Ethical and procedural issues for applying researcher-driven multi-national paediatric clinical trials in and outside the European Union: the challenging experience of the DEEP project.

Background: We describe our experience from a multi-national application of a European Union-funded research-driven paediatric trial (DEEP-2, EudraCT 2012-000353-31; NCT01825512). This paper aims to evaluate the impact of the local and national rules on the trial authorisation process in European and non-European countries. National/local provisions and procedures, number of Ethics Committees and Competent Authorities to be addressed, documentation required, special provisions for the paediatric population, timelines for completing the authorisation process and queries received were collected; compliance with the European provisions were evaluated.

Setup of a Protocol of Molecular Diagnosis of β-Thalassemia Mutations in Tunisia using Denaturing High-Performance Liquid Chromatography (DHPLC).

Backgrounds: β-Thalassemia is one of the most prevalent worldwide autosomal recessive disorders. It presents a great molecular heterogeneity resulting from more than 200 causative mutations in the β-globin gene. In Tunisia, β-thalassemia represents the most prevalent monogenic hemoglobin disorder with 2.

Red cell indices: differentiation between β-thalassemia trait and iron deficiency anemia and application to sickle-cell disease and sickle-cell thalassemia.

Background: In Tunisia, thalassemia and sickle cell disease represent the most prevalent monogenic hemoglobin disorders with 2.21% and 1.89% of carriers, respectively.

Red cell indices: differentiation between β-thalassemia trait and iron deficiency anemia and application to sickle cell disease and sickle cell thalassemia.

Background: In Tunisia, thalassemia and sickle cell disease (SS) represent the most prevalent monogenic hemoglobin disorders with 2.21% and 1.89% of carriers, respectively.

Fortuitous description of hemoglobin Hope in a high-level Tunisian athlete: molecular diagnosis and origin.

In this study we report the fortuitous description of hemoglobin (Hb) Hope in a Tunisian athlete. This Hb is one of hemoglobin variants that show a lower stability and oxygen affinity that is beneficial to tissue oxygen delivery. Hb Hope was isolated by automated high performance liquid chromatography and was unequivocally found to be Hb Hope using DNA-based methods: polymerase chain reaction, denaturing gradient gel electrophoresis, direct DNA sequencing.

A lower-cost protocol for sickle cell disease neonatal screening in Tunisia.

Background And Objectives: Sickle cell disease (SCD) is a group of hereditary chronic anemias that manifest essentially as painful crisis and susceptibility to infection. Neonatal screening is a preventive action that reduces the rates of mortality due to complications arising from infections by encouraging early prophylactic penicillin use and pneumococcal vaccination. The purpose of this pilot study was to set up a neonatal screening protocol at a lower cost than one that uses commercially available screening kits.

Contribution of β-globin cluster polymorphisms to raise fetal hemoglobin levels in normal adults.

Hereditary persistence of fetal hemoglobin (HPFH) is a group of genetically heterogeneous conditions characterized by continued expression of fetal hemoglobin (HbF) in adulthood. HPFH may be due not only to point mutations or large deletions in different regions of the cluster β globin, but also to variations in several polymorphic sequences in this cluster. The objective of this work was to evaluate effects of polymorphic markers within cluster β globin on HbF expression.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up.

Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.

First report of cystic fibrosis mutations in Libyan cystic fibrosis patients.

Background: There are few data on the molecular basis of Cystic Fibrosis (CF) in North Africa, probably due to under-diagnosis.

Aim: This is the first study of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in the Libyan population.

Subjects And Methods: This study analysed the complete coding region and flanking intronic sequences of the CFTR gene in 10 unrelated Libyan CF patients.

The epidemiology of abnormal hemoglobins in Mediterranean high-level athletes.

The aim of this study was to determine the prevalence and nature of hemoglobin (Hb) defects in a Mediterranean high-level (HL) athlete population. Five hundred and ninety-four HL male and female athletes were recruited during the annual follow-up of the members of Tunisian national teams. Hematological data, Hb electrophoresis, and DNA analysis were assessed using conventional techniques.

Cystic fibrosis transmembrane conductance regulator mutation spectrum in patients with cystic fibrosis in Tunisia.

Aim: To determine the frequency and types of mutations causing cystic fibrosis (CF) in Tunisia.

Methods: We analyzed the complete coding region and flanking intronic sequences of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 68 unrelated patients suffering from the classical form of the disease.

Results: Twelve different CFTR mutations accounted for 90% (123/136) of CF alleles, including F508del (47.

An electronic infrastructure for research and treatment of the thalassemias and other hemoglobinopathies: the Euro-mediterranean ITHANET project.

Hemoglobin (Hb) disorders are common, potentially lethal monogenic diseases, posing a global health challenge. With worldwide migration and intermixing of carriers, demanding flexible health planning and patient care, hemoglobinopathies may serve as a paradigm for the use of electronic infrastructure tools in the collection of data, the dissemination of knowledge, the harmonization of treatment, and the coordination of research and preventive programs. ITHANET, a network covering thalassemias and other hemoglobinopathies, comprises 26 organizations from 16 countries, including non-European countries of origin for these diseases (Egypt, Israel, Lebanon, Tunisia and Turkey).

[Clinical characteristics and outcome of cystic fibrosis: report of 16 cases].

Aim: The aim of this report is to determine clinical characteristics and outcome of Cystic Fibrosis (CF).

Methods: Cases of CF managed at Infantile Medicine A Department in Children's Hospital of Tunis during 13 years (1994-2006) were reviewed.

Results: 16 children had CF.

Evolution of hemoglobinopathy prevention in Africa: results, problems and prospect.

Hemoglobinopathies are a group of inherited hemoglobin disorders. Initially described in the subtropical regions, they are now spread all around the world because of migration. Their high frequency and clinical severity make them a major public health problem mostly in Africa due to the limited resources reserved for the management and prevention of these diseases.

[Hemoglobinopathies in Tunisia. An updated review of the epidemiologic and molecular data].

The hemoglobinopathies affect the blood red cells and are the most common monogenic diseases worldwide. The high frequency and clinical severity of the hemoglobinopathies, make them a major public health problem. We report here an updated review on epidemiologic and molecular data of the hemoglobinopathies in Tunisia.

Detection of two rare beta-thalassemia alleles found in the Tunisian population: codon 47 (+A) and codons 106/107 (+G).

We here present the first report of the detection of two rare beta0-thalassemia (thal) mutations in the Tunisian population: codon 47 (+A) and codons 106/107 (+G). To the best of our knowledge this is the second report of the codon 47 (+A) mutation, the first being identified in a Surinamese subject. The codons 106/107 (+G) mutation was first described in American Blacks, subsequently in Egyptians and Palestinians, and now in Tunisians.

Haplotypes linked to three rare beta-thalassemia mutations, originally reported in Tunisia.

The polymorphism of the beta-globin gene haplotypes and frameworks are useful in the determination of the unicentric and multicentric origin of a mutational event. In order to improve our knowledge of the chromosomal background of the beta-globin gene in three beta-thalassemia (thal) mutations originally reported in Tunisia, namely codons 25/26 (+T), codon 30 (G-->C) and IVS-I-2 (T-->G), we have investigated 13 unrelated individuals. There were five non transfusion-dependent patients homozygous for the IVS-I-2 (T-->G) mutation, five others were homozygous for the codon 30 (G-->C) mutation, one was a homozygote for the codons 25/26 (+T) insertion mutation and one patient was a compound heterozygote for the codon 39 (C-->T) and codon 25/26 (+T) mutations; the last patient had a betaS/codon 25/26 (+T) compound heterozygous genotype.

[Prevalence and causal factors of anemia in children in Tunisia].

Anemia continue to be prevalent among children under five years despite the improvement of socioeconomic and sanitary indicators. The purpose of the present cross-sectorial study is to assess the etiologic factors responsible for anemia. Knowledge of the relative importance of the different causes should form a basis for intervention strategies to prevent and control anemia.

First description in Tunisia of a point mutation at codon 119 (CCT-->TCT) in the alpha1-globin gene: Hb Groene Hart in association with the -alpha3.7 deletion.

Herein we describe the case of a Tunisian girl who presented with 3% Hb Bart's (gamma4) at birth. At the age of 3 years, she showed microcytosis and hypochromia in the absence of iron deficiency. The first step of molecular analysis was to test for the common Mediterranean mutations and the classical -alpha3.

A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia.

Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC).

A novel alpha-thalassemia nonsense mutation in codon 23 of the alpha2-globin gene (GAG-->TAG) in a Tunisian family.

Herein we describe a novel alpha-thalassemia (thal) point mutation in the alpha2-globin gene, found in a 3-year-old Tunisian girl who had Hb Bart's (gamma4) at birth, later on presenting with moderate anemia, microcytosis and hypochromia. She had a normal Hb A2 level and no abnormal hemoglobin (Hb) fraction. After excluding most of the common Mediterranean mutations, the alpha2-globin gene was sequenced and found to have a point mutation in the heterozygous state that creates a premature stop signal for translation (GAG-->TAG or Glu-->Term) at codon 23.

Molecular basis of beta-thalassemia in the population of Tunisia.

The present study attempts to delineate the spectrum of beta-thalassemia (thal) mutations in Tunisia by studying a large population from different parts of the country. A total of 285 unrelated subjects, 190 of whom had beta-thal major, 72 with Hb S/beta-thal, one with Hb C/beta-thal, one with Hb O-Arab/beta-thal and 21 beta-thal carriers, were studied. The molecular defects were detected in 97.