ELECTRIC STIMULATION OF A TRANSSECTED NERVE DOES NOT SEEM TO PREVENT LOSS OF SENSORY NEURONS: AN EXPERIMENTAL STUDY IN CATS

Injury to a sensory nerve often results in a clinically poor long term outcome, possibly as a result of the extensive loss of neurons within the dorsal root ganglia (DRG), which has been shown in several experimental studies. This loss is possibly caused by interruption of the sensory input and axonal transport in the damaged afferent nerve. To investigate the importance of sensory afferent input into a nerve a pulsed electric stimulation was applied on the proximal part of the superficial radial nerve after transsection and microsurgical repair. The purpose was to simulate nerve impulses and thereby mask the severity of the injury. To test this hypothesis a pilot study was undertaken in eight cats. The neuronal tracer showed that the median neuronal loss was 38% of the neurons of the dorsal root ganglia that received afferents from the nerve investigated, which corresponds to the figure in a previous study in which electric stimulation was not used. Artificial sensory stimulation during regeneration in a transsected and repaired peripheral nerve therefore does not seem to reduce neuronal loss.     

Age as a Critical Determinant of Atrial Fibrillation: A Two-sided Relationship

The incidence of atrial fibrillation (AF), the most common sustained arrhythmia and a major public health burden, increases exponentially with age. However, mechanisms underlying this long-recognized association remain incompletely understood. Experimental and human studies have demonstrated the involvement of aging in several arrhythmogenic processes, including atrial electrical and structural remodelling, disturbed calcium homeostasis, and enhanced atrial ectopic activity/increased vulnerability to re-entry induction. Given this wide range of putative mechanisms, the task of delineating the specific effects of aging responsible for AF promotion is not simple, as aging is itself associated with increasing prevalence of a host of AF-predisposing conditions, including heart failure, coronary artery disease, and hypertension. Although we usually think of old age promoting AF, there is also evidence that young age may actually have a protective effect against AF occurrence. For example, the low AF incidence among populations of young patients with significant structural congenital heart disease and substantial atrial enlargement/remodelling suggests that younger age might protect against fibrillation in the diseased atrium; efforts at understating how younger age may prevent AF might be helpful in elucidating missing mechanistic links between AF and age. The goal of this paper is to review the epidemiologic and pathophysiologic evidence regarding mechanisms underlying age-related AF. Although the therapeutic options for AF have recently improved, major gaps still remain and a better understanding of the special relationship between age and AF may be important for the identification of new targets for therapeutic innovation.     

mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels

Mechanistic target of rapamycin (mTOR) is a master regulator of cell growth through its ability to stimulate ribosome biogenesis and mRNA translation. In contrast, the p53 tumor suppressor negatively controls cell growth and is activated by a wide range of insults to the cell. The mTOR and p53 signaling pathways are connected by a number of different mechanisms. Chemotherapeutics that inhibit ribosome biogenesis often induce nucleolar stress and activation of p53. Here we have investigated how the p53 response to nucleolar stress is affected by simultaneous mTOR inhibition in osteosarcoma and glioma cell lines. We found that inhibitors of the mTOR pathway including rapamycin, wortmannin, and caffeine blunted the p53 response to nucleolar stress induced by actinomycin D. Synthetic inhibitors of mTOR (temsirolimus, LY294.002 and PP242) also impaired actinomycin D triggered p53 stabilization and induction of p21. Ribosomal protein (RPL11) is known to be required for p53 protein stabilization following nucleolar stress. Treatment of cells with mTOR inhibitors may lead to reduced synthesis of RPL11 and thereby destabilize p53. We found that rapamycin mimicked the effect of RPL11 depletion in terms of blunting the p53 response to nucleolar stress. However, the extent to which the levels of p53 and RPL11 were reduced by rapamycin varied between cell lines. Additional mechanisms whereby rapamycin blunts the p53 response to nucleolar stress are likely to be involved. Indeed, rapamycin increased the levels of endogenous MDM2 despite inhibition of its phosphorylation at Ser-166. Our findings may have implications for the design of combinatorial cancer treatments with mTOR pathway inhibitors.     

Selenium Cytotoxicity in Cancer

Selenium is an essential trace element with growth‐modulating properties. Decades of research clearly demonstrate that selenium compounds inhibit the growth of malignant cells in diverse experimental model systems. However, the growth‐modulating and cytotoxic mechanisms are diverse and far from clear. Lately, a remarkable tumour selective cytotoxicity of selenium compounds has been shown, indicating the potential of selenium in the treatment of cancer. Of particular interest are the redox‐active selenium compounds exhibiting cytotoxic potential to tumour cells. These selenium compounds elicit complex patterns of pharmacodynamics and pharmacokinetics, leading to cell death pathways that differ among compounds. Modern oncology often focuses on targeted ligand‐based therapeutic strategies that are specific to their molecular targets. These drugs are initially efficient, but the tumour cells often rapidly develop resistance against these drugs. In contrast, certain redox‐active selenium compounds induce complex cascades of pro‐death signalling at pharmacological concentrations with superior tumour specificity. The target molecules are often the ones that are important for the survival of cancer cells and often implicated in drug resistance. Therefore, the chemotherapeutic applications of selenium offer great possibilities of multi‐target attacks on tumour cells. This MiniReview focuses on the tumour‐specific cytotoxic effects of selenium, with special emphasis on cascades of cellular events induced by the major groups of pharmacologically active selenium compounds. Furthermore, the great pharmacological potential of selenium in the treatment of resistant cancers is discussed.     

The Cost-Effectiveness of the Kiva Antibullying Program: Results from a Decision-Analytic Model

Bullying causes substantial suffering for children and adolescents. A number of bullying prevention programs have been advocated as effective methods for counteracting school bullying. However, there is a lack of economic evaluations of bullying prevention programs assessing the “value for money.” The aim of this study was to assess the cost-effectiveness of the Finnish bullying prevention program KiVa in comparison to “status quo” (treatment as usual) in a Swedish elementary school setting (grades 1 to 9). The cost-effectiveness analysis was carried out using a payer perspective based on a Markov cohort model. The costs of the program were measured in Swedish kronor and Euros, and the benefits were measured using two different metrics: (1) the number of victim-free years and (2) the number of quality adjusted life years (QALYs). Data on costs, probability transitions, and health-related quality of life measures were retrieved from published literature. Deterministic and probabilistic sensitivity analyses were carried out to establish the uncertainty of the cost-effectiveness results. The base-case analysis indicated that KiVa leads to an increased cost of €829 for a gain of 0.47 victim-free years per student. In terms of the cost per gained QALY, the results indicated a base-case estimate of €13,823, which may be seen as cost-effective given that it is lower than the typically accepted threshold value in Swedish health policy of around €50,000. Further research is needed to confirm the conclusions of this study, especially regarding the treatment effects of KiVa in different school contexts.     

Aetiology of severe mental retardation and further genetic analysis by high‐resolution microarray in a population‐based series of 6‐ to 17‐year‐old children

Aim: To investigate the prevalence, co‐morbidities and aetiologies of severe mental retardation (SMR) in a cohort of Swedish children and to further penetrate aetiologies in the group with undetermined causes by application of updated clinical‐genetic methods. Methods: The study was population‐based and included children living in the County of Halland in western Sweden in 2004 (born 1987–1998; 46 000 children). Patients were identified through habilitation centres, paediatric clinics and school health services. Patients with unclear prenatal aetiology were investigated with single nucleotide polymorphism (SNP)‐array. Results: Severe mental retardation was identified in 133 children from 132 families, corresponding to a prevalence of 2.9 per 1000 children. There were more males than females (90:43).The aetiology was prenatal in 82 (62%), perinatal in 14 (10%) and postnatal in 8 (6%). In 29 (22 %) children, mainly males with autism, the cause could not be related to the time of birth. In the prenatal group, genetic causes dominated, but still 23 children remained undiagnosed; in 5/19 of these patients, a diagnosis could be made after SNP‐array analysis. One or more associated neurological handicaps were found in more than half of the children. Conclusion: Prevalence and co‐morbidity were similar to previous Scandinavian studies. High‐resolution chromosomal micro‐array techniques are valuable diagnostic tools, reducing the number of patients with unexplained SMR.