半乳糖凝集素1与动脉粥样硬化风险之间的因果关联:一项两样本孟德尔随机化研究

目的]探讨遗传预测的半乳糖凝集素1(Gal-1)水平与动脉粥样硬化(As)之间的因果关联。 [方法]采用两样本孟德尔随机化(MR)研究方法,选择与Gal-1相关联的单核苷酸多态性(SNP)位点作为工具变量(IV),评估遗传预测的循环Gal-1水平与不同部位As风险的因果关联。 [结果]逆方差加权法(IVW)分析结果显示,经过Bonferroni校正后遗传预测的循环Gal-1水平与外周动脉粥样硬化及其他部位动脉粥样硬化(除外脑动脉、冠状动脉及外周动脉)的风险呈正相关(OR=1.6,5%CI:1.05～1.27,P＝0.002;OR=1.16,95%CI:1.12～1.20,P＝4.11E－17),而与冠状动脉粥样硬化和脑动脉粥样硬化发生风险均未发现存在因果关联的证据(OR=1.02,95%CI:0.91～1.14,P＝0.765;OR=1.10,95%CI:0.94～1.29,P＝0.220);在应用荟萃分析合并上述不同部位As的效应值后,遗传预测的循环Gal-1水平与As风险呈正相关(OR=1.12,95%CI:1.06～1.19)。 [结论]遗传预测的循环Gal-1水平与As的发病风险存在因果关联,Gal-1是预防As发生的潜在靶点。     

心房颤动与肠道恶性肿瘤因果关系的孟德尔随机化研究

目的:探讨心房颤动(AF)与肠道恶性肿瘤的因果关系。方法:运用单变量孟德尔随机化和全基因组关联研究(GWAS)结合超过100万名受试者的6项相关GWAS研究针对AF鉴定单核苷酸多态性(SNPs)。主要采用逆方差加权(IVW)方法进行孟德尔随机化分析。结果:单变量孟德尔随机化证实AF遗传易感性与结肠恶性肿瘤[OR=1.12,95%CI(1.00,1.25),P=0.043]以及小肠恶性肿瘤[OR=1.34,95%CI(1.04,1.74),P=0.025]风险增加存在明显的因果联系。结论:AF遗传易感性与肠道恶性肿瘤有潜在因果关系,为心血管疾病与消化道肿瘤的治疗和预防提供参考。     

不饱和脂肪酸与炎症性肠病因果关系的孟德尔随机化分析

背景：炎症性肠病（IBD）是一种慢性复发性胃肠道炎症性疾病，包括溃疡性结肠炎（UC）和克罗恩病（CD）。目前尚不清楚不饱和脂肪酸与IBD之间是否存在因果关系。目的：采用两样本孟德尔随机化分析探究不饱和脂肪酸与IBD之间的因果关系。方法：不饱和脂肪酸和IBD的全基因组关联研究（GWAS）数据均来源于网络公开数据库。采用逆方差加权分析法进行两样本孟德尔随机化分析，使用加权中位数法和MR-Egger回归分析验证因果效应，以OR及其95%CI评价不饱和脂肪酸与IBD风险的因果关系。结果：ω-6脂肪酸与CD无直接因果关系，与UC有直接因果关系，逆方差加权分析结果显示ω-6脂肪酸基因水平每增加一个标准差，UC风险增加16%(OR=1.16,95%CI:1.00～1.36,P=0.04)。而ω-3脂肪酸、单不饱和脂肪酸与IBD之间均未发现因果关系。结论：ω-6脂肪酸可能仅与UC存在因果关系，ω-3脂肪酸、单不饱和脂肪酸与IBD之间均未发现因果关系。     

血脂与心力衰竭风险的因果关系及冠状动脉疾病的中介作用：一项孟德尔随机化研究

目的 利用孟德尔随机化分析方法,探究血脂与心力衰竭风险之间的因果关系及冠状动脉疾病的潜在中介效应。方法 主要采用逆方差加权方法,对欧洲人群中的血脂水平(包括甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、载脂蛋白A1和载脂蛋白B)与心力衰竭的因果关系进行单变量孟德尔随机化分析。此外,采用中介分析方法探究冠状动脉疾病的潜在中介效应。结果 单变量孟德尔随机化分析结果显示,血脂与心力衰竭风险之间存在显著关联。其中甘油三酯(OR=1.15,95%CI 1.09～1.21)、低密度脂蛋白胆固醇(OR=1.15,95%CI 1.05～1.25)和载脂蛋白B(OR=1.16,95%CI 1.07～1.26)水平的升高与心力衰竭风险呈正相关。此外,高密度脂蛋白胆固醇(OR=0.88,95%CI 0.84～0.93)和载脂蛋白A1(OR=0.92,95%CI 0.87～0.97)水平的升高与心力衰竭风险呈负相关。敏感性分析验证了以上结果的稳健性。中介分析结果显示冠状动脉疾病在甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、载脂蛋白A1、载脂蛋白B与心力衰竭风险的因果关系中起到部分中介作用(分别为10...     

血残粒胆固醇水平与冠心病和心肌梗死风险的两样本孟德尔随机化研究

[目的]探索血液中残粒胆固醇(RC)水平与冠心病(CHD)和心肌梗死(MI)的因果关系。[方法]采用两样本孟德尔随机化(MR)分析方法研究RC与CHD和MI的潜在因果关系。使用随机效应逆方差加权(IVW)法作为两样本MR分析的主要分析方法,并采用敏感性分析(包括异质性检验、多效性分析和逐个剔除检验)评估MR分析结果的稳健性。[结果] IVW法分析结果显示,RC与CHD和MI发生风险之间的关联具有统计学意义(CHD:OR=1.57,95%CI:1.40～1.76,P=2.01E-14;MI:OR=1.59,95%CI:1.40～1.79,P=1.26E-13)。MR-Egger回归结果提示筛选出的单核苷酸多态性(SNP)与CHD和MI不存在基因多效性(分别为P=0.924 1、P=0.740 5)。[结论]血液中RC水平升高与CHD和MI风险增加存在因果关系。     

老年人群癌症与心血管疾病因果关联的孟德尔随机化研究

目的 采用孟德尔随机化方法(MR)分析欧洲60岁以上人群癌症(乳腺癌、肺癌、胃癌、皮肤癌、前列腺癌)与10种常见心血管病的因果联系。方法 通过公共全基因组关联分析(GWAS)数据库获得工具变量，样本均来自欧洲人群，以逆方差加权法为主要方法进行两样本MR分析，并对结果行敏感性分析。后选择糖尿病、吸烟、体质量指数(BMI)3个混杂因素对癌症进行校正，并行多样本MR研究。结果 通过两样本的MR分析共得到5种检验效能小于0.05的因果关联，分别是乳腺癌与心肌梗死、乳腺癌与脑梗死、肺癌与脑梗死、肺癌与房颤、肺癌与外周动脉疾病。在多样本MR分析中，调整混杂因素后，乳腺癌对心肌梗死，肺癌对外周动脉疾病的效应值仍然较强。结论 在欧洲老年人群中乳腺癌与心肌梗死的发生可能存在负相关风险，肺癌与外周动脉疾病发生率可能存在正相关风险。     

系统免疫炎症指数与颅内外动脉粥样硬化性狭窄的相关性分析

目的]分析系统免疫炎症指数(SII)与颅内外动脉粥样硬化性狭窄之间的关系。 [方法]回顾性分析徐州医科大学附属医院神经内科收治的489例脑梗死患者,所有患者均完成头颈部计算机体层血管成像(CTA)检查,基于这些患者的狭窄程度,相应归入无狭窄组、轻度狭窄组(狭窄程度＜50%)、中度狭窄组(狭窄程度≥50%且＜70%)、重度狭窄组(狭窄程度≥70%),并对患者的基线资料、血脂、血常规等进行记录、统计分析。经由多因素二元Logistic回归分析与狭窄发生相关的独立风险因子。用多因素Logistic回归分析与狭窄程度相关的独立风险因子,用ROC曲线分析SII预测颅内外动脉粥样硬化性狭窄的价值。 [结果]多因素二元Logistic回归分析发现,年龄(OR＝1.185,P＜0.05)、SII(OR＝1.482,P＜0.05)、性别(OR＝2.721,P＝0.003)、高血压(OR＝3.119,P＜0.001)为颅内外动脉粥样硬化性狭窄的独立风险因子。多因素Logistic回归分析发现,hs-CRP(OR＝1.197,P＝0.011)、SII(OR＝1.379,P＜0.001)、Hcy(OR＝1.517,P＝0.013)显著影响血管狭窄程度。ROC曲线分析显示,SII的曲线下面积(AUC)为0.747,最佳截断值为447.89。Spearman相关性分析结果显示,SII水平与颅内外动脉粥样硬化性狭窄、颅内外动脉粥样硬化性狭窄严重程度均呈显著正相关(r＝0.524、0.482,P＜0.05)。 [结论]SII水平与脑梗死患者颅内外动脉粥样硬化性狭窄程度独立正相关,对颅内外动脉粥样硬化性狭窄具一定预测价值。     

高血压与前列腺癌因果关系的孟德尔随机化研究

目的 众多研究阐述了高血压与前列腺癌风险的关系，但由于观察性研究中二者的因果关系并不明确。本研究通过双向两样本孟德尔随机化(MR)探讨高血压与前列腺癌的因果关系。方法 利用全基因组关联研究汇总数据，其中高血压来自于UKB数据库，前列腺癌数据来自于一项大型的全基因组关联研究。利用逆方差加权法、加权中位数法、MR-Egger等方法进行MR分析，然后进行敏感性分析包括水平多效性分析，Cochran Q检验及“留一法”评估结果可靠性。结果 68个与高血压密切相关的单核苷酸多态性位点被筛选出来作为工具变量。基于逆方差加权法，发现高血压与前列腺癌之间存在密切的因果关系(OR=0.53, 95%CI 0.286～0.966,P=0.038),这提示高血压与前列腺癌之间为负向因果关系。反向MR分析显示前列腺癌不是高血压发病风险的危险因素(P=0.208)。MR-Egger截距和Cochran Q检验表明，本研究中不存在水平多效性和异质性的易感性(P>0.05)。结论 MR分析提示高血压与前列腺癌风险反向相关，而前列腺癌并不增加高血压风险。     

基于孟德尔随机化探究高血压与抑郁症的因果关系

目的 采用两样本孟德尔随机化方法探究高血压与抑郁症的相关性,以便指导临床早期干预。方法 从布里斯托尔大学的IEU GWAS数据库中选择高血压与抑郁症的GWAS数据,以高血压作为暴露因素,并从高血压数据集中获取与其显著相关的单核苷酸多态性（SNPs）作为工具变量。抑郁症的数据集作为结局变量。采用逆方差加权法、加权中位数法以及MR-Egger回归等方法进行高血压与抑郁症的两样本孟德尔随机化分析,以OR值来评价高血压与抑郁症之间的因果关系,并借助Cochran’s Q统计量和MR Egger法评估异质性和水平多效性。结果 高血压与抑郁症存在正相关关系,逆方差加权法（OR=1.481,95%CI 1.209-1.815,P<0.001）、加权中位数法（OR=1.626,95%CI 1.188-2.226,P=0.002）以及MR-Egger回归（OR=2.002,95%CI 1.142-3.509,P=0.016）,不存在多效性及异质性。结论 高血压与抑郁症之间存在正向的因果关联,这表明高血压是抑郁症的危险因素,提示临床医师在高血压患者诊疗过程中应积极进行心理疏导。     

FT4/FT3比值对急性心肌梗死患者院内全因死亡风险的临床预测价值

目的]探讨游离甲状腺激素(FT4)/游离三碘甲状腺原氨酸(FT3)比值对急性心肌梗死(AMI)患者院内全因死亡风险的临床预测价值。 [方法]回顾性收集2016年1月─2022年12月于大连医科大学附属第二医院心血管内科进行冠状动脉造影或经皮冠状动脉介入治疗(PCI)的AMI患者的临床资料,其中病史资料完整且发生住院期间死亡的患者共63例,选取同期住院未发生住院期间死亡的AMI患者180例作为对照。 [结果]院内死亡组年龄、ST段抬高型心肌梗死(STEMI)比例、肾功能不全比例、心房颤动比例、心率、KillipⅢ/Ⅳ级比例、多支病变比例、心肌肌钙蛋白I、脑钠肽(BNP)均要高于生存组,射血分数(EF)低于生存组,差异具有统计学意义(P＜0.05);院内死亡组FT4、FT4/FT3比值高于生存组,FT3低于生存组,差异具有统计学意义(P＜0.05)。多因素Logistic回归分析结果显示,FT4/FT3比值与AMI患者院内全因死亡风险正相关(OR＝1.844,95%CI:1.193～2.850,P＜0.05),除此之外,年龄、心率、KillipⅢ/Ⅳ级、STEMI、肾功能不全、低EF也与AMI患者院内全因死亡风险正相关(OR＝1.084、1.031、2.847、2.508、4.085、4.407,P＜0.05)。ROC曲线分析结果显示,FT4/FT3比值预测住院期间全因死亡风险的能力(AUC＝0.774,95%CI:0.708～0.839,P＜0.001)优于FT4(AUC＝0.640,95%CI:0.561～0.719,P＝0.001)或FT3(AUC＝0.719,95%CI:0.647～0.790,P＜0.001)单独预测,ROC曲线下面积差异有统计学意义(P＝0.001和P＝0.042)。 [结论]FT4/FT3比值与AMI患者院内全因死亡风险相关,可预测AMI患者院内全因死亡风险;与单独的FT3或FT4相比,FT4/FT3比值对AMI患者院内全因死亡具有更好的临床预测价值。     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.