Depletion of Beclin-1 Due to Proteolytic Cleavage by Caspases in the Alzheimer\u27s Disease Brain

The Beclin-1 protein is essential for the initiation of autophagy and recent studies suggest this function may be compromised in Alzheimer’s disease (AD). In addition, in vitro studies have supported a loss of function of Beclin-1 due to proteolytic modification by caspases. In the present study we examined whether caspase-cleavage of Beclin-1 occurs in the AD brain by designing a site-directed caspase-cleavage antibody based upon a known cleavage site within the protein at position D149. We confirmed that Beclin-1 is an excellent substrate for caspase-3 and demonstrate cleavage led to the formation of a 35 kDa C-terminal fragment labeled by our novel antibody following Western blot analysis. Application of this antibody termed Beclin-1 caspase-cleavage product antibody or BeclinCCP in frontal cortex tissue sections revealed strong immunolabeling within astrocytes that localized with plaque-regions and along blood vessels in all AD cases examined. In addition, weaker, more variable BeclinCCP labeling was also observed within neurofibrillary tangles that co-localized with the early tau conformational marker, MC-1 as well as the late tangle marker, PHF-1. Collectively, these data support a depletion of Beclin-1 in AD following caspase-cleavage

Recalcitrant chronic bladder pain and recurrent cystitis but negative urinalysis - what should we do?

Purpose: Lower urinary tract symptoms (LUTS) may be associated with chronic urinary tract infection (UTI) undetected by routine diagnostic tests. Antimicrobial therapy might confer benefit for these patients. Materials and Methods: Over ten years, we treated patients with chronic LUTS. Pyuria was adopted as the principal biomarker of infection. Urinary leucocyte counts were recorded from microscopy of fresh midstream urine (MSU) samples. Antibiotics were prescribed and the prescription adjusted to achieve a measurable clinical response and a reduction in pyuria. Results: We treated 624 women (mean age=53.4 years; sd=18) with chronic LUTS and pyuria. The mean duration of symptoms prior to presentation was 6.5 years. Only 16% of MSU cultures submitted were positive (≥105 cfu ml-1). Mean treatment length was 383 days (SD=347; 95% CI=337-428). Treatment was associated with a reduction in total LUTS (F=98; p=.0001), 24-hour frequency (F=75; p=.0001), urinary 3 urgency (F=90; p=.0001), lower urinary tract pain (F=108; p=.0001), voiding symptoms (F=10; p=.002) and pyuria (F=15.4; p=.0001). Full-dose first-generation urinary antibiotic (such as cefalexin, nitrofurantoin, or trimethoprim) was combined with Methenamine Hippurate. We recorded 475 adverse events (AEs) during 273,762 treatment days. There was only one serious adverse event (SAE). We observed no increase in the proportion of resistant bacterial isolates. Conclusion: This large case series demonstrates that patients with chronic LUTS and pyuria experience symptom regression and a reduction in urinary tract inflammation associated with antimicrobial therapy. Disease regression was achieved with a low frequency of AEs. These results provide preliminary data to inform a future RCT

Behavioral Inhibition as a Risk Factor for the Development of Childhood Anxiety Disorders: A Longitudinal Study

This longitudinal study examined the additive and interactive effects of behavioral inhibition and a wide range of other vulnerability factors in the development of anxiety problems in youths. A sample of 261 children, aged 5 to 8 years, 124 behaviorally inhibited and 137 control children, were followed during a 3-year period. Assessments took place on three occasions to measure children’s level of behavioral inhibition, anxiety disorder symptoms, other psychopathological symptoms, and a number of other vulnerability factors such as insecure attachment, negative parenting styles, adverse life events, and parental anxiety. Results obtained with Structural Equation Modeling indicated that behavioral inhibition primarily acted as a specific risk factor for the development of social anxiety symptoms. Furthermore, the longitudinal model showed additive as well as interactive effects for various vulnerability factors on the development of anxiety symptoms. That is, main effects of anxious rearing and parental trait anxiety were found, whereas behavioral inhibition and attachment had an interactive effect on anxiety symptomatology. Moreover, behavioral inhibition itself was also influenced by some of the vulnerability factors. These results provide support for dynamic, multifactorial models for the etiology of child anxiety problems

La comunicación electrónica facilita la investigación de un brote de alta dispersión: salmonella en la super carretera

Los brotes ampliamente dispersos de enfermedades de origen alimenticio son un problema emergente de salud pública. El aumento de la movilidad de la población y la amplia distribución de los alimentos producidos centralmente significan que cuando un brote de enfermedad alimenticia ocurre, las personas afectadas pueden distribuirse a través de el país o aún del mundo. Los brotes ampliamente dispersos desafían los limitados recursos de salud pública; pueden ser difíciles detectar, laboriosos, y consumir mucho tiempo para investigarlos. Nosotros informamos la rápida y eficiente investigación de un brote ampliamente disperso interestatal mediante la comunicación electrónica entre los pacientes posibles y trabajadores de salud pública.Facultad de Ciencias Veterinaria

La comunicación electrónica facilita la investigación de un brote de alta dispersión: salmonella en la super carretera

Los brotes ampliamente dispersos de enfermedades de origen alimenticio son un problema emergente de salud pública. El aumento de la movilidad de la población y la amplia distribución de los alimentos producidos centralmente significan que cuando un brote de enfermedad alimenticia ocurre, las personas afectadas pueden distribuirse a través de el país o aún del mundo. Los brotes ampliamente dispersos desafían los limitados recursos de salud pública; pueden ser difíciles detectar, laboriosos, y consumir mucho tiempo para investigarlos. Nosotros informamos la rápida y eficiente investigación de un brote ampliamente disperso interestatal mediante la comunicación electrónica entre los pacientes posibles y trabajadores de salud pública.Facultad de Ciencias Veterinaria

Brands in international and multi‐platform expansion strategies: economic and management issues

Powerful media branding has historically facilitated successful international expansion on the part of magazine and other content forms including film and TV formats. Multi-platform expansion is now increasingly central to the strategies of media companies and, as this chapter argues, effective use of branding in order to engage audiences effectively and to secure a prominent presence across digital platforms forms a core part of this. Drawing on original research into the experience of UK media companies, this chapter highlights some of the key economic, management and socio-cultural issues raised by the ever-increasing role of brands and branding in the strategies of international and multi-platform expansion that are increasingly common- place across media

La comunicación electrónica facilita la investigación de un brote de alta dispersión: salmonella en la super carretera

Los brotes ampliamente dispersos de enfermedades de origen alimenticio son un problema emergente de salud pública. El aumento de la movilidad de la población y la amplia distribución de los alimentos producidos centralmente significan que cuando un brote de enfermedad alimenticia ocurre, las personas afectadas pueden distribuirse a través de el país o aún del mundo. Los brotes ampliamente dispersos desafían los limitados recursos de salud pública; pueden ser difíciles detectar, laboriosos, y consumir mucho tiempo para investigarlos. Nosotros informamos la rápida y eficiente investigación de un brote ampliamente disperso interestatal mediante la comunicación electrónica entre los pacientes posibles y trabajadores de salud pública.Facultad de Ciencias Veterinaria

Urinary ATP as an indicator of infection and inflammation of the urinary tract in patients with lower urinary tract symptoms

BACKGROUND: Adenosine-5'-triphosphate (ATP) is a neurotransmitter and inflammatory cytokine implicated in the pathophysiology of lower urinary tract disease. ATP additionally reflects microbial biomass thus has potential as a surrogate marker of urinary tract infection (UTI). The optimum clinical sampling method for ATP urinalysis has not been established. We tested the potential of urinary ATP in the assessment of lower urinary tract symptoms, infection and inflammation, and validated sampling methods for clinical practice. METHODS: A prospective, blinded, cross-sectional observational study of adult patients presenting with lower urinary tract symptoms (LUTS) and asymptomatic controls, was conducted between October 2009 and October 2012. Urinary ATP was assayed by a luciferin-luciferase method, pyuria counted by microscopy of fresh unspun urine and symptoms assessed using validated questionnaires. The sample collection, storage and processing methods were also validated. RESULTS: 75 controls and 340 patients with LUTS were grouped as without pyuria (n = 100), pyuria 1-9 wbc ?l(-1) (n = 120) and pyuria ?10 wbc ?l(-1) (n = 120). Urinary ATP was higher in association with female gender, voiding symptoms, pyuria greater than 10 wbc ?l(-1) and negative MSU culture. ROC curve analysis showed no evidence of diagnostic test potential. The urinary ATP signal decayed with storage at 23°C but was prevented by immediate freezing at ??-20°C, without boric acid preservative and without the need to centrifuge urine prior to freezing. CONCLUSIONS: Urinary ATP may have a role as a research tool but is unconvincing as a surrogate, clinical diagnostic marker