Oxidative stress‐induced death in the nervous system: Cell cycle dependent or independent?

Neuronal death, attributable to perturbed redox homeostasis, is the underlying factor in many acute and chronic neurological disorders. The mechanisms employed by oxidatively stressed neurons to commit to cell death pathways are beginning to be characterized, but this is hampered by a lack of good models that extrapolate readily to redox-dependent neuronal death paradigms. In this Mini-Review, we discuss mechanisms by which oxidative stress can result in neurodegeneration. We examine evidence on which terminally differentiated neurons might commit to death under conditions of oxidative stress. In some cases, death may be linked to an aberrant and uncoordinated reentry into the cell cycle and mitotic catastrophe. Other evidence suggests that cell cycle reentry is not mandatory for death execution. Rather, the reexpression of cell cycle proteins may induce apoptotic pathways in a cell cycle-independent manner. In contrast to these models, there is also evidence that oxidative neuronal death is independent of cell cycle proteins. We conclude that oxidative stress-induced neuronal death may be promoted via several pathways, which may be cycle protein dependent or independent. The determining factor for which or how many pathways are induced appears to be context dependent and determined by the level and duration of oxidative stress.     

Impairment in childhood anxiety disorders: preliminary examination of the child anxiety impact scale-parent version

Although anxiety disorders are prevalent among children and adolescents, with a chronic and often disabling course, there is a paucity of research examining the specific ways in which anxiety interferes with various domains of functioning in childhood. The purpose of the current investigation was to examine the initial reliability and construct validity of the Child Anxiety Impact Scale-Parent version (CAIS-P). The CAIS-P is a parent-report measure consisting of School, Social, and Home/Family subscales. In a clinical sample (N = 92), the internal reliability and the convergent and divergent validity were evaluated. Internal consistency was good for the total score as well as each subscale (Cronbach's alpha ranged from 0.73-0.87). The CAIS-P total score demonstrated good construct validity, showing predicted significant correlations with the Child Behavior Checklist Internalizing Scale and the Child Depression Inventory but not the Externalizing Scale of the Child Behavior Checklist. The Social subscale of the CAIS-P was also significantly correlated with measures of social anxiety. The results provide initial support that the CAIS-P is a reliable and valid measure for the assessment of the impact of anxiety on child and adolescent functioning.     

Topical Calcineurin Inhibitors in the Treatment of Atopic Dermatitis

Purpose: To summarize success rates of the topical calcineurin inhibitors tacrolimus and pimecrolimus in treating atopic dermatitis. Methods: Randomized controlled trials (RCTs) comparing either drug to themselves (i.e. dose-ranging studies), each other, the vehicle (or placebo), or corticosteroids were obtained from Medline, EMBASE, and Cochrane databases. Two reviewers identified studies and extracted data, a third reviewer adjudicated disagreements. Outcomes included success, as defined by 90%, 75%, or 50% reductions from baseline in Eczema Area and Severity Index (EASI) scores or equivalent at 1, 3, 6, and 12 months, and also the difference between drug and vehicle (placebo). Rates were combined using a random effects meta-analytic model. Results: Of 180 articles identified, 165 were rejected (142 not RCTs/inappropriate outcome, 23 inappropriate/unextractable data). We included 15 articles reporting on 16 trials (nine tacrolimus and seven pimecrolimus trials) involving a total of 5301 patients, of whom 2107 received tacrolimus, 1225 received pimecrolimus and 1969 patients were controls. Tacrolimus reduced EASI scores by 65.6% at 1 month and 73.0% at 3 months; pimecrolimus reduced scores by 61.5% at 1 month, 60.3% at 6 months, and 61.9% at 12 months. When the difference in EASI score reductions were compared between active drug and placebo, tacrolimus success was 51.5% above placebo at 1 month and pimecrolimus was 45.9% higher at 1 month, 24.9% at 6 months, and 16.1% at 12 months. Conclusions: Success rates for tacrolimus and pimecrolimus were statistically similar. However, tacrolimus rates were consistently higher numerically than those for pimecrolimus, and tacrolimus was used in patients with more severe disease. A head-to-head RCT is required to determine if true differences exist between these drugs.     

Health economic evaluation of non-melanoma skin cancer and actinic keratosis

Non-melanoma skin cancer (NMSC) and actinic keratosis are becoming an increasingly important healthcare problem. There are approximately 1 million cases of NMSC in the US each year, primarily basal cell carcinomas, and the incidence is increasing. Although NMSC is significant in terms of both health risk and the resource implications for treatment within healthcare systems, our understanding of the health economics of NMSC is limited. The purpose of this article was to systematically review and assess published health economic studies of the treatment of NMSC and actinic keratosis, taking into consideration key aspects of guidelines set by drug purchasers and key reimbursement agencies, and to provide recommendations for appropriate modelling approaches and data collection for health economic studies of NMSC and actinic keratosis. We systematically reviewed the published literature from 1965 to 2003 for health economic evaluations of treatments of NMSC and actinic keratosis using the search terms: ('skin cancer' or 'non melanoma skin cancer' or 'basal cell carcinoma' or 'actinic keratosis') and ('decision model' or 'decision theoretic' or 'decision analytic' or 'health economic' or 'cost effective'). Studies using one of the following methodologies were included: cost-effectiveness, cost-benefit, cost-utility, cost-minimisation, cost-of-illness, cost-consequence, and treatment cost analysis. We identified eight studies evaluating NMSC. One of these studies also evaluated actinic keratosis. Although several studies satisfied some of the basic requirements of health economic evaluations, the majority had serious shortcomings that limit their usefulness. There are a few high-quality health economic evaluations assessing treatments for NMSC or actinic keratosis. However, our analysis suggests that additional data on treatment practice patterns and epidemiology need to be collected, and incorporated with efficacy and safety data in a formal decision-analytic framework to assist decision makers in allocating scarce healthcare resources.     

Identification of proteinaceous material in the bone of the dinosaur Iguanodon

This study has directed attention at the search for bone-related proteins in an extract of demineralized rib bone of the 120 mya Iguanodon. The inner compact bone was demineralized and the GuCl extract resolved into 11 fractions using anion exchange chromatography, which all contained silver-reactive proteins with various amino acid profiles. Two specific fractions, iv and xi, revealed characteristics typical of contemporary phosphoproteins and proteoglycans, respectively. Fraction iv, 43-57 kDa, contained a high ratio of aspartate and serine, although no phosphate was discernable. Fraction xi contained a band of 41-47 kDa and was rich in chondroitin sulphate and hyaluronan. In addition an early eluting fraction was immunoreactive with an antibody against osteocalcin. A cancellous bone fraction from the same bone sample was also analyzed using N-terminal sequencing and revealed potential similarities with cystatin. While we do not claim to have identified the presence of intact proteins, this study has value in demonstrating that extruded extracellular matrix is protected by its capacity to induce mineralization, which subsequently is important in conserving detectable protein products in ancient skeletal tissues.