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The geometric structures and the relative stability of the Li+−Nen clusters, with n = 1–20, have been computed using pairwise model potential and density functional theory (DFT) method. The potential energy surface employed in these calculations is based on the Li+-Ne, Ne-Ne and many body interactions V3B. A series of methods and basis sets have been tested by reproduce correctly the experimental Li+-Ne and Ne-Ne potential energies. In addition, both Li+-Ne and Ne-Ne numerical potentials have been fitted by several analytical expressions as Tang and Toennies (TT), Extended Lennard Jones (ELJ) and Lennard-Jones (LJ) formula. The most stable structures of Li+-Nen clusters up to n = 20 have been optimized at Basin Hopping Monte Carlo (BHMC) method. The accuracy of our pairwise potential model has been confirmed by re-optimization at the DFT level of theory. The relative stabilities of Li+-Nen clusters are discussed by calculating the energy per neon atom, the first derivative, the fragmentation energy and the second derivative as well as the Highest Occupied Molecular orbital (HOMO)–Lowest Unoccupied Molecular Orbital(LUMO) energy gap with the size of the clusters. It was shown that n=6, 8, 12, 14, 16 and 17 correspond to the magic numbers. Finally, thermodynamic properties are calculated and showed that the formation process of Li+-Nen clusters is endothermic and non-spontaneous.

Chronic granulomatous disease (CGD) is an inherited autosomal recessive or X-Linked primitive immunodeficiency (PID), due to a defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex impairing anti-infectious and anti-inflammatory role of peripheral blood mononuclear cells. It is characterized by severe bacterial and fungal infections and by excessive inflammation leading to granulomatous complications. This work was made over a period of 34 years on 41 Tunisian patients suffering from CGD. Cumulative follow-up of patients was 2768.5 months, median 31 months. Survival was studied by survival curves according to Kaplan-Meier method. Lymphatic nodes, pulmonary and cutaneous infections predominate as revealing manifestations and as infectious events during patients’ monitoring. At study end 12 patients died mainly of invasive pulmonary aspergillosis and septicemia. Median age of death was 30 months. CGD remains compatible with a decent quality of life. Early diagnosis, anti-infectious prophylaxis, and initiation of adequate management, as soon as complication is perceived, promote pretty good evolution.

We highlight the spectroscopic and electronic structure of BeCs+ ion, theoretically investigating ground and low lying excited states as well as the cold ion–atom elastic collisions proprieties and laser cooling possibility.

Hyper IgE syndromes (HIES) is a heterogeneous group of Inborn Errors of Immunity characterized by eczema, recurrent skin and lung infections associated with eosinophilia and elevated IgE levels. Autosomal dominant HIES caused by loss of function mutations in Signal transducer and activator of transcription 3 (STAT3) gene is the prototype of these disorders. Over the past two decades, advent in genetic testing allowed the identification of ten other etiologies of HIES. Although Dedicator of Cytokinesis 8 (DOCK8) deficiency is no more classified among HIES etiologies but as a combined immunodeficiency, this disease, characterized by severe viral infections, food allergies, autoimmunity, and increased risk of malignancies, shares some clinical features with STAT3 deficiency. The present study highlights the diagnostic challenge in eleven patients with the clinical phenotype of HIES in a resource-limited region. Candidate gene strategy supported by clinical features, laboratory findings and functional investigations allowed the identification of two heterozygous STAT3 mutations in five patients, and a bi-allelic DOCK8 mutation in one patient. Whole Exome Sequencing allowed to unmask atypical presentations of DOCK8 deficiency in two patients presenting with clinical features reminiscent of STAT3 deficiency. Our study underlies the importance of the differential diagnosis between STAT3 and DOCK8 deficiencies in order to improve diagnostic criteria and to propose appropriate therapeutic approaches. In addition, our findings emphasize the role of NGS in detecting mutations that induce overlapping phenotypes.

The BeCs

Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations. In ARA, mutations occur in genes encoding the pre-B cell receptor (pre-BCR) or downstream signaling proteins. In this work, we used candidate gene and whole-exome sequencing to investigate the molecular basis of ARA in 6 patients from 4 consanguineous North-African families. Sanger sequencing of candidate genes encoding the pre-BCR components (ΙGΗΜ, CD79A, CD79B, IGLL1, and VPREB1) was initially performed and determined the genetic defect in five patients. Two novel mutations in IGHM (p.Val378Alafs*1 and p.Ile184Serfs*21) were identified in three patients from two unrelated kindred and a novel nonsense mutation was identified in CD79A (p.Trp66*) in two siblings from a third kindred. Whole-exome sequencing (WES) was performed on the sixth patient who harbored a homozygous stop mutation at position 407 in the RAG2 gene (p.Glu407*). We concluded that conventional gene sequencing, especially when multiple genes are involved in the defect as is the case in ARA, is costly and time-consuming, resulting in delayed diagnosis that contributes to increased morbidity and mortality. In addition, it fails to identify the involvement of novel and unsuspected gene defects when the phenotype of the patients is atypical. WES has the potential to provide a rapid and more accurate genetic diagnosis in ARA, which is crucial for the treatment of the patients.

In Tunisia, beta-thalassemia major is a real public health problem. A study carried out of patients affected shows that for them, this chronic haemoglobinopathy is a disability hampering their physical activities, their social integration, their academic results and their emotional life.

Background/Aims: Hereditary Spherocytosis (HS) is the most common erythrocyte membrane disorder causing hemolytic anemia. The wide heterogeneity of both clinical and laboratory manifestations of HS contributes to difficulties associated with the diagnosis of this disorder. Although massive data previously reported worldwide, there is yet no data on HS among the Tunisian population. Here we aim to characterize HS in Tunisian patients at biochemical and cellular levels, identify the membrane protein deficiency, and compare the accuracy of the diagnostic tests to identify the most appropriate assay for HS diagnosis. Methods: We investigated 81 patients with hemolytic anemia and 167 normal controls. The exploration of HS based on clinical and family history, physical examination, and the results of laboratory tests: blood smear, osmotic fragility test (OFT), cryohemolysis test (CT), pink test (PT), eosine-5’-maleimide (EMA) test, and erythrocyte membrane protein electrophoresis. Results: We identified 21 patients with HS, classified as severe (6/21;28.5%), moderate (10/21;47.6%), and mild (5/21;23.8%). The most prevalent protein deficiency was the band 3 protein detected in ten Tunisian HS patients. The EMA test showed a high specificity (97.5%) and sensitivity (94.7%) for HS diagnosis compared to the other screening tests. Interestingly, fourteen among sixteen patients presenting with homozygous sickle cells HbSS showed an increase of EMA fluorescence intensity compared to other anemic patients. Conclusion: Our study highlights the efficiency of the EMA dye for the detection of HS whatever the nature of the involved protein deficiency. We report for the first time, the most prevalent protein deficiency among Tunisians with HS. Moreover, we found that the combination of the EMA-binding test with PT or incubated OFT improves the diagnosis sensitivity while maintaining a good specificity.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the novel coronavirus SARS-CoV-2, represent an ongoing global health emergency. Common symptoms are mild including fever, cough, myalgia and difficulty breathing. In patients most severely affected, COVID-19 can be complicated by the acute respiratory distress syndrome (ARDS). The management of ARDS mainly focuses on the provision of supportive care, e.g., oxygenation, ventilation, and fluid management. Polyethylene glycol (PEG) is a water soluble non-toxic polymer approved by FDA and widely used in food, cosmetics and pharmaceutics. PEG has interesting properties that makes it suitable for use as an adjuvant treatment in COVID-19 patient with ARDS: (1) PEG could create a physical barrier that inhibits virus entry and invasion; (2) PEG reduces inactivation and enhances the surface activity of pulmonary surfactant; (3) PEG decrease cytokine release and (4) PEG preserve lung endothelial cells integrity.

Aims This study aimed to evaluate the effect of oleuropein (OLE), the main phenolic compound present in olive leaves, on kidney ischemia-reperfusion injury (IRI) and to explore the underlying protective mechanism. Main methods Rat kidneys were subjected to 60 min of bilateral warm ischemia followed by 120 min of reperfusion. OLE was administered orally 48 h, 24 h and 30 min prior to ischemia at doses of 10, 50 and 100 mg/kg body weight. The creatinine, urea, uric acid concentrations and lactate dehydrogenase (LDH) activity in plasma were evaluated. Oxidative stress and inflammation parameters were also assessed. Renal expression of AMP-activated protein kinase (p-AMPK), endothelial nitric oxide synthase (eNOS), mitogen-activated protein kinases (MAPK), inflammatory proteins and apoptotic proteins were evaluated using Western blot. Key findings Our results showed that OLE at 50 mg/kg reduced kidney IRI as revealed by a significant decrease of plasmatic creatinine, urea, uric acid concentrations and LDH activity. In parallel, OLE up-regulated antioxidant capacities. Moreover, OLE diminished the level of CRP and the expression of cyclooxygenase 2 (COX-2). Finally, OLE enhanced AMPK phosphorylation as well as eNOS expression whereas MAPK, and cleaved caspase-3 implicated in cellular apoptosis were attenuated in the ischemic kidneys. Significance In conclusion, this study shows that OLE could be used as therapeutic agent to reduce IRI through its anti-oxidative, anti-inflammatory and anti-apoptotic properties.

Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox.DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (100 mg/kg per day) or deferasirox (40 mg/kg per day; deferasirox is not registered for use in children aged2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512.435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group.In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group.EU Seventh Framework Programme.

Background: Consanguinity increases the incidence of recessive diseases such as beta-thalassaemia major (βTM), one of the most prevalent lethal inherited diseases in the world.Aim: This study aims ...

The potential energy and spectroscopic constants of the ground and many excited states of the Be+He van der Waals system have been investigated using a one-electron pseudo-potential approach, which is used to replace the effect of the Be2+ core and the electron-He interactions by effective potentials. Furthermore, the core–core interactions are incorporated. This permits the reduction of the number of active electrons of the Be+He van der Waals system to only one electron. Therefore, the potential energy of the ground state as well as the excited states is performed at the SCF level and considering the spin–orbit interaction. The core–core interaction for Be2+He ground state is included using accurate CCSD (T) calculations. Then, the spectroscopic properties of the Be+He electronic states are extracted and compared with the previous theoretical and experimental studies. This comparison has shown a very good agreement for the ground and the first excited states. Moreover, the transition dipole mome...

This study was aimed to identify the predictors of splenic sequestration crisis (SSC) among pediatric patients with sickle cell disease (SCD). This prognosis study was carried out in the pediatric immuno-hematology unit, over 20 years (1998 to 2017), enrolling patients with SCD. The cox model was used in multivariate analysis. Among 423 patients with SCD (240 S/S phenotype, 128 S/B0, 30 S/B+, 14 S/O arab and 11 S/C), 150(35.4%) had at least one episode of SSC. The average age of patients at the first episode was 48.3 months ± 32.4(2–168). Recurrence of SSC was observed in 117 patients (78%). Spleen size ≥3 cm at baseline was the strongest predictor of SSC occurrence (HR = 7.27, CI: 4.01–13.20, p = 0.05) and recurrence (HR = 6.37, CI: 1,46–27.83, p = 0.01). Pallor revealing the disease, age at onset of symptoms In conclusion, this study confirmed the high prevalence of SSC in SCD and the high frequency of recurrence after a first episode. The SSC occurrence and recurrence were intimately linked to the presence of splenomegaly, chronic pallor revealing the disease as well as reticulocytosis.

Primary Immunodeficiency (PIDs) is a set of 330 rare hereditary diseases that increase susceptibility to infections, allergies, autoimmunity, and neoplasia. North American registries give higher prevalence than Maghreb ones, whereas consanguinity is high. The purpose of this study is to compare prevalence and coverage rate of Maghreb PID registries with estimates based on USA.We searched the prevalence of PIDs in the Maghreb registers. Next, we estimated the expected values based on recent publications. Finally, we calculated the coverage rate of the Maghreb registries compared to the new estimates and we evaluated the impact of consanguinity.The total number is N1 = 2456 patients. The current Maghreb PID Prevalence is 2.56 / 100,000 inhabitants (population of 94,804,694 Million in 2017). Tunisia leads with a prevalence of 8.70 followed by Morocco 2.09, Libya 1.65 and Algeria 1.46/100.000 habitants. We did not find values for Mauritania. If we extrapolate the prevalence of the USA to the Maghreb population, the number of patients in the Maghreb would be N2 = 27,588 and the coverage rate (N1 / N2) would be 8.90%. This low coverage rate is however better than the World average (1.21%), that of Latin America 1.19% and Africa 0.36%. The Maghreb prevalence is close to that of the Arab world 2.04 / 100,000 (population of 391,449,544 in 2017). Using the incidence found in the USA, the number of patients would be 9765 new patients per year in the Maghreb and 40,319 in Arab countries.PID Maghreb patients number is very low compared to global estimates, whereas consanguinity is very high. Special attention should be given to PIDs by governments and research teams in this region.

BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:143 issue:1 pages:359-368 ispartof: location:United States status: published

The ground and many excited states of the Mg(+)He van der Waals molecular system have been explored using a one-electron pseudopotential approach. In this approach, effective potentials are used to consider the Mg(2+) core and the electron-He effects. Furthermore, a core-core interaction is included. This has reduced the number of active electrons of the Mg(+)He, to be considered in the calculation, to a single valence electron. This has permitted to use extended Gaussian basis sets for Mg and He. Therefore, the potentianl energy and dipole moments calculations are carried out at the Hartree-Fock level of theory, and the spin-orbit effect is included using a semiclassical approach. The core-core interaction for the Mg(2+)He ground state is included using accurate CCSD(T) calculations. The spectroscopic constants of the Mg(+)He electronic states are extracted and compared with the existing theoretical works, where very good agreement is observed. Moreover, the transition dipole function has been determined for a large and dense grid of internuclear distances including the spin-orbit effect.

[Background/aim] The aim of this study was to compare the effects of single and repeated trimetazidine (TMZ) administration against warm hepatic ischemia/reperfusion (I/R) injury and to explore the possible mechanisms affected by TMZ. [Materials and methods] Wistar rats were divided into 4 groups (n = 6). Sham: rats were subjected to dissection. I/R: rats were subjected to 60 min of partial hepatic ischemia followed by 24 h of reperfusion. TMZ1: Same as I/R group but rats were pretreated with a single dose of TMZ (10 mg/kg, intraperitoneal injection) 30 min before warm ischemia. TMZ3: Same as I/R but rats were treated with 10 mg/ kg TMZ for 3 successive days. [Results] TMZ treatment decreased liver injury, lipid peroxidation, and apoptosis. The repeated administration of TMZ conferred more protection than the single dose treatment concerning all studied parameters. In parallel, we noted a significant increase in phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) and endothelial nitric oxide synthase (eNOS) levels in TMZ3 as compared to TMZ1. [Conclusion] Repeated administration of TMZ for 3 days was more efficient than a single dose of TMZ in protecting the liver against I/R induced apoptosis and lipid peroxidation. These effects implicate AMPK and eNOS activation., This study was funded by the Tunisian Ministry of Higher Education and Scientific Research.

Background: Patients with sickle cell disease (SCD) or other rare anemias whose care includes chronic blood transfusions must receive iron chelation to prevent the morbidity of iron overload. Currently, only deferoxamine (DFO) and deferasirox (DFX) are approved chelators in these patient populations. This randomized open-label trial evaluated if the efficacy of deferiprone (DFP) was non-inferior to DFO. DFO was used as the comparator product since DFX was not approved as first-line treatment for SCD at trial initiation. Methods: Participants at 27 sites in 8 countries were randomized in a 2:1 ratio to receive either DFP or DFO for up to 12 months. Those with lower transfusional iron input and/or less severe iron load were prescribed either DFP 25 mg/kg of body weight t.i.d. or DFO 20 mg/kg (children) or 40 mg/kg (adults); those with higher iron input and/or more severe iron load received either DFP 33 mg/kg t.i.d. or DFO up to 40 mg/kg (children) or 50 mg/kg (adults). Dosages could be adjusted over the course of the trial if necessary. Efficacy endpoints were the changes from baseline in liver iron concentration (LIC), cardiac iron, and serum ferritin (SF) at Month 12. The primary endpoint was based on LIC, and for the demonstration of non-inferiority of DFP to DFO, the upper limit of the 95% confidence interval for the difference between treatments had to be no more than 2 mg/g dry weight (dw). All patients had their neutrophil count monitored weekly, whereas other safety assessments and compliance with study therapy were evaluated monthly. Acceptable compliance was defined as taking 80% to 120% of the prescribed dosage. Results: A total of 228 of the targeted 300 patients were dosed with 152 receiving DFP and 76 receiving DFO, to assess non-inferiority. There were no significant differences between the groups in any demographic measures: in each treatment group, 84% of patients had SCD and the remainder had other, rarer forms of transfusion-dependent anemia. Mean age at enrollment was 16.9 years (± 9.6); 53.1% of patients were male; and 77.2% were white, 16.2% black, and 6.6% multi-racial. Over the course of the study, 69% of patients in the DFP group and 79% in the DFO group had acceptable compliance with treatment. Based on the Pocock's α spending function, a more stringent confidence level of 96.01% was applied to the calculation of confidence interval for the evaluation of non-inferiority. For the primary efficacy endpoint, the least squares (LS) mean change in LIC (measured as mg/g dw) was -4.04 for DFP, -4.45 for DFO; the upper limit of the 96.01% confidence interval for the difference was 1.57, thereby demonstrating non-inferiority of DFP to DFO. The upper limit for the subpopulation of patients with SCD also met the non-inferiority criterion. For the secondary endpoints, the change in cardiac iron (measured as ms on MRI T2*, log-transformed) was approximately -0.02 for both; and for SF (measured as μg/L), it was -415 vs. -750 for DFP vs. DFO, respectively. The difference between the groups was not statistically significant for both endpoints. With respect to safety, there was no statistically significant difference between the groups in the overall rate of adverse events (AEs), treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis was seen in 1 DFP patient vs. no DFO patients, while events of less severe episodes of neutropenia occurred in 4 vs. 1, respectively. All episodes of agranulocytosis and neutropenia resolved. There was no significant treatment group difference in the rates of any of the serious AEs. Conclusion: The efficacy of DFP for the treatment of iron overload in patients with SCD or other rare anemias is not inferior to that of DFO, as assessed by changes in liver iron concentration. non-inferiority was supported by the endpoints on cardiac iron load and SF. The safety profile of DFP was acceptable and was similar to that previously seen in thalassemia patients, and its use was not associated with unexpected serious adverse events. The results of this study support the use of DFP for the treatment of iron overload in patients with SCD or other rare transfusion-dependent anemias. Note: The authors listed here are presenting these findings on behalf of all investigators who participated in the study. Disclosures Kwiatkowski: Terumo: Research Funding; Imara: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Apopharma: Research Funding. Fradette:ApoPharma: Employment. Kanter:Sangamo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Modus: Consultancy, Honoraria. Tsang:Apotex Inc.: Employment. Stilman:ApoPharma: Employment. Rozova:ApoPharma: Employment. Sinclair:ApoPharma: Employment. Shaw:ApoPharma: Employment. Chan:ApoPharma: Employment. Toiber Temin:ApoPharma: Employment. Lee:ApoPharma: Employment. Spino:ApoPharma: Employment. Tricta:ApoPharma: Employment. OffLabel Disclosure: Deferiprone is an oral iron chelator.

In beta-thalassemia patients, erythrocyte autoantibodies can remain silent or lead to Autoimmune Hemolytic Anemia (AIHA).The aim of this study was to identify predictors of AIHA in beta-thalassemia patients with positive Direct Antiglobulin Test (DAT), in Tunisia. This longitudinal prognosis study was carried out on beta-thalassemia patients with a positive confirmed DAT. Predictors of AIHA were identified the Kaplan-Meier method. A Cox model analysis was used to identify independent predictors. Among 385 beta thalassemia patients, 87 developed positive DAT (22.6%). Autoimmune hemolytic anemia was occurred in 25 patients. Multivariate analysis showed that AIHA was independently associated with beta-thalassemia intermedia and similar family history of AIHA. Splenectomy in patients with positive DAT was independently associated with an increased risk of AIHA (HR = 6.175, CI: 2.049-18.612, p 0.001). The risk of developing AIHA was higher during the first 72 transfusions. Autoimmune hemolytic anemia was significantly associated with polyspecific DAT (anti-complement and anti-IgG), blood group AB and prior alloimmunization. Whereas transfusion by phenotypic and leukoreduced blood was a protective factor. In summary, splenectomy after autoimmunization, prior alloimmunization, DAT specificity (IgG with complement), thalassemia intermedia, AB blood group and family history of AIHA were strongly associated with AIHA. Leukoreduced blood transfusion had a proven preventive role.

The potential energy interaction, the spectroscopic properties and dipole functions of the RbHe van der Waals dimer have been investigated. We used a one-electron pseudopotential approach and large Gaussian basis sets to represent the two atoms Rb and He. The Rb+ core and the electron-He interactions were replaced by semi-local pseudopotentials and a core-core interaction is included. Therefore, the number of active electrons of RbHe is reduced to only one electron. Consequently, the potential energy curves and dipole moments for many electronic states dissociating into Rb(5s,5p,4d,6s,6p,5d,7s)+He are performed at the SCF level. In addition, the spin-orbit coupling is included in the calculation. The Rb+He interaction, in its ground state, is taken from accurate CCSD (T) calculations and fitted to an analytical expression for a better description of the potential in all internuclear ranges. The spectroscopic properties of the RbHe electronic states are extracted. The comparison of these constants has shown a very good agreement for the ground state as well as for the lower excited states when compared with existing theoretical and experimental studies.

Hammam lif is a Tunisian coastal area threatened by the flooding for years, it underwent exceptional meteorological events which are manifested in 4 major storms 1931, 1981,2003 and 2012. From the study of the anthropogenic and natural damage resulting from each storm, one can deduce the parameters generating the flood in Hammam Lif and generally in each coastal zone threatened by the risk of flooding. The parameters are: rainfall, wave run-up, urbanization and infrastructure. How to highlight the generating parameters of the coastal flood with the aim of mapping a map with detailed flood risk areas that will serve as a flood risk prevention plan for the Hammam Lif area ? and what census methods and tools to use ?

International audience; Primary immunodeficiencies (PIDs) are a large group of diseases characterized by susceptibility to not only recurrent infections but also autoimmune diseases and malignancies. The aim of this study was to describe and analyze the distribution, clinical features and eventual outcome of PID among Tunisian patients. We reviewed the record of 710 patients diagnosed with Primary Immunodeficiency Diseases (PIDs) from the registry of the Tunisian Referral Centre for PIDs over a 25-year period. The male-to-female ratio was 1.4. The median age at the onset of symptoms was 6 months and at the time of diagnosis 2 years. The estimated prevalence was 4.3 per 100,000 populations. The consanguinity rate was found in 58.2 % of families. According to the International Union of Immunological Societies classification, spectrums of PIDs were as follows: combined T-cell and B-cell immunodeficiency disorders account for the most common category (28.6 %), followed by congenital defects of phagocyte (25.4 %), other well-defined immunodeficiency syndromes (22.7 %), predominant antibody deficiency diseases (17.7 %), diseases of immune dysregulation (4.8 %), defect of innate immunity (0.4 %) and complement deficiencies (0.4 %). Recurrent infections, particularly lower airway infections (62.3 %), presented the most common manifestation of PID patients. The overall mortality rate was 34.5 %, mainly observed with combined immunodeficiencies. The distribution of PIDs was different from that reported in Western countries, with a particularly high proportion of Combined Immunodeficiencies and phagocyte defects in number and/or function. More is needed to improve PID diagnosis and treatment in our country.

Following a national out-of-stock of pharmaceutical speciality made with multivitamins formula for intravenous infusion, two hospitalized children with immuno-hematological disorder receiving vitamins-unsupplemented total parenteral nutrition (TPN), had acute lactic acidosis associated with neurological and respiratory symptoms. Clinical and biological signs had quickly resolved after the intravenous administration of thiamine. The thiamine deficiency is an uncommon complication of TPN. This complication remains unrecognized especially in patients with serious diseases in which acidosis could be multifactorial.

Fetal hemoglobin (HbF) plays a dominant role in ameliorating morbidity and mortality of hemoglobinopathies. We evaluated the effects of polymorphic markers within the β-globin gene cluster to identify the genetic mechanics that influence HbF on Tunisian sickling patients (n = 242). Haplotype analysis was carried out by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and the framework polymorphism was established by PCR-sequencing, four independent regions of interest were identified: the 5′ region of β-LCR-HS2 site, the intervening sequence II (IVSII) region of two fetal (Gγ and Aγ) genes and the 5′ region of β-globin gene. The correlation of these various Haplotypes and SNPs with HbF expression and clinical data was studied. Our data showed that among the various polymorphic markers analyzed, only the sequence (AT)xN12(AT)y in LCR HS2 region was significantly associated (p

Melatonin (Mel) is widely used to attenuate ischemia/reperfusion (I/R) injury in several organs. Nevertheless, the underlying mechanisms remain unclear. This study was conducted to explore the effect of Mel on endoplasmic reticulum (ER) stress, Akt and MAPK cascades after renal warm I/R. Eighteen Wistar rats were randomized into three groups: Sham, I/R, and Mel + I/R. The ischemia period was 60 min followed by 120 min of reperfusion. Mel (10 mg/kg) was administrated 30 min prior to ischemia. The creatinine clearance, MDA, LDH levels, and histopathological changes were evaluated. In addition, Western blot was performed to study ER stress and its downstream apoptosis as well as phosphorylation of Akt, GSK-3β, VDAC, ERK, and P38. Mel decreased cytolysis and lipid peroxidation and improved renal function and morphology compared to I/R group. Parallely, it significantly reduced the ER stress parameters including GRP 78, p-PERK, XBP 1, ATF 6, CHOP, and JNK. Simultaneously, p-Akt level was significantly enhanced and its target molecules GSK-3βand VDAC were inhibited. Furthermore, the ERK and P38 phosphorylation were evidently augmented after Mel administration in comparison to I/R group. In conclusion, Mel improves the recovery of renal function by decreasing ER stress and stimulating Akt pathway after renal I/R injury.

This study aims to determine whether Angiotensin IV (Ang IV) addition to Celsior preservation solution could improve hepatic endothelium function and provide better liver protection during subnormothermic machine preservation (SMP). Two experimental models were used: In the first part of the study, rings isolated from rat hepatic artery were preserved in Celsior solution (6 h, 20 °C) with and without Ang IV (10−9 M), then, endothelium–dependent relaxation (EDR) and the concentration of acetylcholine inducing half-maximal relaxation of pre-contracted rings (EC50) were measured. Also, in order to investigate the implication of nitric oxide (NO) on EDR, the rings of hepatic artery were incubated with L-NG-nitroarginine metyl ester (L-NAME). In the second part of the study, rat livers were subjected to SMP with oxygenated Celsior solution (6 h, 20 °C), supplemented or not with Ang IV (10−9 M) and then perfused (2 h, 37 °C) with Krebs Henseleit solution. We found that Ang IV supplementation to Celsior solution decreased EC50 value and improved EDR of hepatic artery rings, 6h after sub-normothermic preservation. Interestingly, Ang IV amplified the vessel relaxation in a NO-dependent manner. Moreover, liver SMP with Ang IV reduced oxidative stress and cell injury and improved organ function. Ang IV activated pAkt, increased eNOS protein level and decreased apoptosis in the preserved liver grafts. In conclusion, we showed that the use of Ang IV in Celsior solution for sub-normothermic graft preservation insured a better NO-dependent relaxation and improved liver functional recovery.

Liver ischemia–reperfusion (IR) injury is inevitable in surgical procedures such as hepatic resection and liver transplantation. It represents a leading cause of liver graft dysfunction and primary nonfunction after transplantation. Phosphodiesterase (PDE) inhibitors are emerging as effective drugs able to reduce IR damage. The aim of this study was to investigate the effect of selective PDE-3 inhibitor olprinone (Olp) against liver IR injury. Male Wistar rats were subjected to 1 h of partial warm ischemia (70%) followed by 6 h of reperfusion. Before ischemia, rats were treated with saline (IR group), Olp (Olp group), or Olp with Akt inhibitor LY294002 (Olp plus LY group). After reperfusion, hepatic injury (transaminase activities), mitochondrial damage (glutamate dehydrogenase activity), oxidative stress (malondialdehyde and glutathione concentrations and catalase and superoxide dismutase activities), and protein kinase Akt activation were evaluated. Rat treatment with Olp reduced liver injury, prevented mitochondrial damage, decreased lipid peroxidation, and enhanced antioxidant enzymes. Also, Olp induced a significant activation in protein kinase Akt. Inhibition of Akt with LY294002 abolished all of the protective effects of Olp. In conclusion, Olp treatment may be an effective strategy in reducing liver IR injury through oxidative stress prevention and Akt activation.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and histiocytes. Often, HLH is an acquired syndrome. We report a case of a nine month-old-boy presented with hepatosplenomegaly, severe anemia, thrombocytopenia, hypertriglyceridemia and high hyperferritinemia. These clinical features of HLH prompted a wide range of infectious and auto-immune tests to be performed. After an extensive diagnostic workup, he was referred to the immune-hematologic unit for HLH suspicion with an unknown cause. Primary HLH due to familial lymphohistiocytosis (FLH) was first evoked in front of consanguinity, probable HLH in the family, early onset, and in the absence of a causative pathology like infection or cancer. However, functional tests were normal. Atypical features like the: absence of fever, hypotonia, recurrent diarrhea since diversification, hematuria, and proteinuria suggested an inborn metabolism error with gastrointestinal involvement. Specific tests were performed to reach a final diagnosis.

Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Mutations in PGM3 gene have been recently shown to underlie a new congenital disorder of glycosylation often associated to elevated IgE. Herein, we report twelve PGM3 deficient patients. They belong to three highly consanguineous families, originating from a rural district in the west central Tunisia. The patient's clinical phenotype is characterized by severe respiratory and cutaneous infections as well as developmental delay and severe mental retardation. Fourteen patients died in early infancy before diagnosis supporting the severity of the clinical phenotype. Laboratory findings revealed elevated IgE, CD4 lymphopenia and impaired T cell proliferation in most patients. Genetic analysis showed the presence, of a unique homozygous mutation (p.Glu340del) in PGM3 gene leading to reduced PGM3 abundance. Segregating analysis using fifteen polymorphic markers overlapping PGM3 gene showed that all patients inherited a common homozygous haplotype encompassing 10-Mb on chromosome 6. The founder mutational event was estimated to have occurred approximately 100 years ago. To date, (p.Glu340del) mutation represents the first founder mutation identified in PGM3 gene. These findings will facilitate the development of preventive approaches through genetic counselling and prenatal diagnosis in the affected families.

Introduction: Ischemia-reperfusion injury (IRI) involves a complex sequence of events and limits the outcome of various surgical interventions. Clinical trials, based on the data of experimental models, aim to prove whether a pharmacological or technical approach could be suitable to provide a beneficial effect in humans. Due to the complexity of IRI, few pharmacological treatments have been investigated in clinical Phase III. Areas covered: In this review we report clinical trials that test specific drugs in clinical trials of organ transplantation. These studies form part of Phase II trials and examine the administration of caspase inhibitors, P-selectin antagonist or an antioxidant component in order to attenuate cold IRI during transplantation. Moreover, we provide a brief description of drugs tested on trials of different clinical situations associated to IRI, such as the coronary artery bypass graft surgery and percutaneous coronary intervention. Expert opinion: Future clinical trials could be centered on the application of techniques suitable for organs with increased vulnerability toward IRI. Furthermore, the standardization of reliable biomarkers and a careful estimation of the impact of high risk factors may be the key in order to achieve a more critical evaluation of the obtained results.

Mediators of adhesion become a potential new target for pharmacological therapy to struggle the complications of sickle cell disease (SCD). Several mechanisms for increased adherence have been postulated and the well-studied are CD36 and VLA4 which encoded by ITGA4. Herein, we sought to determine whether one polymorphism of CD36 namely: rs1984112 and three exons of ITGA4 (4, 5, and 6) are implicated in hemolytic status and clinical events among SCD Tunisian patients.This study enrolled 99 unrelated Tunisian subjects (63SS and 36Sβ). All SCD patients are children (less than 16 years old). The rs1984112 and the ITGA4's exons 4, 5, and 6 were analyzed for all subjects by PCR/sequencing. The association of each genotype found with both clinical complications and hemolytic status was performed using t-test. Clinical events studied included vaso-occlusive crisis (VOC), osteonecrosis, stroke, frequent infection, priapism, and acute syndrome.The results show that rs1984112_G allele at CD36 gene revealed to be associated with higher levels of reticulocyte count (p 0.01). The statistical result show a near significance of homozygous mutant GG genotype with VOC (p = 0.051). No association between rs1984112_G allele and the clinical severity of SCD were found. Mutational screening of exon 4, 5, and 6 of ITGA4 gene revealed absence of mutated variant.Our results are similar to those found in Portuguese population which reported the role of rs1984112_G in increasing reticulocyte level among SCD patients. Consequently, the rs1984112_G of CD36 could be considered as a reliable biomarker for predicting patients at high risk for vascular occlusions and thus, allows earlier and more effective therapeutic management.

Objectif L’objectif de ce travail est d’evaluer la prevalence des anomalies pubertaires a partir d’une serie Tunisienne d’enfants suivis pour beta-thalassemie majeure et de determiner les facteurs de risque de leur survenue. Patients et methodes Il s’agit d’une etude prospective enrolant 28 patients suivis pour beta-thalassemie majeure (βTM) et ayant atteints l’âge pubertaire. Pour chaque patient etait identifies : des parametres demographiques et hematologiques. Tous les malades avaient beneficie d’un bilan hormonal explorant les axes somatotropes, gonadotrope, corticotrope, thyreotrope et des glandes parathyroides. La surcharge en fer etait evaluee selon les donnees de la ferritinemie et l’IRMT2* cardiaque et hepatique. Resultats Le declenchement spontane de la puberte etait obtenu dans 16 cas a un âge moyen de 15 ans pour les garcons et de 13 ans pour les filles. Douze parmi les patients etudies (42,85 %) avaient presente une anomalie pubertaire justifiant le recours au traitement hormonal substitutif. Il s’agit d’une stagnation pubertaire dans 4 cas, un impuberisme dans 6 cas et une amenorrhee primaire dans deux autres cas. Les facteurs associes a la survenue d’une anomalie pubertaire sont : le nombre de transfusions recues avant tout debut de chelation (p = 0,042) et l’existence d’une surcharge cardiaque a l’IRM T2* (p = 0,037). Discussion Les anomalies pubertaires sont frequentes chez les patients porteurs de β TM. Elles sont le plus souvent secondaires a l’hypogonadisme hypogonadotrope. Leurs etiologies sont multifactorielles, mais la surcharge martiale semble etre le mecanisme predominant.

Objectif Nous nous proposons d’evaluer le taux d’IGF1 chez les patients suivis pour beta-thalassemie majeure (βTM) en comparaison avec une population drepanocytaire. Patients et methodes Notre etude avait porte sur 41 patients suivis pour βTM et 40 patients suivis pour syndrome drepanocytaire majeur. Pour chaque malade ont ete evalues : le poids, la taille, le developpement pubertaire, le nombre total de transfusions recues, hemoglobine moyenne pre- et post-transfusionnelle et la ferritinemie moyenne. Tous ces malades avaient beneficie du dosage d’IGF1. Resultats Le taux d’iGF1 etait plus bas chez les patients porteurs de βTM polytransfuses avec un seuil statistique proche de la signification (0,005). Les facteurs qui influencent cette baisse sont : le nombre total de transfusions recues et la ferritinemie moyenne (p Discussion Le taux d’IgF1 est particulierement bas chez les patients beta-thalassemiques majeurs polytransfuses. Son etiologie est multifactorielle et semble etre influencee par l’hemochromatose secondaire au niveau du foie.

Introduction: β-thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect characterized by ineffective erythropoiesis and impaired RBC maturation. Luspatercept is a first-in-class erythroid maturation agent under development to treat patients with β-thalassemia. Luspatercept binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. ClinicalTrials.gov identifier: NCT02604433. Methods: Eligible patients were aged ≥ 18 years; had β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed); and required regular transfusions of 6-20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥ 35 days during that time. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for ≥ 48 weeks. Patients in both treatment arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level. The primary endpoint was a ≥ 33% reduction in transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13-24, when compared with a 12-week baseline period. Key secondary endpoints included: ≥ 33% reduction in RBC transfusion burden at weeks 37-48, ≥ 50% reduction in transfusion burden at weeks 13-24, ≥ 50% reduction in transfusion burden at weeks 37-48, and mean change in transfusion burden at weeks 13-24. Achievement of ≥ 33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated. Results: † A total of 336 patients were randomized, of whom 332 were treated. Median age was 30 years (range 18-66) and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment. 58% of patients in each arm had undergone splenectomy. B0/B0 genotype (classification according to the HbVar database) was observed in 68 of 224 (30.4%) and 35 of 112 (31.3%) patients in the luspatercept and placebo arms, respectively. 48 of 224 (21.4%) patients in the luspatercept arm achieved the primary endpoint versus 5 of 112 (4.5%) patients receiving placebo (odds ratio 5.79, P < 0.0001). 44 of 224 (19.6%) patients receiving luspatercept achieved a ≥ 33% reduction in RBC transfusion burden at weeks 37-48 compared with 4 of 112 (3.6%) patients receiving placebo (P < 0.0001). Of 224 patients receiving luspatercept, 17 (7.6%) and 23 (10.3%) achieved a ≥ 50% reduction in RBC transfusion burden at weeks 13-24 and 37-48, respectively, compared with 2 (1.8%) and 1 of 112 (0.9%) patients receiving placebo (P = 0.0303 and P = 0.0017, respectively). The difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P < 0.0001). 158 of 224 (70.5%) patients receiving luspatercept achieved a ≥ 33% RBC transfusion reduction over any consecutive 12 weeks compared with 33 of 112 (29.5%) patients receiving placebo (P < 0.0001); statistically significant differences were also noted for all other transfusion burden reduction endpoints. Adverse events (AEs) observed in the study were generally consistent with previously reported phase 2 data. Treatment-emergent AEs leading to dose delay or dose reduction were similar between treatment arms. No patient deaths were reported for those treated with luspatercept. Conclusions: Treatment with luspatercept resulted in significant reductions in RBC transfusion burden in adults with transfusion-dependent β-thalassemia. Luspatercept was generally well tolerated in this patient population. † As of May 11, 2018, cutoff date. Disclosures Cappellini: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Taher:Protagonist Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy; La Jolla Pharmaceutical: Research Funding; Celgene Corp.: Research Funding. Georgiev:Alnylam: Consultancy. Coates:Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Forni:Novartis: Research Funding; Roche: Research Funding; Celgene: Research Funding. Perrotta:Acceleron Pharma: Research Funding; Novartis: Research Funding. Lal:Celgene Corporation: Research Funding; Bluebird Bio: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Insight Magnetics: Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding. Kattamis:ApoPharma: Honoraria; Vifor Pharma: Consultancy; CELGENE: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Vlachaki:Novartis: Honoraria. Origa:Cerus Corporation: Research Funding; Bluebird Bio: Consultancy; Novartis: Honoraria; Apopharma: Honoraria. Aydinok:TERUMO: Research Funding; Protagonist: Other: SSC; CRISPR Tech: Other: DMC; Cerus: Honoraria, Research Funding; La Jolla Pharmaceuticals: Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding. Ho:Takeda: Honoraria, Other: travel to meeting; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Other: Travel to meeting. Chew:Celgene: Research Funding. Tantiworawit:Celgene: Honoraria, Research Funding, Speakers Bureau. Shah:Novartis: Honoraria, Speakers Bureau; Sobi/Apotex: Honoraria; Celgene Corp: Other: Steering committee; Roche: Other: Advisory board meeting. Neufeld:Celgene Corp.: Consultancy, Other: Steering committee; Acceleron Pharma: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Shetty:Celgene: Employment, Equity Ownership. Zou:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zinger:Celgene Corporation: Employment. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Erythec: Research Funding; Novartis: Research Funding. Porter:Cerus: Honoraria; Agios: Honoraria; Novartis: Consultancy. Piga:La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acceleron: Research Funding.

Major histocompatibility complex class II (MHC-II) expression deficiency is a combined primary immunodeficiency leading to the impairment of the cellular and humoral immune responses. A majority of affected patients belong to consanguineous families particularly from the Maghreb, where a founder effect for a highly frequent mutation (named c.338-25_338del26) in the RFXANK gene was reported. Herein, we report the largest single Maghrebian country series of MHC-II deficient patients.In Tunisia, among 551 PIDs diagnosed from 1993 to 2011, 54 had an MHC-II deficiency. The clinical features and immunological investigations were retrospectively analyzed in 34 children of them belonging to 28 kindred. The genetic study included the c.338-25_338del26 screening by the amplification of the affected region using polymerase chain reaction (PCR) followed by direct sequencing.Consanguinity was present in 22 out of 28 families. Mean age at the first infection was 6.1 months. Chronic diarrhea with failure to thrive and pulmonary infections were the most common manifestations occurring in 26 and 28 patients respectively. The most specific laboratory findings were the defect of MHC-II (HLA-DR) expression in all patients. The c.338-25_338del26 mutation was identified in 25 of them.In Maghrebian settings, pediatricians should definitely consider this diagnosis in the presence of an early onset of severe and recurrent infections of the respiratory and intestinal tracts, particularly protracted diarrhea with a failure to thrive. The founder effect for the c.338-25_338del26 mutation in the RFXANK gene is also confirmed, facilitating prenatal diagnosis as a preventive approach in the Tunisian affected families with severe forms, particularly in the context of limited access to bone marrow transplantation.

Background Primary immunodeficiencies (PID) are a group of heterogeneous and relatively rare diseases. Aim to determine the clinical characteristics, outcome and genetic data of primary immunodeficiencies in pediatrics patients. Methods A retrospective, descriptive and multicentered study, enrolling 33 children presenting a PID in Tunis, during a period of 22 years (1991-2012). Resultats a masculine predominance has been noticed with a sex ratio at 2,3. Consanguinity was found in 71% of family cases. History of early infant deaths was found in 42% of cases. The media age of diagnosis was of 1 year 2 months. The median diagnosis delay was of 11 months and 1/2. Most frenquently observed PID were combined immunodeficiency (36%), mostly severe combined immunodeficiency (SCID) (21%), followed by congenial defects of phagocyte function (33%), mostly chronic granulomatosis disease (21%). Antibody defects were found in 21% of cases. Most frequently observed out comes were lung infections (66%) recurrent oral thrush (57%) and diarrhea (42%). Most important complications were severe infections and bronchiectasis. 30% of patients were dead by the end of the study. A molecular characterization was performed in 33% of patients, and an antenatal diagnosis was performed in 10% of cases. Conclusion The PID are a group of disease with variable expressions and etiologies. Their frequency remains understimated in Tunisia, and their management, difficult and insufficient. We suggest the establishment of systematic genetic consulting visit, the creation of a national registry and developing bone marrow transplantation in children in Tunisia.

BACKGROUND The ability of nitrite to provide protection following ischemia/reperfusion (I/R) has been demonstrated, but its mechanism is still poorly understood. This study aimed to determine the optimal nitrite concentration to add into Institut Georges Lopez (IGL-1) storage solution and to assess its effect on antioxidant enzymes and autophagy. MATERIAL AND METHODS Livers from Sprague-Dawley rats were conserved in IGL-1 for 24 hours at 4°C or in IGL-1 enriched with nitrite at 50, 500 and 1,000 nM, respectively, before being perfused ex-vivo at 37 °C for 120 minutes. Sham livers were perfused ex vivo without cold preservation. RESULTS All biological and functional parameters of the preserved livers were significantly impaired as compared to shams. Interestingly, the supplementation of nitrite to IGL-1 protected the liver from I/R injury. Among the doses of nitrite evaluated, the 50 nM was proved efficient: it significantly reduced cytolysis, mitochondrial damage, and lipid peroxidation, and enhanced antioxidant enzyme activity (superoxide dismutase, catalase, and glutathione peroxidase activity) and hepatic function parameters (portal resistance, bile flow, and bromosulfophthalein clearance). In addition, increased levels of the autophagy parameters were observed when 50 nM of nitrite were added to IGL-1 solution, but this effect disappeared completely with higher concentrations of nitrite. CONCLUSIONS It seems that 50 nM of nitrite added to IGL-1 is the optimal concentration able to maintain cell integrity and hepatic function through autophagy induction and oxidative stress prevention.

The coastline of Hammamlif is an area characterized by a flooding problem due to the heavy rain and the wave run up phenomenon. This flooding phenomenon is made worse by both an intense urbanization and the badly designed unitary-type sewerage networks which drain rain water and waste water at the same time. These networks, now silted and overburdened, are not able to carry off water. Hammamlif wave is characterized by a run up in the order of 2.50 m (Doctoral thesis, Abir Baklouti). This value causes a major problem for the low zone of the area. The suggested solutions according to our study are to strengthen the drainage networks and even the construction of a new water purification station and the removal of the existing breakwaters because they are badly designed. Instead, we should apply an artificialy recharged beach and the solution of a submerged geotextile artificial reef to fight against wave action in the area. Applying these major solutions requires a geotechnical study of the Hammamlif area which is the subject matter of this paper. This article aims to present the geotechnical study of the site to come out with specific recommendations on the reserved land to be used as support for future studies and provide various foundation designs for different structures planned in the Hammamlif area.

Resume Introduction L’anemie de Fanconi (AF) est une maladie hereditaire caracterisee par une heterogeneite genetique et phenotypique. De nombreux groupes ont mis en place des registres propres a leur pays. En Tunisie, le groupe tunisien d’etude de l’AF (GETAF) a cree le registre tunisien de l’AF « TFAR ». Patients et methodes Tous les services d’hematologie et de pediatrie de Tunisie ont ete contactes pour inclure leurs malades diagnostiques entre janvier 1983 et decembre 2008. Le registre TFAR a ete integre dans le site web du groupe GETAF a l’adresse : www.fanconi-tunisie.net . Resultats Le tri des fiches a permis de retenir 142 patients appartenant a 118 familles. L’âge median de diagnostic etait de 11 ans. Une consanguinite etait notee dans 86 % des cas, un syndrome malformatif dans 91 %, une pancytopenie au moment du diagnostic dans 69 %. Parmi 28 patients, 95 % appartenaient au groupe FANCA. Cent neuf patients etaient traites par androgenes et 27 avaient eu une allogreffe de moelle osseuse geno-identique. Un syndrome myelodysplasique (SMD) avait ete diagnostique dans 4 % des cas, une leucemie aigue (LA) dans 6 % et une tumeur solide dans 2 % des cas. L’âge median de survie etait de 17 ans et 5 mois, il etait significativement meilleur chez les patients allogreffes. Conclusion L’AF parait frequente en Tunisie. L’atteinte hematologique est la circonstance de decouverte la plus frequente. Elle est souvent moderee ou severe et necessite un traitement par androgenes ou allogreffe de moelle osseuse. Celle-ci devrait concerner tous les patients ayant un donneur familial HLA-compatible.

We report a case of autoimmune polyglandular syndrome type II that developed in an 11-year-old boy with homozygous sickle cell disease after allogeneic bone marrow transplant; the donor was his father, who was human leukocyte antigen identical and had vitiligo. On day 24 after transplant, the patient developed grade 1 acute graft-versus-host disease, which was controlled over a period of 3 months with corticosteroid-induced immunosuppression. Full donor engraftment was documented on day 31 after transplant, and this was further confirmed on days 59, 231, 321, 472, 549, and 720. Three months after transplant, the recipient developed adrenal insufficiency, and at 13 months, he developed vitiligo. Seventeen months after transplant, autoimmune thyroid disease, positive for thyroid peroxidase and thyroglobulin autoantibodies, was diagnosed. At the same time, we identified adrenal insufficiency in the donor. We analyzed a serum sample from the recipient for autoantibody markers for type 1 autoimmune diabetes mellitus. The sample was positive for antiglutamic acid decarboxylase. Antibody against 21-hydroxylase enzyme was also found (261 U/mL; normal value, < 1 U/mL). We conclude that the recipient developed autoimmune polyglandular syndrome type II after bone marrow transplant from his father, who was probably affected by the same syndrome.

The study of inbred populations has contributed remarkably to the description of new autosomal recessive primary immunodeficiencies (PIDs). Here, we examine the pattern of PIDs in North African populations and assess the impact of highly prevalent consanguinity. This review reports on the current status of pediatricians' awareness of PIDs in Egypt, Morocco, and Tunisia, where awareness of PIDs is relatively recent. The phenotypic distribution of PIDs is reported and compared among the three countries and with other populations. Data analysis reveals a prevalence of autosomal recessive forms and a peculiar distribution of major PID categories, particularly more combined immunodeficiencies than antibody disorders. In these endogamous communities, molecular diagnosis is critical to developing a genetic-based preventive approach. The organization of diagnosis and care services in these resource-limited settings faces many obstacles. Autosomal recessive PIDs are overrepresented; thus, it is critical to continue investigation of these diseases in order to better understand the underlying mechanisms and to improve patient care.