Mitochondrial oxidative stress causes hyperphosphorylation of tau

Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and beta-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Ass load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.     

Do Psychological Variables Affect Early Surgical Recovery?

Background

Numerous studies have examined the effect of psychological variables on surgical recovery, but no definite conclusion has been reached yet. We sought to examine whether psychological factors influence early surgical recovery.

Methods

We performed a systematic search in PubMed, Scopus and PsycINFO databases to identify studies examining the association of preoperative psychological variables or interventions with objectively measured, early surgical outcomes.

Results

We identified 16 eligible studies, 15 of which reported a significant association between at least one psychological variable or intervention and an early postoperative outcome. However, most studies also reported psychological factors not influencing surgical recovery and there was significant heterogeneity across the studies. Overall, trait and state anxiety, state anger, active coping, subclinical depression, and intramarital hostility appeared to complicate recovery, while dispositional optimism, religiousness, anger control, low pain expectations, and external locus of control seemed to promote healing. Psychological interventions (guided relaxation, couple support visit, and psychiatric interview) also appeared to favor recovery. Psychological factors unrelated to surgical outcomes included loneliness, perceived social support, anger expression, and trait anger.

Conclusion

Although the heterogeneity of the available evidence precludes any safe conclusions, psychological variables appear to be associated with early surgical recovery; this association could bear important implications for clinical practice. Large clinical trials and further analyses are needed to precisely evaluate the contribution of psychology in surgical recovery.     

Dimerisation of N-acetyl-L-tyrosine ethyl ester and Abeta peptides via formation of dityrosine

Alzheimer's disease (AD) is characterised by the formation of amyloid deposits composed primarily of the amyloid beta-peptide (Abeta). This peptide has been shown to bind redox active metals ions such as copper and iron, leading to the production of reactive oxygen species (ROS) and formation of hydrogen peroxide (H(2)O(2)). The generation of H(2)O(2) has been linked with Abeta neurotoxicity and neurodegeneration in AD. Because of the relative stability of a tyrosyl radical, the tyrosine residue (Tyr-10) is believed to be critical to the neurotoxicity of Abeta. This residue has also been shown to be important to Abeta aggregation and amyloid formation. It is possible that the formation of an Abeta tyrosyl radical leads to increased aggregation via the formation of dityrosine as an early aggregation step, which is supported by the identification of dityrosine in amyloid plaque. The role of dityrosine formation in Abeta aggregation and neurotoxicity is as yet undetermined, partly because there are no facile methods for the synthesis of Abeta dimers containing dityrosine. Here we report the use of horseradish peroxidase and H(2)O(2) to dimerise N-acetyl-L-tyrosine ethyl ester and apply the optimised conditions for dityrosine formation to fully unprotected Abeta peptides. We also report a simple fluorescent plate reader method for monitoring Abeta dimerisation via dityrosine formation.     

Understanding of Statistical Terms Routinely Used in Meta-Analyses: An International Survey among Researchers

Objective

Biomedical literature is increasingly enriched with literature reviews and meta-analyses. We sought to assess the understanding of statistical terms routinely used in such studies, among researchers.

Methods

An online survey posing 4 clinically-oriented multiple-choice questions was conducted in an international sample of randomly selected corresponding authors of articles indexed by PubMed.

Results

A total of 315 unique complete forms were analyzed (participation rate 39.4%), mostly from Europe (48%), North America (31%), and Asia/Pacific (17%). Only 10.5% of the participants answered correctly all 4 “interpretation” questions while 9.2% answered all questions incorrectly. Regarding each question, 51.1%, 71.4%, and 40.6% of the participants correctly interpreted statistical significance of a given odds ratio, risk ratio, and weighted mean difference with 95% confidence intervals respectively, while 43.5% correctly replied that no statistical model can adjust for clinical heterogeneity. Clinicians had more correct answers than non-clinicians (mean score ± standard deviation: 2.27±1.06 versus 1.83±1.14, p<0.001); among clinicians, there was a trend towards a higher score in medical specialists (2.37±1.07 versus 2.04±1.04, p = 0.06) and a lower score in clinical laboratory specialists (1.7±0.95 versus 2.3±1.06, p = 0.08). No association was observed between the respondents'' region or questionnaire completion time and participants'' score.

Conclusion

A considerable proportion of researchers, randomly selected from a diverse international sample of biomedical scientists, misinterpreted statistical terms commonly reported in meta-analyses. Authors could be prompted to explicitly interpret their findings to prevent misunderstandings and readers are encouraged to keep up with basic biostatistics.     

Efficacy and safety of telavancin in clinical trials: a systematic review and meta-analysis

Introduction

The epidemiology and antibiotic resistance of Staphylococcus aureus have evolved, underscoring the need for novel antibiotics, particularly against methicillin-resistant S. aureus (MRSA). Telavancin is a bactericidal lipoglycopeptide with potent activity against Gram-positive pathogens.

Objective

To systematically review and synthesize the available evidence from randomized controlled trials (RCTs) evaluating telavancin in the treatment of patients with infections due to Gram-positive organisms with the methodology of meta-analysis.

Results

Six RCTs comparing telavancin with vancomycin were included; 4 (2229 patients) referred to complicated skin and soft tissue infections (cSSTIs) and 2 (1503 patients) to hospital-acquired pneumonia (HAP). Regarding cSSTIs, telavancin and vancomycin showed comparable efficacy in clinically evaluable patients (odds ratio [OR] = 1.10 [95% confidence intervals: 0.82–1.48]). Among patients with MRSA infection, telavancin showed higher eradication rates (OR = 1.71 [1.08–2.70]) and a trend towards better clinical response (OR = 1.55 [0.93–2.58]). Regarding HAP, telavancin was non-inferior to vancomycin in terms of clinical response in two Phase III RCTs; mortality rates for the pooled trials were comparable with telavancin (20%) and vancomycin (18.6%). Pooled data from cSSTIs and HAP studies on telavancin 10 mg/kg indicated higher rates of serum creatinine increases (OR = 2.22 [1.38–3.57]), serious adverse events (OR = 1.53 [1.05–2.24]), and adverse event-related withdrawals (OR = 1.49 [1.14–1.95]) among telavancin recipients.

Conclusion

Telavancin might be an alternative to vancomycin in cases of difficult-to-treat MRSA infections. The potent antistaphylococcal activity of telavancin should be weighted against the potential for nephrotoxicity.