The World Psychiatry Exchange Program in Iran: a unique academic and personal experience.

The World Psychiatry Exchange Program in Iran is an academic experience we are delighted to share. As two participating early career psychiatrists, a local psychiatry faculty member manager, and the lead founder and international coordinator of the programme, we focus in this article on the unfolding of this new learning experience, the difficulties we encountered and the main lessons learned by the participants: commonalities and differences in training and practice in general adult psychiatry and child psychiatry in Tunisia and Iran, as well as in idioms of distress between the Arab and Persian cultures.

Leishmania infantum 5'-Methylthioadenosine Phosphorylase presents relevant structural divergence to constitute a potential drug target.

BACKGROUND: The 5'-methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and polyamine metabolism and in the methionine salvage pathway, is considered as a potential drug target against cancer and trypanosomiasis. In fact, Trypanosoma and Leishmania parasites lack de novo purine pathways and rely on purine salvage pathways to meet their requirements. Herein, we propose the first comprehensive bioinformatic and structural characterization of the putative Leishmania infantum MTAP (LiMTAP), using a comparative computational approach. RESULTS: Sequence analysis showed that LiMTAP shared higher identity rates with the Trypanosoma brucei (TbMTAP) and the human (huMTAP) homologs as compared to the human purine nucleoside phosphorylase (huPNP). Motifs search using MEME identified more common patterns and higher relatedness of the parasite proteins to the huMTAP than to the huPNP. The 3D structures of LiMTAP and TbMTAP were predicted by homology modeling and compared to the crystal structure of the huMTAP. These models presented conserved secondary structures compared to the huMTAP, with a similar topology corresponding to the Rossmann fold. This confirmed that both LiMTAP and TbMTAP are members of the NP-I family. In comparison to the huMTAP, the 3D model of LiMTAP showed an additional α-helix, at the C terminal extremity. One peptide located in this specific region was used to generate a specific antibody to LiMTAP. In comparison with the active site (AS) of huMTAP, the parasite ASs presented significant differences in the shape and the electrostatic potentials (EPs). Molecular docking of 5'-methylthioadenosine (MTA) and 5'-hydroxyethylthio-adenosine (HETA) on the ASs on the three proteins predicted differential binding modes and interactions when comparing the parasite proteins to the human orthologue. CONCLUSIONS: This study highlighted significant structural peculiarities, corresponding to functionally relevant sequence divergence in LiMTAP, making of it a potential drug target against Leishmania.

Primary adrenal lymphoma.

Primary non-Hodgkin's lymphoma of the adrenal gland is rare. We report the case of a 56-year-old patient suffering from B symptoms. The CT scan showed a bilateral adrenal mass without any lymph nodes. Scan-guided biopsies led to the diagnosis of diffuse large B-cell lymphoma. The medullar biopsy eliminated a secondary lymphoma. The patient was treated by immunochemotherapy with a complete response before autologous stem cell transplantation.

High frequency of exon 15 deletion in the FANCA gene in Tunisian patients affected with Fanconi anemia disease: implication for diagnosis.

Tunisian population is characterized by its heterogeneous ethnic background and high rate of consanguinity. In consequence, there is an increase in the frequency of recessive genetic disorders including Fanconi anemia (FA). The aim of this study was to confirm the existence of a founder haplotype among FA Tunisian patients and to identify the associated mutation in order to develop a simple tool for FA diagnosis. Seventy-four unrelated families with a total of 95 FA patients were investigated. All available family members were genotyped with four microsatellite markers flanking FANCA gene. Haplotype analysis and homozygosity mapping assigned 83 patients belonging to 62 families to the FA-A group. A common haplotype was shared by 42 patients from 26 families at a homozygous state while five patients from five families were heterozygous. Among them, 85% were from southern Tunisia suggesting a founder effect. Using multiplex ligation-dependent probe amplification (MLPA) technique, we have also demonstrated that this haplotype is associated with a total deletion of exon 15 in FANCA gene. Identification of a founder mutation allowed genetic counseling in relatives of these families, better bone marrow graft donor selection and prenatal diagnosis. This mutation should be investigated in priority for patients originating from North Africa and Middle East.

Treatment of Acute Promyelocytic Leukemia with AIDA Based Regimen. Update of a Tunisian Single Center Study.

In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens combining ATRA and an anthracycline with cytarabine (APL93), and without cytarabine (LPA99). From 2004, 51 patients with confirmed APL either by t(15;17) or PML/RARA were treated according to the PETHEMA LPA 99 trial. Forty three patients achieved CR (86%). The remaining seven patients had early death (one died before treatment onset): four caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Multivariate analysis revealed that female gender (P=0.045), baseline WBC> 10 G/L (P=0.041) and serum creatinine > 1.4mg/dl (P=0.021) were predictive of mortality during induction. DS was observed in 16 patients (32%) after a median onset time of 15 days from treatment onset (range, 2-29). Body mass index ≥ 30 (P=0.01) remained independent predictor of DS. Occurrence of hypertensive peaks significantly predicted occurrence of DS (P=0.011) and was significantly associated with high BMI (p=0.003). With a median follow-up of 50 months, 5 year cumulative incidence of relapse, event free and overall survival were 4.7%, 74% and 78%, respectively.

Risk factors of septic shock in patients with hematologic malignancies and Pseudomonas infections.

Pseudomonas is a clinically significant and opportunist pathogen, usually associated in causing high mortality nosocomial infections. The aim of this study was to determine the risk factors associated with septic shock in patients diagnosed with hematologic malignancies and Pseudomonas infections. A total of 80 Pseudomonas isolates (77 Pseudomonas aeruginosa) were collected from 66 patients aged 2-64 years: 52 with acute leukemia (79%), 7 with lymphoma (10.5%), and 7 with other hematologic disorders (10.5%), between 2001 and 2009. The median age of the patients was 30 years. Isolates were collected mostly from bloodstreams (45%) and skin lesions (31.5%). The median time for microbiologic documentation was 8 days (range 0-35 days) from onset of neutropenia. At least 11 patients (16.6%) had recurrent (≥2) infections. The clinical symptoms observed were skin lesions (34%), diarrhea (20%), isolated fever (18%), and respiratory symptoms (14%). The isolates tested were found resistant to piperacillin/tazobactam (43%), ceftazidime (31%), imipenem-cilastatin (26%), ciprofloxacin (25%), and amikacin (26%). Septic shock occurred in 16.2% of episodes (13/80). Crude mortality due to septic shock occurred in 19.6% of patients (13/66). The median time for response to antibiotic therapy in the remaining 80.4% of patients (53/66) was 2.5 days. Univariate analysis revealed that factors associated with septic shock were: fever for ≥3 days in patients on antibiotic therapy (P = 0.019), serum lactate >5 mmol (P = 0.05), hemoglobin level <50 g/l (P = 0.042), hypoproteinemia <50 g/l (P = 0.01), procalcitonin >10 ng/ml (P = 0.031), and hypophosphatemia (P = 0.001). Multivariate analysis revealed that hypophosphatemia (P = 0.018), hypoproteinemia (P = 0.028), and high serum lactate (P = 0.012) are significant factors, independently associated with increased risk of septic shock in patients with hematologic malignancies and Pseudomonas infections.

ATRA and anthracycline-based chemotherapy in the treatment of childhood acute promyelocytic leukemia (APL): A 10-year experience in Tunisia.

Reports on childhood APL from developing countries are scarce. We treated 65 APL with two consecutive trials combining ATRA and chemotherapy. Twenty (30.7%) were aged less than 20 years including 11 girls and 9 boys, with a median age of 12 years. Fever at presentation (P=0.002) and variant APL (P=0.044) were more frequent in children, while there were no significant difference between children and adults for WBC count, Sanz's score distribution and additional cytogenetic abnormalities. The CR rate was 95% (19/20) in children and 80% (36/45) in adults (P=0.13). Differentiation syndrome (DS) was less often observed in children (1/20) than in adults (13/45) (P=0.031). Two children relapsed and died during salvage therapy, and 2 died in CR from infection and from cardiac failure attributed to anthracyclines, while other children remained alive in CR. With a median follow-up of 4 years, 4-year EFS was 75% in children and 71.1% in adults (P=0.57), while 4-year OS was 75% in children vs. 73.3% in adults (P=0.72). Our results suggest that, even in the absence of optimal socio-economic condition, ATRA combined with anthracycline-based chemotherapy gives adequate results in childhood APL, as in adults.

[Dysfibrinogenemia and thrombosis. A case report]. / Association dysfibrinogénémie et thrombose. A propos d'un cas.

BACKGROUND: Congenital dysfibrinogenemia is a functional disorder of the fibrinogen that represents a rare cause of thrombophilia. AIM: To report a Tunisian case of the association dysfibrinogenemia and thrombosis. CASE: A woman with inherited dysfibrinogenemia associated with mild tendency to bleeding experienced a deep vein thrombosis of the lower-extremity at 26 years of age and a fatal pulmonary embolism a few years later. Paradoxically coagulation function of fibrinogen was markedly altered in vitro with a significantly prolonged prothrombin time, activated partial thromboplastin time and thrombin time, a functional fibrinogen level that was undetected and a severely impaired fibrin polymerisation. The thromboembolic events in the patient could be related to dysfibrinogenemia since the main causes of thrombophilia were excluded. CONCLUSION: Although it is rare, this cause of thrombophilia must not be misdiagnosed, systematic measuring of prothrombin time, activated partial thromboplastin time and functional fibrinogen might be helpful.

Factors associated with severe sepsis: prospective study of 94 neutropenic febrile episodes.

Severe sepsis defined as infection-induced organ dysfunction or hypoperfusion abnormalities predispose to septic shock and increased mortality in neutropenic setting. We aimed at determining predictors of severe sepsis in neutropenic patients. Between 1 October and 31 December 2007, 41 patients (21 with acute myeloid leukemia, 19 with acute lymphoid leukemia and one with autologous stem cell transplantation for a mantle cell lymphoma) with chemotherapy-induced neutropenia (<0.5 x 10(9)/l) lasting for more than 7 days were included in this study. The median age was 28 years (range: 3-58 years). All patients were on oral antibacterial (colistin and gentamicin) and anti-fungal (amphotericin B) prophylaxis. The first neutropenic febrile episode was treated with piperacillin/tazobactam and colistin IV; if the patient remains febrile at 48 h from the start of this first line of treatment, amphotericin B i.v. is added. Imipenem was introduced in the case of non-response and finally glycopeptides were introduced according to the IDSA criteria. Severe sepsis and septic shock are defined according to the criteria of the consensus conference of the ACCP/SCCM excluding the leukocyte count since all the patients were neutropenic. Ninety-four febrile episodes were observed: 27 microbiologically documented (28.7%), six clinically documented (6.3%) and 61 fever of unknown origin (65%). Microbiologically documented infections were: 13 Gram-negative organisms, 11 Gram-positive organisms and three combined (Gram+ and -). Clinically documented infections were pneumonia (two), neutropenic enterocolitis (one), sinuses infection (one) and cutaneous infection (two). Severe sepsis accounted for 22 febrile episodes. Factors associated with the occurrence of severe sepsis were: hypophosphatemia (<0.8 mmol/l; p=0.05, OR=3.9, 95% CI: 1.3-45.7), hypoproteinemia (<62 g/l; p=0.006, OR=4.1, 95% CI: 1.4-11.4) and non-adapted antibiotherapy at the onset of severe sepsis (p=0.019, OR=2.7, 95% CI: 1.02-7.39). However, heart rate/systolic blood pressure ratio <1.1 (p<0.001, OR=0.1, 95% CI: 0.03-0.31) and Creactive protein <80 mg (p=0.001, OR=0.14, 95% CI: 0.04-0.54) were not predictive.

Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia.

BACKGROUND: The combination of all-trans-retinoic acid (ATRA) and chemotherapy has made acute promyelocytic leukemia (APL) a highly curable leukemia. However, several complications are reported with this treatment the most serious and life threatening being Retinoic Acid Syndrome (RAS). We aimed at identifying factors that could predict complications caused by ATRA during induction treatment of APL. PATIENTS: Forty-two patients with confirmed APL (by t(15;17) and/or PML/RARA) treated at our institution (University hospital of Tunis) between January 1998 and June 2006 using two consecutive protocols: European APL93 trial (24 patients) until February 2004 and Spanish PETHEMA LPA99 trial (18 patients) more recently. Induction regimen consisted of ATRA 45 mg/m(2)/d until CR combined to DNR 60 mg/m(2)/d x 3+Cytarabine 200 mg/m(2)/d x 7 (APL93) and Idarubicin 12 mg/m(2) d2, 4, 6, 8 (LPA99). Prednisone (0.5 mg/kg d1-d15) was added if WBC >10 x 10(9)/L to prevent RAS in LPA 99. RESULTS: Median age was 36 yr (7-64 yr), M/F=16/26 (0.61), median WBC was 2.4 x 10(9)/L (range 0.6-100 x 10(9)/L). WBC >10 x 10(9)/L was noted in 14 patients (33%). Additional cytogenetic abnormalities were seen in 12/42 (28%). Median body mass index (BMI=weight/height(2):N 20-25) was 24 kg/m(2) (range 16-40 kg/m(2)), BMI >30 was noted in nine patients (8F and 1M). Thirty-three patients achieved CR (78.57%):18/24 (75%) in APL93 versus 15/18 (83%) in LPA99. Nine patients (21.42%) had early death. Causes of early death were: RAS (6) and CNS hemorrhage (3). Complications due to ATRA were: RAS (10), Scrotal ulcerations (3), Sweet syndrome (2), Perineal ulcerations (1), and Pseudotumor cerebri (1). Prognostic factors for complications of ATRA (Fisher exact test) were: BMI >35 (p=0.055), induction treatment without cytarabine (LPA99 trial) (p=0.047), whereas age (p=0.74), gender (p=0.51), initial WBC (p=0.47), and additional cytogenetic abnormalities (p=0.83) were not predictive. Retinoic Acid Syndrome was more reported in patients with initial WBC >10 x 10(9)/L (p=0.08). CONCLUSION: We found high BMI (>35) in female and treatment without Cytarabine to increase the risk of developing complications with ATRA.

[Hemoglobin C disease: report of 16 Tunisian cases]. / L'hemoglobinose C: a propos de 16 cas Tunisiens.

AIM: was to provide the clinical and biological patterns hemoglobine disease in Tunisia. METHODS: This retrospective study collected to 16 cases of hemoglobin C disease : 6 homozygotic Hb C and 10 heterozygotic Hb C/beta-thalassemia. RESULTS: The clinical profile is characterized by mild hemolytic anemia (Hb = 11.7 g/dl) associated with splenomegaly and hypersplenism. Contrary to homozygous state, the Hb C/beta-thalassemia is associated with microcytosis and pseudopolycythemia. The diagnosis is based on target cells, specific intraerythrocytic Hb C crystals in blood smear and Hb C level at 100%. CONCLUSION: The Hb C disease must be considered as a benign hemoglobinopathy which is associated with a long survival without major complications.

[Tumor lysis syndrome]. / Syndrome de lyse tumorale.

Tumor lysis syndrome is a potentially life threatening oncologic emergency that requires immediate medical intervention. The syndrome results from the destruction (or lysis) of a large number of rapidly dividing malignant cells spontaneously or during chemotherapy. The resulting metabolic abnormalities include hyperkaliemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia, all of which put patients at risk for renal failure and alteration in cardiac function. The tumor lysis syndrome occurs most often in patients with large tumor burdens that are very sensitive to chemotherapy and radiotherapy, such as acute or chronic leukaemias with high leukocyte counts and high-grade lymphoma. The current standard management for tumor lysis syndrome consists of allopurinol or recombinant urate oxidase for high risk patient in conjunction with i.v. hydratation with or without alkalinization.

[Cytology and immunophenotype feautures of 80 acute myeloid leukemia]. / Caracteristiques cytologiques et immunophenotypiques de 80 leucemies aigues myeloides.

Acute myeloid leukemia (AML)'s diagnosis is clinical and biological. We report here 80 AML with cytology and immunophenotype features to establish correlations. 21 AML1, 23 AML2, 12 AML3, 2 AML4, 18 AML5 and 3 AML6 were diagnosed by cytology. Only one case of AML0 was diagnosed by immunophenotype. Myelogysplasia is present in 29.8% cases. CD19 and CD56 expression was significantly associated to AML +t(8;21). Additionally, concomitant negativity of CD34 and HLA-DR was discrimininatif to AML3 diagnosis. Prognostic value to expression some CD needs time backwards.

Megaloblastic anemia in North Africa.

We prospectively studied 478 patients with megaloblastic anemia living in Tunisia. Overall, 98% of patients had vitamin B12 deficiency. Pernicious anemia accounted for most of these cases, and median age at presentation was 45 years. Megaloblastic anemia occurred in 19 subjects under 15 years of age, and of these, nine had the Immerslund-Graesbeck syndrome.

[Therapeutic results with apl 93 protocol in acute promyelocytic leukemia (34 cases)]. / Resultats therapeutiques dans les leucemies aigues promyelocytaires (34 cas).

BACKGROUND: Acute promyelocytic leukaemia (APL) account for approximately 10% to 15% of all AML in most reports. Clinical features includes the presence in 80% to 90% of patients of a severe hemorrhagic syndrome, a specific balanced translocation between chromosomes 15 and 17 with a fusion of a large pert of the retinoic acid receptor a gene (RARa) on chromosome 17 to a part of the promyelocytic leukaemia (PML) gene on chromosome 15. More than 75% of patients (under 65 years of age) can be cured, with the application of a combination of anthracyclines and all-trans retinoic acid (ATRA), followed by maintenance therapy. AIM: of the study was to assess of the therapeutic management of APL 93 protocol in acute promyelocytic leukemia. METHODS: We present here the results of a retrospective study concerning 34 patients with APL included between 1998 and 2004 in the APL 93 protocol : 20 in group B and 14 in group C. CR was 82 %. RESULTS: Failure is only due to toxic death (18%) Event free survival at 4 years is 63,47% with relapse rate at 14.25%. Overall survival at 4 years is 69,72%. Our results are acceptable and can be improved with reduction of failure due to toxic death, probably with omission of cytarabine from induction and consolidation adapted by the Spanish PETHEMA Group.

[Pseudotumor cerebri with all-trans retinoic acid. A case report]. / Pseudotumeur cerebrale secondaire au traitement par l'acide transretinoïque. A propos d'un cas.

The diagnosis of pseudotumor cerebri (PC) is based on the triad of: (1) papilledema, (2) elevated intracranial pressure with a normal cerebrospinal constituency and (3) normal central nervous system imaging studies. It is an uncommon complication of all-trans-retinoic acid (ATRA) therapy in children treated for acute promyelocytic leukaemia (APL). Its occurrence is rare among adult patients with APL and treated with ATRA . We report a case of an adult with APL who developed PC during induction therapy with ATRA-PC was managed with repeated lumbar punctures and corticotherapy.