Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo

High frequency of Panton-Valentine leukocidin genes in invasive methicillin-susceptible Staphylococcus aureus strains and the relationship with methicillin-resistant Staphylococcus aureus in Córdoba, Argentina

In the study presented here, the genetic characteristics of methicillin-susceptible Staphylococcus aureus (MSSA) strains isolated from patients attending hospitals in the city of Córdoba, Argentina, during 1999-2002 were evaluated to determine their genetic relationship with methicillin-resistant S. aureus (MRSA) clones as part of an effort to control the potential emergence of new epidemic MRSA strains. The results showed there is a high frequency of MSSA strains carrying Panton-Valentine leukocidin genes in invasive infections in Córdoba, Argentina, particularly in those occurring in hospital settings. Panton-Valentine leukocidin genes were found in the genomic background of one clone (ST30-N pulsotype) belonging to a successful internationally distributed MSSA lineage (clonal complex 30), which is closely related to the EMRSA-16 pandemic clone. These genes were also detected in the ancestral clone (ST5-M pulsotype) of the most prevalent MRSA epidemic clone causing healthcare-associated infections in this region, known as the Cordobes/Chilean clone. The molecular characterization of circulating MSSA strains, including the detection of Panton-Valentine leukocidin genes, is thus a useful marker for investigating the evolving epidemiology of hospital- and community-acquired MRSA clones.Fil: Sola, C. Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Ciudad Universitaria, Córdoba 5000, Haya de la Torre y M. Allende s/n, ArgentinaFil: Saka, H.A. Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Ciudad Universitaria, Córdoba 5000, Haya de la Torre y M. Allende s/n, ArgentinaFil: Vindel, A. Laboratorio de Enfermedades Infecciosas Nosocomiales, Instituto de Salud Carlos III, Centro Nacional de Microbiología, Majadahonda, Madrid 28220, SpainFil: Bocco, José Luis. Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Ciudad Universitaria, Córdoba 5000, Haya de la Torre y M. Allende s/n, ArgentinaFil: Monterisi, A. Hospital Nacional de Clínicas, ArgentinaFil: Rocchi, M. Hospital Nacional de Clínicas, ArgentinaFil: Díaz, E. Hospital Militar de CórdobaFil: Lomberghini, R. Hospital Militar de CórdobaFil: Littvik, A.M. Hospital Rawson, ArgentinaFil: López, T. Hospital Rawson, ArgentinaFil: Yudowsky, S. Hospital InfantilFil: Carvajal, L. Hospital de NiñosFil: Culasso, C. Hospital de NiñosFil: Perlo Morales, O. Hospital Córdoba, ArgentinaFil: Aissa, M.S. Hospital Córdoba, ArgentinaFil: Vilaro, M. Hospital Privado de Córdoba, ArgentinaFil: Bongiovanni, M.E.Hospital Italiano de Córdoba, ArgentinaFil: Mangiaterra, S. Hospital Italiano de Córdoba, ArgentinaFil: Barbon, S. Hospital Italiano de Córdoba, ArgentinaFil: Wolff, L. Clinica Privada Velez Sarsfield, ArgentinaFil: Vercelli, B. Clinica Privada Velez Sarsfield, ArgentinaFil: D'Andrea, E.M. Hospital de UrgenciasFil: López, A. Hospital de UrgenciasFil: Pino, Gustavo Ariel. Hospital San Roque, ArgentinaFil: Muñoz, V. Hospital San Roque, ArgentinaFil: Bottiglieri, Marina Teresita. Universidad Católica de Córdoba. Facultad de Ciencias de la Salud; Argentin

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates

Delay in diagnosis of influenza A (H1N1)pdm09 virus infection in critically ill patients and impact on clinical outcome

Background: Patients infected with influenza A (H1N1)pdm09 virus requiring admission to the ICU remain an important source of mortality during the influenza season. The objective of the study was to assess the impact of a delay in diagnosis of community-acquired influenza A (H1N1)pdm09 virus infection on clinical outcome in critically ill patients admitted to the ICU. Methods: A prospective multicenter observational cohort study was based on data from the GETGAG/SEMICYUC registry (2009–2015) collected by 148 Spanish ICUs. All patients admitted to the ICU in which diagnosis of influenza A (H1N1)pdm09 virus infection had been established within the first week of hospitalization were included. Patients were classified into two groups according to the time at which the diagnosis was made: early (within the first 2 days of hospital admission) and late (between the 3rd and 7th day of hospital admission). Factors associated with a delay in diagnosis were assessed by logistic regression analysis. Results: In 2059 ICU patients diagnosed with influenza A (H1N1)pdm09 virus infection within the first 7 days of hospitalization, the diagnosis was established early in 1314 (63.8 %) patients and late in the remaining 745 (36.2 %). Independent variables related to a late diagnosis were: age (odds ratio (OR) = 1.02, 95 % confidence interval (CI) 1.01–1.03, P < 0.001); first seasonal period (2009–2012) (OR = 2.08, 95 % CI 1.64–2.63, P < 0.001); days of hospital stay before ICU admission (OR = 1.26, 95 % CI 1.17–1.35, P < 0.001); mechanical ventilation (OR = 1.58, 95 % CI 1.17–2.13, P = 0.002); and continuous venovenous hemofiltration (OR = 1.54, 95 % CI 1.08–2.18, P = 0.016). The intra-ICU mortality was significantly higher among patients with late diagnosis as compared with early diagnosis (26.9 % vs 17.1 %, P < 0.001). Diagnostic delay was one independent risk factor for mortality (OR = 1.36, 95 % CI 1.03–1.81, P < 0.001). Conclusions: Late diagnosis of community-acquired influenza A (H1N1)pdm09 virus infection is associated with a delay in ICU admission, greater possibilities of respiratory and renal failure, and higher mortality rate. Delay in diagnosis of flu is an independent variable related to death