Evidence of a U-shaped association between factor XII activity and overall survival

INTRODUCTION: The clinical relevance of decreased coagulation factor XII (FXII) plasma activity as a risk factor for both venous and arterial thrombosis is still discussed controversially. The current study evaluated the predictive value of FXII levels for all-cause mortality in a large Viennese patient cohort. PATIENTS AND METHODS: Individuals, whose FXII activity levels were determined for suspected coagulation disorders or thrombophilia screening between 1991-2003 were included in this study (n = 8936, 51% male, 49% female, median age 43 years). Death/survival was determined by record linkage with the Austrian Death Registry. The median observation period was 5 years covering a total of 46 400 person years; the death rate was 17.1%. For Cox regression analysis, FXII plasma activity was divided into 11 categories of 10% steps with the category of > 100% FXII serving as a reference category. RESULTS: With decreasing FXII plasma activity, hazard ratios for all-cause mortality gradually increased linearly from 1.0 in the > 100% category to 1.5 (95% CI: 1.2-1.9) in the 80-90% category to 4.7 (95% CI: 3.4-6.5) in the 10-20% category. Similar results were obtained, when only vascular mortality or death as a result of ischemic heart disease was considered. No significant increase in all-cause mortality (HR: 1.4, 95%CI 0.7-2.8) was observed in the small group of FXII-deficient subjects [0-10% category (n = 58)]. CONCLUSIONS: This study first demonstrates a strong and almost linear association of FXII plasma activity between 90% and 10% with all-cause mortality in a large Viennese patient cohort. Interestingly, mortality rates are not increased when FXII activity is below 10%, resulting in a U-shaped survival curve.     

Hormesis: from marginalization to mainstream: a case for hormesis as the default dose-response model in risk assessment

The paper provides an account of how the hormetic dose response has emerged in recent years as a serious dose-response model in toxicology and risk assessment after decades of extreme marginalization. In addition to providing the toxicological basis of this dose-response revival, the paper reexamines the concept of a default dose model in toxicology and risk assessment and makes the argument that the hormetic model satisfies criteria (e.g., generalizability, frequency, application to risk assessment endpoints, false positive/negative potential, requirements for hazard assessment, reliability of estimating risks, capacity for validation of risk estimates, public health implications of risk estimates) for such a default model better than its chief competitors, the threshold and linear at low dose models. The selection of the hormetic model as the default model in risk assessment for noncarcinogens and specifically for carcinogens would have a profound impact on the practice of risk assessment and its societal implications.     

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.     

Hormesis outperforms threshold model in National Cancer Institute antitumor drug screening database.

Which dose-response model best explains low-dose responses is a critical issue in toxicology, pharmacology, and risk assessment. The present paper utilized the U.S. National Cancer Institute yeast screening database that contains 56,914 dose-response studies representing the replicated effects of 2189 chemically diverse possible antitumor drugs on cell proliferation in 13 different yeast strains. Multiple evaluation methods indicated that the observed data are inconsistent with the threshold model while supporting the hormetic model. Hormetic response patterns were observed approximately four times more often than would be expected by chance alone. The data call for the rejection of the threshold model for low-dose prediction, and they support the hormetic model as the default model for scientific interpretation of low-dose toxicological responses.     

U-shaped Dose Response in Vasomotor Tone: A Mixed Result of Heterogenic Response of Multiple Cells to Xenobiotics

U-shaped response has been frequently encountered in variousbiological areas including epidemiology, toxicology, and oncology.Despite its frequent observation, the theory of U-shaped responsehas been crippled by the lack of a robust mechanism underlyingand incomplete in vitro and in vivo correlation. In the presentstudy, a novel mechanism is provided for a U-shaped response,based on the findings of agonist-induced vasomotor tone changeaffected by menadione (MEN) (synthetic vitamin K₃), a reactiveoxygen species generator, and arsenic, an environmental pollutant,which showed typical U-shaped responses in both in vitro aorticcontractile response and in vivo blood pressure. U-shaped responsesby MEN and arsenic were a combined result from heterogenic susceptibilitiesand responses of multiple target cells composing blood vessels,that is, endothelium and smooth muscle. Notably, endothelium,a regulator of vasomotor tone, was primarily affected by low-dosestimuli, whereas smooth muscle, an effector of vascular contraction,was affected later by high-dose. The dysfunction of smooth musclewas produced by high-dose MEN-induced hydrogen peroxide, resultingin the attenuation of vascular contractile reactivity, whereaslow-dose MEN-induced superoxide led to the quenching of vasodilatorynitric oxide in endothelial cells, resulting in the enhancementof vasoconstriction. This mechanistic theory, the differencein susceptibilities and responses to a common stimulus betweenregulator and effector components of a system, could give anew insight into the explanation of various U-shaped responsesand provide a new evidence for the need of the risk assessmentof toxicants with a wider dose range.     

子宫体马蹄形切除术治疗弥漫性子宫腺肌病

目的探讨子宫体马蹄形切除术在治疗弥漫性子宫腺肌病方面的可行性和安全性。方法将50例弥漫性子宫腺肌病患者分为子宫体马蹄形切除术组和全子宫切除术组,每组为25例。比较两组手术情况、术后3、6以及12个月激素水平,术后6个月性生活质量、痛经强度、糖链抗原125（CAl25）水平以及马蹄形切除术组子宫体积大小。结果全子宫切除术组后3个月E2水平较术前降低,术后6个月下降最为明显．12个月以后逐渐回升,与术前水平比较,差异有统计学意义;术后6、12个月FSH和LH水平较术前增高,差异有统计学意义。两组术后6个月痛经强度、CAl25水平以及马蹄形切除组的子宫体积均较术前下降,差异有统计学意义,全子宫切除组术后性生活质量降低。结论子宫体马蹄形切除术切除病变组织,保留子宫,不影响卵巢血供,且有效治疗子宫腺肌病。在临床可行,是治疗希望保留子宫的需行手术的弥漫性子宫腺肌病患者的首选。     

Converging concepts: adaptive response, preconditioning, and the Yerkes-Dodson Law are manifestations of hormesis

The adaptive response in toxicology and environmental mutagenesis, preconditioning in biomedicine and the Yerkes-Dodson Law in psychology have dominating research themes with widespread and significant scientific and societal implications. This paper suggests that these apparently independent biological dose-response phenomena are manifestations of the common and more general biphasic dose-response relationship concept called hormesis. These three types of dose-response, as well as the hormesis concept, may represent the same general type of adaptation, which were discovered independently in different biological disciplines, amongst which there has been little communication. This intellectual isolation, due principally to progressively greater disciplinary specialization, resulted in the evolution of different terminologies for dose-response phenomena with strikingly similar quantitative features. This lack of recognition of converging dose-response concepts across disciplines has important implications since it limits the recognition of a common and basic biological concept while minimizing collaborations by investigators in related areas. The paper concludes that the broadly recognized biological adaptive responses, as described by the concepts of adaptive response, preconditioning and the Yerkes-Dodson Law, are special cases of the more general hormesis dose-response concept.     

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.