Pharmacological Enhancement of Neuronal Survival

This article is a comprehensive assessment of the quantitative features of the dose response for neuroprotective agents and their underlying mechanistic foundations. The data were derived from published studies using numerous primary neuronal cell cultures and neuronal cell lines. These biological models assessed normal developmental and aging processes, preconditioning adaptive responses, and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. The nature of the dose response was generally U-shaped with quantitative features similar to the hormetic dose-response model and independent of biological model, endpoint measured, and chemical class. The agents displaying the U-shaped dose response for neuronal survival include numerous endogenous agonists, plant-derived agents, synthetic drugs, and widely used chemicals including potent neurotoxins. That neuroprotective agents display similar dose-response relationships regardless of experimental system, potency, and endpoint is an important observation with widespread biomedical and clinical implications.     

The Future of Hormesis: Where Do We Go from Here?

Although the occurrence of U-shaped dose responses in toxicology (i.e., hormetic effects) have been known for more than a century, the concept of hormesis has long been marginalized under the belief that such observations could be explained by a combination of poor study designs and normal variability. However, recent efforts have established that numerous highly reliable studies demonstrating hormetic effects exist and that such findings appear to be highly generalizable across species, endpoint measures, and class of agents assessed. In light of such a long and complicated history, and its significant biomedical/toxicological implications, this article explores the unique challenges that the concept of hormesis confronts in both the experimental and institutional domains with respect to assessing its scientific foundations and validity and the impediments to its intstitutional acceptance and use with society. This perspective is then immediately critiqued by five authors in subsequent articles.     

Inorganics and Hormesis

The article is a comprehensive review of the occurrence of hormetic dose-response relationships induced by inorganic agents, including toxic agents, of significant environmental and public health interest (e.g., arsenic, cadmium, lead, mercury, selenium, and zinc). Hormetic responses occurred in a wide range of biological models (i.e., plants, invertebrate and vertebrate animals) for a large and diverse array of endpoints. Particular attention was given to providing an assessment of the quantitative features of the dose-response relationships and underlying mechanisms that could account for the biphasic nature of the hormetic response. These findings indicate that hormetic responses commonly occur in appropriately designed experiments and are highly generalizeable with respect to biological model responses. The hormetic dose response should be seen as a reliable feature of the dose response for inorganic agents and will have an important impact on the estimated effects of such agents on environmental and human receptors.     

Associations of mitochondrial DNA copy number with incident risks of gastrointestinal cancers: A prospective case–cohort study

Epidemiological investigations implied that mitochondrial DNA copy number (mtDNAcn) variations could trigger predisposition to multiple cancers, but evidence regarding gastrointestinal cancers (GICs) was still uncertain. We conducted a case-cohort study within the prospective Dongfeng-Tongji cohort, including incident cases of colorectal cancer (CRC, n = 278), gastric cancer (GC, n = 138), and esophageal cancer (EC, n = 72) as well as a random subcohort (n = 1173), who were followed up from baseline to the end of 2018. We determined baseline blood mtDNAcn and associations of mtDNAcn with the GICs risks were estimated by using weighted Cox proportional hazards models. Significant U-shaped associations were observed between mtDNAcn and GICs risks. Compared to subjects within the second quartile (Q2) mtDNAcn subgroup, those within the 1st (Q1), 3rd (Q3), and 4th (Q4) quartile subgroups showed increased risks of CRC (hazard ratio [HR] [95% confidence interval, CI] = 2.27 [1.47–3.52], 1.65 [1.04–2.62], and 2.81 [1.85–4.28], respectively) and total GICs (HR [95%CI] = 1.84 [1.30–2.60], 1.47 [1.03–2.10], and 2.51 [1.82–3.47], respectively], and those within Q4 subgroup presented elevated GC and EC risks (HR [95% CI] = 2.16 [1.31–3.54] and 2.38 [1.13–5.02], respectively). Similar associations of mtDNAcn with CRC and total GICs risks remained in stratified analyzes by age, gender, smoking, and drinking status. This prospective case-cohort study showed U-shaped associations between mtDNAcn and GICs risks, but further research works are needed to uncover underlying biological mechanisms.     

Corrosion-Fatigue Life Prediction of the U-Shaped Beam in Urban Rail Transit under a Chloride Attack Environment

The coupled effect of the chloride attack environment and train load seriously affects the safety and durability of urban rail transit viaducts and dramatically reduces their service life. In this research, a corrosion-fatigue life prediction model of the prestressed concrete (PC) beam under the coupled effect of the chloride attack environment and train load was developed. This proposed model was illustrated by a 30 m-span PC U-shaped beam in an urban rail transit viaduct. The competitive relationship between concrete fatigue cracking time, non-prestressed reinforcement corrosion initiation time, and concrete corrosion-induced cracking time was discussed. The effects of train frequency, the chloride attack environment grade, and the environmental temperature and relative humidity were investigated on corrosion-fatigue life. Results indicate that train frequency, the chloride attack environment grade, and the environmental temperature can reduce the corrosion-fatigue life of a U-shaped beam by up to 30.0%, 50.7%, and 21.5%, respectively. A coupled chloride attack environment and train frequency can reduce the corrosion-fatigue life by up to 61.2%. Distinct from the environmental temperature, the change of relative humidity has little effect on the corrosion-fatigue life of the U-shaped beam.     

改良U型分牙簧对牙列拥挤及上颌前突正畸患者的临床应用研究

目的 分析改良U型分牙簧对牙列拥挤及上颌前突正畸患者的临床治疗效果. 方法 将前牙拥挤及上颌前突的患者90例随机分为MBT矫治技术组( A组)、OPA-K矫治技术组( B组)及改良U型分牙簧配合改良前庭盾口外支抗组(C组),每组30例,分析3组的治疗效果. 结果 A 组总有效率为66.7%,B 组为72.3%,C 组为93.3%,C 组疗效最好(P<0.05);A组治疗时间为(39.4 ±4.2)d,B组为(42.1 ±3.9)d,C组为(30.9 ±4.5)d,C组治疗时间最短(P<0.05); A组视觉模拟评分法评分为(7.62 ±1.66)分,B组为(5.89 ±1.53)分,C组为(3.52 ±1.02)分,C组评分最低(P<0.05). 结论 改良U型分牙簧为牙列拥挤及上颌前突正畸患者供了一种痛苦小、疗效好、治疗时间较短的新型矫治技术,值得推广应用.     

Adaptation and Sensitization to Proteotoxic Stress

Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.     

AERs and Detection in Tasks Yielding U-Shaped Backward Masking Functions

In backward masking, psychophysical performance varies as a function of the interval between target and mask (stimulus onset asynchrony—SOA). Early studies of averaged evoked responses (AERs) and backward masking suggested a close, monotonic relationship, i.e., increasing psychophysical performance accompanied by increasingly larger AERs as a function of SOA. We asked what would happen to AERs if the perceptual task were designed to produce a U-shaped performance function, i.e., one in which performance initially decreased and then increased as a function of SOA? In two experiments U-shaped psychophysical performance was accompanied by monotonic AER functions. In a third experiment, comparing backward and forward masking at comparable SOAs, disparate psychophysical performances were obtained from the same subjects accompanied by similar AERs. Target AERs do not necessarily correlate with a subject's behavioral performance.     

自制U形水枕在玻璃体切除术后体位护理中的应用

目的探讨自制U形水枕在玻璃体切除眼内硅油充填术后的护理应用价值。方法回顾性分析60例视网膜脱离患者行玻璃体切除眼内硅油充填术后应用自制U形水枕的临床资料,观察术后视网膜复位情况。结果所有入组的60例视网膜脱离患者中,57例(95.0%)视网膜复位良好,2例(3.3%)发生眼内出血,仅1例(1.7%)再次出血视网膜脱离,术后并发症发生率和复发率分别仅为5.0%和1.7%。结论玻璃体切除眼内硅油充填术后患者应用自制U形水枕可提高患者舒适度,降低术后并发症和复发率,明显改善患者预后。     

U形软枕在妇科腹部手术后病人中的应用

目的探讨U形软枕在妇科腹部手术后病人中的应用效果。方法将100例妇科腹部术后病人随机分为观察组50例和对照组50例,观察组术后病人枕部给予垫U形软枕,对照组术后病人体位为去枕平卧位。观察两组病人头痛、呕吐、颈部肌肉酸痛等症状。结果两组病人术后头痛、呕吐症状比较,差异无统计学意义（均P〉0．05）;而颈肌疼痛不适症状观察组病人明显低于对照组,两组比较,差异具有统计学意义（P〈0．05）。结论妇科腹部手术后病人采用U形软枕卧位可明显改善术后病人颈肌疼痛不适,对术后病人头痛、呕吐无影响,具有一定的安全性,值得临床推广和应用。