Correction: Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations.

Text for Correction.

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations.

TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate421, to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called TauDN-that expresses a Tau mutant that cannot be cleaved by caspases. TauDN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer's disease.

Psychotic Alzheimer's disease (AD+P) is a rapidly progressive variant of AD associated with an increased burden of frontal tau pathology that affects up to 50% of those with AD, and is observed more commonly in females. To date, there are no safe and effective medication interventions with an indication for treatment in this condition, and there has been only very limited exploration of potential animal models for pre-clinical drug development. Pathogenic tau is over represented in the frontal cortex in AD+P, especially in females. In order to develop a candidate animal model of AD+P, we employed a tau mouse model with a heavy burden of frontal tau pathology, the rTg(tauP301L)4510 mouse, hereafter termed rTg4510. We explored deficits of prepulse inhibition of acoustic startle (PPI), a model of psychosis in rodents, and the correlation between pathogenic phospho-tau species associated with AD+P and PPI deficits in female mice. We found that female rTg4510 mice exhibit increasing PPI deficits relative to littermate controls from 4.5 to 5.5 months of age, and that these deficits are driven by insoluble fractions of the phospho-tau species pSer396/404, pSer202, and pThr231 found to be associated with human AD+P. This preliminary data suggests the utility of the rTg4510 mouse as a candidate disease model of human female AD+P. Further work expanded to include both genders and other behavioral outcome measures relevant to AD+P is necessary.

Small molecule inhibitors of human papillomavirus protein - protein interactions.

Human papillomaviruses (HPV) have now been identified as a necessary cause of benign and malignant lesions of the differentiating epithelium, particularly cervical cancer, the second most prevalent cancer in women worldwide. While two prophylactic HPV vaccines and screening programs are available, there is currently no antiviral drug for the treatment of HPV infections and associated diseases. The recent progress toward the identification and characterization of specific molecular targets for small molecule-based approaches provides prospect for the development of effective HPV antiviral compounds. Traditionally, antiviral therapies target viral enzymes. HPV encode for few proteins, however, and rely extensively on the infected cell for completion of their life cycle. This article will review the functions of the viral E1 helicase, which encodes the only enzymatic function of the virus, of the E2 regulatory protein, and of the viral E6 and E7 oncogenes in viral replication and pathogenesis. Particular emphasis will be placed on the recent progress made towards the development of novel small molecule inhibitors that specifically target and inhibit the functions of these viral proteins, as well as their interactions with other viral and/or cellular proteins.

Activation of PKC-beta isoforms mediates HNE-induced MCP-1 release by macrophages.

4-Hydroxynonenal (HNE) in the concentration range detectable in many pathophysiologic conditions is able to modulate signal transduction cascades and gene expression. Here, we report the stimulating effect of 1 microM HNE on the release of the monocyte chemotactic protein-1 (MCP-1) by murine macrophages. MCP-1-increased export following 1-h cell treatment with HNE proved to be comparable to that exerted by standard amounts of bacterial lipopolysaccharide (LPS). However, the key molecular event in HNE-induced secretion of MCP-1 appeared to be the increased activity of beta-PKC isoforms, which are recognized as playing a role in the regulation of cell protein transport and secretion. On the other hand, in LPS-stimulated cells, the delta isoform was seen to be involved and was probably related to LPS-mediated effects on MCP-1 expression and synthesis. In conclusion, HNE might interact with other pro-inflammatory stimuli, like LPS, in a concerted amplification of MCP-1 production and secretion.

Glutathione depletion induces apoptosis of rat hepatocytes through activation of protein kinase C novel isoforms and dependent increase in AP-1 nuclear binding.

Treatment of isolated rat hepatocytes with the glutathione depleting agents L-buthionine-S,R-sulfoximine or diethylmaleate reproduced various cellular conditions of glutathione depletion, from moderate to severe, similar to those occurring in a wide spectrum of human liver diseases. To evaluate molecular changes and possible cellular dysfunction and damage consequent to a pathophysiologic level of GSH depletion, the effects of this condition on protein kinase C (PKC) isoforms were investigated, since these are involved in the intracellular specific regulatory processes and are potentially sensitive to redox changes. Moreover, a moderate perturbation of cellular redox state was found to activate novel PKC isoforms, and a clear relationship was shown between novel kinase activation and nuclear binding of the redox-sensitive transcription factor, activator protein-1 (AP-1). Apoptotic death of a significant number of cells, confirmed in terms of internucleosomal DNA fragmentation was a possible effect of these molecular reactions, and was triggered by a condition of glutathione depletion usually detected in human liver diseases. Finally, the inhibition of novel PKC enzymatic activity in cells co-treated with rottlerin, a selective novel kinase inhibitor, prevented glutathione-dependent novel PKC up-regulation, markedly moderated AP-1 activation, and protected cells against apoptotic death. Taken together, these findings indicate the existence of an apoptotic pathway dependent on glutathione depletion, which occurs through the up-regulation of novel PKCs and AP-1.

Monitoreo ambulatorio de la presión arterial en pacientes diabéticos: detección precoz de la hipertensión y cambios en el ritmo circadiano / Ambulatory monitoring of blood pressure in diabetic patients

El propósito de este trabajo fue establecer el comportamiento de la tensión arterial buscando hipertensión oculta y alteración del ritmo circadiano. Se estudiaron 35 pacientes diabéticos, 20 normotensos y 15 hipertensos,de los cuales 22 eran insulinodependientes y 13 no insulinodependientes, los quefueron comparados con 37 pacientes no diabéticos, 17 normotensos y 20 hipertensos.Se clasificó a los hipertensos según el criterio del Joint National Comittee de los Estados Unidos. A toda la población se le realizó monitoreo ambulatorio depresión arterial de 24 horas, aceptando como hipertensos a los pacientes que presentaban un 30 de las lecturas que excedían los valores 140/85 mm Hg. En la población diabética se evaluó el control metabólico por medio de hemoglobina glicosilada y la presencia de microangiopatía por microalbuminuria y retinofluoresceinografía. De los 35 pacientes diabéticos, 45.7 presentaron alteraciones del ritmo circadiano. Mientras que de los 20 pacientes diabéticos normotensos, al 60 sele diagnosticó hipertensión por medio del monitoreo ambulatorio.Estos resultadosponen en evidencia la necesidad de buscar hipertensión arterial en pacientes diabéticos, mediante el monitoreo ambulatorio de presión arterial de 24 horas, que permitiría el diagnóstico precoz, ofreciendo una posible prevención del daño queproduce en la evolución de las lesiones degenerativas de la diabetes y en el órgano blanco

Alteraciones lipidicas en desnutridos secundarios: pacientes con tuberculosis pulmonar

Se estudiaron 15 pacientes desnutridos, internados en el Servicio de Neumotisiología del Hospital "Enrique Tornú". El grado de desnutrición fue evaluado en función de la pérdida de peso, BMI (Body Mass Index) y de la SMBM (Superficie Muscular del Brazo Medio). Como controles normales, analizaron 15 individuos de edades similares, que concurrieron al chequeo periódico ocupacional. En ambos grupos se valoraron: colesterol, HDL colesterol, HDL, colesterol, triglicéridos, LDL colesterol, apoproteína A1 y apoproteína B. En la comparación de ambos grupos se obtuvieron diferencias significativas (p < 0,001) para el colesterol total, HDL2 colesterol, LDL colesterol, apoproteína a1 y apoproteína B. Sólo la apoproteína A1 mostró una buena correlación estadística -=0,616 con el deterioro del BMI. La variable más afectada por la desnutrición fue la sub-fracción HDL2 la cual situó su valor en el orden del 25% de los controles normales. El análisis de las dos relaciones de riesgo-colesterol total/HDL y LDL/HDL - no trajo aparejadas conclusiones significativas