Occurrence of Hypopituitarism in Tunisian Turner Syndrome patients: familial versus sporadic cases.

OBJECTIVE: To explore unusual association between Turner Syndrome (TS) and Hypopituitarism in a Tunisian cohort. METHODS: We reported 6 patients with TS associated to Hypopituitarism, including three familial cases except the fourth sister who showed only a TS phenotype. Biochemical analysis, resonance magnetic imaging and cytogenetic analyses were performed. RESULTS: The average age of our patients was 17.2 years (11-31 years). They were all referred for short stature and pubertal delay, except for the fourth sister who presented spontaneous puberty with the integrity of the pituitary axis and the presence of an X ring chromosome. Karyotype analysis showed monosomy in 3 cases and a mosaic TS in the 3 remaining cases, including one patient with abnormal X chromosome structure. Somatotropic and corticotropic deficiencies were confirmed in 2 sporadic cases while the gonadotropic and thyrotropic axes were spared. In contrast; familial cases were consistently affected by the integrity of the corticotropic axis. MRI showed pituitary hypoplasia in all familial cases and pituitary stalk interruption syndrome in only one sporadic case. No correlation was found between the chromosome formula and the anterior pituitary involvement. CONCLUSION: Co-segregation of congenital Hypopituitarism with pituitary hypoplasia and X chromosome aberrations could imply a molecular anomaly of transcription factors responsible for the differentiation and development of pituitary cells such as PROP1, POUF1, Hesx1, Lhx3, Lhx4. The etiopathogenic link between X chromosome abnormalities and the occurrence of Hypopituitarism remains unclear; however, the progress of molecular biology may clarify the interrelation between transcription factors and sex chromosome segregation abnormalities.

Adipose tissue inflammation in glucose metabolism.

Obesity is now recognised as a low grade, chronic inflammatory disease that is linked to a myriad of disorders including cancer, cardiovascular disease and type 2 diabetes (T2D). With respect to T2D, work in the last decade has revealed that cells of the immune system are recruited to white adipose tissue beds (WAT), where they can secrete cytokines to modulate metabolism within WAT. As many of these cytokines are known to impair insulin action, blocking the recruitment of immune cells has been purported to have therapeutic utility for the treatment of obesity-induced T2D. As inflammation is critical for host defence, and energy consuming in nature, the blockade of inflammatory processes may, however, result in unwanted complications. In this review, we outline the immunological changes that occur within the WAT with respect to systemic glucose homeostasis. In particular, we focus on the role of major immune cell types in regulating nutrient homeostasis and potential initiating stimuli for WAT inflammation.

Targeting gp130 to prevent inflammation and promote insulin action.

Obesity and type 2 diabetes are now the most prevalent metabolic diseases in the Western world and the development of new strategies to treat these metabolic diseases is most warranted. Obesity results in a state of chronic low-grade inflammation in metabolically active tissues such as the liver, adipose tissue, brain and skeletal muscle. Work in our laboratory has focussed on the role of the cytokine interleukin-6 (IL)-6 and other IL-6-like cytokines that signal through the gp130 receptor complex. We have focussed on the role of blocking IL-6 trans-signalling to prevent inflammation on the one hand, and activating membrane-bound signalling to promote insulin sensitivity on the other hand. Since the cloning of the IL-6 gene nearly 30 years ago, a pattern has emerged associating IL-6 with a number of diseases associated with inflammation including rheumatoid arthritis (RA), Crohn's disease and several cancers. Accordingly, tocilizumab, an IL-6 receptor-inhibiting monoclonal antibody, is now useful for the treatment of RA. However, this may not be the most optimal strategy to block inflammation associated with IL-6 and may result in unwanted side effects that, paradoxically, could actually promote metabolic disease.

[Relevance of plasma exchange in the treatment of myasthenia gravis: study of 11 cases]. / Apport des échanges plasmatiques dans le traitement de la myasthénie: étude de 11 cas.

BACKGROUND: The use of plasma exchange (PE) constituted an advance in the treatment of myasthenia. The objective of our study was to determine the relevance of PE in the treatment of myasthenia and to study the different complications which can be observed during PE. PATIENTS AND METHODS: We studied retrospectively 11 patients who have generalized myasthenia and underwent PE. We used an intermittent flow cell separator and we performed PE three times a week. Biological assessment was performed before and after PE for all patients. The exchange volume was calculated according to the patient weight, gender and the value of hematocrit. RESULTS: Our series included six women and five men. The mean age at onset of the disease was 41.4+/-14.1 years (range: 18 to 68). Indication of PE was myasthenia crisis (eight cases), resistance to classic treatment (two cases) and exacerbation after thymectomy (one case). An improvement was observed rapidly in five cases and delayed in three cases. The remaining three patients did not improve. The most frequent side effects of PE were hypotension (four cases), heart arrhythmia (two cases) and hypoglycemia (one case). Three patients dead in the seven days after the first PE. CONCLUSION: PE represents an interesting tool to treat severe forms of myasthenia and improve prognosis. High incidence of complications in our series can be explained by the initial disease severity, the used method of PE, the existence of associated illness, and a long stay in intensive care unit.

Evidence against a role for NLRP3-driven islet inflammation in db/db mice.

OBJECTIVES: Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1ß (IL-1ß) have been implicated in pancreatic ß cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic ß cell death could allow for selective T2D treatment without compromising all IL-1ß-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic ß cell death, thereby preventing the onset of T2D. METHODS: Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic ß cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention. RESULTS: MCC950 was a potent inhibitor of NLRP3-induced IL-1ß in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1ß. CONCLUSIONS: NLRP3 driven-pancreatic IL-1ß inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

[Autosomal recessive renal tubular dysgenesis: morphologic and genetic study of 2 cases]. / Dysgénésie tubulaire rénale autosomique récessive: étude morphologique et génétique de 2 nouveaux cas.

Renal tubular dysgenesis (RTD) is a rare and severe nephropathy characterized by persistent fetal anuria leading to oligohydramnios with the Potter sequence, and perinatal death. The diagnosis is based on the histological finding of absence or paucity of proximal tubules. A consanguineous family is described in which 2 siblings, born after pregnancies complicated by oligohydramnios were affected with RTD. Patients were small for gestational age at birth. The first patient died after a few hours, the second after a few days of life, with persistent anuria unresponsive to treatment. Histologically, there was marked reduction in the number of proximal tubule sections and no renin was detected by immunohistochemistry. An homozygous mutation of the gene encoding renin was identified in both patients. This study underlines the interest of the histological examination of the kidney for the diagnostic of RTD in anuric fetuses and newborns, and the possibility of mutation analysis of RAS genes for genetic counselling and early prenatal diagnosis.

Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation.

Essentials Vessel stenosis due to large thrombus formation increases local shear 1-2 orders of magnitude. High shear at stenotic sites was exploited to trigger eptifibatide release from nanocapsules. Local delivery of eptifibatide prevented vessel occlusion without increased tail bleeding times. Local nanocapsule delivery of eptifibatide may be safer than systemic antiplatelet therapies. SUMMARY: Background Myocardial infarction and stroke remain the leading causes of mortality and morbidity. The major limitation of current antiplatelet therapy is that the effective concentrations are limited because of bleeding complications. Targeted delivery of antiplatelet drug to sites of thrombosis would overcome these limitations. Objectives Here, we have exploited a key biomechanical feature specific to thrombosis, i.e. significantly increased blood shear stress resulting from a reduction in the lumen of the vessel, to achieve site-directed delivery of the clinically used antiplatelet agent eptifibatide by using shear-sensitive phosphatidylcholine (PC)-based nanocapsules. Methods PC-based nanocapsules (2.8 × 1012 ) with high-dose encapsulated eptifibatide were introduced into microfluidic blood perfusion assays and into in vivo models of thrombosis and tail bleeding. Results Shear-triggered nanocapsule delivery of eptifibatide inhibited in vitro thrombus formation selectively under stenotic and high shear flow conditions above a shear rate of 1000 s-1 while leaving thrombus formation under physiologic shear rates unaffected. Thrombosis was effectively prevented in in vivo models of vessel wall damage. Importantly, mice infused with shear-sensitive antiplatelet nanocapsules did not show prolonged bleeding times. Conclusions Targeted delivery of eptifibatide by shear-sensitive nanocapsules offers site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.

Unusual association of turner syndrome and hypopituitarism in a Tunisian family.

PURPOSE OF THE STUDY: Familial occurrence of either Turner syndrome or hypopituitarism is very rare. Particularly, their association is an uncommon finding. In this context, we describe for the first time 4 sisters with Turner syndrome, hypopituitarism was reported in three among them. PATIENTS AND METHODS: Our cohort consists of four Tunisian adult sisters belonging to a consanguineous family. Biochemical analysis, resonance magnetic imaging and cytogenetic analyses were performed. RESULTS: Turner syndrome was diagnosed at the ages of 14, 17, 31 and 43 years in cases 1, 2, 3 and 4 respectively. They suffered from short stature, dysmorphic syndrome and/or delayed puberty. Interestingly, 3 among them showed also hypopituitarism, hypogonadotrophic hypogonadism and central hypothyroidism. Somatotropic insufficiency was proven in one case. Pituitary MRI has shown an empty sella turcica with hypoplastic pituitary gland in three cases. Their karyotypes were compatible with 45X in one case, 45X/46XX in the second and 45X/46XX/47XXY with x label in two cases. CONCLUSION: Hence, the presence of these familial cases of TS must evoke new etiopathogenetic arguments. Coincidence of hypopituitarism in this family, might suggest common genetic background for the two diseases. This particular family would be a precious tool for an extensive molecular analysis. More attention should be given to other family's members mainly in the presence of delayed puberty and sterility in other members.

PKR is not obligatory for high-fat diet-induced obesity and its associated metabolic and inflammatory complications.

Protein kinase R (PKR) has previously been suggested to mediate many of the deleterious consequences of a high-fat diet (HFD). However, previous studies have observed substantial phenotypic variability when examining the metabolic consequences of PKR deletion. Accordingly, herein, we have re-examined the role of PKR in the development of obesity and its associated metabolic complications in vivo as well as its putative lipid-sensing role in vitro. Here we show that the deletion of PKR does not affect HFD-induced obesity, hepatic steatosis or glucose metabolism, and only modestly affects adipose tissue inflammation. Treatment with the saturated fatty acid palmitate in vitro induced comparable levels of inflammation in WT and PKR KO macrophages, demonstrating that PKR is not necessary for the sensing of pro-inflammatory lipids. These results challenge the proposed role for PKR in obesity, its associated metabolic complications and its role in lipid-induced inflammation.

[Tuberculosis prevention]. / Prévention de la tuberculose.

UNLABELLED: Tuberculosis prevention is classically based on early detection of potential contagious cases and their effective treatment. But due to new parameters such as migration flows around the world, the emergence of Mycobacterium tuberculosis resistant strains and the increase of the population at risk, screening should be more active and target those who are more vulnerable to developing the disease. Traditional screening methods such as chest X-ray and tuberculin skin test, due to their high sensitivity and low cost, remain valid especially in populations with a high prevalence of the disease. The interferon-gamma release assays (IGRAs) seem to be very useful in immunodeficient patients with prior BCG vaccination. The treatment of subjects at high risk of developing active tuberculosis with a daily isoniazid self-administrated dosage for a period of 9 months is a prevention measure not only at the individual level but also at the collective one. All prevention interventions should be part of a national program concordant with the guidelines of the WHO Stop TB program that recommend a universal access to quality diagnosis and treatment focused on the patient. OUTLOOK: New methods of detection based on gene amplification would better suit to detect tuberculosis in immunodeficient patients and identify treatment-resistant strains. The development of the third part of the Stop TB project would reduce the morbidity and mortality of this disease by 2025. CONCLUSION: The prevention of tuberculosis has been a major epidemiological challenge around the world and is continuously improving to adapt to the evolving disease.

[Dermoid cysts: epidemiological, clinical and pathological studies]. / Kystes dermoïdes: études épidémiologique, clinique et anatomopathologique.

We retrospectively analyzed 31 cases of dermoid cysts surgically treated between January 1992 and October 2000. Mean patient age was 18.9 years. The preseptal localization predominated, with 29 cases. Two cases of intraorbital localization required orbitotomy. The surgical result was excellent.

[Epidemiologic aspects of common gastrointestinal food toxin infections in the Bizerte region based on surveillance center analyses from 1994 to 1999]. / Particularités épidémiologiques des toxi-infections alimentaires collectives (T.I.A.C.) dans la région de Bizerte à travers l'analyse des foyers déclares de 1994 à 1999.

The Common Food Toxin Infections has been subject of constant and exhaustive supervision watch over since 1994 in Bizerta. 77 centers in total has been recorded during the six last years (1994 to 1999) and have shown 738 patients. The evolution of incidental rate declared has been considered by annual fluctuations with extreme rates as 11.2 for 10,000 inhabitants in 1995 and 41.5 for 10,000 inhabitants in 1999. The classic season peak each year, and so 58.4% of centers has been notified during the months of July, August and September. The average size of centers is 9.5 persons with an extension of 02 to 40 persons. One death has been deplored a weak spreading rate of 0.14%. The hospitalization recommended for 106 patients (14.4%). About three quarters of the centers has been concerned by the familial. The cooked food is being at the top of contaminating food (49.3%).

[Acquired ptosis in allergic blepharoconjunctivitis in children and adolescents]. / Le ptosis acquis dans la blépharoconjonctivite allergique chez l'enfant et l'adolescent.

Acquired ptosis is a common ophthalmologic problem. It is in the large majority of cases aponeurotic and occurs in the elderly as an involutional disorder or after ophthalmic surgery. In younger patients, it may occur after ocular trauma, periocular infection, contact lens wear, or palpebral edema. Allergic blepharoconjunctivitis is an unsuspected cause of acquired ptosis. Our study investigated patients (5 to 15 years old) with a history of allergic blepharoconjunctivitis and having a unilateral or bilateral ptosis. Physiopathological hypotheses are discussed. Management of acquired ptosis is presented.

Descriptive analyses of Turner syndrome: 49 cases in Tunisia.

Turner syndrome is linked to the absence or abnormality of one of the X chromosome leading to haplo-insufficiency of genes involved in the development and maintenance of the ovarian stock in women. We report the results of a 21-year retrospective study, conducted in 49 patients with Turner syndrome. The purpose of this study was to establish the clinical, hormonal, cytogenetic and evolutive pattern of a Tunisian population with Turner syndrome and to search for correlations between genotype and phenotype. The average age of our patients at diagnosis was 14 years (1 day-42 years). Twenty-four percent of them were diagnosed in adulthood (greater than or equal to 20 years). Turner syndrome was diagnosed later in the case of mosaicism (P=0.001). Short stature was present in 85% of cases; it was more frequent among the youngest and monosomics. The dysmorphic syndrome was observed in 85% of cases; it was significantly more frequent in monosomics (P=0.003). Delayed puberty was present in 62.4% of cases, it was almost constant in monosomics (P=0.05). The loss of ovarian function was more severe in case of monosomia compared to other forms (P=0.04). Our results report a high frequency of autoimmune diseases (18/46 cases) including dysthyroidism (eight cases). Hepato biliary affections were more frequent in mosaicism compared to monosomy. The average final height was greater even in mosaicism estimated at 150.5 cm compared to 141 cm in monosomics and 138.8 cm in mosaics with abnormal structures.

Presence of in vivo-activated T-cells expressing HLA-DR molecules and IL-2 receptors in peripheral blood of patients with nasopharyngeal carcinoma.

Epstein-Barr Virus (EBV) is associated with two malignant diseases, African Burkitt's Lymphoma (BL) and Undifferentiated Nasopharyngeal Carcinoma (UNPC). North Africa is a geographical area with a high incidence of NPC. Our purpose in this study was to explore cell-mediated immunity of peripheral blood lymphocytes (PBL) from patients with UNPC and DNPC. We found an elevated percentage of OKT8 cells and of large granular lymphocytes (LGL) (30-35% HNK-I-positive cells) compared to PBL from healthy matched individuals. PBL from NPC patients contained 35% HLA-DR-positive and 30% Interleukin-2 (IL-2) receptor-positive circulating lymphocytes. PBL from NPC patients exhibited a normal proliferative response to phytohemagglutinin (PHA) and Concanavalin A (Con A) and an increased response to pokeweed mitogen (PWM). Natural killer (NK) activity towards K562 cells was low in our patients who, in addition, exhibited no lytic activity against HLA-matched EBV-transformed B cells. This lack of cytotoxicity against an EBV-transformed B-cell line cannot be explained by an impairment of IL-2 secretion, and is probably a result of the presence of high numbers of OKT8 suppressor T cells.

Prenatal diagnosis of chromosome disorders in Tunisian population.

Cytogenetic prenatal diagnosis (PND) is under national health program in most developed countries, while it concerns a small part of population at risk in developing countries. Finance is common reason of absence of PND development, but socio-cultural believes play an important role in Arab Muslim countries. In this paper we report results of 3110 fetal karyotypes carried out in a Tunisian population, by cultured amniocytes analysis. It is the largest report in a Muslim Arab country in our Knowledge. Abnormal karyotypes rate was 4.18% classified in two groups: bad prognosis (3.05%) and good prognosis (1.13%). Common amniocentesis indication was maternal age. The highest predictive value was observed in balanced karyotype and fetal ultrasound findings indications. Maternal serum markers were not commonly used for trisomy 21 screening. Pregnancy termination that is permitted by legal and religious authorities was accepted by 94,74% parents. Information about PND outcomes was given by genetic counselling prior to fetal sampling, pregnancy interruption was discussed with parents at cytogenetic result announcement. The authors conclude that in order to prevent mental and physical handicap related to cytogenetic disorders we have to promote PND by education for population, genetic counselling and fetal ultrasound screening; all three methods available in Tunisia.