Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

Psychological well‐being and psychosocial work environment characteristics among emergency medical and nursing staff

The aim of this study was to determine if the effect of psychosocial work environment on psychological well‐being was different for doctors and nurses who work in emergency departments in Spain. A cross‐sectional survey was carried out among 945 emergency doctors and nurses staff from Spain. The outcome variable was the psychological well‐being measured by two dimensions of SF‐36 Health Survey (SF‐36) (mental health, vitality) and one dimension of Maslach's Burnout Inventory (emotional exhaustion). The explanatory variable was the psychosocial work environment evaluated according to Karasek and Johnson's demand‐control model that includes the dimensions of psychological demands, job control, supervisor social support and co‐workers' social support. The adjusted odds ratios and their 95 per cent confidence intervals were calculated by logistic regression. The prevalence of low vitality, bad mental health and high emotional exhaustion was higher among doctors than nurses. Exposure to high psychological demands increased the probability of low vitality, bad mental health and high emotional exhaustion among doctors and nurses. Low job control and low co‐workers' social support at work were associated with poor psychological well‐being only among doctors. Low job supervisors' social support increased the risk of bad mental health among doctors and of high emotional exhaustion among nurses. There is a different effect of psychosocial work environment on psychological well‐being between doctors and nurses. Copyright © 2007 John Wiley & Sons, Ltd.     

Mental stress-induced myocardial ischemia in coronary artery disease patients with left ventricular dysfunction

Background  Reduced left ventricular ejection fraction (LVEF) is a risk factor for poor outcomes in patients with coronary artery disease (CAD). Mental stress-induced myocardial ischemia (MSIMI) also identifies a subset of CAD patients at increased risk for future cardiovascular events. Susceptibility to MSIMI in patients with CAD and reduced LVEF is unknown. Methods and Results  We enrolled 182 patients (67 women) with a mean age of 64 years and a documented history of CAD in this study. Baseline resting ejection fraction was determined by use of technetium 99m sestamibi gated single photon emission computed tomography. Abnormal LVEF was defined as less than 45% for men and less than 50% for women (based on published norms for our software [Cedars-Sinai Medical Center]). All participants underwent mental stress testing with a public speaking task. Rest/stress myocardial perfusion single photon emission computed tomography was performed via conventional methodology. Images were visually compared for number and severity of perfusion defects by use of a scoring method from 0 to 4. A summed difference score was calculated as the difference between summed stress and rest scores. A score of greater than 3 was considered abnormal. MSIMI developed in 19% of patients with normal LVEF and 31% of those with reduced LVEF. There is no statistically significant difference between the two groups (P=.11). Conclusions  CAD patients with left ventricular dysfunction are equally susceptible to MSIMI as those with normal LVEF. This study was supported by grants HL 070265 and HL 072059 from the National Heart. Lung, and Blood Institute. This material is also the result of work supported by resources and with the use of facilities at the Department of Veterans. Affairs Medical Center, Gainesville, Fla.     

Perceived occupational stress,affective, and physical well-being among telecommunication employees in Greece

The present study examined four potential roles of work-related negative affectivity on the associations between self-reported occupational stress and physical well-being among telecommunication employees in Greece. Participants (764, predominantly male) completed a battery of self-report measures on perceived occupational stress, negative affectivity, and illness symptoms. In line with previous research, negative affectivity exerted a nuisance effect, by inflating the association between reported stressors and illness symptoms, and significantly predicted illness symptoms, over and above the effects of stressors. In addition, negative affectivity influenced reported illness symptom indirectly, through the effects of stressors, and moderated the relationship between interpersonal conflict at work and illness symptoms. The findings suggest that negative affectivity can largely explain and influence in different ways the associations between self-reported stress and physical strain. It is recommended that future studies of occupational stress should control for the effects of negative affectivity, and that health professionals should be cautious of its effects when interpreting relationships between self-reported occupational stress and physical well-being.     

恐惧应激对大鼠睾丸中Annexin5表达的影响

目的观察大鼠应激条件下睾丸组织中Annexin5表达的变化。方法建立SD大鼠的恐惧应激模型，分别取急性应激、急性对照、慢性应激、慢性对照SD大鼠睾丸，免疫组织化学和Western blotting分析Annexin5免疫定位和蛋白表达。结果急性应激组与对照组相比，免疫组化显示Annexin5都定位在间质细胞、支持细胞和成熟的精子头部，Western blotting分析发现Annexin5的表达降低了10．8％；慢性应激组与对照组相比，免疫组化结果显示Annexin5在精子头部的定位逐渐减少，应激1w和2w组，未见到Annexin5定位于精子头部，到了应激的3w和4w，发现Annexin5重新定位于精子的头部，而在间质细胞和支持细胞上的定位模式没有显著变化。Western blotting分析发现Annexin5的表达降低了17．4％。结论大鼠睾丸Annexin5参与了应激过程，急性应激条件下Annexin5表达降低。随着应激时间的延长，在慢性应激条件下，Annexin5的表达由减少之后而开始有缓慢增加。     

Children and work‐related stress among physicians

The aim of this study was to analyse the influence of gender and children on physicians' stress and burnout and to obtain information on the compromises physicians make between family and work. The study was based on a nationwide survey of 3313 Finnish physicians. The results showed that work was the commonest reason for stress for both male and female physicians. If physicians had children, combining work and family was the commonest reason for stress among the women, but work still remained the commonest reason for stress among the men. The female physicians had made compromises between family and work more often than the male physicians (limited the number of children, delayed having children, given up postgraduate or continuing medical education, worked part‐time because of family, and given up a job because of a spouse's need to move). The female physicians—with or without children—were more likely than the male physicians to experience severe or moderate exhaustion and less likely than the male physicians to experience cynicism as components of burnout. Among both genders of physicians, having children was associated with less cynicism and reduced personal accomplishment, but the children did not affect exhaustion. In conclusion, having children is associated with a lower level of some burnout symptoms. Additional studies are needed to explain the health effects of work–family balance for physicians. Copyright © 2004 John Wiley & Sons, Ltd.     

JNK通路可能介导MPTP诱导的黑质神经元凋亡

目的 探讨氧化应激激活的c-jun NH2-terminal kinase(JNK)细胞凋亡通路在1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)诱导帕金森病(PD)小鼠黑质神经元凋亡中的可能作用。方法 采用MPTP制备PD小鼠模型，应用生化技术检测黑质区域谷胱甘肽(GSH)浓度及超氧化物歧化酶(SOD)活力，尼氏体染色和酪氨酸羟化酶(TH)免疫组织化学染色观察黑质神经元的损害情况，原位缺口末端标记(TUNEL)染色和活化型Caspase 3免疫组织化学染色观察黑质神经元的凋亡情况，同时采用蛋白兔疫印迹法检测磷酸化JNK及磷酸化c-jun蛋白表达水平。结果 MPTP诱导的PD小鼠黑质区域GSH浓度明显降低，SOD活力明显升高，黑质致密带尼氏体阳性神经元和TH阳性神经元显著脱失，磷酸化JNK及磷酸化c-jun蛋白表达水平上升，同时活化型Caspase 3表达阳性细胞增多，黑质神经元TUNEL染色的阳性率增高。结论 MPTP可诱导小鼠黑质神经元凋亡，机制与增强氧化应激并激活JNK细胞凋亡通路有关。     

Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder.

BACKGROUND: Unsupervised fuzzy clustering (UFC) analysis is a mathematical technique that groups together objects in the multidimensional feature space according to a specified similarity measurement, thereby yielding clusters of similar data points that can be represented by a set of prototypes or centroids. METHODS: Since clinical studies of mental disorders distinguish between affected and unaffected individuals, we designed an inclusion/exclusion criteria (cutoff behavioral criteria [CBC]) approach for animal behavioral studies. The effect of classifying the study population into clearly affected versus clearly unaffected individuals according to behaviors on two behavioral paradigms was statistically significant. RESULTS: Here the raw data from previous studies were subjected to UFC algorithms as a means of objectively testing the validity of the concept of the CBC for our experimental model. The first UFC algorithm yielded two clearly discrete clusters, found to consist almost exclusively of the exposed animals in the one and unexposed animals in the other. The second algorithm yielded three clusters corresponding to animals designated as clearly affected, partially affected, and clearly unaffected. The algorithm for physiological data in addition to behavioral data failed to elicit discrete clusters. CONCLUSIONS: The UFC analysis yielded data that support the conceptual contention of the CBC and lends additional validity to our previous behavioral studies.     

氧化反应对糖尿病大鼠造影剂肾病发生的影响

目的 :探讨氧化反应对糖尿病大鼠造影剂肾病发生的影响。方法 :建立SD大鼠糖尿病动物模型 ,8w后分 3组 :正常对照组 (SD组 )、糖尿病对照组 (DM组 )和糖尿病 +造影剂组 (CM组 )。其中CM组大鼠经尾静脉一次性注入 76%泛影葡胺 ( 10ml/kg体重 ,3gI(iodine) /10ml) ,DM组注射等量生理盐水。 3d后收集血标本检测血肌酐、血尿素氮 ;取肾脏组织 ,测定肾组织丙二醛 (MDA)与超氧化物歧化酶 (SOD)的含量。结果 :与正常对照组相比 ,糖尿病组 (DM组 )的MDA含量与SOD活性均明显升高 (P <0 .0 5 ) ;糖尿病大鼠注射造影剂 (CM组 ) 3d后MDA含量明显增加 ,SOD活性明显降低 ,与DM组差异有显著性 (P <0 .0 5 )。结论 :糖尿病大鼠造影剂肾病发生时 ,肾脏组织产生过氧化物增多、清除能力下降 ,提示氧化反应对糖尿病造影剂肾病的发生起一定作用     

Psychosocial factors at work and perceived health among agricultural meat industry workers in France

Objective  The objective of this study was to describe the perceived health status of the meat industry employees—i.e., working in the slaughtering, cutting, and boning of large animals and poultry—and its relation to their organisational and psychosocial constraints at work. Methods  This postal survey included all 3,000 employees of the meat industry (beef, pork and poultry) in four districts in Brittany, France, whose companies were affiliated with the agricultural branch of the national health insurance fund. The questionnaire asked for social and demographic data and information describing their job and the organisation of their work. The psychosocial factors at work were described according to Karasek’s questionnaire (demand, latitude and social support at work). Perceived health was measured with the Nottingham Health Profile perceived health indicator. Results  This study shows the high prevalence of poor health reported by the workers in this industry. This poor perceived health was worse in women and increased regularly with age. Among the psychosocial factors studied, high quantitative and qualitative demand at work, inadequate resources for good work and to a lesser extent, inadequate prospects for promotion appear especially associated with poor perceived health. Other factors often associated with poor perceived health included young age at the first job and work hours that disrupt sleep rhythms (especially for women). Conclusion  Our results show that this population of workers is especially vulnerable from the point of view of perceived physical and psychological health and is exposed to strong physical, organisational and psychosocial constraints at work. They also demonstrate that poor perceived health is associated with some psychosocial (such as high psychological demand and insufficient resources) and organisational factors at work. These results, in conjunction with those from other disciplines involved in studying this industry, may help the companies to develop preventive activities.