Causal effects of circulating vitamin levels on the risk of heart failure:a Mendelian randomization study

BACKGROUND Observational studies suggest inverse associations between serum vitamin levels and the risk of heart failure(HF). However, the causal effects of vitamins on HF have not been fully elucidated. Here, we conducted a Mendelian randomization(MR) study to investigate the causal associations between genetically determined vitamin levels and HF.METHODS Genetic instrumental variables for circulating vitamin levels, including vitamins A, B, C, D, and E, which were assessed as either absolute or metabolite levels were obtained from public genome-wide association studies. Summary statistics for single-nucleotide-polymorphisms and HF associations were retrieved from the HERMES Consortium(47,309 cases and 930,014controls) and FinnGen Study(30,098 cases and 229,612 controls). Two-sample MR analyses were implemented to assess the causality between vitamin levels and HF per outcome database, and the results were subsequently combined by meta-analysis.RESULTS Our MR study did not find significant associations between genetically determined circulating vitamin levels and HF risk. For absolute vitamin levels, the odds ratio for HF ranged from 0.97(95% confidence interval [CI]: 0.85–1.09, P = 0.41) for vitamin C to 1.05(95% CI: 0.61–1.82, P = 0.85) for vitamin A. For vitamin metabolites, the odds ratio ranged between 0.94(95% CI:0.75–1.19, P = 0.62) for α-tocopherol and 1.11(95% CI: 0.98–1.26, P = 0.09) for γ-tocopherol.CONCLUSION Evidence from our study does not support the causal effects of circulating vitamin levels on HF. Therefore,there may be no direct beneficial effects of vitamin intake on the prevention of primary HF.

Disorders of the brain-gut interaction and eating disorders

BACKGROUND Eating disorders(ED)involve both the nervous system and the gastrointestinal tract.A similar double involvement is also found in disorders of the brain-gut interaction(DGBI)and symptoms are sometimes similar.AIM To find out where there is an association and a cause-effect relationship,we looked for the comorbidity of DGBI and ED.METHODS A systematic review was undertaken.A literature search was performed.Inclusion criteria for the articles retained for analysis were:Observational cohort population-based or hospital-based and case-control studies,examining the relationship between DGBI and ED.Exclusion criteria were:Studies written in other languages than English,abstracts,conference presentations,letters to the Editor and editorials.Selected papers by two independent investigators were critically evaluated and included in this review.RESULTS We found 29 articles analyzing the relation between DGBI and ED comprising 13 articles on gastroparesis,5 articles on functional dyspepsia,7 articles about functional constipation and 4 articles on irritable bowel syndrome.CONCLUSION There is no evidence for a cause-effect relationship between DGBI and ED.Their common symptomatology requires correct identification and a tailored therapy of each disorder.

Recombinant human epidermal growth factor combined with vacuum sealing drainage for wound healing in Bama pigs

Background:Vacuum sealing drainage(VSD)and epidermal growth factor(EGF)both play an important role in the treatment of wounds.This study aims to explore the effects of the combination of VSD and EGF on wound healing and the optimal concentration and time of EGF.Methods:We tested the proliferation and migration capacity of HaCaT and L929 cells at different EGF concentrations(0,1,5,10,and 100ng/ml)and different EGF action times(2,10,and 30min).A full-thickness skin defect model was established using male,30-week-old Bama pigs.The experiment included groups as follows:routine dressing change after covering with sterile auxiliary material(Control),continuous negative pressure drainage of the wound(VSD),continuous negative pressure drainage of the wound and injection of EGF 10min followed by removal by continuous lavage(V+E 10min),and continuous negative pressure drainage of the wound and injection of EGF 30min followed by removal by continuous lavage(V+E 30min).The wound healing rate,histological repair effect and collagen deposition were compared among the four groups.Results:An EGF concentration of 10ng/ml and an action time of 10min had optimal effects on the proliferation and migration capacities of HaCaT and L929 cells.The drug dispersion effect was better than drug infusion after bolus injection effect,and the contact surface was wider.Compared with other groups,the V+E 10min group promoted wound healing to the greatest extent and obtained the best histological score.Conclusions:A recombinant human epidermal growth factor(rhEGF)concentration of 10 ng/ml can promote the proliferation and migration of epithelial cells and fibroblasts to the greatest extent in vitro.VSD combined with rhEGF kept in place for 10min and then washed,can promote wound healing better than the other treatments in vitro.

Effects of Simvastatin on Endoplasmic Reticulum Stress-Mediated Apoptosis in Atherosclerotic Calcification

Objective:The effectiveness of statins in reducing atherosclerotic calcification remains controversial.The aim of this study was to confirm that simvastatin reduces atherosclerotic calcification and stabilizes plaque by restricting endoplasmic reticulum stress(ERS)-mediated apoptosis.Methods:Twenty-four 8-week-old male apolipoprotein E(ApoE)-/-mice(C57BL/6J genetic background)were selected and randomly divided into model(n=12)and simvastatin(n=12)groups.Twelve male C57BL/6J mice were selected as control group(n=12).The mice were adaptively fed for 2 weeks and were put on a high-fat diet thereafter.After 9 weeks,they were treated with simvastatin(20 mg/kg)or phosphate-buffered saline daily for 8 weeks.Aortic sinus samples were obtained from ApoE-/-and C57BL/6J mice for hematoxylin and eosin,von Kossa,alizarin Red S,terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling,and immunohistochemical staining after in vivo treatment with simvastatin.In addition,mouse vascular smooth muscle cells were analyzed after exposure to simvastatin in vitro.Results:Administration of simvastatin in vivo drastically attenuated the atherosclerosis,calcification,and apoptosis,and decreased the serum levels of triglycerides,total cholesterol,low-density lipoprotein cholesterol,and high-density lipoprotein cholesterol.The expression levels of glucose-regulated protein,78 kDa(GRP78),C/EBP homologous protein(CHOP),and caspase 12(CASP12)in the aortic sinus decreased in the simvastatin group compared with the model group.In vitro,simvastatin or simvastatin plus ERS inhibitor(taurine)attenuated calcification and apoptosis,and reduced the expression of ERS-related proteins GRP78,CHOP,and CASP12.Conclusion:Treatment with simvastatin suppressed atherosclerotic calcification.This effect may be mediated through the inhibition of ERS-related apoptosis.

A FLUID MECHANICS MODEL OF TISSUE FLUID FLOW IN LIMB CONNECTIVE TISSUE——A MECHANISM OF ACUPUNCTURE SIGNAL TRANSMISSION

This article explores the mechanisms of acupuncture meridians by determining characteristics of the tissue fluid flow in the connective tissue along meridians. Based on deep dissection of acupoints on the upper and lower limbs of the human body and micro and macro observation and measurement, a mathematical model of the flow of tissue fluid in interosseous membranes is constructed. It is shown that the signal transmission along acupuncture meridians may be determined by unique anatomical and physiological factors that govern the flow of tissue fluid in the connective tissue and involve mast cell degranulation. Our results provide a preliminary explanation of the phenomenon of the ＂de qi＂ sensation and the mechanism of acupuncture signal transmission along acupuncture meridians.

Association between thyroid hormone levels and frailty in the community-dwelling oldest-old: a cross-sectional study

Background:Changes in thyroid hormone levels are commonly recognized characters among the elderly,which were reported to potentially influence incident frailty.Therefore,we examined the cross-sectional associations of thyroid hormones(THs)with frailty as well as the five components characterizing frailty(fatigue,resistance,ambulation,number ofillnesses,and loss of weight)among the oldest-old.Methods:Four hundred and eighty-seven community-dwelling oldest-old from a local community in Haidian District,Beijing,participated in our recruitment campaign between April 2019 and May 2020.The primary outcomes were a definitive diagnosis of frailty according to the FRAIL scale(Fatigue,Resistance,Ambulation,Illnesses,Loss of weight)and a positive score for each frailty subdomain.Demographic information(age,sex,marital status,and educational status),comorbidities,and details on the participants lifestyles were recorded.Serum THs including free triodothyronin(fT3),triiodothyronine(T3),free thyroxine(fT4),and thyroxine(T4)and thyroid stimulating hormone(TSH)levels were also measured at the beginning of our study.Logistic regressions were conducted to screen for potential risk factors for frailty and its subdomains.Results:Among the total 487 subjects at enrollment,60(12.23%)of them were diagnosed with subclinical hypothyroidism and 110(22.59%)of the total population scored positive for frailty.Logistic regression analyses adjusted for all potential confounders,showed that frailty was significantly associated with the serum TSH concentration(odds ratio[OR]:1.06),fT3 concentration(OR:0.54),and subclinical hypothyroidism score(OR:2.18).The association between fT4 and frailty was absent in our observational study.The fT3/fT4 ratio characterizing peripheral hormone conversion was also tested to be correlated with frailty.Conclusion:Subclinical hypothyroidism,higher TSH level,lower fT3 level,and decreased fT3/fT4 ratio were all associated with frailty assessed by the FRAIL scale among the community-dwelling oldest-old,suggesting a relevant role of thyroid function in aging.Future longitudinal studies are warranted to determine the casual relationship between thyroid dysfunction and frailty in the oldest-old.

Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study

Background:5-Fluorouracil(5-FU)and capecitabine-associated cardiotoxicity ranging from asymptomatic electro-cardiography(ECG)abnormalities to severe myocardial infarction has been reported in a number of studies,but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date.In the present study,we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5-FU-and capecitabine-associated cardiotoxicity in cancer patients recruited from multiple centers in China.Methods:Among the 527 patients who completed the study,196 received 5-FU-based chemotherapy and 331 received capecitabine-based chemotherapy as either first-line or adjuvant therapy.Adverse events were reported during the treatment and up to 28 days of follow-up.Outcome measures included ECG,myocardial enzymes,cardiac troponin,brain natriuretic peptide and echocardiography.Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents.Results:In total,161 of 527 patients(30.6%)experienced cardiotoxicity.The incidence rate of cardiotoxicity was 33.8%(112/331)in the capecitabine group,which was significantly higher than the rate of 25%(49/196)in the 5-FU group(P=0.0042).110/527 patients(20.9%)suffered arrhythmia,105/527(19.9%)developed ischemic changes,while only 20/527 patients(3.8%)presented heart failure and 6/527 patients(1.1%)had myocardial infarction.Pre-existing cardiac disease,hypertension,capecitabine-based chemotherapy and duration of treatment were identified as sig-nificant risk factors associated with cardiotoxicity.The odds ratio were 15.7(prior history of cardiac disease versus no history),1.86(capecitabine versus 5-FU),1.06(5-8 versus 1-4 chemotherapy cycles)and 1.58(hypertension versus no hypertension),respectively.Conclusions:Cardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clini-cal practice.Close monitoring of patients is recommended,especially for those patients at high risk for cardiotoxicity.Possible risk factors are duration of treatment,capecitabine-based chemotherapy,pre-existing cardiac diseases and hypertension.Trial registration This study was initiated on January 22,2014 and has been retrospectively registered with the registra-tion number ChiCTR1800015434 .

Associations of particulate matter with dementia and mild cognitive impairment in China: A multicenter cross-sectional study

Ambient air pollution has been shown to be associated with the pathogenesis of dementia and mild cognitive impairment(MCI).However,few studies have examined these associations in well-characterized populations with low residential mobility,similar living habits,and a standardized assessment of both air pollution exposure and clinical outcome.This study examined the associations of long-term exposure to particulate matter(PM)air pollution with dementia and MCI,using data from the Chinese Veteran Clinical Research Platform.The cognitive function of elderly veterans from 277 communities in 18 Chinese cities was examined.Participants’daily exposures to aerodynamic diameters%2.5 mm(PM2.5)and%10 mm(PM10)during the 3 years prior to the survey were estimated using a satellite-based prediction.The adjusted odds ratios(ORs)and 95%confidence intervals of MCI associated with each 10 mg/m^(3) increase in PM2.5 and PM10 were 1.52(1.39,1.67)and 1.04(1.00,1.08),and those of dementia associated with PM2.5 and PM10 were 1.27(1.11,1.46)and 1.13(1.05,1.21),respectively.This demonstrates that long-term exposure to PM2.5 and PM10 can increase the prevalence of dementia/MCI among veterans in China.Higher ORs were observed for those with%9 years of educational attainment,those who actively attended physical activities,those who never smoked,former drinkers,and those who did not suffer from cerebral infarction.Improvement of ambient air quality,especially decreasing levels of PM2.5,may help to decrease the risk of dementia/MCI.Given the statistically significant association between PM and cognitive impairment demonstrated here,future studies should focus on examining the causal effect of PM pollution on dementia and MCI.

Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORCl and scavenging ROS

Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied.In this study,we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival(P<0.001)than those who did not.Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice,predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis,resulting in mTORCl activation.mTORCl inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation.In addition,cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione.We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin.These findings indicate that cyst(e)ine;as part of supplemental nutrition,plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

Contact heat evoked potentials in knowledge workers and unskilled labors

Background:Whether occupation has an impact on contact heat evoked potential(CHEP)results has not been investigated.In this study,we investigated the difference of CHEP parameters between knowledge workers and unskilled labors.Methods:A total of 137 healthy participants were recruited between November 20,2014 and December 31,2016.All participants underwent neurologic examination,laboratory examination,and nerve conduction studies.CHEP was performed on four body sites:the upper border of the distal third of the volar forearm,the upper border of the distal third of the lateral leg,the spinous process of seventh cervical vertebrae(C7),and the spinous process of 12th thoracic vertebrae(T12).Independent t test and nonparametric test were performed using SPSS software to compare the difference of the CHEP parameters between knowledge workers and unskilled labors.Results:The“N2 latency/height”(Z=-2.290,P=0.022)and“P2 latency/height”(Z=-2.020,P=0.043)on the volar forearm of unskilled labors significantly increased than those of knowledge workers.The“N2 latency/height”(F=6.348,P=0.016)and“P2 latency/height”(F=5.920,P=0.018)in the distal leg of unskilled labors significantly prolonged than those of knowledge workers.The N2-P2 amplitude(F=5.797,P=0.020)in the distal leg of unskilled labors significantly decreased than those of knowledge workers.Conclusions:Our study found that significantly prolonged N2 latency and P2 latency and significantly decreased N2-P2 amplitude in the distal leg and the volar forearm in unskilled labors as to knowledge workers.