Xavier Stephenne

Catholic University of Louvain, Walloon Region, Belgium

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Publications (42)158.6 Total impact

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    ABSTRACT: Aims • Pentamidine in nebulized form is one of the drugs listed in the primary or secondary prevention of pneumocystis carinii pneumonia in immunosuppressed patients. • This nebulization requires a nebulizer with specific characteristics. These features are the presence of a circuit with expiratory filter preventing the dissemination of droplets into the environment (pentamidine may be toxic) and secondly, to ensure a fine particle size allowing deep lung deposition. • The reference nebulizer used for pentamidine nebulization is currently the Respirgard II®, a disposable pneumatic nebulizer. Several studies remark that all nebulizers with comparable properties could be used for the nebulization. • The aim of our work is to evaluate and compare the results between the reference nebulizer Respirgard II ®, and one of these nebulizers available on the market, the Isoneb ®. • This in vitro study is the first step in the comparison of the two nebulizers. • We found no significant difference in the inhaled dose. • We observed a difference in residual solution but none in calculated lost dose. It could be explained by the drugs concentration in the cuve or by a difference of deposition in the device, in the one-way valves and in the filter positioned on the nebulizer expiratory branch. Nevertheless we have no measure to prove it. The difference in the internal volume is highly significative, it could explain a different deposition in the device. • However the effectiveness of pneumocystis carinii pneumonia prophylaxis is based on the inhaled dose and pulmonary deposition. We will have to measure the pulmonary deposition in a second study to compare the relative effectiveness of the two nebulizers. Results • In this in vitro study, we have tested the inhaled dose corresponding to the two nebulizers. • Based on our results, we can conclude that both nebulizer have similar properties. Methods • A solution of pentamidine (300mg/6mL sterile water) was nebulized by a Respirgard II® (Vital Signs, New Jersey, USA) (RII) or by an Iso-NEB® (Teleflex, Pennsylvania, USA) (Iso). • Nebulizers (Iso and RII) were connected to a dual chamber lung model (5600i Dual Adult Training/Test Lung®, Michigan Instrument Inc., Michigan, USA) simulating usual breathing pattern of an adult. Respiratory frequency and tidal volume driving by a ventilator (SERVO-I®, Maquet, Rastatt, Germany) to the lung model were 15 cycle/min, 500 mL respectively. • During the nebulization, a filter (filter 1) was interposed between the nebulizer and the lung model. The filter was weighed before the nebulization and after drying for 24 hours at ambient air. The resulting weight is the inhaled dose. We expressed the inhaled dose in percentage of the nominal dose.
    ERS ANNUAL CONGRESS 2014, Munich; 09/2014
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    ABSTRACT: Current treatment of inherited liver inborn errors of metabolism in children consists in appropriate diet and drugs and, for unstable patients, final orthotopic liver transplantation. Unfortunately, liver transplantation remains not easily available because of organ shortage and imposes inherent risks and lifelong immunosuppressive therapy. Therefore alternative treatments are required. Hepatocytes transplantation and its limitations led to consider innovative alternative such as transplantation of adult derived human liver stem cells (ADLHSC). These cells present high proliferative capacity, good resistance to cryopreservation and ability to differentiate into hepatocyte-like cells displaying mature hepatocyte functions. Biodistribution of ADHLSC had never been assessed after infusion through the portal vein in patients. This information is required to determine the safety of the method. ADHLSC were efficiently labelled with 111-Indium DTPA radiotracer and SPECT imaging was used for the acquisition of whole body imaging to document short term biodistribution of ADHLSC. Following infusion through the portal vein, ADHLSC diffused homogenously throughout the liver and remained strictly within the targeted organ. Images were acquired until 5 days after infusion. At that time, no signal was observed in any other organs except the liver. Urinary excretion of 111-Indium DTPA was also monitored. For the first time, we documented the short term biodistribution of ADHLSC within the liver after infusion through the portal vein.
    Nuclear Medicine and Biology 04/2014; 41(4):371-375. · 2.52 Impact Factor
  • Journal of pediatric gastroenterology and nutrition 03/2014; · 2.18 Impact Factor
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    ABSTRACT: The microsomal protein per gram of liver (MPPGL) is an important scaling factor in the in vitro-in vivo extrapolation of metabolic data obtained in liver microsomes. This study aimed to determine the MPPGL in 4 biliary atresia patients (0.6 - 1.6 years old) undergoing liver transplantation, as it is known that the MPPGL is affected by age and possibly by liver disease. Due to presence of bilirubin in the homogenates and microsomes, the NADPH-cytochrome reductase activity was used to determine the recovery factor, rather than methods using the dithionite difference spectrum. A mean value of 18.73 (±2.82) mg/g (geometric mean ± SD, n = 4) was observed, which is lower than the expected MPPGL based on the age of the patients (26.60 ± 0.40 mg/g). This suggests a decreased amount of microsomal protein in the livers of biliary atresia patients. Moreover, no differences in MPPGL between different zones of the liver could be detected. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2014; · 2.09 Impact Factor
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    ABSTRACT: The transition from parent-controlled care to self-managed care represents an important challenge for adolescents with chronic conditions. We sought to gain a deeper understanding of the factors influencing the internalization of motivation to self-care in adolescent liver transplant recipients. We conducted a qualitative study using in-depth interviews with 18 young patients. We triangulated the data collected from the patients with data from parents and health care providers, and used an inductive approach to analyze the data. Our results illustrate three interrelated challenges that impact on young patients' motivation to self-care: (a) the cognitive challenge of fully understanding one's condition and personal health risks; (b) the behavioral challenge of developing independence regarding self-management issues; and (c) the psychological challenge of building a sense of self-ownership and purpose. The latter involves overcoming the trauma of survival and coming to terms with feelings of obligation, two challenges inherent to transplantation that warrant further investigation.
    Qualitative Health Research 02/2014; · 2.19 Impact Factor
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    ABSTRACT: To investigate the activity and expression of EAAT2 glutamate transporter in both in vitro and in vivo models of cholestasis. This study was conducted on human hepatoblastoma HepG2 cell cultures, the liver of bile duct ligated rats and human specimens from cholestatic patients. EAAT2 glutamate transporter activity and expression were analyzed using a substrate uptake assay, immunofluorescence, reverse transcription-polymerase chain reaction, and immunohistochemistry, respectively. In HepG2 cells, cholestasis was mimicked by treating cells with the protein kinase C activator, phorbol 12-myristate 13-acetate. Under such conditions, EAAT2 transporter activity was decreased both at the level of substrate affinity and maximal transport velocity. The decreased uptake was correlated with intracellular translocation of EAAT2 molecules as demonstrated using immunofluorescence. In the liver of bile duct ligated rats, an increase in EAAT2 transporter protein expression in hepatocytes was demonstrated using immunohistochemistry. The same findings were observed in human liver specimens of cholestasis in which high levels of γ-glutamyl transpeptidase were documented in patients with biliary atresia and progressive familial intrahepatic cholestasis type 3. This study demonstrates the alteration in glutamate handling by hepatocytes in liver cholestasis and suggests a potential cross-talk between glutamatergic and bile systems.
    World Journal of Gastroenterology 02/2014; 20(6):1554-64. · 2.55 Impact Factor
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    ABSTRACT: A 3-year-old girl suffering from ornithine carbamoyltransferase (OTC) deficiency was poorly equilibrated under conventional diet and scavenger treatment. Following unsuccessful cryopreserved hepatocyte transplantation, she received two infusions of Adult Derived Human Liver Stem/Progenitor Cells (ADHLSCs) expanded in vitro under GMP settings, the quantity being equivalent to 0.75% of her calculated liver mass. Using FISH immunostaining for the Y chromosome, the initial biopsy did not detect any male nuclei in the recipient liver. Two liver biopsies taken 100 days after ADHLSC transplantation showed 3% and 5% of male donor cells in the recipient liver, thus suggesting repopulation by donor cells. Although limited follow-up did not allow us to draw conclusions on long-term improvement, these results provide a promising proof of concept that this therapy is feasible in an OTC patient.
    JIMD reports. 10/2013;
  • Journal of pediatric gastroenterology and nutrition 06/2013; · 2.18 Impact Factor
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    ABSTRACT: The success of liver cell therapy remains closely dependent on how the infused cells can beaccepted after transplantation, which is directly related to their degree of immunogenicity. Inthis study, we investigated the in vitro immunogenic properties of isolated human hepatocytes(hHeps) and adult derived human liver progenitor cells (ADHLPCs), an alternative cellcandidate for LCT. The constitutive expression of immune markers was first analyzed onthese liver-derived cells by flow cytometry. Human liver-derived cells were then coculturedwith allogeneic human adult peripheral blood mononuclear cells (PBMCs) and the resultingactivation and proliferation of PBMCs were evaluated, as well as the cytokine levels in thecoculture supernatant. The effect of liver-derived cells on dendritic cells (DCs) properties wasfurther analyzed in a secondary coculture with naive CD4+ T cells. We report that hHeps andADHLPCs expressed human leukocyte antigen (HLA) class I and Fas but did not expressHLA-DR, Fas ligand and costimulatory molecules. hHeps and ADHLPCs did not induce Tcell activation or proliferation. Moreover, hHeps induced a cell contact-dependent productionof interleukin (IL)-10 that was not observed with ADHLPCs. The IL-10 was produced by amyeloid DC subset characterized by an incomplete mature state. Furthermore, hHep-primedDC induced an antigen-independent hyporesponsiveness of naive CD4+ T lymphocytes thatwas partially reversed by blocking IL-10, whereas DC previously cultured alone did not.CONCLUSION: hHeps and ADHLPCs present a low immunogenic phenotype in vitro. AllogeneichHep but not ADHLPC promote a cell contact-dependent production of IL-10 by myeloidDCs, which induces naive CD4+ T cells antigen-independent hyporesponsiveness.
    Cell Transplantation 04/2013; · 4.42 Impact Factor
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    ABSTRACT: OBJECTIVES:: The management of esophageal varices (EV) in children suffering from biliary atresia (BA) remains controversial. Recent studies in children proposed initiating a prophylactic treatment in patients with severe (Grade III) EV and/or EV associated with red color signs. Our study was aimed at assessing the risk of bleeding from EV in a series of BA patients, identifying risk factors for bleeding in order to develop a predictive model of bleeding. METHODS:: This was a retrospective study including 83 eligible BA patients. Clinical, ultrasonographic, endoscopic, and laboratory parameters were studied from the beginning of medical management up to the occurrence of upper gastrointestinal bleeding. In patients not presenting any bleeding, data were analyzed until liver transplantation, endoscopic treatment of EV was performed or last follow up. Risk factors were investigated using univariate and multivariate statistical analyses. RESULTS:: Seventeen out of 83 patients (20%) presented gastrointestinal bleeding, with a median age of 9.5 months (6-50 months). In univariate and multivariate analyses, high-grade EV, red color signs on endoscopic examination, and low fibrinogen levels, at first endoscopy, were identified as risk factors for bleeding. When tested in more than 10,000 different models, these three variables appeared to play the most significant role in predicting bleeding. CONCLUSIONS:: Our study confirmed that grade III EV and red color signs are risk factors for bleeding in patients followed up for BA. We identified low fibrinogen levels as an additional risk factor. The relevance of these three factors to predict bleeding from EV requires validation in a prospective study.
    Journal of pediatric gastroenterology and nutrition 12/2012; · 2.18 Impact Factor
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    ABSTRACT: pT, under mono- and infratherapeutic calcineurin inhibition, may constitute an optimal condition combining graft acceptance with low IS load and minimal IS-related toxicity. We reviewed 171 pediatric (<15.0 yr) survivors beyond one yr after LT, transplanted between April 1999 and June 2007 under tacrolimus-based regimens (median follow-up post-LT: 6.0 yr, range: 0.8-9.5 yr). Their current status regarding IS therapy was analyzed and correlated with initial immunoprophylaxis. pT was defined as tacrolimus monotherapy, with mean trough blood levels <4 ng/mL during the preceding year of follow-up, combined with normal liver function tests. The 66 children transplanted before April 2001 received a standard tacrolimus-steroid regimen. Beyond April 2001, 105 patients received steroid-free tacrolimus-basiliximab or tacrolimus-daclizumab immunoprophylaxis. In the latter group, 43 (41%) never experienced any acute rejection episode and never received steroids. In the long term, a total of 79 recipients (47%) developed pT (n = 73) or IS-free operational tolerance (n = 6), 27 of them belonging to the 43 steroid-free patients (63%). In contrast, only 52/128 (41%) children treated with steroids subsequently developed prope/operational tolerance (p = 0.012). Steroid-free tacrolimus-based IS seems to promote long-term graft acceptance under minimal/no IS. These results constitute the first evidence that minimization of IS, including steroid avoidance, might be tolerogenic in the long term after pediatric LT.
    Pediatric Transplantation 11/2012; · 1.50 Impact Factor
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    ABSTRACT: To improve modelling and simulation of the pharmacokinetics (PK) in paediatric patients, there is a need for research on developmental and disease-specific determinants. This article describes the evaluation of the in vitro cytochrome P450 activity, an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of 6 CYP isoforms, CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 was evaluated in thirty-one patients with different pathologies, mainly biliary atresia (n=23). A hypervariable activity was observed for all the isoforms. Compared to an average adult activity, low activities were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. In this population, age, co-medication, and genotype could not be used as predictors for the CYP activity. In contrast, the Paediatric End-stage Liver Disease score was negatively correlated with the ln(activity). This suggests a decrease in CYP activity with deteriorating hepatic function. Moreover, the activity of all isoforms was correlated, demonstrating a concomitant decrease of all isoforms in young patients with liver disease. To our knowledge, this is the first study to evaluate CYP activity in children with hepatic impairment. The presented data may provide support in the further optimization of a disease-specific model in this patient population.
    Drug metabolism and disposition: the biological fate of chemicals 11/2012; · 3.74 Impact Factor
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    ABSTRACT: Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and severe psychosocial burden. Oral administration of tetrahydrobiopterin can increase residual enzyme activity, but most patients with severe clinical phenotypes are non-responders. We performed liver cell transplantation in 6 years-old boy with severe tetrahydrobiopterin non-responsive phenylketonuria, who failed to comply with diet prescriptions. The transplanted hepatocytes were obtained in part from an explanted glycogen storage type 1b liver. Following two infusions, blood phenylalanine levels returned within the therapeutic target while the phenylalanine half-life assessed by loading tests decreased from 43 h to 19 h. However, three months later, blood phenylalanine concentrations increased and the phenylalanine intake had to be reduced. Cell based therapy is a promising therapeutic option in phenylketonuria and the domino concept may solve the issue of cell sources for hepatocyte transplantation.
    Cell Transplantation 08/2012; · 4.42 Impact Factor
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    ABSTRACT: Incidence of chronic hepatitis B is declining thanks to universal immunization programs. Nevertheless, hepatitis B virus infection is still one of the most important causes of liver disease worldwide. An accurate knowledge of up-to-date pediatric epidemiologic data, prevalent transmission routes in childhood and available preventive measures is of primary importance to reduce the spread of the disease. Indeed, in spite of a rather benign course of chronic hepatitis B during childhood and adolescence, the lifetime risk of patients infected at birth to die because of liver disease is still too high. The natural history of the disease in childhood has been well described, together with the risks of rare but important complications such as hepatocarcinoma and cirrhosis. Few therapies have been licensed to treat chronic hepatitis B in children. Most are only partially effective, whereas sufficiently safe, and an accurate selection of subject to treat and of right timing for treatment is needed to optimize efficacy and reduce viral resistance. Newer drugs are extremely promising and their licensing for children could change management of pediatric chronic hepatitis B.
    Journal of Hepatology 05/2012; 57(4):885-96. · 9.86 Impact Factor
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    ABSTRACT: A 3-year-old girl with multifocal hepatoblastoma was referred to our clinic for living-donor liver transplantation, the patient's father being the donor. Pretransplant evaluation revealed that the father presented partial asymptomatic antithrombin (AT) deficiency, with no inherited AT deficiency found in the girl. The genetic testing showed an AT type IIb deficiency responsible for a defect in the heparin-binding region of AT which is less thrombogenic but more common than the other AT qualitative defects. Her mother was ABO incompatible. Despite the thrombophilia on the father's side, transplantation was successfully performed under replacement therapy with intravenous AT concentrate and low-molecular-weight heparin thromboprophylaxis given to both the recipient and the donor. No thrombotic complications occurred. In the posttransplantation course, acquired partial AT deficiency was detected in the recipient, who received adjuvant chemotherapy without thrombotic complications. This case report highlights the relevance of full thrombophilic work-up before liver transplantation from a living donor, while illustrating that the procedure can be successfully performed in the case of AT deficiency on the donor's side provided that appropriate AT supplementation and thromboprophylaxis are administered to both the recipient and the donor.
    American Journal of Transplantation 02/2012; 12(5):1329-32. · 6.19 Impact Factor
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    ABSTRACT: Islet and hepatocyte transplantation are associated with tissue factor-dependent activation of coagulation which elicits instant blood mediated inflammatory reaction, thereby contributing to a low rate of engraftment. The aim of this study was i) to evaluate the procoagulant activity of human adult liver-derived mesenchymal progenitor cells (hALPCs), ii) to compare it to other mesenchymal cells of extra-hepatic (bone marrow mesenchymal stem cells and skin fibroblasts) or liver origin (liver myofibroblasts), and iii) to determine the ways this activity could be modulated. Using a whole blood coagulation test (thromboelastometry), we demonstrated that all analyzed cell types exhibit procoagulant activity. The hALPCs pronounced procoagulant activity was associated with an increased tissue factor and a decreased tissue factor pathway inhibitor expression as compared with hepatocytes. At therapeutic doses, the procoagulant effect of hALPCs was inhibited by neither antithrombin activators nor direct factor Xa inhibitor or direct thrombin inhibitors individually. However, concomitant administration of an antithrombin activator or direct factor Xa inhibitor and direct thrombin inhibitor proved to be a particularly effective combination for controlling the procoagulant effects of hALPCs both in vitro and in vivo. The results suggest that this dual antithrombotic therapy should also improve the efficacy of cell transplantation in humans.
    PLoS ONE 01/2012; 7(8):e42819. · 3.53 Impact Factor
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    ABSTRACT: The glucose-lowering drug metformin has been shown to activate hepatic AMP-activated protein kinase (AMPK), a master kinase regulating cellular energy homeostasis. However, the underlying mechanisms remain controversial and have never been investigated in primary human hepatocytes. Hepatocytes isolated from rat, mouse and human livers were treated with various concentrations of metformin. Isoform-specific AMPKα abundance and activity, as well as intracellular adenine nucleotide levels and mitochondrial oxygen consumption rates were determined at different time points. Metformin dose- and time-dependently increased AMPK activity in rat and human hepatocytes, an effect associated with a significant rise in cellular AMP:ATP ratio. Surprisingly, we found that AMPKα2 activity was undetectable in human compared with rat hepatocytes, while AMPKα1 activities were comparable. Accordingly, metformin only increased AMPKα1 activity in human hepatocytes, although both AMPKα isoforms were activated in rat hepatocytes. Analysis of mRNA expression and protein levels confirmed that only AMPKα1 is present in human hepatocytes; it also showed that the distribution of β and γ regulatory subunits differed between species. Finally, we demonstrated that the increase in AMP:ATP ratio in hepatocytes from liver-specific Ampkα1/2 (also known as Prkaa1/2) knockout mice and humans is due to a similar and specific inhibition of the mitochondrial respiratory-chain complex 1 by metformin. Activation of hepatic AMPK by metformin results from a decrease in cellular energy status owing to metformin's AMPK-independent inhibition of the mitochondrial respiratory-chain complex 1. The unique profile of AMPK subunits found in human hepatocytes should be considered when developing new pharmacological agents to target the kinase.
    Diabetologia 09/2011; 54(12):3101-10. · 6.49 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Journal of Pediatric Gastroenterology and Nutrition 08/2011; 53(3):350–354. · 2.20 Impact Factor
  • C Wanty, X Stephenne, E Sokal, F Smets
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    ABSTRACT: The efficacy of infliximab (IFX) in inducing and maintaining remission in pediatric Crohn disease is currently well documented. However, the optimal treatment strategy beyond 1 year has not been established. In particular, systematic continuation of maintenance therapy and its association with immunomodulators have not yet been analyzed. The aim of this study was to describe the long-term outcome of pediatric Crohn disease patients on IFX therapy and to evaluate the clinical response to the therapy and the effect on growth. A single-center and retrospective chart review was conducted. The clinical maintenance response to treatment, effect on the linear growth, and long-term outcome were examined. These parameters were analyzed according to the age of the patients, duration and localization of the disease, as well as associated therapies. We identified 52 children with Crohn disease younger than 16 years of age at the time of diagnosis. Of these patients, 20 (38%) received a biologic therapy at a mean age of 13.9±2 years. Fifteen patients received IFX therapy and 13 (86%) were in clinical remission 10 weeks after the first infusion. Among the responders, 82% were still in remission after 1 year of therapy and 66% after 2 years. Among patients treated for more than 1 year, we observed IFX dependency in 89%. Thirty-eight percent of patients with initial IFX response showed a loss of response after a median of 30 months (range, 3-42 months). At 2 years, the median Z score for height among patients with presumed growth potential had improved slightly, from -0.7 to -0.55 DS. No serious adverse events were observed. Our results confirm the continuous efficacy of IFX in pediatric Crohn disease patients after 1 year of treatment. However, a high level of dependency was observed (89 %). A slight beneficial effect on growth was observed after 2 years of treatment.
    Archives de Pédiatrie 06/2011; 18(8):863-9. · 0.36 Impact Factor

Publication Stats

423 Citations
158.60 Total Impact Points

Institutions

  • 2002–2014
    • Catholic University of Louvain
      • • Institute of Experimental and Clinical Research (IREC)
      • • Laboratory of Pediatric Hepatology and Cell Therapy
      Walloon Region, Belgium
  • 2008–2013
    • Cliniques Universitaires Saint-Luc
      • • Division of Pediatric Gastroenterology
      • • Department of Pediatrics
      Brussels, BRU, Belgium
  • 2012
    • Ghent University
      Gand, Flanders, Belgium