entrainment and failing to habituate to repetitive sounds. In addition, these mice show deficits in social behavior and impaired cognitive flexibility in fear extinction behavior. Such sensory processing alterations, as well as behavioral and cognitive deficits were not observed when Syngap1 was deleted in prenatal SST cells (using the SST promoter). Postnatal deletion of Syngap1 in PV cells in turn showed increased auditory habituation, however these transgenic mice show no deficits in either social or fear extinction behavior. These results suggest that pre- and/or perinatal PV cells are particularly vulnerable to Syngap1 haploinsufficiency at an early sensitive time window during mouse brain development. While specific conditional mouse models help in understanding the fundamental biological function of the Syngap1, they do not encompass the complexity of the genetic disorder caused in SYNGAP1-ID. We therefore extended our study to understand whether PV cells are altered in a mouse model of germline Syngap1 haploinsufficiency. Due to their unique innervation of the soma and proximal dendrites of their postsynaptic targets, PV cells strongly influence network activity and are involved in higher cognitive functions such as selective attention, working memory and cognitive flexibility particularly in the prefrontal cortex (PFC). We investigated PV cell synaptic connectivity and found that they receive reduced excitatory inputs in the adult prefrontal and auditory cortex. In parallel, we showed reduced PV connectivity onto excitatory cells with less recruitment in the PFC of adult mice. The germline transgenic mice also showed deficits in cognitive flexibility (such as in fear extinction behavior) and cued contextual fear conditioning. These results suggest an overall E/I imbalance due to alterations in PV cell connectivity. Our studies therefore explore the role of Syngap1 in both conditional and germline haploinsufficient transgenic lines focusing on distinct GABAergic cell types (PV and/or SST cells), and shows that PV cell deficits, during an early developmental window, is a predominant contributing factor to the pathophysiology underlying Syngap1 mutations. A better understanding of the role of Syngap1 in different cell types and developmental stages will help in designing optimal therapeutic intervention strategies.

No description available.