Lactotripeptides Inhibiting ACE1 Elevate the Plasma Bradykinin Concentration Acutely in a Placebo-Controlled, Double-Blind, Cross-Over, 4-Week Trial in Healthy Volunteers

This placebo-controlled, double-blind, cross-over intervention with twelve normotensive healthy volunteers tested the effects of milk products containing either 5 or 50 mg of ACE1-inhibitory lactotripeptides (isolecine-proline-proline, Ile-Pro-Pro, and valine-proline-proline, Val-Pro-Pro) and placebo milk drink (with similar taste) on plasma bradykinin levels. The subjects consumed one of the three test products in a random order, double-blinded, and four-week trial. On the first day (day 1) and on the last day (day 29) i.e. after four weeks’ treatment with one of the products, the acute effect with the same single dose was assayed. Other markers of the renin-angiotensin-aldosterone system (RAAS) were measured from plasma four times on the same days when we also assessed daytime urinary excretion of biomarkers of endothelial function. Neither acute nor prolonged administration of the ACE-1 inhibiting peptide drinks significantly lowered blood pressure of the normotensive subjects. The most important finding was the dose-dependent, and linear increase in plasma bradykinin concentrations after acute dosing on the first day;it was nearly statistically significant also on the day 29 (p 0.06). Other indicators of RAAS or endothelial function did not differ from those of placebo after the acute or prolonged treatments. Our results suggest that even weak inhibitors of ACE-1, such as the lactotripeptides Ile-Pro-Pro and Val-Pro-Pro, are able to diminish the breakdown of bradykinin and therefore increase plasma bradykinin levels. This may partly explain the blood pressure lowering and vasodilatory effects of lactotripeptides, shown by us earlier in mildly hypertensive subjects.

Recovery after acute kidney injury requiring kidney replacement therapy in patients with left ventricular assist device: A metaanalysis

BACKGROUND Acute kidney injury(AKI)is a common and severe complication after left ventricular assist device(LVAD)implantation with an incidence of 37%;13%of which require kidney replacement therapy(KRT).Severe AKI requiring KRT(AKI-KRT)in LVAD patients is associated with high short and long-term mortality compared with AKI without KRT.While kidney function recovery is associated with better outcomes,its incidence is unclear among LVAD patients with severe AKI requiring KRT.AIM To identify studies evaluating the recovery rates from severe AKI-KRT after LVAD placement,which is defined by regained kidney function resulting in the discontinuation of KRT.Random-effects and generic inverse variance method of DerSimonian-Laird were used to combine the effect estimates obtained from individual studies.METHODS A total of 268 patients from 14 cohort studies that reported severe AKI-KRT after LVAD were included.Follow-up time ranged anywhere from two weeks of LVAD implantation to 12 mo.Kidney recovery occurred in 78%of enrollees at the time of hospital discharge or within 30 d.Overall,the pooled estimated AKI recovery rate among patients with severe AKI-KRT was 50.5%(95%CI:34.0%-67.0%)at 12 mo follow up.Majority(85%)of patients used continuous-flow LVAD.While the data on pulsatile-flow LVAD was limited,subgroup analysis of continuous-flow LVAD demonstrated that pooled estimated AKI recovery rate among patients with severe AKI-KRT was 52.1%(95%CI:36.8%-67.0%).Metaregression analysis did not show a significant association between study year and AKI recovery rate(P=0.08).There was no publication bias as assessed by the funnel plot and Egger's regression asymmetry test in all analyses.RESULTS A total of 268 patients from 14 cohort studies that reported severe AKI-KRT after LVAD were included.Follow-up time ranged anywhere from two weeks of LVAD implantation to 12 mo.Kidney recovery occurred in 78%of enrollees at the time of hospital discharge or within 30 d.Overall,the pooled estimated AKI recovery rate among patients with severe AKI-KRT was 50.5%(95%CI:34.0%-67.0%)at 12 mo follow up.Majority(85%)of patients used continuous-flow LVAD.While the data on pulsatile-flow LVAD was limited,subgroup analysis of continuous-flow LVAD demonstrated that pooled estimated AKI recovery rate among patients with severe AKI-KRT was 52.1%(95%CI:36.8%-67.0%).Metaregression analysis did not show a significant association between study year and AKI recovery rate(P=0.08).There was no publication bias as assessed by the funnel plot and Egger's regression asymmetry test in all analyses.CONCLUSION Recovery from severe AKI-KRT after LVAD occurs approximately 50.5%,and it has not significantly changed over the years despite advances in medicine.

Polystyrene nanoplastics induce glycolipid metabolism disorder via NF-κB and MAPK signaling pathway in mice

Nanoplastics-induced developmental and reproductive toxicity,neurotoxicity and immunotoxicity are a focus of widespread attention.However,the effects of nanoplastics(NPs)on glycolipid metabolism and the precise underlying mechanisms are unclear at present.Here,we showed that oral administration of polystyrene nanoparticles(PS-NPs)disrupts glycolipid metabolism,with reactive oxygen species(ROS)identified as a potential key signaling molecule.After PS-NPs treatment,excessive production of ROS induced the infammatory response and activated the antioxidant pathway through nuclear factor-erythroid factor 2-related factor 2.The activation of nuclear factor-κB(NFκB)signaling pathway induced the phosphorylation of the mitogen-activated protein kinases(MAPK)signaling pathway,which induced the activation of extracellular regulated kinases(ERK)and p38.Constitutive activation of the MAPK signaling proteins induced high continued phosphorylation of insulin receptor substrate-1,in turn,leading to decreased protein kinase B(Akt)activity,which weakened the sensitivity of liver cells to insulin signals and induced insulin resistance.In parallel,phosphorylation of Akt led to loss of control of Fo XO1,a key gene of gluconeogenesis,activating transcription of glucose-6-phosphatase(G6PC)and phosphoenolpyruvate carboxykinase(PEPCK)in a manner dependent on PGC1α.Moreover,the activated ERK promoted lipid accumulation through ERK-PPARγcascades.Therefore,sterol regulatory element-binding protein-1 and levels of its downstream lipogenic enzymes,ACC-1,were up-regulated.Upon treatment with the antioxidant resveratrol,PS-NPs-induced glucose and lipid metabolic disorders were improved by inhibiting ROS-induced activation of NFκB and MAPK signaling pathway in mice.Based on above,PS-NPs exposure disrupts glycolipid metabolism in mice,with ROS identified as a potential key signaling molecule.

Gender differences in the association between elevated serum uric acid, not diuretic-induced, and cardiovascular disease in untreated hypertension patients

Background Studies have been inconsistent regarding whether hyperuricemia, either diureticor non diuretic-induced, is an independent risk factor for cardiovascular events. The study investigated the association of cardiovascular disease with diuretic- and non diuretic-induced elevated serum uric acid. Methods A community-based cross-section study was conducted in 5,235 treated and untreated hypertensive patients aged 40-75 years. Conventional risk factors, serum uric acid and the presence of cardiovascular disease were determined. Hyperuricemia was defined as serum uric acid levels ≥420 μmol/L in men or ≥360 μmol/L in women. Results Hyperuricemia was more common in men than in women （21.5 % vs. 10.2 %, P 〈 0.001）. After adjustment for age and other conventional risk factors, hyperuricemia was associated with metabolic syndrome, decreased creatinine clearance, and use of diuretics in both genders, as well as age in women and alcohol consumption in men. The presence of coronary artery disease or stroke increased significantly with the increase of quartiles of serum uric acid （8.0 %, 11.0 %, 13.4 %, and 16.8 %, respectively, P 〈 0.01）, and the highest serum uric acid quartile was associated with a 1.8-fold risk for cardiovascular disease （OR： 1.83, 95 % CI： 1.24-2.71） in untreated women. But this association was not observed in untreated men as well as in treated patients using diuretics in both genders. Conclusions Hypeuricemia is markedly associated with metabolic syndrome, decreased creatinine clearance, use of diuretics besides alcohol consumption in men and age in women. Elevated serum uric acid, but not that diuretic-induced, may be associated with increased the risk of cardiovascular disease in untreated hypertensive women.

系统性轻链淀粉样变:有望被治愈

Systemic light chain(AL)amyloidosis is a rare protein misfolding and deposition disorder.The clonal plasma cells in the bone marrow of AL amyloidosis patients secrete an abnormal immunoglobulin or its fragment,which is deposited in various organs and leads to organ dysfunction.The incidence in the USA is 8-14/million[1],whereas the incidence in China is undetermined.

Role of plasma C-reactive protein and white blood cell count in predicting in-hospital clinical events of acute type A aortic dissection

Background A few recent studies have reported that inflammation is associated with the prognosis of acute aortic dissection （AD）. There is, however, no systemic investigation regarding the role of plasma C-reactive protein （CRP） and white blood cell （WBC） levels in predicting in-hospital clinical events of acute type AAD. Methods The levels of high-sensitivity CRP and WBC counts were systemically determined after admission in 36 patients with acute type A AD. The variations of plasma CRP and WBC levels in different time windows （admission, 1, 2, 3, 4, 6, 8 days） in patients with acute type AAD were analyzed between patients with events and without events. Results During hospitalization, five patients died, and increased levels of CRP and WBC were found in patients died with acute type A AD compared with patients survived （P 〈0.01, respectively）. Medical treatment may significantly decrease inflammatory response in survived patients with acute type A AD. Additionally, patients with complication of pleural effusion showed higher CRP and WBC levers （P=0.046, P=-0.018, respectively）. Lower WBC levels were found in survived patients treated medically （P=-0.001）. Moreover, mean CRP and WBC levels had positive correlations with aortic diameter （r=0.364, P--0.000; r=0.333, P=0.000, respectively） and age （r=0.270, P=0.000, respectively）, while negative correlations with the time from onset of symptoms to hospital admission （r= -0.229, P=0.000, r= -0.200, P=0.002, respectively）. Univariate analysis showed that age 〉65 years, CRP zl 2.05 rag/L, WBC 〉12.16×10^9/L, aortic diameter 〉48 mm, pleural effusion and diastolic blood pressure 〉105 mmHg were associated with hospital mortality. While CRP 〉12.05 mg/L, WBC ≥12.16×10^9/L, aortic diameter 〉48 mm were strongly associated with hospital mortality in multiple Logistic regression analysis. Conclusions The results suggested that CRP and WBC were preferred markers for predicting the clinical events in patients with acute type A AD, especially death during hospitalization. Therefore, further study enrolling larger cohort, prospective study would be warranted.

Cardiovascular risk and prevalence of metabolic syndrome by differing criteria

Background The prevalence of metabolic syndrome （MetS） in hypertensive population in Chinese countryside is unknown. Firstly, this study compared the prevalence of MetS according to National Cholesterol Education Program （NCEP） ATPIII, revised NCEP and International Diabetes Federation （IDF） definitions. Secondly, it investigated the association between MetS, coronary heart disease （CHD） and stroke in patients with hypertension. Methods In this cross sectional study, the cluster sampling method was used. Three MetS definitions were applied to 1418 normal subjects and 5348 hypertensive patients aged 40-75 years in rural areas in China. The agreement between different MetS definitions was estimated by K statistics. Logistic regression analyses determined the association between MetS defined by the three MetS definitions and CHD and stroke. Results In subjects without hypertension, the prevalence of Mets was 4.1% by NCEP definition, 8.3% revised NCEP definition and 7.8% IDF definition. In hypertensive individuals, the prevalence was 14.0%, 32.9%, and 27.4% in men; 35.6%, 53.1%, and 50.2% in women by the same definitions, respectively. In hypertensive individuals, the agreement was 94.4% in men and 97.0% in women between revised NCEP and IDF definitions. The IDF defined MetS was more strongly associated with CHD than the NCEP or revised NCEP defined MetS （adjusted odds ratio： 1.92 compared with 1.85 and 1.69 in men; 1.64 compared with 1.48 and 1.60 in women）. Conclusions In the patients with hypertension, the revised NCEP and IDF definitions identified more individuals than NCEP definition and their agreement is very high. The IDF defined MetS is more strongly associated with CHD than the NCEP or revised NCEP defined MetS, but weakly or not associated with stroke.

Ghrelin receptor gene polymorphisms are associated with female metabolic syndrome in Chinese population

Background The ghrelin plays an important role in the regulation of food intake and energy homeostasis. Therefore, the ghrelin receptor gene （GHSR） is an excellent candidate for studying metabolic syndrome. This study aimed to investigate whether polymorphisms in ghrelin receptor gene are associated with metabolic syndrome in Chinese population. Methods Subjects consisted of 698 patients aged 41 to 80 years, diagnosed as metabolic syndrome by International Diabetes Federation （IDF） 2005 criteria, and 762 age- and gender-matched controls. Three variants within the GHSR were selected and genotyped using polymerase chain reaction （PCR） and restriction fragment length polymorphism （RFLP）. Odds ratios were estimated using a case-control study design by controlling confounding factors. Results The NA genotype （rs2922126） in the promoter was associated with metabolic syndrome （OR 1.41, 95%C/ 1.03-1.94）, increased waist circumference （OR 1.75, 95%C/1.26-2.42）, and increased fast blood glucose （OR 1.49, 95%CI 1.07-2.06） in women. The NA genotype （rs509030） in the intron was associated with lower plasma high density lipoprotein in women （OR 1.37, 95%C/1.02-1.84）. Conclusion The polymorphisms within GHSR might be a genetic risk factor for metabolic syndrome in women.

Assessment of respiratory support decision and the outcome of invasive mechanical ventilation in severe COVID-19 with ARDS

Background:The coronavirus disease 2019(COVID-19)is an ongoing pandemic.Invasive mechanical ventilation(IMV)is essential for the management of COVID-19 with acute respiratory distress syndrome(ARDS).We aimed to assess the impact of compliance with a respiratory decision support system on the outcomes of patients with COVID-19-associated ARDS who required IMV.Methods:In this retrospective,single-center,case series study,patients with COVID-19-associated ARDS who required IMV at Zhongnan Hospital of Wuhan University,China,from January 8th,2020,to March 24th,2020,with the final follow-up date of April 20th,2020,were included.Demographic,clinical,laboratory,imaging,and management information were collected and analyzed.Compliance with the respiratory support decision system was documented,and its relationship with 28-day mortality was evaluated.Results:The study included 46 COVID-19-associated ARDS patients who required IMV.The median age of the 46 patients was 68.5 years,and 31 were men.The partial pressure of arterial oxygen(PaO_(2))/fraction of inspired oxygen(FiO_(2))ratio at intensive care unit(ICU)admission was 104 mmHg.The median total length of IMV was 12.0(interquartile range[IQR]:6.0–27.3)days,and the median respiratory support decision score was 11.0(IQR:7.8–16.0).To 28 days after ICU admission,18(39.1%)patients died.Survivors had a significantly higher respiratory support decision score than non-survivors(15.0[10.3–17.0]vs.8.5(6.0–10.3),P=0.001).Using receiver operating characteristic(ROC)curve to assess the discrimination of respiratory support decision score to 28-day mortality,the area under the curve(AUC)was 0.796(95%confidence interval[CI]:0.657–0.934,P=0.001)and the cut-offwas 11.5(sensitivity=0.679,specificity=0.889).Patients with a higher score(>11.5)were more likely to survive at 28 days after ICU admission(log-rank test,P<0.001).Conclusions:For severe COVID-19-associated ARDS with IMV,following the respiratory support decision and assessing completion would improve the progress of ventilation.With a decision score of>11.5,the mortality at 28 days after ICU admission showed an obvious decrease.

Association between anemia and ICU outcomes

To the Editor:Anemia is a common finding among patients admitted to intensive care units(ICUs),nearly 60%of ICU patients had serum hemoglobin levels<12 g/dL at baseline,30%of whom had serum hemoglobin levels<9 g/dL,over 95%of critically ill patients were anemic within 3 days of ICU admission.[1]Moreover,anemia may be aggravated or newly developed in critically ill patients during their ICU stay.

Genetics of ischemic and hemorrhagic stroke in Chinese population

Stroke is a major cause of adult death and disability worldwide.Epidemiological and animal studies have provided strong evidence that the pathogenesis of stroke is multi-factorial and induced by a combination of environmental and genetic risk factors,but the identifica-tion of individual causative variants remains little known.Genetic influences are likely to be polygenic with small effect sizes,and stroke itself consists of a number of different subtypes which may each have different genetic profiles.In addition,various ethnic populations may have different stroke risk,such as Asian race.The reasons for high risk of stroke among the Chinese,especially hemorrhagic stroke,remain unknown.Most human studies have taken a candidate gene approach using case-control methodology.To be reliably detected,small relative risks require large sample sizes,probably 1000 patients or more.Genome-wide association(GWA)study is an unbiased and comprehensive approach to identify common risk alleles for complex diseases.Recently,a multistage GWA study has identified three loci on chromosomes 2q,8q and 9p to be associated with intracranial aneurysm in European and Japanese populations.Another GWAfinding is the identification of risk variants for cardioembolic stroke on chromosome 4q25 in European populations.In this review,we mainly focus on the results from case-control association studies on genetic factors that play a role in the risk of ischemic and hemorrhagic stroke in Chinese population.The combined effects of multiple susceptibility genes for stroke risk are also summarized.