Immune Response In Thyroid Cancer: Widening The Boundaries.

The association between thyroid cancer and thyroid inflammation has been repeatedly reported and highly debated in the literature. In fact, both molecular and epidemiological data suggest that these diseases are closely related and this association reinforces that the immune system is important for thyroid cancer progression. Innate immunity is the first line of defensive response. Unlike innate immune responses, adaptive responses are highly specific to the particular antigen that induced them. Both branches of the immune system may interact in antitumor immune response. Major effector cells of the immune system that directly target thyroid cancer cells include dendritic cells, macrophages, polymorphonuclear leukocytes, mast cells, and lymphocytes. A mixture of immune cells may infiltrate thyroid cancer microenvironment and the balance of protumor and antitumor activity of these cells may be associated with prognosis. Herein, we describe some evidences that immune response may be important for thyroid cancer progression and may help us identify more aggressive tumors, sparing the vast majority of patients from costly unnecessary invasive procedures. The future trend in thyroid cancer is an individualized therapy.

The Role Of The Inflammatory Microenvironment In Thyroid Carcinogenesis.

Immune responses against thyroid carcinomas have long been demonstrated and associations between inflammatory microenvironment and thyroid carcinomas repeatedly reported. This scenario has prompted scientists throughout the world to unveil how the inflammatory microenvironment is established in thyroid tumors and what is its influence on the outcome of patients with thyroid carcinoma. Many studies have reported the role of evasion from the immune system in tumor progression and reinforced the weakness of the innate immune response toward thyroid cancer spread in advanced stages. Translational studies have provided evidence that an increased density of tumor-associated macrophages in poorly differentiated thyroid carcinoma (DTC) is associated with an aggressive phenotype at diagnosis and decreased cancer-related survival, whereas well-DTC microenvironment enriched with macrophages is correlated with improved disease-free survival. It is possible that these different results are related to different microenvironments. Several studies have provided evidence that patients whose tumors are not infiltrated by lymphocytes present a high recurrence rate, suggesting that the presence of lymphocytes in the tumor microenvironment may favor the prognosis of patients with thyroid carcinoma. However, the effect of lymphocytes and other immune cells on patient outcome seems to result from complex interactions between the tumor and immune system, and the molecular pattern of cytokines and chemokines helps to explain the involvement of the immune system in thyroid tumor progression. The inflammatory microenvironment may help to characterize aggressive tumors and to identify patients who would benefit from a more invasive approach, probably sparing the vast majority of patients with an indolent disease from unnecessary procedures.

Icam-1 Expression On Immune Cells In Chronic Villitis.

ICAM-1 expression on the villous syncytiotrophoblast (ST) is believed to participate in migration of maternal cells into the inflamed villi regardless of villitis etiology. However, its expression on immune cells in chronic villitis (CV) has yet to be analyzed. ICAM-1 induces cell-cell adhesion allowing intercellular communication, T cell-mediated defense mechanism, and inflammatory response. 21 cases of CV (all without an identifiable etiologic agent) and 3 control placentas were analyzed using ICAM-1, and for immune cells CD45, CD3 and CD68. These cells were subdivided according to their location in inflamed villi: a) within the inflamed villi and b) outside forming perivillous aggregates. Large amounts of CD45, CD3 and CD68 were found within the inflamed villi and forming perivillous aggregates attached to areas of trophoblastic loss. Inflamed villi usually showed ICAM-1+ ST. The majority of immune cells surrounding areas of trophoblastic rupture presented marked expression of ICAM-1. In contrast, a small number of immune cells within the inflamed villi exhibited ICAM-1 expression. Only some (<5%) inflamed villi without trophoblastic rupture and with ICAM-1+ ST presented adherence of immune cells. In inflamed villi of chronic villitis, the level of ICAM-1 expression on immune cells depends on their location: high in number of cells in the perivillous region and low within the villi. The strongest expression of ICAM-1 on immune cells attached to areas of trophoblastic rupture suggests that the loss of trophoblast can lead to an amplification of the inflammatory response.

Endocarditis By Kocuria Rosea In An Immunocompetent Child.

Kocuria rosea belongs to genus Kocuria (Micrococcaceae family, suborder Micrococcineae, order Actinomycetales) that includes about 11 species of bacteria. Usually, Kocuria sp are commensal organisms that colonize oropharynx, skin and mucous membrane; Kocuria sp infections have been described in the last decade commonly affecting immunocompromised patients, using intravenous catheter or peritoneal dialysis. These patients had mainly bacteremia/recurrent sepsis. We hereby describe the case of a 10-year-old girl, immunocompetent, who had endocarditis/sepsis by K. rosea which was identified in five different blood cultures by Vitek 2 ID-GPC card (BioMérieux, France). Negative HIV serology, blood count within normal range of leukocytes/neutrophils and lymphocytes, normal fractions of the complement, normal level of immunoglobulins for the age; lymphocyte immunophenotyping was also within the expected values. Thymus image was normal at chest MRI. No catheters were required. Identification of K. rosea was essential to this case, allowing the differentiation of coagulase-negative staphylococci and use of an effective antibiotic treatment. Careful laboratory analysis of Gram-positive blood-born infections may reveal more cases of Kocuria sp infections in immunocompetent patients, which may collaborate for a better understanding, prevention and early treatment of these infections in pediatrics.

Influence Of The Major Nitrite Transporter Nirc On The Virulence Of A Swollen Head Syndrome Avian Pathogenic E. Coli (apec) Strain.

Avian Pathogenic Escherichia coli (APEC) strains are extra-intestinal E. coli that infect poultry and cause diseases. Nitrite is a central branch-point in bacterial nitrogen metabolism and is used as a cytotoxin by macrophages. Unlike nitric oxide (NO), nitrite cannot diffuse across bacterial membrane cells. The NirC protein acts as a specific channel to facilitate the transport of nitrite into Salmonella and E. coli cells for nitrogen metabolism and cytoplasmic detoxification. NirC is also required for the pathogenicity of Salmonella by downregulating the production of NO by the host macrophages. Based on an in vitro microarray that revealed the overexpression of the nirC gene in APEC strain SCI-07, we constructed a nirC-deficient SCI-07 strain (ΔnirC) and evaluated its virulence potential using in vivo and in vitro assays. The final cumulative mortalities caused by mutant and wild-type (WT) were similar; while the ΔnirC caused a gradual increase in the mortality rate during the seven days recorded, the WT caused mortality up to 24h post-infection (hpi). Counts of the ΔnirC cells in the spleen, lung and liver were higher than those of the WT after 48 hpi but similar at 24 hpi. Although similar number of ΔnirC and WT cells was observed in macrophages at 3 hpi, there was higher number of ΔnirC cells at 16 hpi. The cell adhesion ability of the ΔnirC strain was about half the WT level in the presence and absence of alpha-D-mannopyranoside. These results indicate that the nirC gene influences the pathogenicity of SCI-07 strain.

Arachnoid cyst: adversity ans plasticity

We report four cases of surgically treated intracranial arachnoid cysts, one with cyst-peritoneal shunt and three with craniotomy and arachnoid membrane resection. Their classification and etiopathogeny are discussed, and especially the different methods of treatment comparing the drastic complications (adversities) with the favorable solutions in severe clinical cases (plasticity) treated at our institution.

Derivação ventriculoperitoneal com válvula no tratamento da hidrocefalia infantil

From December-1965 to November-1969, 95 hydrocephalic infants have been operated upon using ventriculoperitoneal shunt with valve (88 cases with a Spitz-Holter valve, 6 cases with a Hakim valve and one case with a Pudenz-Heyer valve). Up to the present time (December, 1970) a total of 54 children are alive with a compensated hydrocephalus and 9 patients died, being impossible to follow-up the 32 remaining cases. The use of the ventriculoperitoneal shunt has eliminated all cardiovascular-pulmonary complications and reduced the number for surgical revisions. Besides, infections involving the draining system are less severe and more easily controlled than those occurring in the ventriculoatrial shunts. After analysis of the surgical techniques as well as complications and results the following conclusions are stated: 1) the use of a valve in the ventriculoperitoneal shunt difficults the oclusion of the peritoneal end of the draining system; 2) good results can be expected without reoperations in about 42,35% of hydrocephalus cases treated by ventriculoperitoneal shunt with valve; 3) ventriculoperitoneal shunts with valve showed better results when compared to ventriculoatrial shunts. This statement is made comparing two groups of hydrocephalic infants submitted to surgery at the same Service and in the same conditions, with the same follow-up period; 4) the cases presented permit to state that at present time the ventriculoperitoneal shunt with valve is the most suitable surgical procedure for hydrocephalus.

Exposição repetida à cafeína aumenta a atividade locomotora induzida pelo femproporex em ratos adolescentes e adultos

A cafeína e o femproporex são substâncias psicoestimulantes. O femproporex é muito utilizado no Brasil como anorexígeno enquanto a cafeína é amplamente consumida como constituinte regular da dieta. A administração repetida de psicoestimulantes induz sensibilização comportamental que se caracteriza pelo aumento progressivo dos seus efeitos locomotores. Pode ocorrer ainda sensibilização cruzada entre essas substâncias. Investigamos se a administração repetida de cafeína aumenta a locomoção induzida pelo femproporex em ratos adolescentes e adultos. Quarenta e oito ratos adolescentes (dia pós-natal 27) e 32 adultos (dia pós-natal 60) foram distribuídos em dois grupos que receberam injeção intra-peritoneal de 10,0 mg/kg de cafeína (CAF) (adolescentes N = 24; adultos N = 16) ou salina (SAL) (adolescentes N = 24; adultos N = 16) diariamente durante 10 dias. Três dias após a última injeção, cada grupo CAF ou SAL foi subdividido em dois subgrupos que receberam injeção i.p. de salina (SAL) (1 mL/kg) ou femproporex (FEM) (2,0 mg/kg). Após as injeções, a atividade locomotora foi avaliada automaticamente em intervalos de 5 minutos durante 1 hora. Nossos resultados demonstraram que em ratos adolescentes e adultos o pré-tratamento com CAF aumenta a atividade locomotora induzida pela administração aguda de FEM, sugerindo que a cafeína causa sensibilização aos efeitos locomotores desse derivado anfetamínico.

Achados clínico patológicos durante um surto de disenteria de inverno em bovinos no Rio Grande do Sul

Descreve-se um surto de disenteria de inverno que afetou 10 vacas leiteiras de uma propriedade localizada em Viamão, Rio Grande do Sul. O quadro clínico caracterizou-se por uma diarréia inicialmente líquida esverdeada com estrias de sangue e muco, evoluindo, em alguns animais, para uma diarréia de coloração marrom escura à sanguinolenta, que persistiu, em média, cinco dias. Drástica diminuição na produção de leite e no consumo de alimentos, além de graus variados de depressão também foram observados. Apenas um dos 10 animais afetados morreu. Durante a necropsia, observaram-se mucosas pálidas, conteúdo sanguinolento com presença de grande quantidade de coágulos, principalmente no cólon espiral e petéquias na mucosa do cólon. Os principais achados histológicos foram encontradas no cólon espiral, onde havia criptas dilatadas, sem epitélio de revestimento ou revestidas por epitélio pavimentoso e/ou cuboidal, por vezes com núcleos grandes e nucléolos proeminentes. Algumas criptas eram preenchidas por debris necróticos e polimorfonucleares. Na imuno-histoquímica com anticorpo monoclonal para coronavírus bovino (8F2) em cortes do cólon espiral, havia marcações positivas no citoplasma de enterócitos das criptas, nos debris necróticos destas e em macrófagos na lâmina própria.

A hepcidina como parâmetro bioquímico na avaliação da anemia por deficiência de ferro

A anemia por deficiência de ferro caracteriza-se como o mais prevalente problema nutricional em todo o mundo. Nesta revisão reuniu-se informações a respeito do metabolismo da hepcidina, avaliando-se seu valor como parâmetro bioquímico na anemia por deficiência de ferro. Realizou-se um levantamento bibliográfico nas bases de dados PUBMED e LILACS, período 2006-2010, referentes à hepcidina como um biomarcador para a regulação do metabolismo do ferro. Foram localizados 35 estudos publicados em revistas internacionais e um estudo sobre o assunto em revista nacional. A produção de hepcidina é regulada homeostaticamente pela anemia e hipóxia. Quando a oferta de oxigênio está inadequada ocorre diminuição do nível de hepcidina. Consequentemente, maior quantidade de ferro proveniente da dieta e dos estoques dos macrófagos e hepatócitos se tornam disponíveis. A hepcidina possui a função de se ligar à ferroportina, regulando a liberação do ferro para o plasma. Quando as concentrações de hepcidina estão baixas, as moléculas de ferroportina são expostas na membrana plasmática e liberam o ferro. Quando os níveis de hepcidina aumentam, a hepcidina liga-se às moléculas de ferroportina induzindo sua internalização e degradação, e o ferro liberado diminui progressivamente. Aparentemente o desenvolvimento do diagnóstico e terapia da anemia baseados no bioindicador hepcidina pode oferecer uma abordagem mais efetiva. Estudos epidemiológicos são necessários para comprovar o valor da hepcidina no diagnóstico diferencial das anemias, incluindo protocolos de amostragem para análise, com padronização similar às utilizadas em outras avaliações bioquímicas, e estabelecimento de pontos de corte para a expressão urinária e plasmática desse peptídeo

Changes in Glucose and Glutamine Lymphocyte Metabolisms Induced by Type I Interferon alpha

In lymphocytes (LY), the well-documented antiproliferative effects of IFN-alpha are associated with inhibition of protein synthesis, decreased amino acid incorporation, and cell cycle arrest. However, the effects of this cytokine on the metabolism of glucose and glutamine in these cells have not been well investigated. Thus, mesenteric and spleen LY of male Wistar rats were cultured in the presence or absence of IFN-alpha, and the changes on glucose and glutamine metabolisms were investigated. The reduced proliferation of mesenteric LY was accompanied by a reduction in glucose total consumption (35%), aerobic glucose metabolism (55%), maximal activity of glucose-6-phosphate dehydrogenase (49%), citrate synthase activity (34%), total glutamine consumption (30%), aerobic glutamine consumption (20.3%) and glutaminase activity (56%). In LY isolated from spleen, IFN alpha also reduced the proliferation and impaired metabolism. These data demonstrate that in LY, the antiproliferative effects of IFN alpha are associated with a reduction in glucose and glutamine metabolisms.

Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis

Background: Toll-like receptor 4 (TLR4) is widely recognized as an essential element in the triggering of innate immunity, binding pathogen-associated molecules such as Lipopolysaccharide (LPS), and in initiating a cascade of pro-inflammatory events. Evidence for TLR4 expression in non-immune cells, including pancreatic beta-cells, has been shown, but, the functional role of TLR4 in the physiology of human pancreatic beta-cells is still to be clearly established. We investigated whether TLR4 is present in beta-cells purified from freshly isolated human islets and confirmed the results using MIN6 mouse insulinoma cells, by analyzing the effects of TLR4 expression on cell viability and insulin homeostasis. Results: CD11b positive macrophages were practically absent from isolated human islets obtained from nondiabetic brain-dead donors, and TLR4 mRNA and cell surface expression were restricted to beta-cells. A significant loss of cell viability was observed in these beta-cells indicating a possible relationship with TLR4 expression. Monitoring gene expression in beta-cells exposed for 48h to the prototypical TLR4 ligand LPS showed a concentration-dependent increase in TLR4 and CD14 transcripts and decreased insulin content and secretion. TLR4-positive MIN6 cells were also LPS-responsive, increasing TLR4 and CD14 mRNA levels and decreasing cell viability and insulin content. Conclusions: Taken together, our data indicate a novel function for TLR4 as a molecule capable of altering homeostasis of pancreatic beta-cells.

Paracoccidioides brasilinsis-Induced Migration of Dendritic Cells and Subsequent T-Cell Activation in the Lung-Draining Lymph Nodes

Paracoccidioidomycosis is a mycotic disease caused by a dimorphic fungus, Paracoccidioides brasiliensis (Pb), that starts with inhalation of the fungus; thus, lung cells such as DC are part of the first line of defense against this microorganism. Migration of DC to the lymph nodes is the first step in initiating T cell responses. The mechanisms involved in resistance to Pb infection are poorly understood, but it is likely that DC play a pivotal role in the induction of effector T cells that control Pb infection. In this study, we showed that after Pb Infection, an important modification of lung DC receptor expression occurred. We observed an increased expression of CCR7 and CD103 on lung DC after infection, as well as MHC-II. After Pb infection, bone marrow-derived DC as well lung DC, migrate to lymph nodes. Migration of lung DC could represent an important mechanism of pathogenesis during PCM infection. In resume our data showed that Pb induced DC migration. Furthermore, we demonstrated that bone marrow-derived DC stimulated by Pb migrate to the lymph nodes and activate a T helper (Th) response. To the best of our knowledge, this is the first reported data showing that Pb induces migration of DC and activate a T helper (Th) response.

Modification of composition of a nanoemulsion with different cholesteryl ester molecular species: Effects on stability, peroxidation, and cell uptake

Purpose: Use of lipid nanoemulsions as carriers of drugs for therapeutic or diagnostic purposes has been increasingly studied. Here, it was tested whether modifications of core particle constitution could affect the characteristics and biologic properties of lipid nanoemulsions. Methods: Three nanoemulsions were prepared using cholesteryl oleate, cholesteryl stearate, or cholesteryl linoleate as main core constituents. Particle size, stability, pH, peroxidation of the nanoemulsions, and cell survival and uptake by different cell lines were evaluated. Results: It was shown that cholesteryl stearate nanoemulsions had the greatest particle size and all three nanoemulsions were stable during the 237-day observation period. The pH of the three nanoemulsion preparations tended to decrease over time, but the decrease in pH of cholesteryl stearate was smaller than that of cholesteryl oleate and cholesteryl linoleate. Lipoperoxidation was greater in cholesteryl linoleate than in cholesteryl oleate and cholesteryl stearate. After four hours' incubation of human umbilical vein endothelial cells (HUVEC) with nanoemulsions, peroxidation was minimal in the presence of cholesteryl oleate and more pronounced with cholesteryl linoleate and cholesteryl stearate. In contrast, macrophage incubates showed the highest peroxidation rates with cholesteryl oleate. Cholesteryl linoleate induced the highest cell peroxidation rates, except in macrophages. Uptake of cholesteryl oleate nanoemulsion by HUVEC and fibroblasts was greater than that of cholesteryl linoleate and cholesteryl stearate. Uptake of the three nanoemulsions by monocytes was equal. Uptake of cholesteryl oleate and cholesteryl linoleate by macrophages was negligible, but macrophage uptake of cholesteryl stearate was higher. In H292 tumor cells, cholesteryl oleate showed the highest uptakes. HUVEC showed higher survival rates when incubated with cholesteryl stearate and smaller survival with cholesteryl linoleate. H292 survival was greater with cholesteryl stearate. Conclusion: Although all three nanoemulsion types were stable for a long period, considerable differences were observed in size, oxidation status, and cell survival and nanoemulsion uptake in all tested cell lines. Those differences may be helpful in protocol planning and interpretation of data from experiments with lipid nanoemulsions.

Increased Endothelial Cell-Leukocyte Interaction in Murine Schistosomiasis: Possible Priming of Endothelial Cells by the Disease

Background and Aims: Schistosomiasis is an intravascular parasitic disease associated with inflammation. Endothelial cells control leukocyte transmigration and vascular permeability being modulated by pro-inflammatory mediators. Recent data have shown that endothelial cells primed in vivo in the course of a disease keep the information in culture. Herein, we evaluated the impact of schistosomiasis on endothelial cell-regulated events in vivo and in vitro. Methodology and Principal Findings: The experimental groups consisted of Schistosoma mansoni-infected and age-matched control mice. In vivo infection caused a marked influx of leukocytes and an increased protein leakage in the peritoneal cavity, characterizing an inflamed vascular and cellular profile. In vitro leukocyte-mesenteric endothelial cell adhesion was higher in cultured cells from infected mice as compared to controls, either in the basal condition or after treatment with the pro-inflammatory cytokine tumor necrosis factor (TNF). Nitric oxide (NO) donation reduced leukocyte adhesion to endothelial cells from control and infected groups; however, in the later group the effect was more pronounced, probably due to a reduced NO production. Inhibition of control endothelial NO synthase (eNOS) increased leukocyte adhesion to a level similar to the one observed in the infected group. Besides, the adhesion of control leukocytes to endothelial cells from infected animals is similar to the result of infected animals, confirming that schistosomiasis alters endothelial cells function. Furthermore, NO production as well as the expression of eNOS were reduced in cultured endothelial cells from infected animals. On the other hand, the expression of its repressor protein, namely caveolin-1, was similar in both control and infected groups. Conclusion/Significance: Schistosomiasis increases vascular permeability and endothelial cell-leukocyte interaction in vivo and in vitro. These effects are partially explained by a reduced eNOS expression. In addition, our data show that the disease primes endothelial cells in vivo, which keep the acquired phenotype in culture.