Embryonic Stem Cells: New Possible Therapy for Degenerative Diseases That Affect Elderly People

The capacity of embryonic stem (ES) cells for virtually unlimited self renewal and differentiation has opened up the prospect of widespread applications in biomedical research and regenerative medicine. The use of these cells would overcome the problems of donor tissue shortage and implant rejection, if the cells are made immunocompatible with the recipient. Since the derivation in 1998 of human ES cell lines from preimplantation embryos, considerable research is centered on their biology, on how differentiation can be encouraged toward particular cell lineages, and also on the means to enrich and purify derivative cell types. In addition, ES cells may be used as an in vitro system not only to study cell differentiation but also to evaluate the effects of new drugs and the identification of genes as potential therapeutic targets. This review will summarize what is known about animal and human ES cells with particular emphasis on their application in four animal models of human diseases. Present studies of mouse ES cell transplantation reveal encouraging results but also technical barriers that have to be overcome before clinical trials can be considere

Dual effect of Plasmodium-infected erythrocytes on dendritic cell maturation

<p>Abstract</p> <p>Background</p> <p>Infection with <it>Plasmodium </it>is the cause of malaria, a disease characterized by a high inflammatory response in the blood. Dendritic cells (DC) participate in both adaptive and innate immune responses, influencing the generation of inflammatory responses. DC can be activated through different receptors, which recognize specific molecules in microbes and induce the maturation of DC.</p> <p>Methods</p> <p>Using <it>Plasmodium yoelii</it>, a rodent malaria model, the effect of <it>Plasmodium</it>-infected erythrocytes on DC maturation and TLR responses have been analysed.</p> <p>Results</p> <p>It was found that intact erythrocytes infected with <it>P. yoelii </it>do not induce maturation of DC unless they are lysed, suggesting that accessibility of parasite inflammatory molecules to their receptors is a key issue in the activation of DC by <it>P. yoelii</it>. This activation is independent of MyD88. It was also observed that pre-incubation of DC with intact <it>P. yoelii</it>-infected erythrocytes inhibits the maturation response of DC to other TLR stimuli. The inhibition of maturation of DC is reversible, parasite-specific and increases with the stage of parasite development, with complete inhibition induced by schizonts (mature infected erythrocytes). <it>Plasmodium yoelii</it>-infected erythrocytes induce a broad inhibitory effect rendering DC non-responsive to ligands for TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9.</p> <p>Conclusions</p> <p>Despite the presence of inflammatory molecules within <it>Plasmodium</it>-infected erythrocytes, which are probably responsible for DC maturation induced by lysates, intact <it>Plasmodium</it>-infected erythrocytes induce a general inhibition of TLR responsiveness in DC. The observed effect on DC could play an important role in the pathology and suboptimal immune response observed during the disease. These results help to explain why immune functions are altered during malaria, and provide a system for the identification of a parasite-derived broad inhibitor of TLR-mediated signaling pathways.</p

Plasmodium-Induced Inflammation by Uric Acid

Infection of erythrocytes with the Plasmodium parasite causes the pathologies associated with malaria, which result in at least one million deaths annually. The rupture of infected erythrocytes triggers an inflammatory response, which is induced by parasite-derived factors that still are not fully characterized. Induced secretion of inflammatory cytokines by these factors is considered a major cause of malaria pathogenesis. In particular, the inflammatory cytokine tumor necrosis factor (TNF) is thought to mediate most of the life-threatening pathologies of the disease. Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells. We found that erythrocytes infected by Plasmodium accumulate high concentrations of hypoxanthine and xanthine. Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF. Since uric acid is considered a “danger signal” released by dying cells to alert the immune system, Plasmodium appears to have co-evolved to exploit this warning system. Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease

Diagnóstico del estado nutricional de micronutrientes y evaluación antropométrica en una población infantil suburbana de la Provincia de Buenos Aires

Objetivo: determinar el estado nutricional evaluado por antropometría, y el estado nutricional de micronutrientes en una población infantil. Métodos: se estudiaron 205 niños de 4 a 10 años de una comunidad suburbana de La Plata, Argentina. Se determinó Peso/ edad, Talla/edad y Peso/talla y se comparó las referencias. Para determinar las deficiencias de micronutrientes y anemia se establecieron los siguientes puntos de corte: deficiencia zinc y cobre < 70 mcg/dl (absorción atómica), hierro por ferritina < 12 ng/dl (quimioluminiscencia), hemoglobina < 11,5 g/dl (Coulter). Se realizó una encuesta social y de ingesta y hábitos alimentarios. Los datos se analizaron con EpiInfo 6. Se utilizaron las correlaciones de Pearson y Spearman. Resultados: la media de edad fue de 6,69 (± 2,04), 46,6% de sexo femenino. El número de integrantes por familia fue de 6 (± 1,98). La dieta cubría las recomendaciones de proteínas, pero el 19,4 % no cubría las recomendaciones de calorías y 30, 33, y 40 % de los niños no cubrieron las recomendaciones de hierro, zinc y vitamina A respectivamente. La prevalencia de Insuficiente progresión de peso fue 4,5% (Score Z < -2 de P/E), y por < Percentilo 10 de P/E 19,2 %; retraso crónico de crecimiento (< -2 score Z T/E) fue 5,6%, y 23,2% (< percentilo 10); por el indicador P/T la emaciación de primer grado alcanzó el 5%, sobrepeso y la obesidad llegó al 17,7%. La prevalencia de anemia fue 21,6%. El 6,8% de los niños presentó deficiencia de hierro, 5,1% deficiencia de cobre y 11,3% deficiencia de zinc. No se halló correlación significativa entre Peso/edad, peso/talla y talla/edad, con los niveles séricos de micronutrientes y Hb, ni al comparar el estado nutricional y la prevalencia de deficiencia de cada micronutrientes, excepto la prevalencia deficiencia de hierro en niños con retraso crónico de crecimiento que fue mayor que en el resto de los niños (p:0,01). Conclusión: la carencia de micronutrientes afecta a todos los estados nutricionales estimados por antropometría en los niños estudiados. El sobrepeso y la obesidad aparecen como un problema nutricional emergente.Aim: determine the micronutrient nutritional statusin an infant suburban population and its relationwith nutritional status as assessed by anthropometry,eating habits, and socioeconomic situation

Fluctuations in phenylalanine concentrations in phenylketonuria: a review of possible relationships with outcomes.

International audience; Fluctuations in blood phenylalanine concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). This review evaluates the studies on phenylalanine fluctuations, factors affecting fluctuations, and if stabilizing phenylalanine concentrations affects outcomes, particularly neurocognitive outcome. Electronic literature searches of Embase and PubMed were performed for English-language publications, and the bibliographies of identified publications were also searched. In patients with PKU, phenylalanine concentrations are highest in the morning. Factors that can affect phenylalanine fluctuations include age, diet, timing and dosing of protein substitute and energy intake, dietary adherence, phenylalanine hydroxylase genotype, changes in dietary phenylalanine intake and protein metabolism, illness, and growth rate. Even distribution of phenylalanine-free protein substitute intake throughout 24h may reduce blood phenylalanine fluctuations. Patients responsive to and treated with 6R-tetrahydrobiopterin seem to have less fluctuation in their blood phenylalanine concentrations than controls. An increase in blood phenylalanine concentration may result in increased brain and cerebrospinal fluid phenylalanine concentrations within hours. Although some evidence suggests that stabilization of blood phenylalanine concentrations may have benefits in patients with PKU, more studies are needed to distinguish the effects of blood phenylalanine fluctuations from those of poor metabolic control

Rapid generation of stable transgenic embryonic stem cell lines using modular lentivectors

Generation of stable transgenic embryonic stem (ES) cell lines by classic transfection is still a difficult task, requiring time-consuming clonal selection, and hampered by clonal artifacts and gene silencing. Here we describe a novel system that allows construction of lentivectors and generation of stable ES cell lines with > 99% transgene expression within a very short time frame. Rapid insertion of promoters and genes of interest is obtained through a modular recombinational cloning system. Vectors contain central polypurine tract from HIV-1 element and woodchuck hepatitis virus post-transcriptional regulatory element as well as antibiotic resistance to achieve optimal and homogenous transgene expression. We show that the system 1) is functional in mouse and human ES cells, 2) allows the generation of ES cells expressing genes of interest under the control of ubiquitous or tissue-specific promoters, and 3) allows ES cells expressing two constructs through selection with different antibiotics to be obtained. The technology described herein should become a useful tool in stem cell research

Optimizing the design and analysis of clinical trials for antibacterials against multidrug-resistant organisms:a white paper from COMBACTE's STAT-Net

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge

Adenylyl Cyclase α and cAMP Signaling Mediate Plasmodium Sporozoite Apical Regulated Exocytosis and Hepatocyte Infection

Malaria starts with the infection of the liver of the host by Plasmodium sporozoites, the parasite form transmitted by infected mosquitoes. Sporozoites migrate through several hepatocytes by breaching their plasma membranes before finally infecting one with the formation of an internalization vacuole. Migration through host cells induces apical regulated exocytosis in sporozoites. Here we show that apical regulated exocytosis is induced by increases in cAMP in sporozoites of rodent (P. yoelii and P. berghei) and human (P. falciparum) Plasmodium species. We have generated P. berghei parasites deficient in adenylyl cyclase α (ACα), a gene containing regions with high homology to adenylyl cyclases. PbACα-deficient sporozoites do not exocytose in response to migration through host cells and present more than 50% impaired hepatocyte infectivity in vivo. These effects are specific to ACα, as re-introduction of ACα in deficient parasites resulted in complete recovery of exocytosis and infection. Our findings indicate that ACα and increases in cAMP levels are required for sporozoite apical regulated exocytosis, which is involved in sporozoite infection of hepatocytes

Antibiotic research and development: business as usual?

This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner