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Contact investigations following the diagnosis of active tuberculosis (TB) are paramount for the control of the disease. Epidemiological data are very powerful for contact tracing but might be delayed and/or difficult to integrate, especially in the setting of multiple contact-tracing investigations. The aim of this study was to address the added-value of whole-genome sequencing (WGS) to routine local TB surveillance systems. From November 2016 to July 2017, the local TB surveillance system identified three clusters that could constitute a unique larger outbreak. Epidemiological and clinical information were integrated with WGS genotyping data of Mycobacterium tuberculosis strains obtained using a simple DNA extraction method coupled with sequencing using an Illumina MiSeq platform and an in-house bioinformatics pipeline for single nucleotide polymorphism (SNP) analysis. Epidemiological investigations identified three putative TB clusters potentially interrelated including eight patients with active TB. Seven M. tuberculosis isolates were available and analysed by WGS. Using a 5-SNP threshold to define recent transmission, WGS-based genotyping supported the occurrence of the three clusters as well as a link between clusters 1 and 2 (SNP ≤1), constituting a larger outbreak. This outbreak was clearly delineated by refuting a potential link with the third cluster (SNP >500). Genotyping data did not support the belonging of patient 7 to any studied cluster. This study illustrates the usefulness of WGS genotyping for routine TB surveillance systems in local communities to rapidly confirm or disprove epidemiological hypotheses and delineate TB clusters, especially in the context of multiple contact-tracing investigations. Keywords: Contact investigation, genotyping outbreak, molecular epidemiology, Mycobacterium tuberculosis, whole-genome sequencing

Biallelic loss-of-function variants in STRC contribute to mild-moderate hearing loss (DFNB16). Here, we report a female patient with mild hearing loss. Exome sequencing and MLPA analysis revealed STRC biallelic inactivation due to a nonsense and a CKMT1B-STRC deletion. Analysis of the self-reported normal-hearing parents revealed inconsistent Mendelian inheritance. Indeed, the mother was a heterozygous carrier of a CKTM1B-STRC-CATSPER2 deletion, and the father shared the same genotype as his daughter. He was later found to also have mild-moderate hearing loss. To address these discrepancies, we used long-read sequencing and optical genome mapping. We demonstrated that the father, in fact, carried a CKMT1B-STRC-CATSPER2 deletion in trans with the STRC nonsense variant and a tandem duplication of CATSPER2-CKMT1A. The proband inherited this latter haplotype, together with the maternal CKMT1B-STRC-CATSPER2 deletion. Combining these two technologies allowed us to fully elucidate the complex structural rearrangements at the STRC locus and provide appropriate genetic counselling., Competing Interests: Conflict of interest statement The authors have no conflict of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Context: Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes., Objectives: To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients., Methods: We conducted a systematic review that included all pharmacological studies published after 2000., Results: Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy., Conclusions: Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Vaccine reactogenicity is well documented at the clinical level but the mechanism involved at the local or systemic level are still poorly understood. Muscular tissue where most vaccines are administered is the first place of interaction between the vaccine formulation and the host's immune cells. So far, this site of vaccine administration is not well documented from a mechanistic standpoint. The study of early molecular events at the injection site is crucial to understand the local response to vaccines. In this paper, we report a standardized workflow, from the injection of vaccine formulations in rabbit muscle, to the analysis by desorption electrospray ionization and histology staining to understand the role of lipids involved in the inflammation and its resolution on striated muscular tissue. The analysis of lipid mediators was optimized at the site of needle insertion to allow the spatial comparison of cellular infiltrates at the injection site. We showed that lipids were distributed across the spatial tissue morphology in a time-dependent manner. The MS imaging applied to vaccinology could pave the way to a better understanding of vaccine reactogenicity and mechanism of action., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Emilie Chautard reports a relationship with Sanofi that includes: equity or stocks. Sebastien Laurent reports a relationship with Sanofi-Aventis Research and Development Montpellier that includes: equity or stocks. Patrick Syntin reports a relationship with Sanofi that includes: equity or stocks. Fabienne Piras-Douce reports a relationship with Sanofi that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The diffusion of the SARS-CoV-2 Delta (B.1.617.2) variant and the waning of immune response after primary Covid-19 vaccination favoured the breakthrough SARS-CoV-2 infections in vaccinated subjects. To assess the impact of vaccination, we determined the severity of infection in hospitalised patients according to vaccine status., Methods: We performed a retrospective observational study on patients hospitalised in 10 centres with a SARS-CoV-2 infection (Delta variant) from July to November 2021 by including all patients who had completed their primary vaccination at least 14 days before hospital admission and the same number of completely unvaccinated patients. We assessed the impact of vaccination and other risk factors through logistic regression., Results: We included 955 patients (474 vaccinated and 481 unvaccinated). Vaccinated patients were significantly older (75.0 [63.25-84.0] vs. 55.0 [38.0-73.0]; p < 0.001), more frequently males (55.1% (261/474) vs. 46.4% (223/481); p = 0.009), and had more comorbidities (2.0 [1.0-3.0] vs. 1.0 [0.0-2.0]; p < 0.001). Vaccinated patients were less often admitted for Covid-19 (59.3% (281/474) vs. 75.1% (361/481); p < 0.001), had less extended lung lesions (≤25%: 64.3% (117/182) vs. 38.4% (88/229); p < 0.001), required oxygen less frequently (57.5% (229/398) vs. 73.0% (270/370); p < 0.001), at a lower flow (3.0 [0.0-8.7] vs. 6.0 [2.0-50.0] L/min, p < 0.001), and for a shorter duration (3 [0.0-8.0] vs. 6 [2.0-12.0] days, p < 0.001)., and required less frequently intensive care unit admission (16.2% (60/370) vs. 36.0% (133/369); p < 0.001) but had comparable mortality in bivariate analysis (16.7% (74/443) vs. 12.2% (53/433); p = 0.075). Multivariate logistic regression showed that vaccination significantly decreased the risk of death (0.38 [0.20-0.70](p = 0.002), ICU admission (0.31 [0.21-0.47](p < 0.001) and oxygen requirement (0.16 [0.10-0.26](p < 0.001), even among older patients or with comorbidities., Conclusions: Among patients hospitalised with a delta variant SARS-CoV-2 infection, vaccination was associated with less severe forms, even in the presence of comorbidities., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies., Patients and Methods: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis., Results: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals., Conclusion: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting., Clinical Trial Registration: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914)., Competing Interests: Disclosure AD received travel support and fees for ad-board participations from Bayer. MP received grants and fees from Bayer. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Among them, ICIs-induced systemic sclerosis (SSc) is poorly known., Methods: To better characterize this irAE, our comprehensive approach combined the description of ICIs-induced scleroderma cases, the systematic review of the literature and the analysis of VigiBase, the WHO pharmacovigilance database., Results: We identified two cases with underlying limited cutaneous SSc who presented a dramatic increase in the skin thickening following pembrolizumab, associated with scleroderma renal crisis in one case. In the literature, four cases of scleroderma and four cases of morphea have been reported with pembrolizumab or nivolumab. None following ipilimumab, atezolizumab or durvalumab were retrieved. Skin changes appeared or worsened more quickly with pembrolizumab than nivolumab, and had different patterns between both drugs. Patients with generalized skin changes required high-dose prednisone to improve skin thickening. Among the 2527 scleroderma cases identified in VigiBase, 35 were associated with ICIs. Nivolumab and pembrolizumab showed a disproportionality in scleroderma reporting. No disproportionality was found for ipilimumab, atezolizumab or durvalumab., Conclusion: The risk of scleroderma or fibrosis extension in SSc patients should be considered when initiating anti-PD-1 agents. It suggests the role of PD-1/PD-L1 interaction in the pathophysiology of SSc., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Gold nanoparticles (AuNPs) with unique physicochemical properties have received a great deal of interest in the field of biological, chemical and biomedical implementations. Despite the widespread use of AuNPs in chemical and biological sensing, catalysis, imaging and diagnosis, and more recently in therapy, no comprehensive summary has been provided to explain how AuNPs could aid in developing improved sensing and catalysts systems as well as medical settings., Scope of Review: The chemistry of Au-based nanosystems was followed by reviewing different applications of Au nanomaterials in biological and chemical sensing, catalysis, imaging and diagnosis by a number of approaches, and finally synergistic combination therapy of different cancers. Afterwards, the clinical impacts of AuNPs, future application of AuNPs, and opportunities and challenges of AuNPs application were also discussed., Major Conclusions: AuNPs show exclusive colloidal stability and are considered as ideal candidates for colorimetric detection, catalysis, imaging, and photothermal transducers, because their physicochemical properties can be tuned by adjusting their structural dimensions achieved by the different manufacturing methods., General Significance: This review provides some details about using AuNPs in sensing and catalysis applications as well as promising theranostic nanoplatforms for cancer imaging and diagnosis, and sensitive, non-invasive, and synergistic methods for cancer treatment in an almost comprehensive manner., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mucositis, an acute inflammation of the digestive mucosa, is one of the main toxicities secondary to oncological treatments. Among its consequences, mucositis-related pain is an important complication due to its intensity and repercussion, especially on quality of life. Treatment of pain plays a central role in management of mucositis. It must be multimodal, combining local and general opioid or non-opioid treatments, adapted to pain intensity and based on international recommendations updated in 2014. A systemic analgesic treatment with morphine with a patient-controlled analgesia device is often necessary in severe mucositis. In case of insufficient analgesia, use of co-analgesics (paracetamol, ketamine, anticonvulsants, and antidepressants) can improve analgesic control and reduce morphine doses. Non-drug strategies (distraction, relaxation, hypnosis) and preventive measures must be a major concern. Among them, laser therapy using a low power athermal laser beam, is a promising therapeutic strategy whose effectiveness is based on its analgesic, anti-inflammatory, and healing properties. Despite many available studies, there is a limited number of clinically effective therapies. New therapeutic agents for the prevention and treatment of mucositis and its pain, based on the biological phenomena involved, must be further developed to improve the efficacy of analgesia., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Arterial stiffness may contribute to late-life depression via cerebral microvascular damage, but evidence is scarce. No longitudinal study has evaluated the association between arterial stiffness and risk of depressive symptoms. Therefore, we investigated the association between carotid artery stiffness and incident depressive symptoms in a large community-based cohort study., Methods: This longitudinal study included 7013 participants (mean age 59.7 ± 6.3 years; 35.8% women) free of depressive symptoms at baseline. Carotid artery stiffness (high-resolution echo tracking) was determined at baseline. Presence of depressive symptoms was determined at baseline and at 4 and 6 years of follow-up, and was defined as a score ≥7 on the validated Questionnaire of Depression, Second Version, Abridged and/or new use of antidepressant medication. Logistic regression and generalized estimating equations were used., Results: In total, 6.9% (n = 484) of the participants had incident depressive symptoms. Individuals in the lowest tertile of carotid distensibility coefficient (indicating greater carotid artery stiffness) compared with those in the highest tertile had a higher risk of incident depressive symptoms (odds ratio: 1.43; 95% confidence interval: 1.10-1.87), after adjustment for age, sex, living alone, education, lifestyle, cardiovascular risk factors, and baseline Questionnaire of Depression, Second Version, Abridged scores. Results were qualitatively similar when we used carotid Young's elastic modulus as a measure of carotid stiffness instead of carotid distensibility coefficient, and when we used generalized estimating equations instead of logistic regression., Conclusions: Greater carotid stiffness is associated with a higher incidence of depressive symptoms. This supports the hypothesis that carotid stiffness may contribute to the development of late-life depression., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Consistent with the fact that ribonucleotides (rNTPs) are in excess over deoxyribonucleotides (dNTPs) in vivo, recent findings indicate that replicative DNA polymerases (DNA Pols) are able to insert ribonucleotides (rNMPs) during DNA synthesis, raising crucial questions about the fidelity of DNA replication in both Bacteria and Eukarya. Here, we report that the level of rNTPs is 20-fold higher than that of dNTPs in Pyrococcus abyssi cells. Using dNTP and rNTP concentrations present in vivo, we recorded rNMP incorporation in a template-specific manner during in vitro synthesis, with the family-D DNA Pol (PolD) having the highest propensity compared with the family-B DNA Pol and the p41/p46 complex. We also showed that ribonucleotides accumulate at a relatively high frequency in the genome of wild-type Thermococcales cells, and this frequency significantly increases upon deletion of RNase HII, the major enzyme responsible for the removal of RNA from DNA. Because ribonucleotides remain in genomic DNA, we then analyzed the effects on polymerization activities by the three DNA Pols. Depending on the identity of the base and the sequence context, all three DNA Pols bypass rNMP-containing DNA templates with variable efficiency and nucleotide (mis)incorporation ability. Unexpectedly, we found that PolD correctly base-paired a single ribonucleotide opposite rNMP-containing DNA templates. An evolutionary scenario is discussed concerning rNMP incorporation into DNA and genome stability., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate the short- and long-term outcomes of liver first approach (LFA) in patients with synchronous colorectal liver metastases (CRLM), evaluating the predictive factors of survival., Methods: Sixty-two out of 301 patients presenting with synchronous CRLM underwent LFA between 2007 and 2016. All patients underwent neoadjuvant chemotherapy. After neoadjuvant treatment patients were re-evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Liver resection was scheduled after 4-6 weeks. Changes in non-tumoral parenchyma and the tumor response according to the Tumor Regression Grade score (TRG) were assessed on surgical specimens. Primary tumor resection was scheduled 4-8 weeks following hepatectomy., Results: Five patients out of 62 (8.1%) showed "Progressive Disease" at re-evaluation after neoadjuvant chemotherapy, 22 (35.5%) showed "Stable Disease" and 35 (56.5%) "Partial Response"; of these latter, 29 (82%) showed histopathologic downstaging. The 5-year survival (OS) rate was 55%, while the 5-year disease-free survival (DFS) rate was 16%. RECIST criteria, T-stage, N-stage and TRG were independently associated with OS. Bilobar presentation of disease, RECIST criteria, R1 margin and TRG were independently associated with DFS. Patients with response to neoadjuvant chemotherapy had better survival than those with stable or progressive disease (radiological response 5-y OS: 65% vs. 50%; 5-y DFS: 20% vs. 10%; pathological response 5-y OS: 75% vs. 56%; 5-y DFS: 45% vs. 11%)., Conclusions: LFA is an oncologically safe strategy. Selection is a critical point, and the best results in terms of OS and DFS are observed in patients having radiological and pathological response to neoadjuvant chemotherapy., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: Cutaneous manifestations (CM) in ANCA-associated vasculitides (AAV) are frequent, but data on clinical significance and clinical-pathological correlations are lacking., Methods: We conducted a multicenter, retrospective study including 1553 AAV patients. Clinical, biological and pathological features have been analyzed, and tissue samples from 46 biopsies were reviewed in a blind manner., Results: CM were more frequent in EGPA (53.0%) and MPA (51.9%) than in GPA (36.7%). Lesions more frequently associated with GPA were oral ulcers (4.6% vs. 2.5% in EGPA and 0.3% in MPA), while pyoderma gangrenosum and palpebral xanthoma were specific to GPA. Lesions associated with MPA were segmentary edema (19.5% vs. 12.7% in EGPA and 4.3% in GPA) and livedo (12.4% vs. 0.5% and 2.6%, respectively), whereas those associated with EGPA were urticarial lesions (11.5% vs. 1.9% in GPA and 3.5% in MPA) and nodules (12,2% vs. 8.9% in GPA and 4.7% in MPA). In GPA, CM patients had more frequent vasculitis than granulomatous phenotype, and poorer relapse-free and overall survival. Pathological analysis showed vasculitis and/or granulomatous infiltrates in 87.5% of GPA, in 61.1% of EGPA and in all MPA. Vasculitis was more frequently observed in purpura and nodules, while granulomas were differently located and organized within vessels or interstitium according to the type of lesions., Conclusion: Each AAV seemed to be associated with a peculiar pattern of cutaneous lesions. CM are associated with poorer prognosis in GPA. Clinical-pathological correlations showed no specific feature of each AAV, whereas granulomatous infiltrates differ according to the type of lesions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Kingella kingae, producing the cytotoxic RTX protein, is a causative agent of serious infections in humans such as bacteremia, endocarditis and osteoarticular infection, especially in young children. Recently, Kingella negevensis, a related species, has been isolated from the oral cavity of healthy children. In this study, we report the isolation of K. negevensis strain eburonensis, initially misidentified as K. kingae with MALDI-TOF MS, from a vaginal specimen of a patient suffering of vaginosis. The genome sequencing and analysis of this strain together with comparative genomics of the Kingella genus revealed that K. negevensis possesses a full homolog of the rtx operon of K. kingae involved in the synthesis of the RTX toxin. We report that a K. kingae specific diagnostic PCR, based on the rtxA gene, was positive when tested on K. negevensis strain eburonensis DNA. This cross-amplification, and risk of misidentification, was confirmed by in silico analysis of the target gene sequence. To overcome this major diagnostic issue we developed a duplex real-time PCR to detect and distinguish K. kingae and K. negevensis. In addition to this, the identification of K. negevensis raises a clinical issue in term of pathogenic potential given the production of a RTX hemolysin., (Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators., (Copyright © 2017. Published by Elsevier Ltd.)

Syntheses and characterizations of biocompatible superparamagnetic iron oxide nanoparticles with embedded curcumin and coated with ultrathin layer of hyaluronic acid-curcumin (HA-Cur) conjugate have been reported. Zeta potential measurements confirmed effective coating of native iron oxide nanoparticles stabilized by cationic derivative of chitosan (SPION-CCh) with the synthesized HA-Cur conjugate. Both SPIONs with embedded curcumin and the ones coated with HA-Cur (SPION-CCh/HA-Cur) revealed desired magnetic characteristics while fluorescent properties were much better for the coated nanoparticles. SPION-CCh/HA-Cur nanoparticles were shown to be very promising candidates for T 2 MRI contrast agents as they can easily penetrate cell membrane and their relaxivity is exceptionally high (ca. 470mM -1 s -1 ). They may be also tracked using confocal fluorescence microscopy due to the presence of fluorescent curcumin in the coating. In vitro studies indicated that the obtained SPIONs-CCh/HA-Cur were non-toxic for EA.hy926 endothelial cells., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Proximal aorta stiffens and dilates with aging. Aortic stiffening is a well known process, carrying prognostic implications. On the contrary, few data are available about proximal aorta dilatation. It is not known if "out of proportion" aortic remodeling, i.e. in excess for age, sex and body size, could be a marker of early vascular ageing; there is controversy on how it would be accelerated by classical risk factors or would associate with validated markers of cardiovascular organ damage., Aim: We conducted a systematic review in order to evaluate the determinants of proximal aortic dimensions, focusing on the association with arterial hypertension, cardiovascular risk factors and markers of organ damage., Determinants of Proximal Aorta Remodeling: Age, gender and body size explain 40-50% of the variability of aortic dimensions; genetic predisposition accounts for nearly 20%. Among cardiovascular risk factors obesity and hypertension seem to be associated with faster outward aortic remodeling. Arterial hypertension would account for a 0.60-0.78 mm greater diameter at the ascending aorta. Moreover, in hypertension, left ventricular mass showed a strict association with aortic diameter in nearly all studies. Other classical risk factors for atherogenesis such as dyslipidemia and smoking showed a weak influence on proximal aortic dimensions. No study reported a greater aortic remodeling in diabetics., Conclusions: "Out of proportion" proximal aortic remodeling, could represent a subclinical marker of early vascular ageing, describing the cumulative influence of genetic predisposition, arterial hypertension and obesity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The association between psychological factors and cardiovascular diseases may depend upon socio-economic status. The present cross-sectional study examined the potential moderating role of occupational status on the association between perceived stress and intima-media thickness (IMT), using baseline examination data of the Paris Prospective Study III., Methods: IMT was measured in the right common carotid artery (CCA-IMT) 1cm below the bifurcation, in a zone free of discrete plaques, using non-invasive high-resolution echotracking. Perceived stress was measured with the 4-item Perceived Stress Scale. The association between perceived stress and CCA-IMT was explored using linear regression analysis and regression coefficients (b) were given per 1-point increment., Results: The study population included 5140 participants (3539 men) in the labor force aged 55.9years on average (standard deviation: 3.9), and who were free of personal history of cardiovascular disease and not on psychotropic drugs. There was a non-significant trend between perceived stress and CCA-IMT after adjustment for socio-demographic, self-rated health and cardiovascular risk factors (b [95% CI] 1.02 [-0.08;2.12]; p=0.069). However, multivariable stratified analysis indicates a significant and robust association between perceived stress and CCA-IMT in unemployed participants (b [95% CI] 3.30 [0.44;6.17]), and an association of same magnitude in working participants with low occupational status but without reaching statistical significance., Conclusions: The association between perceived stress and CCA-IMT may depend upon employment status. These results may explain why psychological stress is more tightly linked to cardiovascular disease among individuals facing social adversity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: We assess the respective relationship of high depressive symptoms and antidepressant use (ATD) with baroreflex sensitivity (BRS) in subjects from the community who enrolled the Paris Prospective Study III., Methods: Recruitment took place in a large health preventive centre in Paris (France), between May 2008 and June 2012. BRS was investigated by spectral analysis of the spontaneous carotid distension rate and RR intervals using non-invasive high-resolution ultrasound carotid-echotracking. A total score ≥7 on a 13-item standardized questionnaire defined the presence of high depressive symptoms. Information on ATD use was obtained on a face-to-face interview with a medical doctor who checked the most recent medical prescriptions and/or medical package., Results: There were 9213 participants aged 50-75 years (38.6% of women), including 5.6% with high-depressive symptoms and 5.2% on ATD. High depressive symptoms were not associated with low BRS (below the median) even in unadjusted logistic regression analysis (OR = 1.09; 95%CI: 0.91-1.30). Instead, ATD use was related to low BRS in multivariate logistic regression analysis (OR = 1.27; 95% CI: 1.04-1.54). This association remains after adjusting for and matching on propensity score of receiving ATD. A specific association with serotonin and norepinephrine reuptake inhibitors was observed (OR = 1.94; 95% CI: 1.16-3.22)., Conclusions: ATD use and serotonin and norepinephrine reuptake inhibitors in particular, but not high depressive symptoms, is associated with low BRS. If confirmed, these results may bring novel insights into the mechanisms linking depressive symptoms and/or ATD use with cardiovascular disease onset., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background and Aims: Acute hypertensive response (AHR) affects more than 60% of patients with ischemic stroke and is associated with poor outcomes. We hypothesized that its development is related to arterial stiffening. "The gold standard" estimate of arterial stiffness is carotid-femoral pulse wave velocity (CF-PWV). We compared CF-PWV and indirect indices of arterial stiffness (central augmentation index (cAIxHR), central systolic (cSBP) and pulse (cPP) pressures) between acute ischemic stroke patients who developed AHR and those who were normotensive in the early phase of stroke., Methods: AHR was assessed through hourly BP measurements within 24 h from admission using an oscillometric device. The stiffness was assessed using applanation tonometry with a SphygmoCor(®) device (Atcor, Sydney, Australia) 7 ± 2 days after stroke., Results: Among 102 patients with acute ischemic stroke, 73(71.5%) met AHR criteria. In an univariate analysis, CF-PWV, cAIxHR, cSBP and cPP were higher in those who developed AHR (10.9 vs. 8.3 m/s, p < 0.001; 30.8 vs. 23.9%, p = 0.004; 138.2 vs. 117.2 mmHg, p < 0.001; 54.6 vs. 44 mmHg, p = 0.005, respectively). In a multivariate logistic regression analysis, CF-PWV was independently associated with AHR after adjustment for age and peripheral mean blood pressure (pMBP) (p = 0.04), for age, pMBP and diabetes mellitus (DM) (p = 0.045), and age, pMBP, DM and hypertension (p = 0.047)., Conclusion: This study revealed for the first time that AHR in ischemic stroke is associated with elevated aortic stiffness independently of other clinical factors including age and hypertension preceding stroke. A potential pathophysiological mechanism responsible for this relationship includes impaired baroreceptor function in stiff arteries resulting in impaired BP autoregulation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The characterization of synthetic superparamagnetic iron oxide nanoparticle (SPION) surfaces prior to functionalization is an essential step in the prediction of their successful functionalization, and in uncovering issues that may influence their selection as magnetically targeted drug delivery vehicles (prodrugs). Here, three differently functionalized magnetite (Fe3O4) SPIONs are considered. All were identically prepared by the alkaline coprecipitation of Fe(2+) and Fe(3+) salts. We use X-ray photoelectron spectroscopy, electron microscopy, time-of-flight SIMS, FTIR spectroscopy and magnetic measurements to characterize their chemical, morphological and magnetic properties, in order to aid in determining how their surfaces differ from those prepared by Fe(CO)5 decomposition, which we have already studied, and in assessing their potential use as drug delivery carriers., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The growing interest in the clinical measurement of arterial aging through the noninvasive assessment of arterial stiffness is associated with important developments in novel methods and apparatus. In this review, we aimed to describe the major principles of the measurement of arterial stiffness and to critically review the advantages and limitations of the different methods. The measurement of regional stiffness is recommended by international guidelines for routine clinical practice. It is most often determined through pulse wave velocity (PWV) between 2 arterial sites. Methods using a single-site cuff-based measurement are promising. Local determination of arterial stiffness, obtained either with the well-established, high-resolution echo tracking systems or more recently with magnetic resonance imaging, is indicated for pathophysiological and pharmacologic studies. Novel apparatus that were developed for determining arterial stiffness claimed superiority over pioneering methods either through greater simplicity of use, better repeatability, or a more pertinent arterial pathway. However, the true additive value of measuring arterial aging with a given apparatus had to be translated into the predictive value of arterial stiffness as an intermediate end point, ie, the higher the arterial stiffness the higher the number of cardiovascular (CV) events. Thus, another important aim of this review was to analyze the amount of epidemiologic evidence obtained with a given method regarding the predictive value of arterial stiffness for CV events., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Adsorption of proteins on surfaces placed in biological fluids is a ubiquitous and mostly irreversible phenomenon, desirable or not, but often uncontrolled. Adsorption of most proteins on poly(ethylene oxide) (PEO) brushes is very limited, while the amount of proteins adsorbed on poly(acrylic acid) (PAA) brushes varies with the pH and ionic strength (I) of the protein solution. Mixed brushes of PEO and PAA are designed here to reversibly adsorb and desorb albumin, lysozyme, collagen and immunoglobulin G, four very different proteins in terms of size, solubility and isoelectric point. Protein adsorption and desorption are monitored using X-ray photoelectron spectroscopy, as well as with quartz crystal microbalance for in situ and real-time measurements. Large amounts of protein are adsorbed and then nearly completely desorbed on mixed PEO/PAA brushes by a simple pH and I trigger. The mixed brushes thus nicely combine the properties of pure PAA and pure PEO brushes. These adsorption/desorption cycles are shown to be repeated with high efficiency. The high-performance smart substrates created here could find applications in domains as diverse as biosensors, drug delivery and nanotransport., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Inflammatory bowel diseases (IBD) are associated with an increased cardiovascular risk that is not fully explained by traditional cardiovascular risk factors but may be due to inflammation and mediated by an increased arterial stiffness., Aims: Study 1, to investigate the relationship between inflammation and arterial stiffening; Study 2, to look whether aortic stiffening is reduced by immunomodulatory therapy in IBD., Methods: Study 1 (Cross-sectional study): pulse wave velocity (PWV) was measured in 74 IBD subjects (40 ulcerative colitis and 34 Crohn's disease) and 80 matched controls. Study 2 (Longitudinal study): the effect of therapy on PWV was measured at baseline and 3.4 ± 0.5 years later in 14 IBD subjects treated only with salicylates, 11 subjects treated with steroids and azathioprine, 7 subjects treated with anti TNF-alpha and 30 matched controls., Results: Study 1: All parameters were comparable between subjects with ulcerative colitis and Crohn's disease. Compared to controls, subjects with ulcerative colitis and those with Crohn's disease have both higher carotid-femoral PWV (7.0 ± 1.1, 7.8 ± 1.7 and 8.0 ± 1.6 m/s, respectively; P < 0.001) and carotid-radial PWV (7.2 ± 0.9, 8.8 ± 1.4 and 8.8 ± 1.3 m/s, respectively; P < 0.001). In fully adjusted models carotid-femoral PWV was positively associated with disease duration whereas carotid-radial PWV was associated with C-reactive protein and history of relapse. Study 2: in fully adjusted model carotid-femoral PWV increased significantly at follow-up in IBD subjects treated with salicylates but not in those treated with steroids and azathioprine or anti TNF-alpha., Conclusion: Increased arterial stiffness in IBD is dependent upon inflammation and reduced by immunomodulatory drugs., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aims: Liver resection is considered the standard treatment of colorectal metastases (CRLM). However, to date, no long term oncological results and data regarding repeat hepatectomy after laparoscopic approach are known. The aim of this study is to analyze single center long-term surgical and oncological outcomes after liver resection for CRLM., Methods: A total of 57 open resections (OR) were matched with 57 laparoscopic resections (LR) for CRLM. Matching was based mainly on number of metastases, tumor size, segmental position of lesions, type of hepatectomy and type of resection., Results: Morbidity rate was significantly less in the LR group (p = 0.002); the length of hospital stay was 6.5 ± 5 days for the LR group and 9.2 ± 4 days for the OR group (p = 0.005). After a median follow up of 53.7 months for the OR group and 40.9 months for the LR group, the 5-y overall survival rate was 65% and 60% respectively (p = 0.36) and the 5-y disease free survival rate was 38% and 29% respectively (p = 0.24). More patients in the LR group received a third hepatectomy for CRLM relapse than in the OR group (80% vs. 14.3% respectively; p = 0.015)., Conclusions: Laparoscopic resection for CRLM offers advantages in terms of reduced blood loss, morbidity rate and hospital stay. It provides comparable long-term oncological outcomes but can improve further resectability in patients with recurrent disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in ≥3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components--even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus--in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV)., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Carotid-femoral pulse wave velocity (PWV), as a parameter of aortic stiffness, is an established marker of cardiovascular risk. There has been increasing use of arterial stiffness parameters combining aortic and muscular stiffness or a parameter derived from PWV - the stiffness index beta (BETA = ln(systolic/diastolic pressure) × 2 blood viscosity/pulse pressure × PWV(2)). The aim of this study was to compare different arterial stiffness parameters in a general population random sample., Methods and Results: In 809 individuals from the Czech post-MONICA study (aged 54 ± 13.5 years, 47% men), we compared the association of carotid-femoral PWV (cfPWV), carotid-ankle PWV (caPWV), and BETA with cardiovascular risk factors, parameters of subclinical organ damage, and presence of manifest cardiovascular disease. Both cfPWV and caPWV were similarly associated with blood pressure and glucose level, while cfPWV was more strongly associated with age, cholesterol level and glomerular filtration rate whereas caPWV with Sokolow-Lyon index. BETA derived from cfPWV and caPWV was less dependent on blood pressure, while it showed a closer association with coronary heart disease presence, as compared to cfPWV and caPWV., Conclusions: Addition of lower extremity to aortic stiffness has an effect on the association with cardiovascular risk factors while having no effect on the association with manifest cardiovascular disease. Beta transformation of PWV decreases its dependence on blood pressure and may increase its power in cardiovascular risk prediction., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Cholangiocarcinomas are uncommon tumours with a poor prognosis, that frequently present epidermal growth factor receptor overexpression., Methods: In a multi-centre phase II trial, patients with unresectable cholangiocarcinoma, naïve to chemotherapy, received Cetuximab (400 mg/m(2) at week 1, then 250 mg/m(2)/week) and Gemcitabine (1 g/m(2) on day 1, 8 and 15 every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months, using a Simon 2-stage design. Moreover, we assessed the impact of KRAS status and skin toxic effect on efficacy., Results: Forty-four patients (41% locally advanced/59% metastatic) were enrolled. Median age was 61.5 years; ECOG PS was 0 (68%) or 1. Six months PFS reached 47%. Median OS was 13.5 months [95% confidence interval (CI) 9.8-31.8 months]. Nine patients (20.4%) had PR and disease-control rate was 79.5%. Grade 3/4-related toxic effects were haematological (52.2%), skin rash (13.6%) and fatigue (11.4%). KRAS mutations were found in 7 of 27 patients and had no influence on PFS. Skin toxic effect ≥grade 2 was associated with increased PFS (P = 0.05)., Conclusion(s): Our study met its primary end point, suggesting that Gemcitabine-Cetuximab has activity in cholangiocarcinoma. KRAS status was not associated with PFS, unlike skin toxic effect, which could be used as a surrogate marker for efficacy. ClinicalTrials.gov Identifier: NCT00747097.

Previous studies reported that normobaric hyperoxia influences heart rate, arterial pressure, cardiac output and systemic vascular resistance, but the mechanisms underlying these changes are still not fully understood. Several factors are considered including degeneration of endothelium-derived nitric oxide by reactive oxygen species, the impact of oxygen-free radicals on tissues and alterations of autonomic nervous system function. Recently, new devices for the detailed non-invasive assessment of large and small arteries have been developed. Therefore, the aim of our study was to assess heart rate variability (HRV) as a potential indicator of autonomic balance and its relation to blood pressure and vascular properties during medical air (MAB) and 100% oxygen breathing (OXB) in healthy volunteers. In 12 healthy subjects we assessed heart rate and blood pressure variability, baroreflex sensitivity, respiratory frequency, common carotid artery diameter and its wall distensibility, as well as changes in the digital artery pulse waveform, stroke index and systemic vascular resistance during MAB and OXB. Mean and systolic blood pressure have increased significantly while digital pulse amplitude and carotid artery diameter were significantly lower during hyperoxia. Heart rate variability measures did not differ during MAB and OXB. However, the correlations between spectral HRV components and those hemodynamic parameters which have changed due to hyperoxia varied substantially during MAB (correlated significantly) and OXB (no significant correlations were noted). Our findings suggest that autonomic nervous system might not be the main mediator of the cardiovascular changes during 100% oxygen breathing in healthy subjects. It seems that the direct vascular responses are initial consequences of hyperoxia and other cardiovascular parameter alterations are secondary to them., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Unlabelled: Macrophagic myofasciitis (MMF) is a specific histological lesion assessing the persistence of vaccine-derived aluminum oxyhydroxide in muscle tissue, at a site of previous immunization. Long-lasting MMF is usually detected in patients with arthromyalgias, chronic fatigue, and stereotyped cognitive dysfunction. MMF diagnosis requires muscle biopsy, an invasive procedure not suitable for the routine investigation of all patients with musculoskeletal pain. To help decision making in routine practice, we designed a retrospective analysis of 130 consecutive arthro-myalgic patients, previously immunized with aluminum-containing vaccines, in whom deltoid muscle biopsy was performed for diagnostic purposes. According to biopsy results, the patients were ascribed to either the MMF or the non-MMF group. MMF was diagnosed in 32.3% of the patients. MMF and non-MMF groups were similar according to both the injected vaccines and the delay between vaccination and biopsy. MMF patients had less frequent fibromyalgia than non-MMF patients (≥11 fibromyalgic tender points in 16.6 vs 55.5%, p < 0.04), and more often abnormal evoked potentials suggestive of CNS demyelination (38.5 vs 5.7%, p < 0.01). Predictive bioclinical scores based on simple variables such as the number of fibromyalgic tender points, arthralgias, and spinal pain, had sensitivity ranging from 50 to 88.1% and specificity from 36.4 to 76.1%., In Conclusion: (i) most aluminum-containing vaccine receivers do not have long-lasting MMF in their muscle, but the prevalence of MMF among patients with arthromyalgia following immunization is substantial; (ii) patients with MMF have more CNS dysfunction and less fibromyalgic tender points than non-MMF patients; (iii) predictive scores may help to identify patients at high vs low risk of MMF., (© 2013.)

Graphene nanomaterials are recognized as one of the most promising nanomaterials because of their unique and highly attractive physicochemical properties (e.g., thermal conductivity, superlative mechanical strength, and ultrahigh surface-to-volume ratios). It is well established that when nanomaterials interact with biological medium, biomolecules and in particular proteins attach to their surfaces, which form a complex between surface of nanoparticles and proteins called corona. Thus, the interaction of the biological system with the nanomaterials depends on the composition of the protein layer, rather than the surface characteristics of the nanomaterials itself. Although there is a significant increase of interest in the application of graphene in medical science, there has been a little attention to the nanotoxicological aspects of these newly developed materials. For this reason, we aimed to investigate whether the effect of the interactions between graphene-sheets with various human plasma concentrations (i.e. both in vitro (cells/tissues) and in vivo simulating states) is toxic. The results showed that by increasing the human plasma concentration, the affinity of proteins with low molecular weights to graphene-sheets surface is significantly increased. Fluorescence microscopy of Hela and Panc-1 cell lines showed a reduction of nuclei number and an increase of reactive oxygen species (ROS) production respectively after a longer incubation of graphene-sheets with plasma proteins. ROS production was higher in Panc-1 cell line, when used as protein source for graphene-sheets than HeLa cell line., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To evaluate the incidence, the impact on survival and the predictive factors of bile leakage (BL) in a recent large monocentric series of liver resections performed in a referral tertiary care centre., Background: Previous reports dealing with bile leakage (BL) after liver resection are rare and have displayed conflicting results regarding incidence, impact on follow-up and predictive factors., Methods: A retrospective review of the records of 912 patients who underwent a total of 1001 consecutive liver resections without biliary reconstruction, performed between January 2005 and May 2011. BL was defined by the presence of bile in the abdominal drains, a radiologically or surgically drained bilioma or biliary peritonitis. BL severity was established according to the Clavien-Dindo classification. Fifty-eight pre-, per- and post-resection variables were analysed and the independent BL predictive factors were identified using logistic regression., Results: The incidence of BL was 8%. Clavien-Dindo I-II, IIIa, IIIb or IV rates were 29%, 35%, 32.5% and 2.5%, respectively. BL did not increase in-hospital mortality (2.5% versus 2.9%, P = 1.0), but doubled the median duration of hospital stay (16 versus 9 days, P < 0.001) and increased 1-year mortality (11% versus 5%, P = 0.03). Multivariate analysis identified that pre-operative bevacizumab [odds ratio (OR) = 2.9, confidence interval (CI) 95% = 1.58-5.41] P = 0.001], a major hepatectomy [OR = 2.6 (CI 95% = 1.48-4.76) P = 0.001], a two-stage hepatectomy [OR = 2.5 (CI 95% = 1.17-5.52) P = 0.018], the selective clamping technique [OR = 2.6 (CI 95% = 1.03-6.78) P = 0.042], R1 or R2 resection [OR = 2.6 (CI 95% = 1.52-4.64) P = 0.001] and the absence of a methylene blue test [OR = 2.6 (IC 95% = 1.43-4.65) P = 0.002] were independent risk factors of BL., Conclusion: BL remains frequent after liver resection. It has a dramatic impact on patient survival and care costs. Its incidence could be reduced by avoiding the pre-operative use of bevacizumab, avoiding selective clamping and performing a blue dye test in all resections., (© 2012 International Hepato-Pancreato-Biliary Association.)

Background and Purposes: Pulse wave analysis (PWV), a marker of aortic stiffness, has independent predictive value for cardiovascular morbidity and mortality in both healthy and high-risk populations, especially fatal stroke, and for long-term functional stroke prognosis. Whether arterial stiffness and wave reflection are related to stroke in-hospital short-term outcome has never been demonstrated., Methods: In a prospective study, we enrolled 134 patients with acute ischemic stroke, aged 63.4 ± 12.5 years, mean ± SD, National Institutes of Health stroke scale (NIHSS) scored 7.1 ± 6.5 at admission. Carotid-femoral (CF) PWV and central augmentation index (cAIx) were measured (SphygmoCor) one week after stroke onset. At hospital discharge, favorable outcome was defined as a 4 or more point improvement from baseline NIHSS or NIHSS of 0-1. Data were analyzed with logistic regression., Results: In univariate analysis, low CF-PWV (P = 0.000,001), but not cAIx, was significantly associated with early favorable outcome. In multivariate analysis, CF-PWV > 9.0 m/s remained significantly associated with favorable early outcome after adjustment for age, NIHSS and blood glucose level on admission, as well as heart rate, systolic and mean blood pressure, measured at day 7 (OR = 0.17 [95% CI, 0.05-0.60];P = 0.006)., Conclusions: In ischemic stroke, low aortic stiffness (CF-PWV) is associated with early favorable outcome, independently of other known prognostic factors., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug, and the value of strategies to combat the effect of adverse lifestyle behaviours on blood pressure. In this paper, we discuss two promising therapeutic alternatives for patients with resistant hypertension: novel drugs, including new pharmacological classes (such as vasopeptidase inhibitors and aldosterone synthase inhibitors) and new molecules from present pharmacological classes with additional properties in blood-pressure or metabolism pathways; and new procedures and devices, including stimulation of arterial baroreceptors and catheter-based renal denervation. Although several pharmacological targets have been discovered with promising preclinical results, the clinical development of novel antihypertensive drugs has been more difficult and less productive than expected. The effectiveness and safety of new devices and procedures should be carefully assessed in patients with resistant hypertension, thus leading to a new era of outcome trials and evidence-based guidelines., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We recognize that increased systolic pressure is the most challenging form of hypertension today and that pulse pressure as an independent cardiovascular risk factor has focused attention on arterial stiffness and wave reflections as the most important factors determining these pressures. In recent years, many studies emphasized the role of arterial rigidity in the development of cardiovascular diseases, and it was shown that stiffening of arteries is associated with increased cardiovascular mortality and morbidity. Moreover,arterial stiffening is linked to decreased glomerular filtration rate, and is predictive of kidney disease progression and the patient’s cardiovascular outcome. Premature vascular aging and arterial stiffening are observed with progression of chronic kidney disease (CKD) and in end-stage renal disease(ESRD). This accelerated aging is associated with outward remodeling of large vessels, characterized by increased arterial radius not totally compensated for by artery wall hypertrophy. Arterial stiffening in CKD and ESRD patients is of multifactorial origin with extensive arterial calcifications representing a major covariate. With aging, the rigidity is more pronounced in the aorta than in peripheral conduit arteries, leading to the disappearance or inversion of the arterial stiffness gradient and less protection of the microcirculation from high-pressure transmission. Various non-pharmacological or pharmacological interventions can modestly slow the progression of arterial stiffness,but arterial stiffness is, in part, pressure dependent and treatments able to stop the process mainly include antihypertensive drugs.

Biofilms on biomaterial implants are hard to eradicate with antibiotics due to the protection offered by the biofilm mode of growth, especially when caused by antibiotic-resistant strains. Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used in various biomedical applications, such as targeted drug delivery and magnetic resonance imaging. Here, we evaluate the hypothesis that SPIONs can be effective in the treatment of biomaterial-associated infection. SPIONs can be targeted to the infection site using an external magnetic field, causing deep penetration in a biofilm and possibly effectiveness against antibiotic-resistant strains. We report that carboxyl-grafted SPIONs, magnetically concentrated in a biofilm, cause an approximately 8-fold higher percentage of dead staphylococci than does gentamicin for a gentamicin-resistant strain in a developing biofilm. Moreover, magnetically concentrated carboxyl-grafted SPIONs cause bacterial killing in an established biofilm. Thus magnetic targeting of SPIONs constitutes a promising alternative for the treatment of costly and recalcitrant biomaterial-associated infections by antibiotic-resistant strains., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Due to their unique magnetic properties, excellent biocompatibility as well as multi-purpose biomedical potential (e.g., applications in cancer therapy and general drug delivery), superparamagnetic iron oxide nanoparticles (SPIONs) are attracting increasing attention in both pharmaceutical and industrial communities. The precise control of the physiochemical properties of these magnetic systems is crucial for hyperthermia applications, as the induced heat is highly dependent on these properties. In this review, the limitations and recent advances in the development of superparamagnetic iron oxide nanoparticles for hyperthermia are presented., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: The purpose of this study was to correlate the arterial mechanics of carotid atherosclerotic plaques assessed from echotracking with their composition by high-resolution magnetic resonance imaging (HR-MRI)., Background: Analysis of the relationship between mechanical parameters and structure of the plaque allows better understanding of the mechanisms leading to mechanical fatigue of plaque material, plaque rupture, and ischemic events. A specific longitudinal gradient of strain (reduced strain, i.e., lower radial strain at the plaque level than at the adjacent segment) has been shown in atherosclerotic plaques on the common carotid artery (CCA) in patients with hypertension, dyslipidemia, or type 2 diabetes mellitus. The structural abnormalities underlying this functional behavior have not been determined., Methods: Forty-six carotid plaques from 27 patients were evaluated; plaques were present at the site of the carotid bifurcation and extended to the CCA. Among the 27 patients, 9 had previous ischemic stroke ipsilateral to carotid stenosis (symptomatic) and 18 had not (asymptomatic). Mechanical parameters were measured at 128 sites on a 4-cm long CCA segment by noninvasive echotracking system, and strain gradient was calculated. Plaque composition was noninvasively determined by HR-MRI., Results: Complex plaques at HR-MRI (i.e., American Heart Association [AHA] stages IV to VIII) more often displayed a reduced strain than the simple plaques (i.e., AHA stages I to III; p = 0.046). HR-MRI verified complex plaques were associated with an outer remodeling upon echotracking, and had a lower distensibility than adjacent CCA (17.0 ± 5.0 MPa⁻¹ vs. 21.7 ± 7.3 MPa⁻¹; p = 0.007). An outer remodeling was observed in plaques with a lipid core at HR-MRI and was more frequent in symptomatic carotids., Conclusions: These findings indicate that the longitudinal mechanics of "complex" plaques follows a specific pattern of reduced strain. They also suggest that reduced strain, associated with an outer remodeling, may be a feature of high-risk plaques., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β(1)-adrenoceptor antagonist with a β(2)-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome., Methods: Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptritrated by 100 mg steps every 6 months to a maximum of 400 mg per day. [DOSAGE ERROR CORRECTED]. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411., Findings: 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15-0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration., Interpretation: We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established., Funding: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Amyloid plaques (AP) represent one of the main molecular hallmarks of Alzheimer's disease (AD). In order to develop new AP-specific contrast agents for AD molecular imaging, the phage display technology was used to identify peptides specific to amyloid-beta (A beta(42)). A random disulfide constrained heptapeptide phage display library was screened against A beta(42). After biopanning, 72 phage clones were isolated and their binding affinity to A beta(42) was evaluated by enzyme-linked immunosorbent assay (ELISA). The final library was enriched in two peptide sequences. The K(d) of candidate phage clones for binding to A beta(42) are in the picomolar range. The binding affinity for A beta(42) of two selected peptides was confirmed by ELISA, and the specific interaction with AP was validated by immunohistochemistry on brain sections. The preliminary MRI in vivo study, which was performed with a peptide functionalized contrast agent on AD transgenic mouse, showed encouraging results. To conclude, low molecular weight peptides presenting a specific affinity for A beta(42) were identified by phage display. As specific carriers, they have a real potential for molecular imaging of AD thanks to AP binding., ((c) 2008 Elsevier Inc. All rights reserved.)

Chronic traumatic brain injury is rare in man and has not been previously documented in dogs. This report describes a 2-year-old female American Staffordshire bull terrier that was referred with forelimb and hindlimb ataxia, decreased vigilance and disorientation following repeated aggression and physical abuse by its owner. A diffuse cortical lesion was suspected. Cerebrospinal fluid analysis revealed neutrophilic pleocytosis and computed tomography showed marked widening of the cerebral sulci with mild bilateral ventriculomegaly. The dog was humanely destroyed in view of the poor prognosis. Necropsy examination revealed narrowing of the cerebral cortical gyri and consequent widening of the sulci without distortion or displacement of the neural parenchyma. These features were consistent with bilateral diffuse cortical atrophy. Microscopically, there were chronic subarachnoid haemorrhages and the cortical subpial layer displayed spongiosis, capillary hyperplasia, astrocytosis, microgliosis and frequent neuronal necrosis occurring in a characteristic laminar pattern. This histopathological pattern of damage was significantly different from that previously described in people suffering from repeated traumatic brain injuries over a long period of time., ((c) 2009 Elsevier Ltd. All rights reserved.)

A glycine-rich motif described as being involved in human polymerase delta proliferating cell nuclear antigen (PCNA) binding has also been identified in all euryarchaeal DNA polymerase D (Pol D) family members. We redefined the motif as the (G)-PYF box. In the present study, Pol D (G)-PYF box motif mutants from Pyrococcus abyssi were generated to investigate its role in functional interactions with the cognate PCNA. We demonstrated that this motif is not essential for interactions between PabPol D (P. abyssi Pol D) and PCNA, using surface plasmon resonance and primer extension studies. Interestingly, the (G)-PYF box is located in a hydrophobic region close to the active site. The (G)-PYF box mutants exhibited altered DNA binding properties. In addition, the thermal stability of all mutants was reduced compared to that of wild type, and this effect could be attributed to increased exposure of the hydrophobic region. These studies suggest that the (G)-PYF box motif mediates intersubunit interactions and that it may be crucial for the thermostability of PabPol D., ((c) 2010 Elsevier Ltd. All rights reserved.)