The New Political History

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66569/2/10.1177_000276427702100204.pd

Antisense PMO cocktails effectively skip dystrophin exons 45-55 in myotubes transdifferentiated from DMD patient fibroblasts

Antisense-mediated exon skipping has made significant progress as a therapeutic platform in recent years, especially in the case of Duchenne muscular dystrophy (DMD). Despite FDA approval of eteplirsen-the first-ever antisense drug clinically marketed for DMD-exon skipping therapy still faces the significant hurdles of limited applicability and unknown truncated protein function. In-frame exon skipping of dystrophin exons 45-55 represents a significant approach to treating DMD, as a large proportion of patients harbor mutations within this "hotspot" region. Additionally, patients harboring dystrophin exons 45-55 deletion mutations are reported to have exceptionally mild to asymptomatic phenotypes. Here, we demonstrate that a cocktail of phosphorodiamidate morpholino oligomers can effectively skip dystrophin exons 45-55 in vitro in myotubes transdifferentiated from DMD patient fibroblast cells. This is the first report of substantive exons 45-55 skipping in DMD patient cells. These findings help validate the use of transdifferentiated patient fibroblast cells as a suitable cell model for dystrophin exon skipping assays and further emphasize the feasibility of dystrophin exons 45-55 skipping in patients

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy.This article is freely available via Open Access

Experience from early tort reforms: comparative negligence since 1974

Abstract: Insurance consumers in states that have adopted comparative negligence pay more for automobile liability insurance than do consumers in states that retain contributory negligence. Through the use of a transformed generalized least squares regression model, allowance is made for: no-fault, population density, state-specific price-level, and automobile safety/fatality differences. States with pure comparative have much higher costs than do states with modified comparative negligence; states with modified comparative have higher costs than those with contributory negligence. The influence of alternative liability rules on the cost of insurance is of public concern. In recent years many states have changed from contributory negligence to either pure or modified comparative negligence. This article examines the cost of automobile insurance under three liability rules. The authors conclude that states with either type of comparative negligence have higher automobile insurance costs. Article: Negligence Standards Contributory negligence provides that in order to be awarded damages, plaintiffs must be free of fault, however slight, in causing those damages. As recently as 1970, 38 states had contributory negligence rules. Only five states retain a contributory negligence tandard. Under a system of pure comparative negligence, a contributorily negligent plaintiff "may recover even though his negligence was greater than [the] defendant's but his damage award will be reduced in proportion to the amount of negligence attributable to him" Still other states do not bar recovery if the plaintiff is as much as half responsible; (the "50 Percent Rule"). In this study observations are classified as contributory; modified comparative, including slight/gross, 49 percent, and 50 percent; and pure comparative negligence. Morale Hazard and Liability Rules Research concerning the efficiency of alternative liability rules has been done by The insurance premium includes factors representing each of the social costs of accidents, although it cannot be argued that the insurance mechanism absorbs all accident costs. Insurance premiums include some of the cost of loss prevention. (2) Liability insurance contracts include the defendant's legal costs. Likewise it is presumed that awards or settlements include a plaintiff's legal costs. Indeed, it is strongly argued by the plaintiff bar that the contingency fee system meets social equity goals by providing access to the judicial system. Finally, even with the existence of insurance, there will almost certainly be a residual disutility not captured in the insurance premium due to inadequate limits and uninsured persons. Research Objective The research purpose is to identify and measure any automobile insurance cost differentials between negligence standards. Only the cost of automobile insurance is cosidered. Attitude differences, safety implications, and administrative costs that are not included in the insurance premium are beyond the scope of this article. No effort is made to measure the benefits of the negligence systems; only the costs are measured. Dependent Variables Two dependent variables were used: total system bodily injury pure premium (BIPP), including basic and excess liability limits, medical payments, and uninsured motorist protection; and total system bodily injury and property damage pure premium (BIPDPP). The dates in Independent Variables The explanatory independent variables used in this study control for extraneous effects. These variables are whether or not the state has no fault insurance, the state's relative population density, interstate and time trend differences in the price level (using manufacturing wages as a proxy), and the relative safety and driving conditions in the 47 states. Each of the independent variables is discussed later. The null hypothesis tested is that comparative negligence standards, either pure or modified, have had no effect on the cost of automobile insurance. Research Methods The states were classified as traditionals fault states or no-fault states. The classification of no fault states included true no fault states, add-on no-fault states, and optional no fault states Results The results of the ordinary least squares (OLS) model are shown in Summary and Conclusions These data indicate that states with comparative negligence standards have higher automobile insurance costs. The research findings clearly indicate that those states which retain contributory negligence should undertake a change only after recognizing the ccost differentials. It should be emphasized that this study considers only automobile insurance costs. The qualitative arguments in favor of comparative negligence standards are compelling and may outweigh the costs identified here

Social stress induces neurovascular pathology promoting depression

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depressio