Gp120/CD4 blocking antibodies are frequently elicited in ART-naïve chronically HIV-1 infected individuals

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/ CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV- 1 vaccine.

Asignaturas pendientes del DSM-5

El presente artículo analiza las críticas generadas a partir de la publicación del Manual diagnóstico y estadístico de los trastornos mentales, quinta edición (DSM-5), ya anunciadas parcialmente durante las últimas fases de su elaboración. Una parte de las críticas se ha centrado en los cambios de los criterios diagnósticos para determinados trastornos y en la incorporación al DSM de nuevas entidades. Sin embargo, otra vertiente crítica va dirigida a la falta de validez de los diagnósticos del DSM, por cuyo motivo se ha cuestionado su eficiencia en el campo de la investigación. El fallo básico del DSM se centra en la incoherencia de un modelo basado en un amplio repertorio de definiciones de entidades categóricas, todas ellas con un alto componente de comorbilidad. Como propuesta para superar el bloqueo generado en la investiga ción y la parquedad de avances terapéuticos, el Instituto Nacional de Salud Mental de estados Unidos ha propuesto una estrategia de investigación cuyo punto de partida se sustenta en la identificación y el estudio de las dimensiones básicas de las disfunciones que se presentan de modo transversal en los trastornos mentales.

A Novel Missense Mutation, I890T, in the Pore Region of Cardiac Sodium Channel Causes Brugada Syndrome

Brugada syndrome (BrS) is a life-threatening, inherited arrhythmogenic syndrome associated with autosomal dominant mutations in SCN5A, the gene encoding the cardiac Na₊ channel alpha subunit (Naᵥ1.5). The aim of this work was to characterize the functional alterations caused by a novel SCN5A mutation, I890T, and thus establish whether this mutation is associated with BrS. The mutation was identified by direct sequencing of SCN5A from the proband’s DNA. Wild-type (WT) or I890T Naᵥ1.5 channels were heterologously expressed in human embryonic kidney cells. Sodium currents were studied using standard whole cell patch-clamp protocols and immunodetection experiments were performed using an antibody against human Naᵥ1.5 channel. A marked decrease in current density was observed in cells expressing the I890T channel (from -52.0 ± 6.5 pA/pF, n=15 to 35.9 ± 3.4 pA/pF, n = 22, at -20 mV, WT and I890T, respectively). Moreover, a positive shift of the activation curve was identified (V½ =-32.0 ± 0.3 mV, n = 18, and -27.3 ± 0.3 mV, n = 22, WT and I890T, respectively). No changes between WT and I890T currents were observed in steady-state inactivation, time course of inactivation, slow inactivation or recovery from inactivation parameters. Cell surface protein biotinylation analyses confirmed that Nav1.5 channel membrane expression levels were similar in WT and I890T cells. In summary, our data reveal that the I890T mutation, located within the pore of Nav1.5, causes an evident loss-of-function of the channel. Thus, the BrS phenotype observed in the proband is most likely due to this mutation

Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle

Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hall- mark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM (the calcein acetoxymethyl-ester) on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phos-phate pathway was significantly altered. To elucidate whe-ther these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.

Tratamiento farmacológico de la osteomielitis

La osteomielitis será una de las afecciones, que mas complicaciones nos dará en la práctica podológica, tanto como complicación quirúrgica, como en el tratamiento del pie diabético. En este artículo, intento hacer un repaso del concepto, clasificación y etiología de la osteomielitis, así como una explicación del tratamiento, sobre todo farmacológico indicado para cada tipo de osteítis, citando y explicando los antibióticos más efectivos para cada momento, dependiendo del germen y de su localización.

Prevención de la infección neonatal precoz por estreptococo del grupo B

El estreptococo del grupo B (EGB) constituye la principal causa de morbimortalidad neonatal y de morbilidad materna durante el embarazo y el posparto. Coloniza el aparato digestivo y el genitourinario en un 10-30% de las gestantes, con una tasa de transmisión vertical del 50%. De entre los recién nacidos colonizados, un 1-2% desarrollará una sepsis grave precoz. Se ha realizado una revisión bibliográfica con el objetivo de conocer las estrategias de prevención de la infección neonatal por EGB. Los resultados ponen de manifiesto que las recomendaciones para su prevención consisten en el cribado universal prenatal de colonización por EGB mediante cultivo vaginorrectal a las 35-37 semanas, y la administración de profilaxis antibiótica intraparto a todas las embarazadas portadoras.

Prevención de la infección neonatal precoz por estreptococo del grupo B

El estreptococo del grupo B (EGB) constituye la principal causa de morbimortalidad neonatal y de morbilidad materna durante el embarazo y el posparto. Coloniza el aparato digestivo y el genitourinario en un 10-30% de las gestantes, con una tasa de transmisión vertical del 50%. De entre los recién nacidos colonizados, un 1-2% desarrollará una sepsis grave precoz. Se ha realizado una revisión bibliográfica con el objetivo de conocer las estrategias de prevención de la infección neonatal por EGB. Los resultados ponen de manifiesto que las recomendaciones para su prevención consisten en el cribado universal prenatal de colonización por EGB mediante cultivo vaginorrectal a las 35-37 semanas, y la administración de profilaxis antibiótica intraparto a todas las embarazadas portadoras.

El cervell i la butxaca

Un dels camps de recerca més destacats dels darrers mesos és el que ha obert la descoberta d'un nombre creixent de gens relacionats amb malalties mentals. Això implica que molts processos cerebrals tenen una base genètica, inclosos els processos que ens permeten prendre decisions de la vida diària, com per exemple si volem comprar una cosa o no [...].

Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors

Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer"s disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer"s related beta-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD.

Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors

Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer"s disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer"s related beta-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD.

De qui és el teu genoma?

Les notícies sobre els descobriments al voltant del genoma humà, que arran de la seva seqüenciació s'han incrementat espectacularment, han generat expectatives immenses per a la millora de la salut. Però la seva extraordinària aptitud per pronosticar malalties i tractaments fan témer sobre un ús il·legítim per discriminar persones.

Prehospital ticagrelor in ST-segment elevation myocardial infarction

Background:The direct-acting platelet P2Y receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown. Methods: We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours' duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days. Results: The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used

The burden of disease in Spain: results from the global burden of disease study 2010

BackgroundWe herein evaluate the Spanish population¿s trends in health burden by comparing results of two Global Burden of Diseases, Injuries, and Risk Factors Studies (the GBD studies) performed 20 years apart.MethodsData is part of the GBD study for 1990 and 2010. We present results for mortality, years of life lost (YLLs), years lived with disability, and disability-adjusted life years (DALYs) for the Spanish population. Uncertainty intervals for all measures have been estimated.ResultsNon-communicable diseases accounted for 3,703,400 (95% CI 3,648,270¿3,766,720) (91.3%) of 4,057,400 total deaths, in the Spanish population. Cardiovascular and circulatory diseases were the main cause of mortality among non-communicable diseases (34.7% of total deaths), followed by neoplasms (27.1% of total deaths). Neoplasms, cardiovascular and circulatory diseases, and chronic respiratory diseases were the top three leading causes for YLLs. The most important causes of DALYs in 2010 were neoplasms, cardiovascular and circulatory diseases, musculoskeletal disorders, and mental and behavioral disorders.ConclusionsMortality and disability in Spain have become even more linked to non-communicable diseases over the last years, following the worldwide trends. Cardiovascular and circulatory diseases, neoplasms, mental and behavioral disorders, and neurological disorders are the leading causes of mortality and disability. Specific focus is needed from health care providers and policy makers to develop health promotion and health education programs directed towards non-communicable disorders.

HIV-1 immune activation induces siglec-1 expression and enhances viral trans-infection in blood and tissue myeloid cells

Background: Myeloid cells are key players in the recognition and response of the host against invading viruses. Paradoxically, upon HIV-1 infection, myeloid cells might also promote viral pathogenesis through trans-infection, a mechanism that promotes HIV-1 transmission to target cells via viral capture and storage. The receptor Siglec-1 (CD169) potently enhances HIV-1 trans-infection and is regulated by immune activating signals present throughout the course of HIV-1 infection, such as interferon α (IFNα). Results: Here we show that IFNα-activated dendritic cells, monocytes and macrophages have an enhanced ability to capture and trans-infect HIV-1 via Siglec-1 recognition of viral membrane gangliosides. Monocytes from untreated HIV-1-infected individuals trans-infect HIV-1 via Siglec-1, but this capacity diminishes after effective antiretroviral treatment. Furthermore, Siglec-1 is expressed on myeloid cells residing in lymphoid tissues, where it can mediate viral trans-infection. Conclusions: Siglec-1 on myeloid cells could fuel novel CD4+ T-cell infections and contribute to HIV-1 dissemination in vivo.