Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice

5XFAD is an early-onset mouse transgenic model of Alzheimer disease (AD). Up to now there are no studies that focus on the epigenetic changes produced as a result of Aß-42 accumulation and the possible involvement in the different expression of related AD-genes. Under several behavioral and cognition test, we found impairment in memory and psychoemotional changes in female 5XFAD mice in reference to wild type that worsens with age. Cognitive changes correlated with alterations on protein level analysis and gene expression of markers related with tau aberrant phosphorylation, amyloidogenic pathway (APP, BACE1), Oxidative Stress (iNOS, Aldh2) and inflammation (astrogliosis, TNF-¿ and IL-6); no changes were found in non-amyloidogenic pathway indicators such as ADAM10. Epigenetics changes as higher CpG methylation and transcriptional changes in DNA methyltransferases (DNMTs) family were found. Dnmt1 increases in younger 5XFAD and Dnmt3a and b high levels in the oldest transgenic mice. Similar pattern was found with histone methyltransferases such as Jarid1a andG9a. Histone deacetylase 2 (Hdac2) or Sirt6, both related with cognition and memory, presented a similar pattern. Taken together, these hallmarks presented by the 5XFAD model prompted its use in assessing different potential therapeutic interventions based on epigenetic targets after earlier amyloid deposition.This study was supported by Spanish MINECO, and the European Regional Development Funds (SAF-2012- 39852, BFU2013-48822-R and CSD2010-00045). CGF, AC, and MP belong to 2014 SGR 525; and SS and CS to 2014 SGR 625.Peer Reviewe

Effectiveness of measures to eradicate Staphylococcus aureus carriage in patients with community-associated skin and soft-tissue infections: A randomized trial

BACKGROUND: Despite a paucity of evidence, decolonization measures are prescribed for outpatients with recurrent Staphylococcus aureus skin and soft tissue infections (SSTI). OBJECTIVE: Compare the effectiveness of four regimens for eradicating S. aureus carriage. DESIGN: Open-label, randomized controlled trial. Colonization status and recurrent SSTI were ascertained at one and four months. SETTING: Barnes-Jewish and St. Louis Children’s Hospitals, St. Louis, Missouri, 2007–2009. PARTICIPANTS: Three hundred patients with community-onset SSTI and S. aureus colonization in the nares, axilla, or inguinal folds. INTERVENTIONS: Participants were randomized to receive no therapeutic intervention (controls) or perform one of three 5-day regimens: 2% mupirocin ointment applied to the nares twice daily, intranasal mupirocin plus daily 4% chlorhexidine body washes, or intranasal mupirocin plus daily dilute bleach water baths. RESULTS: Among 244 participants with one-month colonization data, modified intention-to-treat analysis revealed S. aureus eradication in 38% of participants in the education only (control) group; 56% in the mupirocin group (p=0.03 vs. controls); 55% in the mupirocin/chlorhexidine group (p=0.05); and 63% in the mupirocin/bleach group (p=0.006). Of 229 participants with four-month colonization data, eradication rates were 48% in controls; 56% for mupirocin only (p=0.40 vs. controls); 54% for mupirocin/chlorhexidine (p=0.51); and 71% for mupirocin/bleach (p=0.02). At one and four months, respectively, recurrent SSTI was reported by 20% and 36% of participants. CONCLUSIONS: An inexpensive regimen of dilute bleach baths, intranasal mupirocin, and hygiene education effectively eradicated S. aureus over four months. High rates of recurrent SSTI suggest factors other than endogenous colonization as important determinants of infection

Attributable costs of enterococcal bloodstream infections in a nonsurgical hospital cohort

BACKGROUND: Vancomycin-resistant enterococcal (VRE) bloodstream infections (BSI) are associated with increased morbidity and mortality. OBJECTIVE: To determine the attributable costs of vancomycin-sensitive (VSE) and VRE BSI and the independent impact of vancomycin-resistance on hospital costs. METHODS: A retrospective cohort study was conducted of 21,154 non-surgical patients admitted to an academic medical center between 2002 and 2003. Using administrative data, attributable hospital costs (inflation adjusted to $2007) and length of stay were estimated with multivariate generalized least squares (GLS) models and propensity score matched-pairs. RESULTS: The cohort included 182 VSE and 94 VRE BSI cases. After adjustment for demographics, comorbidities, procedures, non-enterococcal BSI, and early mortality, the attributable costs of VSE BSI were$2,250 (95% confidence interval [CI], $1,758–$2,880) in the standard GLS model and $2,023 (95$1,588–$2,575) in the propensity-score weighted GLS model and the attributable costs of VRE BSI were$4,479 (95% CI, $3,500–$5,732) in the standard GLS model and $4,036 (95$3,170–$5,140) in the propensity-score weighted GLS model. The median of the difference in costs between matched-pairs was$5,282 ($2,042–$8,043) for VSE BSI and $9,949 (95$1,579–$24,693) for VRE BSI. The attributable costs of vancomycin-resistance were$1,713 (95% CI, $1,338–$2,192) in the standard GLS model and $1,546 (95$1,214–$1,968) in the propensity-score weighted GLS model. Attributable length of stay ranged from 1.1–2.2 days for VSE BSI and 2.2–3.5 days for VRE BSI cases. CONCLUSIONS: VSE and VRE BSI were independently associated with hospital costs and length of stay. Vancomycin-resistance was associated with increased costs

Childhood socioeconomic status and childhood maltreatment: Distinct associations with brain structure

The present study examined the relationship between childhood socioeconomic status (SES), childhood maltreatment, and the volumes of the hippocampus and amygdala between the ages of 25 and 36 years. Previous work has linked both low SES and maltreatment with reduced hippocampal volume in childhood, an effect attributed to childhood stress. In 46 adult subjects, only childhood maltreatment, and not childhood SES, predicted hippocampal volume in regression analyses, with greater maltreatment associated with lower volume. Neither factor was related to amygdala volume. When current SES and recent interpersonal stressful events were also considered, recent interpersonal stressful events predicted smaller hippocampal volumes over and above childhood maltreatment. Finally, exploratory analyses revealed a significant sex by childhood SES interaction, with women’s childhood SES showing a significantly more positive relation (less negative) with hippocampus volume than men’s. The overall effect of childhood maltreatment but not SES, and the sex-specific effect of childhood SES, indicate that different forms of stressful childhood adversity affect brain development differently

Prescripción de antibióticos en la infección del tracto urinario: adecuación a criterios de calidad en atención primaria

ObjetivoDeterminar la prevalencia de insuficiencia renal crónica (IRC) sin tratamiento sustitutivo (TSR), describir el tipo de enfermedades renales primarias y los factores de riesgo asociados que pueden favorecer su evolución hacia la insuficiencia renal terminal.DiseñoEstudio descriptivo, transversal.EmplazamientoPoblación atendida por un centro de atención primaria.ParticipantesMayores de 14 años con historia clínica abierta en el CAP Bon Pastor.ResultadosDurante el período 1-I-1997 hasta 1-XII-1997 se revisaron 12.241 historias clínicas. Se identificaron 64 pacientes que cumplían criterios de IRC sin TSR; prevalencia, 5.228 pacientes por millón de habitantes (pmp) (IC del 95%, 3.950–6.510 pmp). Un 71,9% era varón, la edad media era de 72 años (DE, 13,5). La media de la última creatinina plasmática fue de 2 mg/dl (DE, 0,66). La frecuencia según tipo de nefropatía fue: glomerular, 3 (4,7%); diabética, 5 (7,8%); intersticial, 3 (4,7%); vascular (HTA), 41 (64,1%); indeterminada, 2 (3,1%), e inclasificable, 10 (15,6%). Los factores de riesgo asociados en estos pacientes fueron: hipertensos, 47 (73,4%); diabéticos, 16 (25%); hipercolesterémicos, 26 (40,6%); consumidores crónicos de analgésicos, 20 (31,3%), y 10 (15,6%), fumadores. Un 51,6% de los pacientes presentaba otras enfermedades cardiovasculares.ConclusionesLa prevalencia estimada de IRC sin TRS en la población es de 5.228 pmp, y la hipertensión es el factor de riesgo más frecuente asociado a esta patología.ObjectiveTo determine the prevalence of chronic renal failure (CRF) without replacement treatment (RT), and to describe the primary renal diseases and associated risk factors that might favour its evolution to terminal renal failure.DesignCross-sectional, descriptive study.SettingPopulation attended at a primary care centre (PCC).ParticipantsOver-14s with a clinical history opened at the Bon Pastor PCC.ResultsBetween the 1st of January 1997 and the 1st of December 1997, 12241 clinical histories were reviewed. 64 patients were identified who satisfied criteria of CRF without RT, a prevalence of 5228 patients per million inhabitants (95% CI, 3,950–6,510). 71.9% were men, and mean age was 72 (SD, 13.5). The most recent plasma creatinine averaged 2 mg/dl (SD, 0.66). Frequency according to kind of nephropathy was: 3 (4.7%) glomerular, 5 (7.8%) diabetic, 3 (4.7%) interstitial, 41 (64.1%) vascular (hypertension), 2 (3.1%) indeterminate and 10 (15.6%) unclassifiable. Associated risk factors in these patients were: 47 (73.4%) with hypertension, 16 (25%) diabetic, 26 (40.6%) with hypercholesterolaemia, 20 (31.3%) chronic consumers of analgesics, and 10 (15.6%) smokers. 51.6% of the patients suffered other cardiovascular illnesses.ConclusionsThe estimated prevalence in the population of CRF without RT is 5,228 per million inhabitants. Hypertension is the risk factor most closely associated with this pathology

Epigallocatechin-3-gallate PEGylated poly(lactic-co-glycolic) acid nanoparticles mitigate striatal pathology and motor deficits in 3-nitropropionic acid intoxicated mice

AIM:To compare free and nanoparticle (NP)-encapsulated epigallocatechin-3-gallate (EGCG) for the treatment of Huntington’s disease (HD)-like symptoms in mice. MATERIALS & METHODS: EGCG was incorporated into PEGylated poly(lactic-co-glycolic) acid NPs with ascorbic acid (AA). HD-like striatal lesions and motor deficit were induced in mice by 3-nitropropionic acid-intoxication. EGCG and EGCG/AA NPs were co-administered and behavioral motor assessments and striatal histology performed after 5 days. RESULTS: EGCG/AA NPs were significantly more effective than free EGCG in reducing motor disturbances and depression-like behavior associated with 3-nitropropionic acid toxicity. EGCG/AA NPs treatment also mitigated neuroinflammation and prevented neuronal loss. CONCLUSION: NP encapsulation enhances therapeutic robustness of EGCG in this model of HD symptomatology. Together with our previous findings, this highlights the potential of EGCG/AA NPs in the symptomatic treatment of neurodegenerative diseases

Mupirocin and chlorhexidine resistance in Staphylococcus aureus in patients with community-onset skin and soft tissue infections

Decolonization measures, including mupirocin and chlorhexidine, are often prescribed to prevent Staphylococcus aureus skin and soft tissue infections (SSTI). The objective of this study was to determine the prevalence of high-level mupirocin and chlorhexidine resistance in S. aureus strains recovered from patients with SSTI before and after mupirocin and chlorhexidine administration and to determine whether carriage of a mupirocin- or chlorhexidine-resistant strain at baseline precluded S. aureus eradication. We recruited 1,089 patients with community-onset SSTI with or without S. aureus colonization. In addition to routine care, 483 patients were enrolled in a decolonization trial: 408 received intranasal mupirocin (with or without antimicrobial baths), and 258 performed chlorhexidine body washes. Patients were followed for up to 12 months with repeat colonization cultures. All S. aureus isolates were tested for high-level mupirocin and chlorhexidine resistance. At baseline, 23/1,089 (2.1%) patients carried a mupirocin-resistant S. aureus strain and 10/1,089 (0.9%) patients carried chlorhexidine-resistant S. aureus. Of 4 patients prescribed mupirocin, who carried a mupirocin-resistant S. aureus strain at baseline, 100% remained colonized at 1 month compared to 44% of the 324 patients without mupirocin resistance at baseline (P = 0.041). Of 2 patients prescribed chlorhexidine, who carried a chlorhexidine-resistant S. aureus strain at baseline, 50% remained colonized at 1 month compared to 48% of the 209 patients without chlorhexidine resistance at baseline (P = 1.0). The overall prevalence of mupirocin and chlorhexidine resistance is low in S. aureus isolates recovered from outpatients, but eradication efforts were less successful in patients carrying a mupirocin-resistant S. aureus strain at baseline

Epigallocatechin-3-gallate PEGylated poly(lactic-co-glycolic) acid nanoparticles mitigate striatal pathology and motor deficits in 3-nitropropionic acid intoxicated mice

Huntington's disease (HD) is a debilitating neurodegenerative disease that affects around 5-10/100,000 individuals in developed countries. It is caused by genetic alterations in the huntingtin (htt) gene. Efforts are being made to find treatments which will correct the genetic alterations or their pathophysiological consequences associated with HD,3 however none of these options are yet available to patients. Thus, therapies that address and ameliorate the symptomatology of HD, which include motor dysfunction and a wide range of behavioural disturbances, are also needed. Epigallocatechin-3-gallate (EGCG) is a powerful compound extracted from the green tea plant that may possess beneficial effects for HD patients, but whose therapeutic success is limited because of its chemical instability. Here, we show that protective encapsulation of EGCG rendered it much more efficient in attenuating motor deficits and depression-like behaviour in a mice model of HD-like neurodegeneration. Importantly, behavioural improvement was also associated with a reduction of neuronal damage. These results, together with our previous findings using nanoparticle-encapsulated EGCG in mouse models of Alzheimer's disease and epilepsy, highlight their potential effectiveness for symptomatic treatment of neurodegenerative diseases