Immune-Complex Mimics as a Molecular Platform for Adjuvant-Free Vaccine Delivery

Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role

Efeito do treinamento físico na pressão arterial de adolescentes com obesidade Efecto del entrenamiento físico en la presión arterial de adolescentes con obesidad Effect of physical training on the blood pressure of adolescents with obesity

OBJETIVO: Descrever, por meio de uma revisão sistemática, os efeitos do treinamento físico sobre a pressão arterial em adolescentes com obesidade. FONTES DE DADOS: Recorreu-se à revisão sistemática de ensaios clínicos randomizados que analisaram o efeito do treinamento físico sobre a pressão arterial de adolescentes obesos, publicados em periódicos indexados nas bases de dados PubMed/Medline, Lilacs, SciELO e ISI Web of KnowledgeSM. Foram incluídos os estudos que avaliaram adolescentes publicados até 2010, e que possuíam Grupo Controle. SÍNTESE DOS DADOS: Oito estudos atenderam aos critérios de inclusão. Dois deles utilizaram exercícios de força combinados com aeróbios, enquanto seis empregaram apenas os aeróbios. Cinco estudos utilizaram intervenções complementares, sendo a nutricional a mais frequente. Quatro estudos observaram redução da pressão arterial sistólica no Grupo Exercício comparado ao Controle. Nesses quatro estudos, além da redução da pressão arterial, notou-se diminuição da massa corpórea. Todos aqueles que verificaram redução da pressão arterial utilizaram 12 a 24 semanas de exercícios aeróbios, três a seis sessões semanais, com duração de 50 a 90 minutos e intensidade entre 55 e 75% da frequência cardíaca máxima. CONCLUSÕES: O efeito do treinamento físico na pressão arterial de adolescentes obesos é controverso. A redução da pressão arterial parece ocorrer com programas de treinamento aeróbios que promovam também a redução da massa corpórea.<br>OBJETIVO: Describir, mediante una revisión sistemática, los efectos del entrenamiento físico sobre la presión arterial en adolescentes con obesidad. FUENTES DE DATOS: Se recurrió a la revisión sistemática de ensayos clínicos aleatorios que analizaron el efecto del entrenamiento físico sobre la presión arterial de adolescentes obesos, publicados en periódicos indexados en las bases de datos PubMed/MedLine, LILACS, SciELO e ISI Web of knowledgeSM. Se incluyeron los estudios que evaluaron a adolescentes, publicados hasta el año de 2010 y que poseían grupo control. SÍNTESIS DE LOS DATOS: Ocho estudios atendieron a los criterios de inclusión. Dos de ellos utilizaron ejercicios de fuerza combinados con aeróbicos, mientras que seis emplearon solamente ejercicios aeróbicos. Cinco estudios utilizaron intervenciones complementarias, siendo la intervención nutricional la más frecuente. Cuatro estudios observaron reducción de la presión arterial sistólica en el grupo ejercicio comparado al control. En esos cuatro estudios, además de la reducción de la presión arterial, se notó disminución de la masa corporal. Todos los estudios que verificaron reducción de la presión arterial utilizaron de 12 a 24 semanas de ejercicios aeróbicos. El programa de entrenamiento tuvo lugar con tres a seis sesiones semanales con duración de 50 a 90 minutos e intensidad entre 55 y 75% de la frecuencia cardíaca máxima. CONCLUSIONES: El efecto del entrenamiento físico en la presión arterial de adolescentes obesos es controvertido. Sin embargo, la reducción de la presión arterial parece ocurrir con programas de entrenamiento aeróbicos que promueven también la reducción de la masa corporal.<br>OBJECTIVE: To systematically review the results of studies that analyzed the effects of physical training on the blood pressure of obese adolescents. DATA SOURCES: A systematic review of randomized clinical trials was performed and examined the effect of physical training on the blood pressure of obese adolescents, published in journals indexed at PubMed/Medline, Lilacs, SciELO, and ISI Web of knowledgeSM databases. Studies that evaluated adolescents published until 2010 and that had a Control Group were included. DATA SYNTHESIS: Eight studies met the inclusion criteria. Two of them used strength exercises combined with aerobics, while six used only aerobics. Five studies used complementary intervention, especially nutritional. Four studies found decreased systolic blood pressure in the Training Group compared to Controls, together with the reduction in body mass. All studies that found a reduction in systolic blood pressure used aerobic exercises from 12 to 24 weeks three to six times per week, lasting 50 to 90 minutes, and with intensity between 55 and 75% at the maximum heart rate. CONCLUSIONS: The effect of physical training on the systolic blood pressure of obese adolescents is controversial. However, the reduction in systolic blood pressure seems to occur with aerobic training programs, that also reduce body mass

Ezetimibe added to statin therapy after acute coronary syndromes

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ( 6530 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). Rates of pre-specified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit