The complement system in neurodegenerative and inflammatory diseases of the central nervous system

Neurodegenerative and neuroinflammatory diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, affect millions of people globally. As aging is a major risk factor for neurodegenerative diseases, the continuous increase in the elderly population across Western societies is also associated with a rising prevalence of these debilitating conditions. The complement system, a crucial component of the innate immune response, has gained increasing attention for its multifaceted involvement in the normal development of the central nervous system (CNS) and the brain but also as a pathogenic driver in several neuroinflammatory disease states. Although complement is generally understood as a liver-derived and blood or interstitial fluid operative system protecting against bloodborne pathogens or threats, recent research, particularly on the role of complement in the healthy and diseased CNS, has demonstrated the importance of locally produced and activated complement components. Here, we provide a succinct overview over the known beneficial and pathological roles of complement in the CNS with focus on local sources of complement, including a discussion on the potential importance of the recently discovered intracellularly active complement system for CNS biology and on infection-triggered neurodegeneration

Obtenção de isolados de rizóbios com características agronômicas desejáveis provenientes de solos da região do Amazonas

The majority of the Amazonian soils is acid with low concentration of nitrogen and phosphorus. The use of leguminosae-rizhobia symbiosis is an alternative for the development of a sustainable agriculture of low input. Reaserches have showed that some isolates of rhizobia, besides fixing the atmospheric N, can still solubilize phosphate, availabiliting more P for the plants, then it is necessary to develop research to select strains of rhizobia more efficient in several favorable characteristics for use by plants. This research work had as objectives, to laboratory evaluations about the tolerance to acidity and toxic Al, the capacity to solubilize calcium (P-Ca) and aluminum (P-Al) phosphates and the indole-acetic acid production (AIA). To test acidity and aluminum toxicity, Among the 100 isolates tested, 91 and 82 presented tolerance with growth scale above 3,06 at 15th days in the treatment with pH 6,5 and pH 4,5 + Al, respectively. The most limiting factor the growth of the isolates ones was acidity and the aluminum. As for phosphate solubilization of the 71 isolates, where 46 isolated solubilized P-Ca and 25 solubilized P-Al, and 19 solubilized P-Ca as well as P-Al. Among the isolates able to solubilize calcium phosphate, 46 were considered as precocious and 1 as delayers and all the isolate evaluated presented capacity to solubilize aluminum phosphate, 24 were considered as precocious and 1 as delayers, the other not shown solubilizers. For the production of aia, 38 of the 71 isolates induced growth rate of root system of cucumber greater than in non-inoculated plants with them. Among the isolates, which had the best result was the INPA R670 in time of 24h.A maioria dos solos da Amazônia é ácida e com baixa concentração de nitrogênio e fósforo. A utilização da simbiose leguminosa-rizóbia é uma alternativa para o desenvolvimento de uma agricultura sustentável e de baixos insumos. Pesquisas têm mostrado que alguns isolados de rizóbio, além de fixarem o N atmosférico, podem ainda solubilizar fosfatos pouco solúveis existentes no solo, disponibilizando mais P para as plantas, faz-se necessário, desenvolver pesquisas para selecionar estirpes de rizóbios mais eficientes quanto às diversas características favoráveis para sua utilização pelas plantas. Este trabalho teve como objetivos, avaliar em laboratório, a tolerância à acidez e Al tóxico, a capacidade de solubilização de fosfato de cálcio (P-Ca) e alumínio (P-Al) e a produção de acido indol-acético (AIA). Para o teste de acidez e alumínio tóxico, entre os 100 isolados testados 91 e 82 apresentaram tolerância com crescimento acima de 3,06 aos 15 dias nos tratamento com pH 6,5 e pH 4,5 + Al, respectivamente. O fator mais limitante para o crescimento dos isolados foi a acidez e o alumínio. Já para solubilização de fosfatos, dos 71 isolados, onde 46 solubilizaram P-Ca e 25 solubilizaram P-Al, sendo que 19 isolados solubilizaram tanto P–Ca quanto P–Al. Dentre os que solubilizaram fosfato de cálcio, 46 se comportaram como precoces e somente 1 como tardio já nos solubilizadores de alumínio, 24 se comportaram como precoces e 1 como tardio, os outros não se mostraram solubilizadores. Para a produção de AIA, 38 dos 71 isolados induziram taxas de crescimento radicular das plantas de pepino maiores do que nas plantas não inoculadas com os mesmos. Dentre os isolados avaliados, o que obteve melhor resultado foi o INPA R670 no tempo de 24h

Carcinogênese experimental na mucosa orofaríngea de ratos com ácido clorídrico, nitrato de sódio e pepsina

PURPOSE: To investigate the carcinogenic action of hydrochloric acid, pepsin and sodium nitrate on the oropharyngeal mucosa of rats, simulating the reflux of gastric contents. METHODS: Eighty-two Wistar rats were divided in seven groups and submitted to 2 or 3 weekly applications of hydrochloric acid, pepsin and sodium nitrate on the pharyngeal mucosa during six months. Study groups comprised 12 animals each. Rats in groups I and II were submitted to 2 (GI) or 3 (GII) weekly applications of 0.1N hydrochloric acid. Groups III and IV were submitted to 2 (GIII) or 3 (GIV) weekly applications of 0.1N hydrochloric acid solution with pepsin. Groups V and VI were submitted to 2 (GV) or 3 (GVI) weekly applications of 0.1N hydrochloric acid and treated with daily nitrate diluted in water. Group VII consisted of 10 animals submitted to 2 weekly applications of filtered water. RESULTS: No dysplasia, intra-epithelial neoplasia or invasive carcinomas were detected. Inflammatory changes were observed in varying degrees and mast cells were more common in Groups V and VI (p=0.006). CONCLUSION: The data of the current study could not corroborate the hypothesis that gastroesophageal and pharyngolaryngeal refluxes are carcinogenic factors to the laryngopharyngeal mucosa, and more studies are necessary in the future.OBJETIVO: Investigar a ação carcinogênica do ácido clorídrico, pepsina e nitrato de sódio na mucosa orofaríngea de ratos, simulando o refluxo do conteúdo gástrico à mucosa do faringo-laringea. MÉTODOS: Oitenta e dois ratos Wistar foram divididos em 7 grupos e submetidos a 2 ou 3 aplicações semanais de ácido clorídrico, pepsina e nitrato de sódio na mucosa orofaríngea durante 6 meses. Os grupos de estudo envolveram 12 animais cada. Os ratos nos grupos I e II foram submetidos à 2 (GI) ou 3 (GII) aplicações semanais de ácido clorídrico 0,1N. Nos grupos III e IV foram 2 (GIII) ou 3 (GIV) aplicações semanais de ácido clorídrico e pepsina. Nos grupos V e VI foram 2 (GV) ou 3 (GVI) aplicações semanais de ácido clorídrico além da oferta de nitrato diluído em água diariamente. Grupo VII era composto por 10 animais submetidos a 2 aplicações semanais de água filtrada. RESULTADOS: Não se observou displasia, neoplasia intra-epitelial ou neoplasia invasora. Alterações inflamatórias em graus variados foram observadas, com infiltrado mastocitário mais intenso nos grupos V e VI. (p=0,006). CONCLUSÃO: Os dados do presente estudo não confirmam a hipótese que o refluxo gastro-esofágico e faringo-laringeo são fatores carcinogênicos para a mucosa laringo-faringea e mais estudos são necessários no futuro.33734

BBB-targeting, protein-based nanomedicines for drug and nucleic acid delivery to the CNS

The increasing incidence of diseases affecting the central nervous system (CNS) demands the urgent development of efficient drugs. While many of these medicines are already available, the Blood Brain Barrier and to a lesser extent, the Blood Spinal Cord Barrier pose physical and biological limitations to their diffusion to reach target tissues. Therefore, efforts are needed not only to address drug development but specially to design suitable vehicles for delivery into the CNS through systemic administration. In the context of the functional and structural versatility of proteins, recent advances in their biological fabrication and a better comprehension of the physiology of the CNS offer a plethora of opportunities for the construction and tailoring of plain nanoconjugates and of more complex nanosized vehicles able to cross these barriers. We revise here how the engineering of functional proteins offers drug delivery tools for specific CNS diseases and more transversally, how proteins can be engineered into smart nanoparticles or 'artificial viruses' to afford therapeutic requirements through alternative administration routes

Eficácia do balonete do tubo endotraqueal sobre a traqueia: aspectos físicos e mecânicos

Introduction: The inflation pressure of the endotracheal tube cuff can cause ischemia of the tracheal mucosa at high pressures; thus, it can cause important tracheal morbidity and tracheal microaspiration of the oropharyngeal secretion, or it can even cause pneumonia associated with mechanical ventilation if the pressure of the cuff is insufficient. Objective: In order to investigate the effectiveness of the RUSCH® 7.5 mm endotracheal tube cuff, this study was designed to investigate the physical and mechanical aspects of the cuff in contact with the trachea. Methods: For this end, we developed an in vitro experimental model to assess the flow of dye (methylene blue) by the inflated cuff on the wall of the artificial material. We also designed an in vivo study with 12 Large White pigs under endotracheal intubation. We instilled the same dye in the oral cavity of the animals, and we analyzed the presence or not of leakage in the trachea after the region of the cuff after their deaths (animal sacrifice). All cuffs were inflated at the pressure of 30 cmH2O. Results: We observed the passage of fluids through the cuff in all in vitro and in vivo experimental models. Conclusion: We conclude that, as well as several other cuff models in the literature, the RUSCH® 7.5 mm tube cuffs are also not able to completely seal the trachea and thus prevent aspiration of oropharyngeal secretions. Other prevention measures should be taken.The inflation pressure of the endotracheal tube cuff can cause ischemia of the tracheal mucosa at high pressures, thus, it can cause important tracheal morbidity and tracheal microaspiration of the oropharyngeal secretion, or it can even cause pneumonia a294552558SEM INFORMAÇÃOSEM INFORMAÇÃODobell, A.R., The origins of endotracheal ventilation (1994) Ann Thorac Surg, 58 (2), pp. 578-584Mehta, S., Tracheal tube cuff pressure (1989) Anaesthesia, 44 (12), pp. 1001-1002Mehta, S., Mickiewicz, M., Pressure in large volume, low pressure cuffs: Its significance, measurement and regulation (1985) Intensive Care Med, 11 (5), pp. 267-272Luna, C.M., Legarreta, G., Esteva, H., Laffaire, E., Jolly, E.C., Effect of tracheal dilatation and rupture on mechanical ventilation using a low-pressure cuff tube (1993) Chest, 104 (2), pp. 639-640Bernhard, W.N., Yost, L., Turndorf, H., Danziger, F., Cuffed tracheal tubes--physical and behavioral characteristics (1982) Anesth Analg, 61 (1), pp. 36-41Nordin, U., The trachea and cuff-induced tracheal injury. An experimental study on causative factors and prevention (1977) Acta Otolaryngol Suppl, 345, pp. 1-71Sole, M.L., Su, X., Talbert, S., Penoyer, D.A., Kalita, S., Jimenez, E., Evaluation of an intervention to maintain endotracheal tube cuff pressure within therapeutic range (2011) Am J Crit Care, 20 (2), pp. 109-117Benumof, J.L., Cooper, S.D., Quantitative improvement in laryngoscopic view by optimal external laryngeal manipulation (1996) J Clin Anesth, 8 (2), pp. 136-140Keller, C., Brimacombe, J., Boehler, M., Loeckinger, A., Puehringer, F., The influence of cuff volume and anatomic location on pharyngeal, esophageal, and tracheal mucosal pressures with the esophageal tracheal combitube (2002) Anesthesiology, 96 (5), pp. 1074-1077Cooper, J.D., Grillo, H.C., The evolution of tracheal injury due to ventilatory assistance through cuffed tubes: A pathologic study (1969) Ann Surg, 169 (3), pp. 334-348Seegobin, R.D., Van Hasselt, G.L., Endotracheal cuff pressure and tracheal mucosal blood flow: Endoscopic study of effects of four large volume cuffs (1984) Br Med J (Clin Res Ed), 288 (6422), pp. 965-968Joseph, N.M., Sistla, S., Dutta, T.K., Badhe, A.S., Parija, S.C., Ventilator-associated pneumonia: A review (2010) Eur J Intern Med, 21 (5), pp. 360-368Dave, M.H., Koepfer, N., Madjdpour, C., Frotzler, A., Weiss, M., Tracheal fluid leakage in benchtop trials: Comparison of static versus dynamic ventilation model with and without lubrication (2010) J Anesth, 24 (2), pp. 247-252Lucangelo, U., Zin, W.A., Antonaglia, V., Petrucci, L., Viviani, M., Buscema, G., Effect of positive expiratory pressure and type of tracheal cuff on the incidence of aspiration in mechanically ventilated patients in an intensive care unit (2008) Crit Care Med, 36 (2), pp. 409-413Young, P.J., Burchett, K., Harvey, I., Blunt, M.C., The prevention of pulmonary aspiration with control of tracheal wall pressure using a silicone cuff (2000) Anaesth Intensive Care, 28 (6), pp. 660-665Dave, M.H., Frotzler, A., Spielmann, N., Madjdpour, C., Weiss, M., Effect of tracheal tube cuff shape on fluid leakage across the cuff: An in vitro study (2010) Br J Anaesth, 105 (4), pp. 538-543Pavlin, E.G., Vannimwegan, D., Hornbein, T.F., Failure of a high-compliance low-pressure cuff to prevent aspiration (1975) Anesthesiology, 42 (2), pp. 216-219Macrae, W., Wallace, P., Aspiration around high-volume, low-pressure endotracheal cuff (1981) Br Med J (Clin Res Ed), 283 (6301), p. 1220Windsor, H.M., Shanahan, M.X., Cherian, K., Chang, V.P., Tracheal injury following prolonged intubation (1976) Aust N Z J Surg, 46 (1), pp. 18-25Lewis, F.R., Jr., Schiobohm, R.M., Thomas, A.N., Prevention of complications from prolonged tracheal intubation (1978) Am J Surg, 135 (3), pp. 452-457Servin, S.O., Barreto, G., Martins, L.C., Moreira, M.M., Meirelles, L., Neto, J.A., Atraumatic endotracheal tube for mechanical ventilation (2011) Rev Bras Anestesiol, 61 (3), pp. 311-319Lima, L.C., Avelar, S.F., Westphal, F.L., Lima, I., Lung nodule, tracheal stenoses and coronary disease: How to approach when are all associated to? (2007) Rev Bras Cir Cardiovasc, 22 (3), pp. 359-361Conti, M., Pougeoise, M., Wurtz, A., Porte, H., Fourrier, F., Ramon, P., Management of postintubation tracheobronchial ruptures (2006) Chest, 130 (2), pp. 412-418Marjot, R., Pressure exerted by the laryngeal mask airway cuff upon the pharyngeal mucosa (1993) Br J Anaesth, 70 (1), pp. 25-29. , Erratum in: Br J Anaesth. 1993;70(6):711Peták, F., Janosi, T.Z., Myers, C., Fontao, F., Habre, W., Impact of elevated pulmonary blood flow and capillary pressure on lung responsiveness (2009) J Appl Physiol (1985), 107 (3), pp. 780-786Iglesias, J.L., Lanoue, J.L., Rogers, T.E., Inman, L., Turnage, R.H., Physiologic basis of pulmonary edema during intestinal reperfusion (1998) J Surg Res, 80 (2), pp. 156-163Dullenkopf, A., Gerber, A., Weiss, M., Fluid leakage past tracheal tube cuffs: Evaluation of the new Microcuff endotracheal tube (2003) Intensive Care Med, 29 (10), pp. 1849-1853Lomholt, N., A device for measuring the lateral wall cuff pressure of endotracheal tubes (1992) Acta Anaesthesiol Scand, 36 (8), pp. 775-778Young, P.J., Pakeerathan, S., Blunt, M.C., Subramanya, S., A low-volume, low-pressure tracheal tube cuff reduces pulmonary aspiration (2006) Crit Care Med, 34 (3), pp. 632-639Blunt, M.C., Young, P.J., Patil, A., Haddock, A., Gel lubrication of the tracheal tube cuff reduces pulmonary aspiration (2001) Anesthesiology, 95 (2), pp. 377-381Sanjay, P.S., Miller, S.A., Corry, P.R., Russell, G.N., Pennefather, S.H., The effect of gel lubrication on cuff leakage of double lumen tubes during thoracic surgery (2006) Anaesthesia, 61 (2), pp. 133-137A pressão de insuflação do balonete (cuff) do tubo endotraqueal tanto pode causar isquemia de mucosa traqueal em pressões elevadas, e assim ocasionar morbidade traqueal importante, quanto pode causar microaspiração traqueal de secreção de orofaringe ou,

CD300f immunoreceptor contributes to peripheral nerve regeneration by the modulation of macrophage inflammatory phenotype

Background: It has recently become evident that activating/inhibitory cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). The immunoreceptor CD300f expressed on monocytes, neutrophils, and mast cells modulates inflammation, phagocytosis, and outcome in models of autoimmune demyelination, allergy, and systemic lupus erythematosus. On the other hand, a finely regulated inflammatory response is essential to induce regeneration after injury to peripheral nerves since hematogenous macrophages, together with resident macrophages and de-differentiated Schwann cells, phagocyte distal axonal and myelin debris in a well-orchestrated inflammatory response. The possible roles and expression of CD300f and its ligands have not been reported under these conditions. Methods: By using quantitative PCR (QPCR) and CD300f-IgG2a fusion protein, we show the expression of CD300f and its ligands in the normal and crush injured sciatic nerve. The putative role of CD300f in peripheral nerve regeneration was analyzed by blocking receptor-ligand interaction with the same CD300f-IgG2a soluble receptor fusion protein in sciatic nerves of Thy1-YFP-H mice injected at the time of injury. Macrophage M1/M2 polarization phenotype was also analyzed by CD206 and iNOS expression. Results: We found an upregulation of CD300f mRNA and protein expression after injury. Moreover, the ligands are present in restricted membrane patches of Schwann cells, which remain stable after the lesion. The lesioned sciatic nerves of Thy1-YFP-H mice injected with a single dose of CD300f-IgG2a show long lasting effects on nerve regeneration characterized by a lower number of YFP-positive fibres growing into the tibial nerve after 10 days post lesion (dpl) and a delayed functional recovery when compared to PBS- or IgG2a-administered control groups. Animals treated with CD300f-IgG2a show at 10 dpl higher numbers of macrophages and CD206-positive cells and lower levels of iNOS expression than both control groups. At later time points (28 dpl), increased numbers of macrophages and iNOS expression occur. Conclusions: Taken together, these results show that the pair CD300f ligand is implicated in Wallerian degeneration and nerve regeneration by modulating both the influx and phenotype of macrophages

Effect of Specific Mutations in Cd300 Complexes Formation; Potential Implication of Cd300f in Multiple Sclerosis.

Herein, we have used bioinformatics tools to predict five clusters defining ligand-binding sites on the extracellular domain of human CD300b receptor, presumably involved in the formation of both homodimers and heterodimers with other CD300 family members. Site-directed mutagenesis revealed residues glutamic acid 28 and glutamine 29 in cluster 5 to be necessary for the formation of CD300b complexes. Surprisingly, the disruption of cluster 2 and 4 reconstituted the binding capability lost by the mutation of residues glutamic acid 28 to alanine, glutamine 29 to alanine (E28A-Q29G). We identified a missense mutation arginine 33 to glutamine (R33Q) in CD300f by direct sequencing of exon 2 in peripheral blood samples from 50 patients with multiple sclerosis (MS). Levels of expression of CD300f were almost undetectable on monocytes from the patient bearing the R33Q mutation compared with healthy individuals. Whereas R33Q mutation had no effect in the formation of CD300f complexes, the inhibition of protein synthesis with cycloheximide indicated that CD300f R33Q is less stable than native CD300f. Finally, we report that the levels of expression of CD300f on the surface of classical and intermediate monocytes from MS patients are significantly lower when compared to the same cell populations in healthy individuals

IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study

Background: Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective: We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods: A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality. Results: One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients. Conclusions: Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administrationThis study was funded by Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and Instituto de Salud Carlos III (grant nos. RD16/0011/0012 and PI18/ 0371 to I.G.A., grant no. PI19/00549 to A.A., and grant no. SAF2017-82886-R to F.S.-M.) and co-funded by the European Regional Development Fund. The study was also funded by ‘‘La Caixa Banking Foundation’’ (grant no. HR17-00016 to F.S.-M.) and ‘‘Fondos Supera COVID19’’ by Banco de Santander and CRUE. None of these sponsors have had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publicatio