Abrogation of p53 function affects gadd gene responses to DNA base-damaging agents and starvation

The tumor suppressor p53 is required for induction of its downstream effector genes such as GADD45 and CIP1/WAF1 by ionizing radiation (IR). This response is probably mediated through defined p53 binding sites located in the promoter of CIP1/WAF1 and in the third intron of GADD45. In contrast, the gadd gene stress response to base-damaging agents, such as methylmethane sulfonate (MMS) or UV radiation, or medium depletion (starvation) occurs in all mammalian cells examined to date regardless of p53 status for both GADD45 and also GADD153, which is not IR-responsive in many lines with functional p53. These agents strongly induce the p53 protein and raise the possibility that, although p53 is not required for the typical "gadd" response to these agents, p53 may contribute to these non-IR stress responses. This possibility was confirmed by the finding that disruption of p53 function by transfection with dominant-negative vectors expressing HPV E6, mutant p53, or SV40 T Ag reduced the induction of GADD45 and GADD153 as measured by increases in mRNA and protein levels in human lines with wild-type p53. Similarly, induction of these genes by MMS or UV radiation was consistently stronger in the parental mouse embryo fibroblasts compared to cells derived from mice where both p53 alleles had been deleted. Similar qualitative responses were also seen for CIP1/WAF1. In agreement with reduced induction of p53-regulated genes, the G1 checkpoint activated by MMS or UV radiation was markedly abrogated in p53-wt human MCF-7 breast carcinoma cells by E6 expression. Interestingly, induction of reporter constructs driven by the GADD45 or GADD153 promoters was substantially reduced in human cells transfected with mutant p53 or E6 expression vectors or in cells lacking p53 following treatment with MMS, UV radiation, or starvation. Because neither promoter is inducible by IR, and neither contains a strong p53 binding site, these results indicate that p53 has a synergistic or cooperative role in these non-IR stress responses for both GADD45 and GADD153, and that this role is not mediated through identifiable p53-binding sites.     

Does prolonged sitting with limited legroom affect the flexibility of a healthy subject and their perception of discomfort?

This study examined for differences in subjective ratings of discomfort and comfort (Numerical Rating Scale) and objective measures of hamstring (Sit-Reach test), lumbar (Schöber’s test) and neck (Cervical Range of Motion) flexibility in healthy young subjects (n = 24) following 4 h of sitting on stacking chairs with or without limited legroom.When comparing the limited and unlimited legroom groups for differences in subjective and objective measures over 4 h, no significant findings were seen at the 5% level of confidence. However, differences in buttock, neck, shoulder and average discomfort were significantly negatively correlated to differences between post-warm up Sit-Reach scores (Correlation Co-efficients: −.763, −.434, −.408, and −.445; p values of .004, .034, .048, and .029, respectively). The difference in buttock discomfort was significantly negatively correlated to the difference between pre-warm up Sit-Reach scores (Correlation Coefficient: −.750; p = 0.005), post-sitting/pre-warm up and pre-sitting/post-warm up Sit-Reach scores (Correlation Coefficient: −.756; p = 0.004), and Schöber’s tests (Correlation Coefficient: −.578; p = 0.049).Although the above results suggest a relationship between a loss in flexibility and an increase in discomfort, the mechanism influencing this relationship is not clear from this study. What does appear clear is that the limiting of legroom to the parameters used in this study does not seem to exacerbate change in flexibility and discomfort which are a consequence of prolonged sitting.

Relevance to industry

Many forms of public transport provide limited legroom for their passengers, which may have an adverse affect on the user’s flexibility or experience of discomfort. Determining which objectively measurable parameters are associated with the subjective level of discomfort during sitting should allow for a greater appreciation of the changes that underpin such subjective perceptions.     

Towards Focused Plan Monitoring: A Technique and an Application to Mobile Robots

Until recently, techniques for AI plan generation relied on highly restrictive assumptions that were almost always violated in real-world environments; consequently, robot designers adopted reactive architectures and avoided AI planning techniques. Some recent research efforts have focused on obviating such assumptions by developing techniques that enable the generation and execution of plans in dynamic, uncertain environments. In this paper, we discuss one such technique, rationale-based monitoring, originally introduced by Veloso, Pollack, and Cox (Proceedings for the Fourth International Conference on AI Planning Systems, Pittsburgh, PA, 1998, pp. 171–179) and we describe our use of it in a simple mobile robot environment. We review the original approach, describe how it can be adapted for a causal-link planner, and provide experimental results demonstrating that it can lead to improved plans without consuming excessive overhead. We also describe our use of rationale-based monitoring in a mobile robot office-assistant project currently in progress.     

Analysis of factors contributing to success in a program of micromanipulation-assisted fertilization

OBJECTIVE: To determine factors important to clinical success in micromanipulation-assisted in vitro fertilization (IVF). DESIGN: Procedures invoked in two separate series of micromanipulation-assisted IVF cycles, one unsuccessful (series I) and the other successful (series II), were compared in an effort to identify changes that led to clinical success. SETTING: University-based IVF clinic. PATIENTS: In both IVF series involving micromanipulation, patients consisted of infertile couples who fit any of five categories of male-factor related infertility. The female patients underwent controlled hyperstimulation for oocyte retrieval and the oocytes were inseminated normally or were subjected either to partial zona dissection or subzonal sperm insertion to assist fertilization. Results in all groups were compared between the two patient series. RESULTS: In the successful series II, a noticeable improvement in fertilization rate and embryo quality was observed compared with series I. A significant increase in the percentage of patients reaching embryo transfer, the pregnancy rate per transfer, and the pregnancy rate per retrieval were noted in series II; a 25% ongoing pregnancy rate per retrieval was observed overall in this successful group, with "ongoing" defined as manifestation of at least a fetal sac on ultrasound with no detectable problems. Patients with a mixed transfer of embryos derived from manipulated and normally inseminated oocytes had a 75% rate of pregnancy per transfer in series II. Differences between the two series could not be attributed to patient selection or biases in selection of oocytes relegated to micromanipulation. However, oocyte handling, micromanipulation, and culture protocols differed significantly between the two series in that temperature and pH of oocytes was better controlled, and micromanipulation time was minimized in series II. CONCLUSION: Success in micromanipulation depends on maintenance of the oocyte in a stable and supportive environment throughout the micromanipulation procedure. It is also important to minimize trauma to the eggs by performing micromanipulation rapidly and with minimal distortion of the egg. Patients with a poor fertilization rate in standard IVF may experience a substantial increase in the likelihood of pregnancy when micromanipulation-assisted fertilization is performed on some eggs.     

Carotid endarterectomy for asymptomatic patients. Assessing results of a quantitative synthesis

Carotid endarterectomy (CE) surgery for asymptomatic patients remains controversial despite hundreds of published studies and recent randomized trials. Safety and efficacy are assessed using a quantitative synthesis method derived from meta-analysis and a "critical multiplist" inference approach. In addition, multivariate analyses reveal that use of a surgical shunt could further improve CE outcomes. Methods are examined for both their "confirmatory" and "exploratory" value.     

Acute kidney failure in hypothermia

Two cases with acute renal failure after prolonged hypothermia are presented. Both patients were found in come, became rapidly uremic and required hemodilaysis treatment. Although the laboratory findings were typical of severe muscle damage, e.g. elevated levels of serum creatinine phosphokinase, serum lactic dehydrogenase and serum aldolase activities, visible "crush-injuries" were not found. Acute renal failure was characterized by extreme catabolism and severe metabolic acidosis. After 4 and 10 hemodialyses respectively, the patients became polyuric and finally were discharges with normal renal and muscle function. Hypotension with diminished renal perfusion and nontraumatic rhabdomyolysis due to prolonged hypothermia are regarded as the dominant pathogenetic factors in the acute renal failure.     

Diagnosis and treatment of aortic valve stenosis

The present review has attempted to summarize the classic symptoms and signs of aortic valve stenosis, especially in an adult. It is emphasized that all the classic signs rarely are present and their absence may mislead an unwary clinician. The diagnostic help provided by noninvasive tests, including echocardiography and phonocardiography, has been emphasized. A need for cardiac catheterization and angiography in most patients prior to corrective surgery is stressed. The natural history of the disease without operative intervention is dim and a significant risk of sudden death exists. The current surgical approach with immediate and long-term results is summarized. Finally, attention has been drawn to the special clinical circumstances when the aortic valve stenosis provides a strinkingly different clinical picture. We cannot find a better way to end this review than by quoting a warning note given by Thomas Lewis in 1920: "It is the faint cry of an anguished and fast failing muscle, which, when it comes, all should strain to hear, for it is not long repeated. A few months, a few years at most, and the end comes."