Multi-Compartment SCFA Quantification in Human

Short-chain fatty acids (SCFA) play an important role in human biochemistry. They originate primarily from the digestive system through carbohydrates microbial fermentation. Most SCFA produced in the colon are absorbed by the intestinal wall and enter the bloodstream to be distributed throughout the body for multiple purposes. At the intestinal level, SCFA play a role in controlling fat storage and fatty acid metabolism. The effects of these beneficial compounds therefore concern overall health. They facilitate energy expenditure and are valuable allies in the fight against obesity and diabetes. SCFA are also involved in the regulation of the levels of several neurotransmitters such as GABA (γ-aminobutyric acid), glutamate, serotonin, dopamine, and norepinephrine. Their role is also highlighted in many inflammatory and neurodegenerative diseases such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). To have a realistic picture of the distribution of SCFA in different biological compartments of the human body, we propose to study SCFA simultaneously in five human biological samples: feces, saliva, serum, cerebrospinal fluid (CSF), and urine, as well as in Dried Blood Spot (DBS). To evaluate their concentration and repeatability, we used 10 aliquots from pooled samples, analyzed by 3-nitrophenylhydrazine (3-NPH) derivation and liquid chromatography coupled with high sensitivity mass spectrometry (LC-QqQ-MS). We also evaluated the SCFA assay on Dried Blood Spot (DBS). In this work, we adapted the pre-analytical parts for each sample to be able to use a common calibration curve, thus facilitating multi-assay quantification studies and so being less time-consuming. Moreover, we proposed new daughter ions from the same neutral loss (43 Da) to quantify SCFAs, thus improving the sensitivity. In conclusion, our methodology, based on a unique calibration curve for all samples for each SCFA, is well-suited to quantified them in a clinical context.

移植肾动脉狭窄:血管成形术径路和方法

目的用于评价两种径路的血管成形术的方法对移植肾动脉狭窄的治疗作用。材料与方法 18例移植肾动脉狭窄并高血压患者成功进行了血管成形术。18例中,15例患者血管狭窄位于外科手术血管吻合处或吻合处远侧端移植肾动脉主干,3例位于移植肾的肾内分支动脉。同侧股动脉径路用于治疗端-侧血管吻合的患者(n=10),对侧股动脉径路,用于治疗端-端血管吻合的患者(n=6)。16例采用股动脉径路,2例经肱动脉径路。疗效以临床随访、血管造影和超声追踪为评价。结果 18例移植肾动脉狭窄患者成功地施行了血管成形术。成形术后,所有病人均治愈。1例患者因为复发动脉狭窄,而再次作血管扩张,同时放置1个支撑器。第二次血管成形术后6个月,考虑病人已治愈。结论血管成形术是移植肾动脉狭窄所致长期高血压和肾功能减退的有效的、首选治疗方法。

Solid,non-skin,post-liver transplant tumors:Key role oflifestyle and immunosuppression management

Liver transplantation has been the treatment of choice for end-stage liver disease since 1983.Cancer has emerged as a major long-term cause of death for liver transplant recipients.Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers postliver transplantation;some have also studied risk factors.Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers.Risk of head and neck,lung,esophageal,cervical cancers and Kaposi’s sarcoma is high,but risk of colorectal cancer is not clearly demonstrated.There appears to be no excess risk of developing breast or prostate cancer.Environmental risk factors such as viral infection and tobacco consumption,and personal risk factors such as obesity play a key role,but recent data also implicate the role of calcineurin inhibitors,whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis.In this paper,we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and,ultimately,discuss how to prevent these cancers.Immunosuppressive protocol changes,including a calcineurin inhibitor-free regimen,combined with dietary guidelines and smoking cessation,are theoretically the best preventive measures.

腕管综合征时正中神经的扩散张量成像和纤维束示踪的初步研究结果

目的是为了显示在1.5TMR设备上进行人活体正中神经扩散张量成像和纤维束示踪的可行性,并评估健康志愿者与腕管综合征病人扩散成像的潜在不同。

Does gastric atrophy exist in children?

Several clinical reports confirmed that gastric atrophy is a pathology not only limited to adult patients. In pediatrics, it is most olden described in association with a H pylori infection but this bacteria does not seem to be the only etiological factor of this preneoplastic state in children. The frequency of gastric atrophy and intestinal metaplasia in children are unknown because they are not systematically sought during upper gastrointestinal endoscopy. The lack of specific histological classification of children＇s gastropathies makes their diagnosis difficult for pathologists. Based on our knowledge to date, we think that it is necessary to describe, in detail, the natural course of this lesion during childhood. A close and prolonged clinical and endoscopic follow-up is important for children with gastric atrophy.

Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

Neurodegenerative diseases, such as Alzheimer＇s, Parkinson＇s and Huntington＇s diseases, are all character- ized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

Alpha-7 nicotinic acetylcholine receptor agonist treatment in a rat model of Huntington's disease and involvement of heme oxygenase-1

Neuroinflammation is a common element involved in the pathophysiology of neurodegenerative diseases.We recently reported that repeated alpha-7 nicotinic acetylcholine receptor（α7 n ACh R） activations by a potent agonist such as PHA 543613 in quinolinic acid-injured rats exhibited protective effects on neurons.To further investigate the underlying mechanism,we established rat models of early-stage Huntington＇s disease by injection of quinolinic acid into the right striatum and then intraperitoneally injected 12 mg/kg PHA 543613 or sterile water,twice a day during 4 days.Western blot assay results showed that the expression of heme oxygenase-1（HO-1）,the key component of the cholinergic anti-inflammatory pathway,in the right striatum of rat models of Huntington＇s disease subjected to intraperitoneal injection of PHA 543613 for 4 days was significantly increased compared to the control rats receiving intraperitoneal injection of sterile water,and that the increase in HO-1 expression was independent of change in α7 n ACh R expression.These findings suggest that HO-1 expression is unrelated to α7 n ACh R density and the increase in HO-1 expression likely contributes to α7 n ACh R activation-related neuroprotective effect in early-stage Huntington＇s disease.

Frequent mutations of the CA simple sequence repeat in intron 1 of EGFR in mismatch repair-deficient colorectal cancers

AIM:To investigate the polymorphic simple sequencerepeat in intron 1 of the epidermal growth factor receptorgene(EGFR)(CA-SSRⅠ),which is known to affect theefficiency of gene transcription as a putative target of themismatch repair(MMR)machinery in colorectal tumors.METHODS:The CA-SSRⅠgenotype was analyzed ina total of 86 primary colorectal tumors,selected upontheir microsatellite instability(MSI)status[42 with highfrequency MSI(MSI-H)and 44 microsatellite stable(MSS)]and their respective normal tissue.The effect of the CA-SSRⅠgenotype on the expression of the EGFR gene wasevaluated in 18 specimens using quantitative real-timereverse transcription PCR and immunohistochemistry.RESULTS:Mutations in CA-SSRⅠwere detected in 86%(36 of 42)of MSI-H colorectal tumors and 0%(0 of 44)ofMSS tumors,indicating the EGFR gene as a novel putativespecific target of the defective MMR system(P<0.001).Impaired expression of EGFR was detected in most ofthe colorectal tumors analyzed[6/12(50%)at the mRNAlevel and 15/18(83%)at the peptide level].However,noassociation was apparent between EGFR expression andCA-SSRⅠstatus in tumors or normal tissues.CONCLUSION:Our results suggest that CA-SSRⅠsequence does not contribute to the regulation of EGFRtranscription in colon,and should thus not be consideredas a promising predictive marker for response to EGFRinhibitors in patients with colorectal cancer.

Allogenic banking of dental pulp stem cells for innovative therapeutics

Medical research in regenerative medicine and cellbased therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells(DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products(ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen(HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues(dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice(GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.

Genetic diversity of the hepatitis C virus: Impact and issues inthe antiviral therapy

The hepatitis C Virus (HCV) presents a high degree of genetic variability which is explained by the combination of a lack of proof reading by the RNA dependant RNA polymerase and a high level of viral replication. The re- sulting genetic polymorphism defines a classification in clades, genotypes, subtypes, isolates and quasispecies. This diversity is known to reflect the range of responses to Interferon therapy. The genotype is one of the pre- dictive parameters currently used to define the antiviral treatment strategy and the chance of therapeutic suc- cess. Studies have also reported the potential impact of the viral genetic polymorphism in the outcome of antivi- ral therapy in patients infected by the same HCV geno- type. Both structural and non structural genomic regions of HCV have been suggested to be involved in the Inter- feron pathway and the resistance to antiviral therapy. In this review, we first detail the viral basis of HCV diversity. Then, the HCV genetic regions that may be implicated in resistance to therapy are described, with a focus on the structural region encoded by the E2 gene and the non- structural genes NS3, NS5A and NS5B. Both mechanisms of the Interferon resistance and of the new antiviral drugs are described in this review.

Evaluation of Doppler-ultrasonography in the diagnosis of transjugular intrahepatic portosystemic shunt dysfunction: A prospective study

AIM To prospectively evaluate the performance of Dopplerultrasonography(US) for the detection of transjugular intrahepatic portosystemic shunt(TIPS) dysfunction within a multicenter cohort of cirrhotic patients.METHODS This study was conducted in 10 french teaching hospitals. After TIPS insertion, angiography and liver Doppler-US were carried out every six months to detect dysfunction(defined by a portosystemic gradient ≥ 12 mm Hg and/or a stent stenosis ≥ 50%). The association between ultrasonographic signs and dysfunction was studied by logistic random-effects models, and the diagnostic performance of each Doppler criterion was estimated by the bootstrap method. This study was approved by the ethics committee of Tours.RESULTS Two hundred and eighteen pairs of examinations performed on 87 cirrhotic patients were analyzed. Variables significantly associated with dysfunction were: The speed of flow in the portal vein(P = 0.008), the reversal of flow in the right(P = 0.038) and left(P = 0.049) portal branch, the loss of modulation of portal flow by the right atrium(P = 0.0005), ascites(P = 0.001) and the overall impression of the operator(P = 0.0001). The diagnostic performances of these variables were low; sensitivity was < 58% and negative predictive value was < 73%. Therefore, dysfunction cannot be ruled out from Doppler-US. CONCLUSION The performance of Doppler-US for the detection of TIPS dysfunction is poor compared to angiography. New tools are needed to improve diagnosis of TIPS dysfunction.

Hepatitis B virus mutations potentially conferring adefovir/ tenofovir resistance in treatment-naive patients

Anti-hepatitis B virus(HBV)therapy leads to the emer- gence of mutant viral strains during the treatment of chronic hepatitis B with nucleos(t)ides analogues. The existence of HBV variants with primary antiviral resistance may be important for treatment choice. We studied two patients with chronic HBV infection by sequencing the HBV polymerase gene.They had adefovir-and tenofovir-related mutations in the viral polymerase,although they had never been treated. These mutations were rtV214A/rtN238T in one patient and rtA194T in the other.Thus,mutations in untreated patients deserve cautious surveillance.These data indicate that mutations that can theoretically confer adefovir or tenofovir resistance may emerge in treatmentnaive patients.

Methodology for Constructing a Short-Term Event Risk Score in Heart Failure Patients

We present a methodology for constructing a short-term event risk score in heart failure patients from an ensemble predictor, using bootstrap samples, two different classification rules, logistic regression and linear discriminant analysis for mixed data, continuous or categorical, and random selection of explanatory variables to build individual predictors. We define a measure of the importance of each variable in the score and an event risk measure by an odds-ratio. Moreover, we establish a property of linear discriminant analysis for mixed data. This methodology is applied to EPHESUS trial patients on whom biological, clinical and medical history variables were measured.

Alfapump®implantable device in management of refractory ascites:An update

Refractory ascites(RA)is a frequent and life-threatening complication of cirrhosis.In selected patients with RA,transjugular intrahepatic portosystemic shunt(TIPS)placement and liver transplantation(LT)are currently considered the best therapeutic alternatives to repeated large volume paracentesis.In patients with a contraindication to TIPS or LT,the alfapump®system(Sequana Medical,Ghent,Belgium)has been developed to reduce the need for iterative paracentesis,and consequently to improve the quality of life and nutritional status.We report here recent data on technical progress made since the first implantation,the efficacy and tolerance of the device,the position of the pump in the therapeutic arsenal for refractory ascites,and the grey areas that remain to be clarified regarding the optimal selection of patients who are potential candidates for this treatment.

Construction of Parsimonious Event Risk Scores by an Ensemble Method. An Illustration for Short-Term Predictions in Chronic Heart Failure Patients from the GISSI-HF Trial

Selecting which explanatory variables to include in a given score is a common difficulty, as a balance must be found between statistical fit and practical application. This article presents a methodology for constructing parsimonious event risk scores combining a stepwise selection of variables with ensemble scores obtained by aggregation of several scores, using several classifiers, bootstrap samples and various modalities of random selection of variables. Selection methods based on a probabilistic model can be used to achieve a stepwise selection for a given classifier such as logistic regression, but not directly for an ensemble classifier constructed by aggregation of several classifiers. Three selection methods are proposed in this framework, two involving a backward selection of the variables based on their coefficients in an ensemble score and the third involving a forward selection of the variables maximizing the AUC. The stepwise selection allows constructing a succession of scores, with the practitioner able to choose which score best fits his needs. These three methods are compared in an application to construct parsimonious short-term event risk scores in chronic HF patients, using as event the composite endpoint of death or hospitalization for worsening HF within 180 days of a visit. Focusing on the fastest method, four scores are constructed, yielding out-of-bag AUCs ranging from 0.81 (26 variables) to 0.76 (2 variables).

Transit time ultrasound perivascular flow probe technology is superior to MR imaging on hepatic blood flow measurement in a porcine model

Background: The hepatic hemodynamics is an essential parameter in surgical planning as well as in various disease processes. The transit time ultrasound(TTUS) perivascular flow probe technology is widely used in clinical practice to evaluate the hepatic inflow, yet invasive. The phase-contrast-MRI(PC-MRI) is not invasive and potentially applicable in assessing the hepatic blood flow. In the present study, we compared the hepatic inflow rates using the PC-MRI and the TTUS probe, and evaluated their predictive value of post-hepatectomy adverse events. Methods: Eighteen large white pigs were anaesthetized for PC-MRI and approximately 75% hepatic resection was performed under a unified protocol. The blood flow was measured in the hepatic artery(Qha), the portal vein(Qpv), and the aorta above the celiac trunk(Qca) using PC-MRI, and was compared to the TTUS probe. The Bland-Altman method was conducted and a partial least squares regression(PLS) model was implemented. Results: The mean Qpv measured in PC-MRI was 0.55 ± 0.12 L/min, and in the TTUS probe was 0.74 ± 0.17 L/min. Qca was 1.40 ± 0.47 L/min in the PC-MRI and 2.00 ± 0.60 L/min in the TTUS probe. Qha was 0.17 ± 0.10 L/min in the PC-MRI, and 0.13 ± 0.06 L/min in the TTUS probe. The Bland-Altman method revealed that the estimated bias of Qca in the PC-MRI was 32%(95% CI:-49% to 15%); Qha 17%(95% CI:-15% to 51%); and Qpv 40%(95% CI:-62% to 18%). The TTUS probe had a higher weight in predicting adverse outcomes after 75% resection compared to the PC-MRI( β= 0.35 and 0.43 vs β = 0.22 and 0.07, for tissue changes and premature death, respectively). Conclusions: There is a tendency of the PC-MRI to underestimate the flow measured by the TTUS probes. The TTUS probe measures are more predictive of relevant post-hepatectomy outcomes.

无线胶囊内镜与回肠结肠镜在诊断克罗恩病术后复发中的比较:一项前瞻性研究

Background and aims: Following ileocolonic resection for Crohn’s disease (CD), early endoscopic recurrence predicts recurrence of symptoms. The aim of the study was to compare ileocolonoscopy and wireless capsule endoscopy(WCE) for the detection of postoperative recurrence in CD. Methods: WCE and ileocolonoscopy were performed within six months following surgery in 32 prospectively enrolled patients. Two independent observers interpreted the results of WCE. Recurrence in the neoterminal ileum was defined by a Rutgeerts score ≥1. When observers at WCE did not concur,WCE results were considered as either true negative or true positive and sensitivity and specificity were calculated according to both assumptions. Results: Recurrence occurred in 21 patients (68%) and was detected by ileocolonoscopy in 19 patients. Sensitivity was 90%and specificity 100%. Sensitivity of WCE was 62%and 76%and specificity was 100%and 90%, respectively, depending on assumptions. There was a correlation between the severity of the lesions measured by both methods (p< 0.05). Lesions located outside the scope of conventional endoscopy were detected by WCE in two thirds of patients with excellent interobserver agreement (kappa >0.9) for all lesions with the exception of ulceration (kappa = 0.7). Conclusions: The sensitivity of WCE in detecting recurrence in the neoterminal ileum was inferior to that of ileocolonoscopy. In contrast,WCE detected lesions outside the scope of ileocolonoscopy in more than two thirds of patients. Additional follow up studies are needed to assess the clinical relevance of such lesions. At the present time, it seems that WCE cannot systematically replace ileocolonoscopy in the regular management of patients after surgery.

埋藏式心脏复律除颤器植入患者中“电风暴”的临床预测因素和预后价值

Aims: Insufficient data exists regarding predictors of electrical storms(ES) and clinical outcome in patients treated with an implantable cardioverter defibrillator(ICD). The purpose of this study was to delineate a subgroup of patients likely to experience ES and to determine the impact of ES on mortality in ICD recipients. Methods and results: Baseline characteristics of 307 ICD-treated patients were retrospectively analysed. ES was defined as two or more ventricular tachyarrhythmias within 24 h leading to an immediate electrical therapy(antitachycardia pacing and/or shock), separated by a period of sinus rhythm. Clinical characteristics and survival of 123 patients experiencing a total of 294 episodes of ES(median 2 ES/ patient, range 1-9), were compared with those of 184 ES-free patients during a median follow-up of 826 days(inter-quartile 1141 days). Median actuarial duration for the first ES occurrence after ICD implant was 1417 days [95% confidence interval(CI) 1061-2363] with a median follow-up of 816 days(7-4642 days) in ES-free patients. Univariate analysis identified older age, depressed left ventricular ejection fraction(LVEF), ventricular tachycardia(VT) as index arrhythmia, chronic renal failure and absence of lipid-lowering drugs as variables significantly associated with an increased risk of ES. Multivariable Cox analysis confirmed an independent predictive value for chronic renal failure [hazard ratio(HR) 1.54, 95% CI 0.95-2.51, P=0.052], VT(HR 2.20, 95% CI 1.44-3.37, P=0.0003), and LVEF(HR 0.98, 95% CI 0.97-0.99, P=0.027). In contrast, diabetics(HR 0.49, 95% CI 0.27-0.90, P=0.022) were less affected by ES. There was no difference in survival between both groups. Conclusion: ES is frequent but does not increase mortality in ICD s recipients. Patients with severe systolic dysfunction, chronic renal failure and VT as initial arrhythmia are likely to experience ES. Diabetics are less affected by ES.

结肠切除术联合回肠直肠吻合术可维持女性溃疡性结肠炎患者的生殖能力

Objectives -Restorative proctocolectomy with ileoanal anastomosis (IPAA) is the surgical standard for patients with ulcerative colitis (UC). Significant reduction in female fertility and fecundity after IPAA has been shown in recent studies. In selected cases, colectomy with ileorectal anastomosis (IRA) is another surgical option. The aim of this study was to evaluate fertility in women with UC who underwent IRA. Patients and methods -This study included all women with UC who underwent IRA between 1962 and 1999 and who were 40 years old or younger at the time of surgery, and older than 18 years of age at the time of the interview. Data were collected using a structured telephone interview concerning reproductive behavior and waiting times to pregnancy. Results -Among 40 eligible patients, 37 whose mean age at IRA was 28 years (range 11-39) answered the questionnaire. Twenty-two were unmarried, not wishful of pregnancy and / or already had children. Among 15 females wishing children after IRA, 10 (66%) became pregnant: one had therapeutic abortion, two had a miscarriage, four had 1 child, two had 2 children and one had 4 children. Five patients were sterile after IRA. Conclusion -These preliminary results suggest that IRA for UC preserves female fertility. If confirmed in other series this information should be provided to young women with UC before deciding surgical option.

泛发性裂纹湿疹作为系统性淋巴瘤的表现特征:7例病例报道

Eczema craquele, or asteatotic eczema, has been associated with malignant lymphoma although this is rare. Since 1986,we have observed seven patients, six men and one woman,mean age 71.5 years (range 43-86 years), with systemic lymphoma and concurrent eczema craquele. Five patients had T-cell lymphoma, one had a B-cell lymphoma and one had Hodgkin’s disease. All patients shared several characteristics: (1) a synchronous onset of eczema craquele and lymphoma,(2) generalized eczema, (3)absence of alternative disease or conditions that could favour the onset of eczema craquele, and (4) eczema refractory to topical corticosteroids and emollients, but which resolved upon lymphoma remission and invariably recurred with the lymphoma relapse. All the patients except one died within 1 year, most with active lymphoma. The finding of recalcitrant generalized eczema craquele should prompt a search for lymphoma, particularly in older men. Lymphoma-associated eczema craquele has most characteristics of paraneoplastic syndromes and may be a hallmark of aggressive lymphoma.