A psoríase é uma doença de pele inflamatória crônica, que afeta cerca de 2-4% da população mundial. Se desenvolve ao longo do tempo, principalmente no final da adolescência ou início da idade adulta e depende de uma complexa interação entre fatores genéticos e ambientais. Dados experimentais demostram que a dermatite induzida por imiquimode (IMQ) em camundongos assemelha-se estreitamente às lesões de psoríase humana, tanto nas características fenotípicas e histológicas como no desenvolvimento das lesões na epiderme. O estudo avaliou os efeitos anti-inflamatórios do óleo de semente de maracujá (Passiflora edulis) no tratamento da psoríase, utilizando a análise histológica e imunológica da epiderme. O experimento foi realizado com 36 camundongos Balb/c, os quais foram submetidos à indução da psoríase por imiquimode, por 10 dias consecutivos. O tratamento foi realizado com óleo de semente de maracujá in natura 100%, pomada LECIGEL® 2%, pomada associação de óleo de semente de maracujá 20% e LECIGEL® 2%, por 15 dias. Tanto o óleo da semente do maracujá quanto a associação do mesmo ao LECIGEL® diminuíram o quadro inflamatório induzido por imiquimode nas orelhas tratadas. Através das análises imuno-histoquímicas realizadas na epiderme (PCNA, IL-6, VEGF, CD34), observou-se um aumento na formação de corpos apoptóticos, diminuição a hiperplasia epitelial e redução do infiltrado inflamatório. Os resultados deste experimento demonstraram que o óleo da semente do maracujá desempenha um efeito anti-inflamatório no tratamento da psoríase induzida por imiquimode. / Psoriasis is a chronic inflammatory skin disease that affects about 2-4% of the world\'s population. It develops over time, especially in late adolescence or early adulthood and depends on a complex interaction between genetic and environmental factors. Experimental data show that imiquimode-induced dermatitis (IMQ) in mice closely resembles human psoriasis lesions, both in phenotypic and histological characteristics and in the development of lesions in the epidermis. The study evaluated the anti-inflammatory effects of passion fruit (Passiflora edulis) oil in the treatment of psoriasis, using the histological and immunological analysis of the epidermis. The experiment was performed with 36 Balb / c mice, which were submitted to psoriasis induction by imiquimode, for 10 consecutive days. The treatment was carried out with 100% fresh passion fruit seed oil, LECIGEL ® 2% ointment, 20% passion fruit seed oil ointment and LECIGEL ® 2% for 15 days. Both passionflower seed oil and its association with LECIGEL ® decreased the imiquimod-induced inflammation in the treated ears. Through the immunohistochemical analyzes performed on the epidermis (PCNA, IL-6, VEGF, CD34), an increase in the formation of apoptotic bodies, decrease in epithelial hyperplasia and reduction of inflammatory infiltrate was observed. The results of this experiment suggest that passion fruit seed oil has an anti-inflammatory effect in the treatment of imiquimode-induced psoriasis.

Made available in DSpace on 2016-03-22T17:27:00Z (GMT). No. of bitstreams: 1 bere.pdf: 472003 bytes, checksum: 24fe342b360c117b2eb9ab787fef47c4 (MD5) Previous issue date: 2012-02-29 / BACKGROUND: In hemodialysis patients, depression appears as the most common psychopathological condition. States of advanced chronic kidney disease and dialysis are associated with a state of chronic inflammation. Depression has been linked to activation of the immune system characterized by high levels of pro-inflammatory cytokines. In this study we investigated the possible correlations between depression, and interleukin-6 (IL-6) in hemodialysis patients. METHODS: Seventy-five hemodialysis patients were enrolled in a cross-sectional study from September to November of 2011 in Pelotas/RS. Demographic data was obtained from a questionnaire and the Beck Depression Inventory (BDI), used to determine the presence or absence of depression symptoms. Biochemical parameters, dialysis dosage delivery, and IL-6 serum levels were measured. RESULTS: Prevalence of depression among hemodialysis patients was 48% (BDI ≥ 14). In biochemical assessments, depressed patients showed a decrease in urea (p = 0.01) and increase of IL-6 (p = 0.04) levels. The correlation analysis between BDI scores and the biochemical variables showed that BDI was negative correlated with urea (p = 0.03) and potassium (p = 0.04), but not with IL-6 levels. CONCLUSION: Hemodialysis patients with depression showed higher levels of IL-6 but the severity of depressive symptom was not correlated with levels of this cytokine. / A insuficiência renal crônica (IRC) é definida como a perda progressiva e irreversível da função renal. Em sua fase mais avançada, (chamada de fase terminal da insuficiência renal crônica) na qual os rins não conseguem mais manter a normalidade do meio interno, é necessário realizar a substituição da função renal. Tal procedimento pode ser realizado através de hemodiálise, diálise peritoneal ou transplante renal8. Atualmente, no Brasil, mais de 70.000 pacientes são dependentes de terapia renal substitutiva, com gasto anual de cerca de R$ 2,0 bilhões. Com base no grande número de grupos de risco, a previsão é que esse número possa duplicar nos próximos 5 anos, ultrapassando os 125 mil casos em 201016. As causas mais comuns de IRC são: diabetes (42,9%), hipertensão, doença de grandes vasos (26,4%), glomerulonefrite (9,9%) entre outras causas5. Alexander Almeida e Alexandrina Meleiro, em 2000, descreveram que a depressão maior, apesar de provavelmente ser a desordem psiquiátrica mais comum nos pacientes com IRC, permanece largamente subdiagnosticada. Existem evidências de que a depressão diminui a aderência ao tratamento da IRC e influencie negativamente a qualidade de vida. Diante disto, revela-se um fator importante de risco para mortalidade cardiovascular, e aumente em até 15 vezes a taxa de suicídio, podendo ser um preditor independente de menor sobrevida1. Estudos de revisão da literatura citam que a prevalência de depressão em pacientes em diálise varia de 0 a 100%, sugerindo que a prevalência dessa doença nesta população é ainda incerta10. A depressão maior, de acordo com os critérios do DSM-IV, pode se apresentar através de: humor deprimido, perda de prazer ou interesse notavelmente diminuído nas atividades prazerosas, distúrbios do sono, alteração do apetite e peso, perda de energia, ideação suicida entre outros6. A depressão tem sido associada à ativação do sistema imunológico caracterizada por elevados níveis de citocinas proinflamatórias e proteínas positivas da fase aguda14. Alguns estudos demonstraram que os níveis de citocinas e TNF-α estão aumentados em pacientes com depressão14. As citocinas são um grupo de proteínas (polipeptídeos) responsáveis pelas mediações das conexões imunocerebrais e desempenham um papel importante na patogênese da depressão devido ao seu efeito nos neurotransmissores e neuro-hormonios15. Neste respeito à depressão maior, esta tem sido associada com o aumento continuado dos níveis de citocinas; inclusive, tem sido significativamente implicada no desenvolvimento das desordens psiquiátricas, principalmente na depressão maior 13. As citocinas e outras moléculas têm impacto nas funções neuropsiquiátricas como o humor e a cognição, através da modulação da anatomia e da função neuronal. A plasticidade neuronal é importante para a regulação do humor, cognição e comportamento durante toda a vida. As citocinas e outros fatores imunológicos desempenham um papel fundamental na modulação cerebral; entretanto, exposição crônica a citocinas proinflamatórias podem causar dano na plasticidade neuronal, contribuindo para desordens cognitivas e alteração de humor13. Assim, uma vez que entre pacientes com IRC há grande incidência de sintomas depressivos, os objetivos deste estudo consistem em determinar a prevalência de depressão dos pacientes com IRC, em um serviço de hemodiálise, na cidade de Pelotas e identificar os possíveis biomarcadores, como a IL-6, nos fatores causadores do desenvolvimento da depressão. Tais fenômenos podem ajudar a melhorar o reconhecimento e o monitoramento dessa patologia

As leishmanioses são um conjunto de doenças causadas pela infecção com protozoários do gênero Leishmania. No Brasil, o parasita L. infantum provoca a manifestação de uma doença sistêmica e crônica, conhecida como leishmaniose visceral (VL), que, quando não tratada, pode levar o indivíduo à óbito. A gravidade da leishmaniose visceral vem sendo associada ao aumento do nível sistêmico de IL- 6 em pacientes sintomáticos. Ainda não está claro como o aumento dessa citocina coordena a progressão da doença. Nós demonstramos durante a infecção por L. infantum experimental há produção dessa citocina nos órgãos alvos. Em decorrência dessa via, animais deficientes para IL-6 (IL-6-/-) são suscetíveis a infecção por apresentar maior número de parasitos nos órgãos alvo e por desenvolverem uma fraca resposta inflamatória em função da diminuição do infiltrado inflamatório. Como consequência, há o aumento de CXCL2 que medeia o recrutamento de neutrófilos no baço. Apesar de aumentada em animais IL-6-/- os neutrófilos apresentam um estado menos ativado. A produção dos principais mediadores de morte dos parasitos, como espécies reativas de oxigênio (ROS) e o óxido nítrico (NO), estão comprometidas e favorecem a disseminação do parasito em animais IL-6-/-. Por outro lado, a Il-6 não interfere na produção de citocinas pró-inflamatórias e na proliferação de linfócitos Th1, atuando somente em linfócitos Th17 no início da infecção, sugerindo que o controle da resposta inflamatória é dependente de mecanismos inatos. Em humanos, identificamos dois genes modulados pela via de sinalização da IL-6. Os genes Hsbp1 e AR estão up-regulados em pacientes com a doença ativa e são genes associados com a migração e a produção de neutrófilos na medula óssea, possivelmente envolvidos com a neutropenia em pacientes com LV. Juntos, os dados mostram que a via de sinalização da IL-6 tem papel importante na modulação da resposta imune de neutrófilos, e em promover proteção durante a LV. / Leishmaniasis is a group of diseases caused by infection with protozoa of the genus Leishmania. In Brazil, the parasite L. infantum causes the manifestation of a systemic and chronic disease, known as visceral leishmaniasis (VL), which, when left untreated, can lead to death. The severity of visceral leishmaniasis has been associated with an increase in the systemic level of IL-6 in symptomatic patients. It is not yet clear how the increase in this cytokine coordinates the progression of the disease. We demonstrated during the infection by experimental L. infantum there is production of this cytokine in the target organs. As a result of this pathway, IL-6 ( IL- 6-/-) deficient animals are susceptible to infection because they present a higher number of parasites in the target organs and they develop a poor inflammatory response due to the decrease of the inflammatory infiltrate. As a consequence, there is an increase in CXCL2 that mediates the recruitment of neutrophils in the spleen. Although increased in IL-6-/- animals the neutrophils have a less activated state. The production of the main mediators of parasite death, such as reactive oxygen species (ROS) and nitric oxide (NO), are compromised and favor the spread of the parasite in IL-6-/- animals. On the other hand, IL-6 does not interfere in the production of proInflammatory cytokines and Th1 lymphocyte proliferation, acting only on Th17 lymphocytes at the beginning of the infection, suggesting that the control of the inflammatory response is dependent on innate mechanisms. In humans, we identified two genes modulated by the IL-6 signaling pathway. The Hsbp1 and AR genes are up-regulated in patients with the active disease and are genes associated with the migration and production of neutrophils in the bone marrow, possibly involved with neutropenia in patients with VL. Together, the data show that the IL-6 signaling pathway plays an important role in modulating the neutrophil immune response, and in promoting protection during LV.

A psoríase é uma doença de pele inflamatória crônica, que afeta cerca de 2-4% da população mundial. Se desenvolve ao longo do tempo, principalmente no final da adolescência ou início da idade adulta e depende de uma complexa interação entre fatores genéticos e ambientais. Dados experimentais demostram que a dermatite induzida por imiquimode (IMQ) em camundongos assemelha-se estreitamente às lesões de psoríase humana, tanto nas características fenotípicas e histológicas como no desenvolvimento das lesões na epiderme. O estudo avaliou os efeitos anti-inflamatórios do óleo de semente de maracujá (Passiflora edulis) no tratamento da psoríase, utilizando a análise histológica e imunológica da epiderme. O experimento foi realizado com 36 camundongos Balb/c, os quais foram submetidos à indução da psoríase por imiquimode, por 10 dias consecutivos. O tratamento foi realizado com óleo de semente de maracujá in natura 100%, pomada LECIGEL® 2%, pomada associação de óleo de semente de maracujá 20% e LECIGEL® 2%, por 15 dias. Tanto o óleo da semente do maracujá quanto a associação do mesmo ao LECIGEL® diminuíram o quadro inflamatório induzido por imiquimode nas orelhas tratadas. Através das análises imuno-histoquímicas realizadas na epiderme (PCNA, IL-6, VEGF, CD34), observou-se um aumento na formação de corpos apoptóticos, diminuição a hiperplasia epitelial e redução do infiltrado inflamatório. Os resultados deste experimento demonstraram que o óleo da semente do maracujá desempenha um efeito anti-inflamatório no tratamento da psoríase induzida por imiquimode. / Psoriasis is a chronic inflammatory skin disease that affects about 2-4% of the world\'s population. It develops over time, especially in late adolescence or early adulthood and depends on a complex interaction between genetic and environmental factors. Experimental data show that imiquimode-induced dermatitis (IMQ) in mice closely resembles human psoriasis lesions, both in phenotypic and histological characteristics and in the development of lesions in the epidermis. The study evaluated the anti-inflammatory effects of passion fruit (Passiflora edulis) oil in the treatment of psoriasis, using the histological and immunological analysis of the epidermis. The experiment was performed with 36 Balb / c mice, which were submitted to psoriasis induction by imiquimode, for 10 consecutive days. The treatment was carried out with 100% fresh passion fruit seed oil, LECIGEL ® 2% ointment, 20% passion fruit seed oil ointment and LECIGEL ® 2% for 15 days. Both passionflower seed oil and its association with LECIGEL ® decreased the imiquimod-induced inflammation in the treated ears. Through the immunohistochemical analyzes performed on the epidermis (PCNA, IL-6, VEGF, CD34), an increase in the formation of apoptotic bodies, decrease in epithelial hyperplasia and reduction of inflammatory infiltrate was observed. The results of this experiment suggest that passion fruit seed oil has an anti-inflammatory effect in the treatment of imiquimode-induced psoriasis.

A endometriose é uma doença ginecológica crônica que afeta pelo menos 10% das mulheres em idade reprodutiva. É caracterizada pelo crescimento de tecido endometrial fora da cavidade uterina. Embora sua etiologia permaneça controversa, estudos propõem que alterações imunológicas e inflamatórias estão correlacionadas com a causa da endometriose e podem contribuir para o crescimento e sobrevida de implantes ectópicos. Como parte integrante desse processo, um microambiente peritoneal anormal pode ser constituído por níveis aumentados de células imunológicas. Dentre estas, a elevação de citocinas pró-inflamatórias no ambiente peritoneal e sistêmico participariam desse processo. Citocinas incluindo a interleucina-6 (IL-6), uma glicoproteína com atuação na resposta imune e considerada como um marcador de inflamação tem sido proposta na patogênese da endometriose. Recentemente, demonstramos que as concentrações de IL-6 no fluído peritoneal (FP) apresentam-se elevadas em mulheres com endometriose em comparação com mulheres hígidas (Andrade et al., 2017, in press). No entanto, a fonte do aumento de IL-6 no FP ainda não foi totalmente elucidada e seu potencial envolvimento com a endometriose merece maior investigação. No presente estudo, avaliamos a expressão proteica de IL-6 no tecido endometrial e sua concentração no FP de mulheres com endometriose pélvica e comparamos com mulheres hígidas. Um total de 18 pacientes com endometriose e 12 mulheres com pelve normal foram incluídas neste estudo caso-controle. Foram realizadas avaliações clínicas e laboratoriais. Os níveis de IL-6 no FP e a expressão proteica no tecido endometrial foram determinados utilizando ensaio imunoenzimático (ELISA) e imuno-histoquímica respectivamente. A concentração de IL-6 no FP foi significativamente mais elevada no grupo endometriose em comparação com o grupo controle [48,2 (36,7 - 89,9) ng/ml versus 23,1 (11,8 - 35,3) ng/ml, P = 0,002]. A expressão proteica de IL-6 foi positiva na maior parte das amostras de ambos os grupos sendo significativamente mais intensa no tecido endometriótico em comparação com a expressão no endométrio de mulheres com pelve normal (P < 0,05). Os resultados do presente estudo sugerem que a fonte da IL6 no FP de pacientes com endometriose possa ser, pelo menos em parte, proveniente dos focos endometrióticos. / Endometriosis is a chronic gynecological disease that affects at least 10% of women of reproductive age. It is characterized by growth of endometrial tissue outside the uterine cavity. Although its etiology remains controversial, studies suggest that immunological and inflammatory changes are associated with endometriosis and may contribute to the growth and survival of ectopic implants. As part of this process, an abnormal peritoneal microenvironment may be constituted by increased levels of immune cells. Among these, the elevation of proinflammatory cytokines in the peritoneal and systemic environment would participate in this process. Cytokines including interleukin-6 (IL-6), a glycoprotein that acts on the immune response and is considered as a marker of inflammation has been proposed to play a role in the pathogenesis of endometriosis. Recently, we have shown that IL-6 concentrations in the peritoneal fluid (PF) were higher in women with endometriosis compared to healthy women (Andrade et al., 2017, in press). However, the source of IL-6 in PF has not yet been fully elucidated and its potential involvement with endometriosis warrants further investigation. In the present study, we evaluated the protein expression of IL-6 in endometrial tissue and its concentration in PF of women with pelvic endometriosis and compared them with healthy women. A total of 18 patients with endometriosis and 12 women with normal pelvis were included in this case-control study. Clinical and laboratory evaluations were performed. IL-6 levels in PF and protein expression in endometrial tissue were determined using enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry respectively. The concentrations of IL-6 in PF were significantly higher in the endometriosis group compared to the control group [48.2 (36.7-89.9) ng / ml versus 23.1 (11.8-35, 3) ng / ml, P = 0.002]. Protein expression of IL-6 was positive in most samples from both groups being significantly more intense in the endometriotic tissue of patients with endometriosis compared to the endometrial expression in women with normal pelvis (P < 0.05). The results of the present study suggest that the source of IL6 in the PF of patients with endometriosis may come, at least in part, from the endometriotic focus.

Angiotensin II (Ang II) promotes vascular disease and hypertension, in part, by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Extensive studies have demonstrated that SOCS3 plays an important role in suppressing the IL-6/STAT3 pathway in the immune system and in cancer biology. In contrast, the functional importance of SOCS3 in cardiovascular disease is largely unknown. Thus, the overall goal of these studies was to investigate the role of SOCS3 in models of Ang II-dependent vascular disease and hypertension. To examine direct effects of Ang II on the vessel wall, carotid arteries from SOCS3 haplodeficient (SOCS3+/-) mice and wild-type littermates (SOCS3+/+) were incubated with the peptide or vehicle for 22 hrs, followed by examination of endothelial function using acetylcholine. Relaxation to acetylcholine was similar in all arteries incubated with vehicle. A low concentration of Ang II (1 nmol/L) did not affect acetylcholine-induced vasodilation in SOCS3+/+ mice, but reduced responses in arteries from SOCS3+/- mice by ~50% (P<0.05). This Ang II-induced endothelial dysfunction in SOCS3+/- mice was prevented by inhibitors of NF-êB or STAT3, an IL-6 neutralizing antibody, or a scavenger of superoxide. Responses to nitroprusside, an endothelium-independent vasodilator, were similar in all groups. To test the importance of SOCS3 in vivo, mice were infused systemically with a pressor dose of Ang II (1.4 mg/kg per day) or vehicle for 14 days via osmotic mini-pumps. Acetylcholine-induced vasodilation in carotid and resistance arteries in brain from SOCS3+/- mice was reduced by ~60% (P<0.05). Surprisingly, genetic deficiency in SOCS3 prevented the majority of Ang II-induced endothelial dysfunction without affecting the pressor response to Ang II. To investigate potential mechanisms underlying divergent results when studying effects of local versus systemic effects of Ang II, we performed bone marrow transplantation followed by infusion of vehicle or Ang II for two weeks. Lethally irradiated WT (CD45.1) mice reconstituted with SOCS3+/- bone marrow were protected from Ang II-induced endothelial dysfunction (P<0.05), while reconstitution of irradiated SOCS3+/- mice with WT (CD45.1) bone marrow exacerbated Ang II-induced vascular dysfunction (P<0.05). WT (CD45.1) into SOCS3+/+ and SOCS3+/- into SOCS3+/- bone marrow chimeras exhibited vascular function consistent with non-irradiated controls. In addition, the pressor response to Ang II was reduced by ~50% in WT mice reconstituted with bone marrow from SOCS3+/- mice (P<0.05). These data suggest that SOCS3 exerts divergent or context-dependent effects depending on whether vascular dysfunction was due to local versus systemic administration of Ang II. SOCS3 deficiency in the vessel wall enhanced local detrimental effects of Ang II on vascular function. In contrast, bone marrow-derived cells that are haplodeficient in SOCS3 protect against systemically administered Ang II and the resulting vascular dysfunction and hypertension. To my knowledge, these are the first experimental studies that begin to define the importance of SOCS3 in Ang II-induced hypertension and endothelial dysfunction. Results obtained from these experiments provide new insight into mechanisms which regulate oxidative stress and inflammation within the vasculature. The studies also revealed that bone marrow-derived cells that are haplodeficient in SOCS3 protect against pressor and endothelial effects of Ang II. These findings may eventually contribute to the development of novel therapeutic approaches for hypertension and hypertension associated end-organ damage.

Title: Inhibition of interleukin-6 trans-signaling by sgp130Fc is anti-tumorigenic in head and neck squamous cell carcinoma. Background: Head and neck squamous cell carcinoma (HNSCC) is a highly inflammatory cancer type, and interleukin-6 (IL-6) is associated with this phenotype. Elevated expression of IL-6 is linked to tumor progression, recurrence, metastasis, and resistance to therapy in HNSCC. However, targeting IL-6 or IL-6 receptor (IL-6R) has demonstrated little to no clinical efficacy. IL-6 signals through a classical signaling pathway via membrane IL-6R or a trans-signaling pathway via soluble IL-6R (sIL-6R). Recent evidence suggests that classical signaling induces acute, transient inflammation, eventually resulting in homeostasis; whereas trans-signaling may induce chronic, pro-tumorigenic inflammation. Therefore we propose that IL-6 trans-signaling is associated with the pro-inflammatory phenotype observed in HNSCC. We wanted to determine whether inhibition of IL-6 trans-signaling by sgp130Fc would better demonstrate anti-tumor efficacy and increase HNSCC tumor response to radiation, chemotherapy, and targeted therapy (cetuximab) compared to global IL-6 pathway inhibition. Method/Results: Baseline levels of IL-6, IL-6R, sIL-6R, and sgp130 proteins in HNSCC cells were determined using ELISA and flow cytometry. Cisplatin, radiation, and cetuximab treatments each induced HNSCC cell secretion of IL-6 and sIL-6R in vitro, yet adding sgp130Fc to those treatments did not further reduce clonogenic survival. Sgp130Fc treatment significantly suppressed SQ20B tumor growth in nude mice, whereas global IL-6 pathway inhibition by IL-6R antagonist tocilizumab did not; however, cetuximab reduced the efficacy of sgp130Fc in this animal model. Sgp130Fc also sensitized SQ20B xenograft tumors to radiation and chemotherapy in nude mice and suppressed SCCVII tumor growth in male but not female C3H/HeJ mice. Conclusion: Inhibition of IL-6 trans-signaling by sgp130Fc displayed significant anti-tumor effects as a single therapy and sensitized resistant HNSCC tumors to radiation and chemotherapy in vivo; however, sgp130Fc did not reduce survival of HNSCC cells in vitro. These results suggest that the efficacy of sgp130Fc relies on targeting another part of the microenvironment instead of tumor cells directly. Sgp130Fc has promise both as a single therapy and potentially as combined therapy with radiation and chemotherapy in HNSCC.

Background Cardiovascular disease (CVD) remains the number one killer even after years of advances and preventative measures. Identifying and reducing modifiable risk factors is a health care priority. CVD Risk assessments are calculated using several traditional risk factors including age, gender, race, blood pressure, cholesterol, history of diabetes, and smoking to estimate a persons’ risk of developing CVD (heart disease or stroke) in the next 10-years. In addition to the traditional risk factors for CVD, there is increasing evidence of metabolic disorders, depressive symptoms, inflammation and sleep quality posing a greater risk for CVD. However, these factors are not included in the current risk prediction models including the Framingham Risk Score, Reynolds Risk Score, and Pooled Cohort Risk Equations. Therefore, this study examined the effect of depressive symptoms, inflammation, and sleep quality on the independent risk for CVD. Objective The primary objective of this study was to evaluate the independent relationships between traditional cardiac risk factors, depressive symptoms, inflammation, and sleep quality, on long-term risk of major adverse cardiovascular events (MACE). The secondary objective was to evaluate whether gender modifies the relationships between depressive symptoms, inflammation, and sleep quality on long-term risk of MACE. Design A secondary analysis was conducted on data obtained from the Longitudinal prospective cohort study Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) conducted by the University of Pittsburgh. The ongoing Heart SCORE study has been prospectively examining cardiovascular disease (CVD) risk factors and CVD events on an initial cohort of 2,000 enrolled adults ages 45 to 75 at study entry. A Cox proportional-hazard model was used to evaluate the relationship between traditional risk factors as well as independently and collectively for depressive symptoms, inflammation and sleep quality and risk of MACE. Models were reanalyzed adding gender as an interaction term and in stratified analyses to evaluate whether gender modifies the relationships between sleep quality, depressive symptoms, and inflammation and long-term risk of MACE. Results The participants (N= 1,895) included in this study were, 1256 females (66%), 639 males (34%), ranging from 45 to 75 years of age with a median age of 60 years, 42% Blacks, 55% Whites and 3% other race. Six percent, (n =113) of the participants experienced a major cardiac event during a mean of nearly 10 year follow up. Results indicated that men as compared with women with high levels of interleukin-6 had particularly high risk for CVD, as defined by two separate definitions of MACE, MACE1: Hazard Ratio (HR) 3.44 vs. 1.72 for males and females, respectively, MACE6: HR 2.51 vs. 1.69 for males and females, respectively. These results suggest the high inflammation in men is strongly associated with future risk of CVD. The addition of depressive symptoms to the initial traditional risk factor model was associated with a modest increase in the risk of both definitions of MACE (HR range from 1.20 to 1.68) with similar results observed by gender. Sleep quality/Insomnia was not associated with long-term risk of MACE overall or when evaluated separately by gender. Conclusion Primary prevention with early identification of potential modifiable risk factors is a key strategy in planning interventions to reduce the risk of CVD. Results from this study suggest that depression and inflammation (e.g. IL-6) should be studied in other populations to estimate their independent predictive value in risk stratification. Whereas sleep quality was not associated with long-term risk of CVD in this analysis, future studies should consider the use of objective measures of sleep quality, such as actigraphy in addition to standard use of self-report measures and sleep diaries.

Abstract not available

<p>Alzheimer’s disease is the most common form of dementia. It is a neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles. The main constituent of the senile plaques is the neurotoxic β-amyloid peptide. Surrounding the senile plaques are activated astrocytes and microglia, believed to contribute to neurotoxicity through secretion of proinflammatory cytokines, like interleukin-1β and interleukin-6. For many inflammatory actions, including the cytokine induction in glial cells, the transcription factor NFκB plays a key role. This suggests that therapeutical strategies aimed to control the development of Alzheimer’s disease could include administration of drugs that hinder NFκB activation.</p><p>The major aim of this thesis was to examine the effects of β-amyloid together with interleukin-1β on cytokine expression as well as NFκB activation in glial cells. The possibility to block NFκB activation, and downstream effects like interleukin-6 expression, by using an NFκB decoy was investigated. The possibility to improve the cellular uptake of the decoy by linking it to a cell-penetrating peptide was also investigated.</p><p>The results obtained provide supportive evidence that inflammatory cytokines are induced by β-amyloid, and that they can indeed potentiate its effects. The results further demonstrate that by blocking NFκB activation, the induction of interleukin-6 expression can be inhibited. By using an improved cellular delivery system, the uptake of the NFκB decoy and hence the downstream cytokine inhibition could be increased. In conclusion, these results demonstrate the possibility to decrease the inflammatory reactions taken place in Alzheimer’s disease brains, which may ultimately lead to a possible way of controlling this disorder.</p>