Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

Nitrate reduction capacity of the oral microbiota is impaired in periodontitis:potential implications for systemic nitric oxide availability

The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with periodontal health, but the impact of periodontitis on nitrate-reducing capacity(NRC)and, therefore, nitric oxide availability has not been evaluated. The current study aimed to evaluate how periodontitis affects the NRC of the oral microbiota. First, 16S rRNA sequencing data from five different countries were analyzed, revealing that nitratereducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals(P < 0.05 in all five datasets with n = 20–82 samples per dataset). Secondly, subgingival plaque, saliva, and plasma samples were obtained from 42 periodontitis patients before and after periodontal treatment. The oral NRC was determined in vitro by incubating saliva with 8 mmol/L nitrate(a concentration found in saliva after nitrate-rich vegetable intake) and compared with the NRC of 15healthy individuals. Salivary NRC was found to be diminished in periodontal patients before treatment(P < 0.05) but recovered to healthy levels 90 days post-treatment. Additionally, the subgingival levels of nitrate-reducing bacteria increased after treatment and correlated negatively with periodontitis-associated bacteria(P < 0.01). No significant effect of periodontal treatment on the baseline saliva and plasma nitrate and nitrite levels was found, indicating that differences in the NRC may only be revealed after nitrate intake. Our results suggest that an impaired NRC in periodontitis could limit dietary nitrate-derived nitric oxide levels, and the effect on systemic health should be explored in future studies.

Dietary (poly)phenol intake is associated with cardiometabolic health parameters in adolescents

The protective role of(poly)phenols against metabolic disorders has been extensively studied in adults but not in adolescents.To assess associations of dietary(poly)phenols and their subclasses with cardiometabolic health parameters in adolescents.A cross-sectional study was conducted in 944 individuals aged 11–14 years enrolled in the SI!Program for Secondary Schools trial(NCT03504059).(Poly)phenol intake was assessed using semiquantitative food frequency questionnaires and the Phenol-Explorer database.The measured cardiometabolic parameters were waist circumference(WC)age-sex Z-score,blood pressure(BP)age-sex Z-score,blood glucose(BG),triglycerides(TG),and high-density lipoprotein cholesterol(HDL-c).Multilevel mixedeffect linear regression models were applied to examine the association between(poly)phenol quintiles and cardiometabolic health parameters.Compared to the lowest quintile,adolescents in the highest quintile of total(poly)phenol intake had lower WC Z-scores,mean arterial pressure Z-scores,and HDL-c after multivariable adjustment.The WC Z-scores and HDL-c were lower in the highest quintile of flavonoid intake compared to the lowest quintile.The highest quintile of phenolic acid intake was associated with a lower WC Z-score and TG levels,and the highest quintile of stilbene intake with lower BG and TG,and with higher HDL-c compared to the lowest quintile.A higher intake of(poly)phenols,especially flavonoids,phenolic acids,and stilbenes,was associated with better cardiometabolic parameters in adolescents.

Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability:Insights from McArdle disease

Background:This study aimed to determine the effect of different carbohydrate(CHO)doses on exercise capacity in patients with McArdle disease—the paradigm of“exercise intolerance”,characterized by complete muscle glycogen unavailability—and to determine whether higher exogenous glucose levels affect metabolic responses at the McArdle muscle cell(in vitro)level.Methods:Patients with McArdle disease(n=8)and healthy controls(n=9)underwent a 12-min submaximal cycling constant-load bout followed by a maximal ramp test 15 min after ingesting a non-caloric placebo.In a randomized,double-blinded,cross-over design,patients repeated the tests after consuming either 75 g or 150 g of CHO(glucose:fructose=2:1).Cardiorespiratory,biochemical,perceptual,and electromyographic(EMG)variables were assessed.Additionally,glucose uptake and lactate appearance were studied in vitro in wild-type and McArdle mouse myotubes cultured with increasing glucose concentrations(0.35,1.00,4.50,and 10.00 g/L).Results:Compared with controls,patients showed the“classical”second-wind phenomenon(after prior disproportionate tachycardia,myalgia,and excess electromyographic activity during submaximal exercise,all p<0.05)and an impaired endurance exercise capacity(-51%ventilatory threshold and55%peak power output,both p<0.001).Regardless of the CHO dose(p<0.05 for both doses compared with the placebo),CHO intake increased blood glucose and lactate levels,decreased fat oxidation rates,and attenuated the second wind in the patients.However,only the higher dose increased ventilatory threshold(+27%,p=0.010)and peak power output(+18%,p=0.007).In vitro analyses revealed no differences in lactate levels across glucose concentrations in wild-type myotubes,whereas a doseresponse effect was observed in McArdle myotubes.Conclusion:CHO intake exerts beneficial effects on exercise capacity in McArdle disease,a condition associated with total muscle glycogen unavailability.Some of these benefits are dose dependent.

Microbial phenolic metabolites are associated with better frontal lobe cognition

With increasing life expectancy,neurodegenerative diseases have become one of the leading causes of illhealth in the elderly.Preventive strategies include following healthy diets,such as the Mediterranean diet,which is particularly rich in polyphenols,bioactive compounds with neuroprotective properties.The aim of this study was to assess the association of microbial phenolic metabolites(MPM)with cognition.This cross-sectional analysis was performed with 200 participants of the PREDIMED trial(Barcelona-Clinic recruitment center).A novel method based on liquid chromatography coupled to mass spectrometry was used to identify urinary MPM(protocatechuic acid,enterodiol glucuronide,enterolactone glucuronide,urolithin B glucuronide,and vanillic acid glucuronide),and cognitive function was evaluated with neuropsychological tests.Multivariable-adjusted ordinary least squares regression was used to assess the associations between cognitive function and MPM,and a score was calculated as the weighted sum of MPM.A higher MPM score was associated with better frontal lobe function.Among individual metabolites,vanillic acid glucuronide was correlated with frontal cognitive performance.Participants with higher concentrations of vanillic acid glucuronide and urolithin B glucuronide obtained better scores in the Color Trail Test part 2.A higher score for urinary multiMPM was associated with better frontal cognitive performance in an older Mediterranean population.

Effects of 12 weeks of power-oriented resistance training plus high-intensity interval training on metabolic syndrome factors in older people with COPD

Objectives To assess the effects of an exercise training program combining power-oriented resistance training(RT)and high-intensity interval training(HIIT)on metabolic syndrome(MetS)markers in older people with COPD.Methods Twenty-nine older people(66–90 years old)with COPD were randomly assigned to 12 weeks of exercise training(ET;power-oriented RT+HIIT)or a control group(CON).Waist circumference,diastolic(DBP)and systolic blood pressure(SBP),and serum fasting glucose,triglycerides and HDL cholesterol levels were assessed at baseline and after 12 weeks.Linear mixed-effects models were used to assess the effects of the intervention,and data were reported as mean and 95%confidence interval values.Results Waist circumference increased in the CT group,but not in the ET group(2.0[0.2,3.7]vs.1.0[−1.3,3.2]cm,respectively).No changes in fasting glucose(−4.1[−10.3,2.1]vs.−1.0[−8.7,6.7]mg dL−1),triglycerides(3.9[−13.4,21.3]vs.−13.9[−35.6,7.7]mg dL−1)or HDL cholesterol(1.0[−3.4,5.4]vs.2.9[−2.6,8.4]mg dL−1)were found in the CT or ET group,respectively.The ET group exhibited decreased DBP(−5.2[−9.5,−0.8]mmHg)and SBP(−2.7[−22.7,−2.7]mmHg),while no changes were found in the CT group(0.3[−3.2,3.7]and−3.5[−11.4,4.5]mmHg).MetS z-score declined in ET but remained unchanged in CT(−0.88[−1.74,−0.03]vs.0.07[−0.62,0.76],respectively).Conclusions A 12-week exercise training program led to a reduction in blood pressure and MetS z-score in older people with COPD.

实时经支气管超声引导针吸活检在肺癌分期中的应用

线性经支气管超声引导针吸活检(endobronchial ultrasound-guided transbronchial needle aspiration,EBUS-TBNA)是新引进的技术,它是实时超声下可视淋巴结的针吸活检。尽管有研究显示,其为肺癌纵隔分期的有效方法,但全世界多数机构并未应用该技术。本报道旨在分享我们应用EBUS-TBNA的经验,并对相关文献做一简要概述。我们对有关该技术的已有文献进行综述,并特别介绍了我们应用该技术方面的经验。EBUS-TBNA用以探查肺癌患者的转移性纵隔淋巴结和/或肺门淋巴结是有效且安全的。在其它病理状态下,其亦为有效的诊断方法。

Neurodegeneration:An early event of diabetic retinopathy

Diabetic retinopathy(DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia.However,retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination.In other words,retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR.Therefore,the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR.Elevated levels of glutamate and the overexpression of the renin-angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina.Among neuroprotective factors,pigment epithelial derived factor,somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review.Nevertheless,it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye.New strategies,based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors,are currently being tested in experimental models and in clinical pilot studies.Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.

Familial aggregation in inflammatory bowel disease:Is it genes or environment?

Inflammatory bowel disease (IBD) develops in genetically susceptible individuals due to the influence of environmental factors, leading to an abnormal recognition of microbiota antigens by the innate immune system which triggers an exaggerated immune response and subsequent bowel tissue damage. IBD has been more frequently found in families, an observation that could be due to either genetic, environmental or both types of factors present in these families. In addition to expanding our knowledge on IBD pathogenesis, defining the specific contribution to familial IBD of each one of these factors might have also clinical usefulness. We review the available evidence on familial IBD pathogenesis.

Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

Inflammatory bowel disease (IBD) includes two entities, Crohn’s disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient’s quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependant disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn’s disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunossupressants is now advocated by some authors. The rational includes: (1) failure to modify IBD natural history of present therapeutic approach, (2) demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn’s disease and ulcerative colitis, and (3) demonstration that early immunossupression has a very positive impact on pediatric, recently diagnosed Crohn’s disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab (SONIC Study), and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn’s disease patients (AZTEC study).

Tools for the diagnosis of hepatitis C virus infection and hepatic fibrosis staging

Hepatitis C virus(HCV)infection represents a major public health issue.Hepatitis C can be cured bytherapy,but many infected individuals are unaware of their status.Effective HCV screening,fast diagnosis and characterization,and hepatic fibrosis staging are highly relevant for controlling transmission,treating infected patients and,consequently,avoiding end-stage liver disease.Exposure to HCV can be determined with high sensitivity and specificity with currently available third generation serology assays.Additionally,the use of point-of-care tests can increase HCV screening opportunities.However,active HCV infection must be confirmed by direct diagnosis methods.Additionally,HCV genotyping is required prior to starting any treatment.Increasingly,high-volume clinical laboratories use different types of automated platforms,which have simplified sample processing,reduced hands-on-time,minimized contamination risks and human error and ensured full traceability of results.Significant advances have also been made in the field of fibrosis stage assessment with the development of non-invasive methods,such as imaging techniques and serum-based tests.However,no single test is currently available that is able to completely replace liver biopsy.This review focuses on approved commercial tools used to diagnose HCV infection and the recommended hepatic fibrosis staging tests.

Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications

Hepatocellular carcinoma(HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor(HGF)/c-mesenchymal-epithelial transition receptor(c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microR NAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.

社会媒体对多媒体网络平台的推荐研究：基于Europeana的案例分析

Europeanaeu是一个多语言网站，提供了数以百万计的来自于欧洲博物馆、图书馆、档案馆以及多媒体资源收藏的数字化条目。本文研究了该网站的使用情况，尤其是社会媒体对该网站的推荐。我们采用了三种方法搜集相关数据，包括GoogleAnalytics、ClickStream日志及http服务器日志。本文特别展示了利用GoogleAnalytics分析得到的结果。

Cardiorespiratory fitness measured with cardiopulmonary exercise testing and mortality in patients with cardiovascular disease:A systematic review and meta-analysis

Background Cardiorespiratory fitness(CRF)is inversely associated with mortality in apparently healthy subjects and in some clinical populations,but evidence for the association between CRF and all-cause and/or cardiovascular disease(CVD)mortality in patients with established CVD is lacking.This study aimed to quantify this association.Methods We searched for prospective cohort studies that measured CRF with cardiopulmonary exercise testing in patients with CVD and that examined all-cause and CVD mortality with at least 6 months of follow-up.Pooled hazard ratios(HRs)were calculated using random-effect inverse-variance analyses.Results Data were obtained from 21 studies and included 159,352 patients diagnosed with CVD(38.1%female).Pooled HRs for all-cause and CVD mortality comparing the highest vs.lowest category of CRF were 0.42(95%confidence interval(95%CI):0.28–0.61)and 0.27(95%CI:0.16–0.48),respectively.Pooled HRs per 1 metabolic equivalent(1-MET)increment were significant for all-cause mortality(HR=0.81;95%CI:0.74–0.88)but not for CVD mortality(HR=0.75;95%CI:0.48–1.18).Coronary artery disease patients with high CRF had a lower risk of all-cause mortality(HR=0.32;95%CI:0.26–0.41)than did their unfit counterparts.Each 1-MET increase was associated with lower all-cause mortality risk among coronary artery disease patients(HR=0.83;95%CI:0.76–0.91)but not lower among those with heart failure(HR=0.69;95%CI:0.36–1.32).Conclusion A better CRF was associated with lower risk of all-cause mortality and CVD.This study supports the use of CRF as a powerful predictor of mortality in this population.

Self-reported Taste and Smell Disorders in Patients with COVID-19:Distinct Features in China

Last December 2019,a cluster of viral pneumonia cases identified as coronavirus disease 2019(COVID-19)was reported in Wuhan,China.We aimed to explore the frequencies of nasal symptoms in patients with COVID-19,including loss of smell and taste,as well as their presentation as the first symptom of the disease and their association with the severity of COVID-19.In this retrospective study,1206 laboratory-confirmed COVID-19 patients were included and followed up by telephone one month after discharged from Tongji Hospital,Wuhan.Demographic data,laboratory values,comorbidities,symptoms,and numerical rating scale scores(0–10)of nasal symptoms were extracted from the hospital medical records,and confirmed or reevaluated by the telephone follow-up.From patients(n=1172)completing follow-up,199(17%)subjects had severe COVID-19 and 342(29.2%)reported nasal symptoms.20.6%COVID-19 patients had loss of taste(median score=6),while 11.4%had loss of smell(median score=5).Loss of taste scores,but not loss of smell scores,were significantly increased in severe vs.nonsevere COVID-19 patients.Interleukin(IL)-6 and lactose dehydrogenase(LDH)serum levels were positively correlated with loss of taste scores.About 80%of COVID-19 patients recovered from smell and taste dysfunction in 2 weeks.In this cohort,only 1 out of 10 hospital admitted patients had loss of smell while 1 out of 5 reported loss of taste which was associated to severity of COVID-19.Most patients recovered smell and taste dysfunctions in 2 weeks.

Atrial fibrillation in the elderly

Atrial fibrillation （AF） is the most frequent arrhythmia. Due to population aging, AF is a growing epidemic and its importance will continue to increase in the next decades. Although the prevalence of AF is high in advanced age, the number of subjects with predisposing factors for AF is even higher. Most of these factors increase the risk of atrial fibro- sis, an important component of atrial arrhythmia mecha- nisms. In fact, the new techniques to detect atrial fibrosis are showing the strong association between atrial fibrosis and AF risk. Regarding predisposing factors for AF, interatrial block （LAB） seems to be a key factor.

Surgically induced weight loss by gastric bypass improves non alcoholic fatty liver disease in morbid obese patients

AIM: To evaluate the effects of surgical weight loss (Roux-en-Y gastric bypass with a modified Fobi-Capella technique) on non alcoholic fatty liver disease in obese patients.

Polyethylene glycol rinse solution:An effective way to prevent ischemia-reperfusion injury

AIM: To test whether a new rinse solution containing polyethylene glycol 35 (PEG-35) could prevent ischemia-reperfusion injury (IRI) in liver grafts.

Mechanisms of autophagy and apoptosis:Recent developments in breast cancer cells

Autophagy,the pathway whereby cell components are degraded by lysosomes,is involved in the cell response to environmental stresses,such as nutrient deprivation,hypoxia or exposition to chemotherapeutic agents.Under these conditions,which are reminiscent of certain phases of tumor development,autophagy either promotes cell survival or induces cell death. This strengthens the possibility that autophagy could be an important target in cancer therapy,as has been proposed.Here,we describe the regulation of survival and death by autophagy and apoptosis,especially in cultured breast cancer cells.In particular,we discuss whether autophagy represents an apoptosis-independent process and/or if they share common pathways. We believe that understanding in detail the molecular mechanisms that underlie the relationships between autophagy and apoptosis in breast cancer cells could improve the available treatments for this disease.

3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease

Back pain is a common condition with a high social impact and represents a global health burden.Intervertebral disc disease(IVDD)is one of the major causes of back pain;no therapeutics are currently available to reverse this disease.The impact of bone mineral density(BMD)on IVDD has been controversial,with some studies suggesting osteoporosis as causative for IVDD and others suggesting it as protective for IVDD.Functional studies to evaluate the influence of genetic components of BMD in IVDD could highlight opportunities for drug development and repurposing.By taking a holistic 3D approach,we established an aging zebrafish model for spontaneous IVDD.Increased BMD in aging,detected by automated computational analysis,is caused by bone deformities at the endplates.However,aged zebrafish spines showed changes in bone morphology,microstructure,mineral heterogeneity,and increased fragility that resembled osteoporosis.Elements of the discs recapitulated IVDD symptoms found in humans:the intervertebral ligament(equivalent to the annulus fibrosus)showed disorganized collagen fibers and herniation,while the disc center(nucleus pulposus equivalent)showed dehydration and cellular abnormalities.We manipulated BMD in young zebrafish by mutating sp7 and cathepsin K,leading to low and high BMD,respectively.Remarkably,we detected IVDD in both groups,demonstrating that low BMD does not protect against IVDD,and we found a strong correlation between high BMD and IVDD.Deep learning was applied to high-resolution synchrotron\iCJ image data to analyze osteocyte 3D lacunar distribution and morphology,revealing a role of sp7 in controlling the osteocyte lacunar 3D profile.Our findings suggest potential avenues through which bone quality can be targeted to identify beneficial therapeutics for IVDD.