Rotterdam, Netherlands
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Jonckheere N.,French Institute of Health and Medical Research | Jonckheere N.,University of Lille Nord de France | Velghe A.,French Institute of Health and Medical Research | Ducourouble M.-P.,French Institute of Health and Medical Research | And 7 more authors.
FEBS Journal | Year: 2011

MUC5B is one of the major mucin genes expressed in the respiratory tract. Previous studies in our laboratory have demonstrated that MUC5B is expressed in human lung adenocarcinomas and during lung morphogenesis. Moreover, in human lung adenocarcinoma tissues, a converse correlation between MUC5B and thyroid transcription factor-1 (TTF-1) expression, a lung-specific transcription factor, has been established. However, the molecular mechanisms that govern the regulation of MUC5B expression in the lung are largely unknown. In order to better understand the biological role of MUC5B in lung pathophysiology, we report the characterization of the promoter region of the mouse Muc5b mucin gene. The promoter is flanked by a TATA box (TACATAA) identical to that in the human gene. Human and murine promoters share 67.5% similarity over the first 170 nucleotides. By RT-PCR, co-transfection studies and gel-shift assays, we show that Muc5b promoter activity is completely inhibited by TTF-1, whereas factors of the GATA family (GATA-4/GATA-5/GATA-6) are activators. Together, these results demonstrate, for the first time, that Muc5b is a target gene of transcription factors (TTF-1, GATA-6) involved in lung differentiation programs during development and carcinogenesis, and identify TTF-1 as a strong repressor of Muc5b. The characterization of the structural and functional features of the Muc5b mucin gene will provide us with a strong base to develop studies in murine models aimed at the identification of its biological role in lung pathophysiology. © 2010 FEBS.


Pelc R.,CHI de Creteil | Redant S.,Queen Fabiola Hospital | Julliand S.,University Paris Diderot | Llor J.,The Surgical Center | And 6 more authors.
BMC Pediatrics | Year: 2014

Background: Based on European recommendations of ESPGHAN/ESPID from 2008, first line therapy for dehydration caused by acute gastroenteritis (AGE) is oral rehydration solution (ORS). In case of oral route failure, nasogastric tube enteral rehydration is as efficient as intra-venous rehydration and seems to lead to fewer adverse events. The primary objective was to describe rehydration strategies used in cases of AGE in pediatric emergency departments (PEDs) in Belgium, France, The Netherlands, and Switzerland. Methods: An electronic survey describing a scenario in which a toddler had moderate dehydration caused by AGE was sent to physicians working in pediatric emergency departments. Analytical data were analyzed with descriptive statistics and Kruskal -Wallis Rank test. Results: We analyzed 68 responses, distributed as follows: Belgium N = 10, France N = 37, The Netherlands N = 7, and Switzerland N = 14. Oral rehydration with ORS was the first line of treatment for 90% of the respondents. In case of first line treatment failure, intravenous rehydration was preferred by 95% of respondents from France, whereas nasogastric route was more likely to be used by those from Belgium (80%), The Netherlands (100%) and Switzerland (86%). Serum electrolyte measurements were more frequently prescribed in France (92%) and Belgium (80%) than in The Netherlands (43%) and Switzerland (29%). Racecadotril was more frequently used in France, and ondansetron was more frequently used in Switzerland. No respondent suggested routine use of antibiotics.Conclusion: We found variations in practices in terms of invasiveness and testing. Our study supports the need for further evaluation and implementation strategies of ESPGHAN/ESPID guidelines. We plan to extend the study throughout Europe with support of the Young ESPID Group. © 2014 Pelc et al.; licensee BioMed Central Ltd.


Kadam R.S.,InnoPharma | van Den Anker J.N.,Childrens National Health System | van Den Anker J.N.,University of Basel | van Den Anker J.N.,Erasmus MC Sophia Hospital
Clinical Pharmacokinetics | Year: 2016

Voriconazole is a potent antifungal agent used for the treatment of invasive fungal infections caused by Aspergillus and Candida species in adult and pediatric patients. Voriconazole has a narrow therapeutic index and a large intra- and inter-individual pharmacokinetics (PK) variability. Several factors including non-linear PK, age, body weight, cytochrome P450 2C19 genotype, concomitant drugs, liver function, and food are responsible for the large variability in voriconazole PK. A combination of a narrow therapeutic index with a large PK variability results in treatment failure in many patients at clinically recommended doses. There is an urgent need to establish an optimal dosing regimen for pediatric patients <2 years of age because of a lack of recommended dosing guidelines and high (>60 %) treatment failure rates. Therapeutic drug monitoring is commonly used in clinical practice to optimize the voriconazole dosing regimens in pediatric patients, but it is associated with several practical limitations. Implementation of a PK model-guided individualized dose selection will help in reducing the PK variability and will improve therapeutic outcomes. In this review, we have summarized the covariates influencing the PK of voriconazole in adult and pediatric patients, emphasizing that the clearance of voriconazole is significantly different between adult and pediatric patients owing to developmental changes in the major clearance pathways. Moreover, we have provided the limitations of the current dosing regimens and have proposed a new dosing method using a PK model-guided dose individualization of voriconazole in pediatric patients. © 2016 Springer International Publishing Switzerland

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