Clinical trial:Lactobacillus plantarum 299v(DSM 9843)improves symptoms of irritable bowel syndrome

AIM:To assess the symptomatic efficacy of Lactobacillus plantarum 299v(L.plantarum 299v)(DSM 9843) for the relief of abdominal symptoms in a large subset of irritable bowel syndrome(IBS) patients fulfilling the Rome Ⅲ criteria.METHODS:In this double blind,placebo-controlled,parallel-designed study,subjects were randomized to daily receive either one capsule of L.plantarum 299v(DSM 9843) or placebo for 4 wk.Frequency and intensity of abdominal pain,bloating and feeling of incomplete rectal emptying were assessed weekly on a visual analogue scale while stool frequency was calculated.RESULTS:Two hundred and fourteen IBS patients were recruited.After 4 wk,both pain severity(0.68 + 0.53 vs 0.92 + 0.57,P < 0.05) and daily frequency(1.01 + 0.77 vs 1.71 + 0.93,P < 0.05) were lower with L.plantarum 299v(DSM 9843) than with placebo.Similar results were obtained for bloating.At week 4,78.1 % of the patients scored the L.plantarum 299v(DSM 9843) symptomatic effect as excellent or good vs only 8.1 % for placebo(P < 0.01).CONCLUSION:A 4-wk treatment with L.plantarum 299v(DSM 9843) provided effective symptom relief,particularly of abdominal pain and bloating,in IBS patients fulfilling the Rome Ⅲ criteria.

Epithelial-mesenchymal transition transcription factors and mi RNAs: “Plastic surgeons” of breast cancer

Growing evidence suggests that breast cancer cell plasticity arises due to a partial reactivation of epithelialmesenchymal transition(EMT) programs in order to give cells pluripotency, leading to a stemness-like phenotype. A complete EMT would be a dead end program that would render cells unable to fully metastasize to distant organs. Evoking the EMT-mesenchymal-toepithelial transition(MET) cascade promotes successful colonization of distal target tissues. It is unlikely that direct reprogramming or trans-differentiation without passing through a pluripotent stage would be thepreferred mechanism during tumor progression. This review focuses on key EMT transcriptional regulators, EMT-transcription factors involved in EMT(TFs) and the mi RNA pathway, which are deregulated in breast cancer, and discusses their implications in cancer cell plasticity. Cross-regulation between EMT-TFs and mi RNAs, where mi RNAs act as co-repressors or co-activators, appears to be a pivotal mechanism for breast cancer cells to acquire a stem cell-like state, which is implicated both in breast metastases and tumor recurrence. As a master regulator of mi RNA biogenesis, the ribonuclease type Ⅲ endonuclease Dicer plays a central role in EMTTFs/mi RNAs regulating networks. All these EMT-MET key regulators represent valuable new prognostic and predictive markers for breast cancer as well as promising new targets for drug-resistant breast cancers.

Defect of insulin signal in peripheral tissues: important role of ceramide

In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions:to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver.Interestingly,dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues.Normally,the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods.Thus,adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides.When the buffering action of adipose tissue to store fatty acids is impaired,fatty acids that build up in othertissues are metabolized as sphingolipid derivatives such as ceramides.Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.

Impact of venous thromboembolism on the natural history of pancreatic adenocarcinoma

Few studies have analyzed the effect of ve- nous thromboembolism （VTE） events on the prognosis of pancreatic cancer, but their results were conflicting. The pres- ent study was undertaken to determine the effect of VTE on pancreatic adenocarcinoma （PA） outcomes. METHODS： All consecutive patients diagnosed with PA from May 2004 to January 2012 in a single oncology center were retrospectively studied. Clinical, radiological and histologi- cal data at time of diagnosis or within the first 3 months after surgery, including the presence （＋） or absence （-） of VTE were collected. VTE was defined as radiological evidence of either pulmonary embolism （PE）, deep venous thrombosis without infection or catheter-related thrombosis. PA with and without PE was compared for survival using the Kaplan-Meier method to estimate overall survival. RESULTS： Among 162 PA patients with a median follow-up of 15 （3-92） months after diagnosis, 28 demonstratedVTE （＋）. PA patients with and without PE were similar for age, American Society of Anesthesiologist score, body mass index, and histo- ry of treatment. The distribution of cancer stages was similarbetween the two groups VTE （＋） and VTE （-）. The median du- ration of survival was significantly worse in the VTE （＋） group vs VTE （-） （12 vs 18 months, P=0.010）. In multivariate analysis, the presence of VTE and surgical treatment were independent prognostic factors for overall survival. CONCLUSION： VTE （＋） at time of diagnosis or within the first 3 months after surgery during treatment is an indepen- dent factor of poor prognosis in PA.

Extracellular vesicles:General features and usefulness in diagnosis and therapeutic management of colorectal cancer

In the world,among all type of cancers,colorectal cancer(CRC)is the third most commonly diagnosed in males and the second in females.In most of cases,(RP1)patients’prognosis limitation with malignant tumors can be attributed to delayed diagnosis of the disease.Identification of patients with early-stage disease leads to more effective therapeutic interventions.Therefore,new screening methods and further innovative treatment approaches are mandatory as they may lead to an increase in progression-free and overall survival rates.For the last decade,the interest in extracellular vesicles(EVs)research has exponentially increased as EVs generation appears to be a universal feature of every cell that is strongly involved in many mechanisms of cell-cell communication either in physiological or pathological situations.EVs can cargo biomolecules,such as lipids,proteins,nucleic acids and generate transmission signal through the intercellular transfer of their content.By this mechanism,tumor cells can recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination.This review intends to cover the most recent literature on the role of EVs production in colorectal normal and cancer tissues.Specific attention is paid to the use of EVs for early CRC diagnosis,follow-up,and prognosis as EVs have come into the spotlight of research as a high potential source of‘liquid biopsies’.The use of EVs as new targets or nanovectors as drug delivery systems for CRC therapy is also summarized.

Next generation sequencing, inter-tumor heterogeneity and prognosis of hepatitis B related hepatocellular carcinoma

Hepatocellular carcinoma（HCC）is one of the leading causes of cancer related death in Asia and Africa（1）.It reflects the high burden of hepatitis B virus（HBV）infection in these areas.Curative treatments of HCC as radiofrequency ablation and resection are impaired by a high rate of tumor recurrence.However,most of the time,HCC is frequently diagnosed at advanced stages where only

High doses of catecholamines activate glucose transport in human adipocytes independently from adrenoceptor stimulation or vanadium addition

BACKGROUND When combined with vanadium salts,catecholamines strongly activate glucose uptake in rat and mouse adipocytes.AIM To test whether catecholamines activate glucose transport in human adipocytes.METHODS The uptake of 2-deoxyglucose(2-DG)was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery.Pharmacological approaches with amine oxidase inhibitors,adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline(also named epinephrine).RESULTS In human adipocytes,45-min incubation with 100μmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin.This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium.Among various natural amines and adrenergic agonists tested,no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake.The effect of the catecholamines was not impaired by pargyline and semicarbazide,contrarily to that of benzylamine or methylamine,which are recognized substrates of semicarbazide-sensitive amine oxidase.Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone,and only the former was potentiated by vanadate.Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.CONCLUSION High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes.At submillimolar doses,vanadium did not enhance this catecholamine activation of glucose transport.Consequently,this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.

Aging and Geriatric Dentistry

Five theories shed lights on the potential mechanisms of aging:somatic mutations,telomere loss,mitochondrial defects,and accumulation of altered proteins inside proteasomes.The existence of a program of aging is not yet identified,but overlaps with a program for risks of death.On the other hand,organisms are programmed for survival,which ultimately fails.This failure results in aging,notabily,focusing on alterations of specific genes.Irregular examinations,dysfunctions,insufficient use of fluoride,and removable partial dentures,are favoring the formation of caries and periodontal pathologies.Oral lesions are due to local trauma,related gingival recession,and formation of pockets.They are associated to insufficient removal of food/plaque.Epithelial thinning,and reduction of extracellular matrix components,lead to plications and foldings of the mucosal surface,and subsequently to bacterial colonization.Geriatric dentistry(or gerodontology)is an increasing field of dentistry,mostly associated with the growing percentage of patients over 80+years.

Dental stem cells: Progress and perspectives

Dental pulp stem cells(DPSCs) are thought to contribute to reparative dentin formation, and that they may correspond to heterogenous populations of precursor cells or represent distinct differentiation stages along the odontoblastic lineage. DPSCs share many similarities with mesenchymal stem cells of the bone marrow(BMSCs). It appears that the distribution of tissue stem cells is not random and, within the dental pulp, there are potentially several distinct niches of stem/progenitor cells. In addition to DPSCs, other dental stem cell populations have been isolated. As for DPSCs, further studies are still needed to evaluate their potential of differentiation and their regenerative activity. Up today,(1) the formal demonstration that pulpal resident stem cells are actually the reparative dentin-forming cells recruited in response to injury is still lacking; and(2) the origin, localization and precise identity of odontogenic stem cells remain largely unknown. Dental clonal cell lines may represent valuable tool to answer some fontamental questions concerning the dental stem cell biology. Altogether, the presence of dental cell populations displaying stem cell properties has opened new paths for considering regenerative therapies. This might be aprerequisite to design alternative strategies for capping and endodontic treatment, using stem cells.

Deciphering the Role of Klf10 in the Cerebellum

Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.

Isolation and Spasmolytic Evaluation of New Alkaloids from Dichrostachys cinerea (L.) Wight et Arn. (Fabaceae)

Dichrostachys cinerea (L.) Wight et Arn. (Fabaceae) root bark is used in Ivorian Traditional Medicine to treat asthma, which is a respiratory disorder characterized by inflammation and the restriction of tracheal muscles obstructing the air circulation. The tracheal relaxant effect of a crude aqueous-alcoholic extract of the plant root bark was previously shown. For the present study, alkaloids were isolated from the same extract and investigated ex vivo in C57Bl/6j mice isolated trachea contracted with carbachol 1 μM, in comparison with a reference bronchodilatator, i.e. salbutamol. Two extraction procedures allowed isolating 2 Alkaloids that monodimensional and bi-dimensional nuclear magnetic resonance (NMR) and mass specters allowed identifying a pyrolidine structure type nucleus with a long bi-hydroxyled alkyl chain. Alkaloid 1, carrier of a sugar, is a glycoside of Alkaloid 2. Both alkaloids induced similar spasmolytic effects, but Alkaloid 1 was more effective than Alkaloid 2 at 9 × 10-6 M (p < 0.01), 3 × 10-5 M, and 9 × 10-5 M (p <0.001). Salbutamol induced its spasmolytic effect in a different way, and its maximal effect Emax (less than 30%) was obtained at 9 × 10-6 M, while Emax of both alkaloids (100%) was obtained at 3 × 10-4 M.

Diabetes and pulmonary infection:how hyperglycaemia shapes the immune system

In a recent study published in Nature,Nobs and colleagues aimed to identify novel mechanisms that may explain why diabetes is associated with an increased susceptibility to viral respiratory infections.Their analyses revealed a central role of lung dendritic cells(DC)which exhibited several functional defects induced by hyperglycaemia and consequently result in impaired antiviral immune responses.

Severe asthma exacerbation:Changes in patient characteristics,management,and outcomes from 1997 to 2016 in 40 ICUs in the greater Paris area

Background Despite advances in asthma treatments,severe asthma exacerbation(SAE)remains a life-threatening condition in adults,and there is a lack of data derived from adult patients admitted to intensive care units(ICUs)for SAE.The current study investigated changes in adult patient characteristics,management,and outcomes of SAE over a 20-year period in 40 ICUs in the greater Paris area.Methods In this retrospective observational study,admissions to 40 ICUs in the greater Paris area for SAE from January 1,1997,to December 31,2016 were analyzed.The primary outcome was the proportion of ICU admissions for SAE during 5-year periods.Secondary outcomes were ICU and hospital mortality,and the use of mechanical ventilation and catecholamine.Multivariate analysis was performed to assess factors associated with ICU mortality.Results A total of 7049 admissions for SAE were recorded.For each 5-year period,the proportion decreased over time,with SAE accounting for 2.84%of total ICU admissions(n=2841)between 1997 and 2001,1.76%(n=1717)between 2002 and 2006,1.05%(n=965)between 2007 and 2011,and 1.05%(n=1526)between 2012 and 2016.The median age was 46 years(interquartile range[IQR]:32–59 years),55.41%were female,the median Simplified Acute Physiology Score II was 20(IQR:13–28),and 19.76%had mechanical ventilation.The use of mechanical ventilation remained infrequent throughout the 20-year period,whereas the use of catecholamine decreased.ICU and hospital mortality rates decreased.Factors associated with ICU mortality were renal replacement therapy,catecholamine,cardiac arrest,pneumothorax,acute respiratory distress syndrome,sepsis,and invasive mechanical ventilation(IMV).Non-survivors were older,had more severe symptoms,and were more likely to have received IMV.Conclusion ICU admission for SAE remains uncommon,and the proportion of cases decreased over time.Despite a slight increase in symptom severity during a 20-year period,ICU and hospital mortality decreased.Patients requiring IMV had a higher mortality rate.

Epidemiology and risk factors for mortality in critically ill patients with pancreatic infection

Background:The AbSeS-classification defines specific phenotypes of patients with intra-abdominal infection based on the(1)setting of infection onset(community-acquired,early onset,or late-onset hospital-acquired),(2)presence or absence of either localized or diffuse peritonitis,and(3)severity of disease expression(infection,sepsis,or septic shock).This classification system demonstrated reliable risk stratification in intensive care unit(ICU)patients with intra-abdominal infection.This study aimed to describe the epidemiology of ICU patients with pancreatic infection and assess the relationship between the components of the AbSeS-classification and mortality.Methods:This was a secondary analysis of an international observational study(“AbSeS”)investigating ICU patients with intra-abdominal infection.Only patients with pancreatic infection were included in this analysis(n=165).Mortality was defined as ICU mortality within 28 days of observation for patients discharged earlier from the ICU.Relationships with mortality were assessed using logistic regression analysis and reported as odds ratio(OR)and 95%confidence interval(CI).Results:The overall mortality was 35.2%(n=58).The independent risk factors for mortality included older age(OR=1.03,95%CI:1.0 to 1.1 P=0.023),localized peritonitis(OR=4.4,95%CI:1.4 to 13.9 P=0.011),and persistent signs of inflammation at day 7(OR=9.5,95%CI:3.8 to 23.9,P<0.001)or after the implementation of additional source control interventions within the first week(OR=4.0,95%CI:1.3 to 12.2,P=0.013).Gramnegative bacteria were most frequently isolated(n=58,49.2%)without clinically relevant differences in microbial etiology between survivors and non-survivors.Conclusions:In pancreatic infection,a challenging source/damage control and ongoing pancreatic inflammation appear to be the strongest contributors to an unfavorable short-term outcome.In this limited series,essentials of the AbSeS-classification,such as the setting of infection onset,diffuse peritonitis,and severity of disease expression,were not associated with an increased mortality risk.

Prognostication algorithm for non-cirrhotic non-B non-C hepatocellular carcinoma-a multicenter study under the aegis of the French Association of Hepato-Biliary Surgery and liver Transplantation

Background:Liver resection and local ablation are the only curative treatment for non-cirrhotic hepatocellular carcinoma(HCC).Few data exist concerning the prognosis of patients resected for non-cirrhotic HCC.The objectives of this study were to determine the prognostic factors of recurrence-free survival(RFS)and overall survival(OS)and to develop a prognostication algorithm for non-cirrhotic HCC.Methods:French multicenter retrospective study including HCC patients with non-cirrhotic liver without underlying viral hepatitis:F0,F1 or F2 fibrosis.Results:A total of 467 patients were included in 11 centers from 2010 to 2018.Non-cirrhotic liver had a fibrosis score of F0(n=237,50.7%),F1(n=127,27.2%)or F2(n=103,22.1%).OS and RFS at 5 years were 59.2%and 34.5%,respectively.In multivariate analysis,microvascular invasion and HCC differentiation were prognostic factors of OS and RFS and the number and size were prognostic factors of RFS(P<0.005).Stratification based on RFS provided an algorithm based on size(P=0.013)and number(P<0.001):2 HCC with the largest nodule≤10 cm(n=271,Group 1);2 HCC with a nodule>10 cm(n=176,Group 2);>2 HCC regardless of size Conclusions:We developed a prognostication algorithm based on the number(≤or>2)and size(≤or>10 cm),which could be used as a treatment decision support concerning the need for perioperative therapy.In case of bifocal HCC,surgery should not be a contraindication.

Mosaic theory revised:inflammation and salt play central roles in arterial hypertension

The mosaic theory of hypertension was advocated by Irvine Page~80 years ago and suggested that hypertension resulted from the close interactions of different causes.Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by the proposed mechanisms that result in hemodynamic injury.Inflammation plays an important role in the pathophysiology and contributes to the deleterious consequences of arterial hypertension.Sodium intake is indispensable for normal body function but can be detrimental when it exceeds dietary requirements.Recent data show that sodium levels also modulate the function of monocytes/macrophages,dendritic cells,and different T-cell subsets.Some of these effects are mediated by changes in the microbiome and metabolome due to high-salt intake.The purpose of this review is to propose a revised and extended version of the mosaic theory by summarizing and integrating recent advances in salt,immunity,and hypertension research.Salt and inflammation are placed in the middle of the mosaic because both factors influence each of the remaining pieces.

Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver

Mitochondria-associated endoplasmic reticulum membranes(MAM)play a key role in mitochondrial dynamics and function and in hepatic insulin action.Whereas mitochondria are important regulators of energy metabolism,the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown.In this study,we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver.Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity both in vitro and in vivo.Glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A(PP-PP2A)pathway,induced mitochondria fission,and impaired respiration.Blocking MAM reduction counteracted glucose-induced mitochondrial alterations.Furthermore,disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function.This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice,both characterized by chronic disruption of MAM integrity,mitochondrial fission,and altered mitochondrial respiration.These data indicate that MAM contribute to the hepatic glucose-sensing system,allowing regulation of mitochondria dynamics and function during nutritional transition.Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance.

High-throughput multiplexed fluorescence-activated droplet sorting

Fluorescence-activated droplet sorting(FADS)is one of the most important features provided by droplet-based microfluidics.However,to date,it does not allow to compete with the high-throughput multiplexed sorting capabilities offered by flow cytometery.Here,we demonstrate the use of a dielectrophoretic-based FADS,allowing to sort up to five different droplet populations simultaneously.Our system provides means to select droplets of different phenotypes in a single experimental run to separate initially heterogeneous populations.Our experimental results are rationalized with the help of a numerical model of the actuation of droplets in electric fields providing guidelines for the prediction of sorting designs for upscaled or downscaled microsystems.

ASAF: altered spontaneous activity fingerprinting in Alzheimer’s disease based on multisite fMRI

Several monocentric studies have noted alterations in spontaneous brain activity in Alzheimer's disease (AD), although there is no consensus on the altered amplitude of low-frequency fluctuations in AD patients. The main aim of the present study was to identify a reliable and reproducible abnormal brain activity pattern in AD. The amplitude of local brain activity (AM), which can provide fast mapping of spontaneous brain activity across the whole brain, was evaluated based on multisite rs-fMRI data for 688 subjects (215 normal controls (NCs), 221 amnestic mild cognitive impairment (aMCI) 252 AD). Two-sample t-tests were used to detect group differences between AD patients and NCs from the same site. Differences in the AM maps were statistically analyzed via the Stouffer's meta-analysis. Consistent regions of lower spontaneous brain activity in the default mode network and increased activity in the bilateral hippocampus/parahippocampus, thalamus, caudate nucleus, orbital part of the middle frontal gyrus and left fusiform were observed in the AD patients compared with those in NCs. Significant correlations (P?<?0.05, Bonferroni corrected) between the normalized amplitude index and Mini-Mental State Examination scores were found in the identified brain regions, which indicates that the altered brain activity was associated with cognitive decline in the patients. Multivariate analysis and leave-one-site-out cross-validation led to a 78.49% prediction accuracy for single-patient classification. The altered activity patterns of the identified brain regions were largely correlated with the FDG-PET results from another independent study. These results emphasized the impaired brain activity to provide a robust and reproducible imaging signature of AD.

Molecular Determinants of Prognosis in Hepatocellular Carcinoma

Hepatocellular carcinoma is one of the leading causes of death by cancer worldwide.Prognosis of hepatocellular carcinoma is determined by characteristics of the tumor and the surrounding cirrhotic liver.Several molecular signatures reflecting tumor biology and derived from tumor analyses predict early tumor recurrence and survival.In contrast,molecular signatures from cirrhotic non-tumor samples are enriched in immunity/inflammation related genes and could predict late tumor recurrence.Moreover,combination of clinical,pathological,and molecular features may refine prognosis prediction in these patients.Finally,molecular signatures from both tumor and non-tumor tissues will be helpful in the future to guide treatments in different clinical settings.