Native Hypovitaminosis D in CKD Patients : From Experimental Evidence to Clinical Practice

Native hypovitaminosis D (n-hVITD) is frequently found from the early stages of chronic kidney disease (CKD) and its prevalence increases with CKD progression. Even if the implications of n-hVITD in chronic kidney disease-mineral bone disorder (CKD-MBD) have been extensively characterized in the literature, there is a lot of debate nowadays about the so called "unconventional effects" of native vitamin D (25(OH)VitD) supplementation in CKD patients. In this review, highlights of the dimension of the problem of n-hVITD in CKD stages 2-5 ND patients will be presented. In addition, it will focus on the "unconventional effects" of 25(OH)VitD supplementation, the clinical impact of n-hVITD and the most significant interventional studies regarding 25(OH)VitD supplementation in CKD stages 2-5 ND

Gut microbiota composition and frailty in elderly patients with Chronic Kidney Disease

Background Frailty is common in older patients affected by chronic kidney disease (CKD). Since gut microbiota (gMB) may contribute to frailty, we explored possible associations between gMB and frailty in CKD. Methods We studied 64 CKD patients (stage 3b-4), categorized as frail (F, 38) and not frail (NF, 26) according to Fried criteria, and 15 controls (C), all older than 65 years. In CKD we assessed serum C-reactive protein, blood neutrophil/lymphocyte ratio, Malnutrition-inflammation Score (MIS); gMB was studied by denaturing gel gradient electrophoresis (DGGE), high-throughput sequencing (16S r-RNA gene), and quantitative real-time PCR (RT-PCR). Results No differences in alpha diversity between CKD and C and between F and NF patients emerged, but high-throughput sequencing showed significantly higher abundance of potentially noxious bacteria (Citrobacter, Coprobacillus, etc) and lower abundance of saccharolytic and butyrate-producing bacteria (Prevotella spp., Faecalibacterium prausnitzii, Roseburia spp.), in CKD respect to C. Mogibacteriaceae family and Oscillospira genus abundance was positively related to inflammatory indices in the whole CKD cohort, while that of Akkermansia, Ruminococcus and Eubacterium genera was negatively related. Compared with NF, in F there was a higher abundance of some bacteria (Mogibacteriacee, Coriobacteriacee, Eggerthella, etc), many of which have been described as more abundant in other diseases. Conclusions These results suggest that inflammation and frailty could be associated to gMB modifications in CKD

The human papillomavirus type 18 E6 oncoprotein induces Vascular Endothelial Growth Factor 121 (VEGF121) transcription from the promoter through a p53-independent mechanism

Altered angiogenic response is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix. Vascular Endothelial Growth Factor (VEGF) is one of the most potent inducers of angiogenesis and is up-regulated in carcinoma of the cervix. Infection by high-risk human papillomavirus and persistent expression of viral oncogene E6 are etiologically linked to the development of cervical cancer. E6 is able to immortalize cells and induce malignant transformation by inactivating p53. In cervical cancer, regulation of VEGF expression is poorly described. Thus, we investigated whether E6 oncoprotein could regulate VEGF expression in HPV18-positive cervical cancer-derived HeLa cells harboring a wild-type p53. The alternative splicing of vegf mRNA renders three major isoforms of 121, 165 and 189 amino-acids in humans. We have designed isoform specific real time QRT-PCR assays to quantitate vegf transcripts and VEGF121 was the predominant isoform. Silencing HPV18 E6 mRNA with specific siRNA reduced VEGF121 expression by at least 50% whereas silencing of p53 did not alter its expression. Treatment with cycloheximide did not inhibit E6-induced VEGF121 expression. Collectively, these results suggest that HPV18 E6 oncoprotein contributes to tumor angiogenesis by inducing VEGF transcription from the promoter in a p53-independent manner

Sarcopenia is Associated with Malnutrition but Not with Systemic Inflammation in Older Persons with Advanced CKD

Background: In patients with chronic kidney disease (CKD), sarcopenia can be determined by a wide spectrum of risk factors. We evaluated the association of sarcopenia with nutritional, behavioral and inflammatory patterns in older patients with advanced CKD. Methods: we cross-sectionally evaluated 113 patients with CKD stages 3b-5. Sarcopenia was defined according to the EWGSOP2 criteria. We assessed: anthropometry, bioelectrical impedance analysis, physical, and psychological performance. Nutritional status was assessed using the Malnutrition Inflammation Score (MIS) and by verifying the eventual presence Protein Energy Wasting syndrome (PEW). Systemic inflammation was assessed by dosing: CRP, IL6, TNF\u3b1, MCP1, IL10, IL17, fetuin, IL12. Results: 24% of patients were sarcopenic. Sarcopenic individuals had lower creatinine clearance (18 \ub1 11 vs. 23 \ub1 19 mL/min; p = 0.0087) as well as lower BMI (24.8 \ub1 3.0 vs. 28.4 \ub1 5.5 Kg/m2; p < 0.0001) and a lower FTI (11.6 \ub1 3.9 vs. 14.4 \ub1 5.1 kg/m2, p = 0.023). Sarcopenic persons had higher prevalence of PEW (52 vs. 20%, p < 0.0001) and a tendency to have higher MIS (6.6 \ub1 6.5 vs. 4.5 \ub1 4.0, p = 0.09); however, they did not show any difference in systemic inflammation compared to non-sarcopenic individuals. Conclusions: CKD sarcopenic patients were more malnourished than non-sarcopenic ones, but the two groups did not show any difference in systemic inflammation

Clinical Effectiveness of Transversus Abdominis Plane (TAP) Block versus Local Anesthesia Wound Infiltration for Postoperative Pain Relief After Laparoscopic Appendicectomy in Children: A Study Protocol for a Multicenter Double-Blind Randomized Controlled Phase III Trial

Geoffrey Bloy,1 Amelie Jurine,1 Yann Chaussy,2 Frederic Auber,2 Pierre-Gregoire Guinot,3 Belaid Bouhemad,3 Michel Francois,4 Lucie Vettoretti,1 Sebastien Pili-Floury,5 Maxime Nguyen,3 Guillaume Besch5 1CHU Besançon, Département d’Anesthésie Réanimation Chirurgicale, Besançon, F-25000, France; 2Université de Franche-Comté, CHU Besançon, SINERGIES, Service de Chirurgie Pédiatrique, Besançon, F-25000, France; 3University of Burgundy and Franche-Comté, Dijon University Hospital, INSERM LNC UMR1231, FCS Bourgogne Franche-Comté LipSTIC LabEx, Dijon, F-21000, France; 4Université de Bourgogne, CHU Dijon, Service de Chirurgie Pédiatrique, Dijon, F-21000, France; 5Université de Franche-Comté, CHU Besançon, SINERGIES, Département d’Anesthésie Réanimation Chirurgicale, Besançon, F-25000, FranceCorrespondence: Guillaume Besch, Département d’Anesthésie Réanimation Chirurgicale, CHU Besançon, 3 bvd Alexandre Fleming, Besançon, 25030, France, Tel +3381218958, Fax +3381669331, Email [email protected]: Postoperative pain relief after laparoscopic appendicectomy is a key determinant of early rehabilitation in children. Recent guidelines recommend performing either a transversus abdominis plane (TAP) block or local anesthesia (LA) wound infiltration as part of multimodal postoperative analgesia after appendectomy. To date, the clinical effectiveness of TAP block versus LA wound infiltration has never been compared. The hypothesis of this study is that the TAP block may provide a greater opioid-sparing effect after laparoscopic appendicectomy in children than LA wound infiltration.Study Design and Methods: We designed a multicenter double-blind randomized controlled phase III trial and aim to include 110 children who undergo laparoscopic appendicectomy. Children are randomized to receive either TAP block (TAP group) or LA wound infiltration (infiltration group). Multimodal analgesia is standardized in the two groups using the same protocol, which includes the stepwise prescription of paracetamol, phloroglucinol, ketoprofene, and nalbuphine according to the hetero-evaluation of pain performed by the nurses who were blinded to the treatment allocated using the validated FLACC scale. The primary outcome is the total dose of nalbuphine administered within 24 hours after surgery.Discussion: No study has specifically compared the clinical effectiveness of TAP block versus LA wound infiltration for postoperative pain relief after laparoscopic appendectomy in children. This paper describes the protocol for a randomized trial that addresses this issue. The results of this trial will be useful for editing guidelines with a higher level of evidence on this topic.Keywords: laparoscopic appendectomy, TAP block, wound infiltration, analgesia, childre

Mechanisms of Endothelial Dysfunction in Resistance Arteries from Patients with End-Stage Renal Disease

The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications

Southern Ocean deep convection as a driver of Antarctic warming events

Simulations with a free-running coupled climate model show that heat release associated with Southern Ocean deep convection variability can drive centennial-scale Antarctic temperature variations of up to 2.0 °C. The mechanism involves three steps: Preconditioning: heat accumulates at depth in the Southern Ocean; Convection onset: wind and/or sea-ice changes tip the buoyantly unstable system into the convective state; Antarctic warming: fast sea-ice–albedo feedbacks (on annual–decadal timescales) and slow Southern Ocean frontal and sea-surface temperature adjustments to convective heat release (on multidecadal–century timescales) drive an increase in atmospheric heat and moisture transport toward Antarctica. We discuss the potential of this mechanism to help drive and amplify climate variability as observed in Antarctic ice-core records

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

The cystic fibrosis microbiome in an ecological perspective and its impact in antibiotic therapy

The recent focus on the cystic fibrosis (CF) complex microbiome has led to the recognition that the microbes can interact between them and with the host immune system, affecting the disease progression and treatment routes. Although the main focus remains on the interactions between traditional pathogens, growing evidence supports the contribution and the role of emergent species. Understanding the mechanisms and the biological effects involved in polymicrobial interactions may be the key to improve effective therapies and also to define new strategies for disease control. This review focuses on the interactions between microbe-microbe and host-microbe, from an ecological point of view, discussing their impact on CF disease progression. There are increasing indications that these interactions impact the success of antimicrobial therapy. Consequently, a new approach where therapy is personalized to patients by taking into account their individual CF microbiome is suggested.Portuguese Foundation for Science and Technology (FCT), the strategic funding of UID/BIO/04469/2013-CEB and UID/EQU/00511/2013-LEPABE units. This study was also supported by FCT and the European Community fund FEDER, through Program COMPETE, under the scope of the Projects “DNA mimics” PIC/IC/82815/2007, RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462), “BioHealth—Biotechnology and Bioengineering approaches to improve health quality”, Ref. NORTE-07-0124-FEDER-000027 and NORTE-07-0124-FEDER-000025—RL2_ Environment and Health, co-funded by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, FEDER. The authors also acknowledge the grant of Susana P. Lopes (SFRH/BPD/95616/2013) and of the COST-Action TD1004: Theragnostics for imaging and therapy

Cumulative Prognostic Score Predicting Mortality in Patients Older Than 80 Years Admitted to the ICU.

OBJECTIVES: To develop a scoring system model that predicts mortality within 30 days of admission of patients older than 80 years admitted to intensive care units (ICUs). DESIGN: Prospective cohort study. SETTING: A total of 306 ICUs from 24 European countries. PARTICIPANTS: Older adults admitted to European ICUs (N = 3730; median age = 84 years [interquartile range = 81-87 y]; 51.8% male). MEASUREMENTS: Overall, 24 variables available during ICU admission were included as potential predictive variables. Multivariable logistic regression was used to identify independent predictors of 30-day mortality. Model sensitivity, specificity, and accuracy were evaluated with receiver operating characteristic curves. RESULTS: The 30-day-mortality was 1562 (41.9%). In multivariable analysis, these variables were selected as independent predictors of mortality: age, sex, ICU admission diagnosis, Clinical Frailty Scale, Sequential Organ Failure Score, invasive mechanical ventilation, and renal replacement therapy. The discrimination, accuracy, and calibration of the model were good: the area under the curve for a score of 10 or higher was .80, and the Brier score was .18. At a cut point of 10 or higher (75% of all patients), the model predicts 30-day mortality in 91.1% of all patients who die. CONCLUSION: A predictive model of cumulative events predicts 30-day mortality in patients older than 80 years admitted to ICUs. Future studies should include other potential predictor variables including functional status, presence of advance care plans, and assessment of each patient's decision-making capacity