[Inherited kidney stones: A nephrology center experience]. / Lithiase urinaire héréditaire : expérience d'un service de néphrologie.

INTRODUCTION: Genetic factors must be considered in etiological diagnosis of urinary lithiasis. The aim of this study was to determine clinical, metabolic characteristics and the progression of hereditary urinary lithiasis in our patients. METHODS: A retrospective study was conducted between 2008 and 2018 and 60 patients were included. Patients were referred to our department from pediatrics departments to be followed-up in adulthood in 9 cases, for etiological investigation in 42 cases and for chronic renal failure in 9 cases. RESULTS: Thirty-five men and twenty-five women were enrolled in this study with a M/F sex ratio equal to 1.4. The mean age at the time of diagnosis of the hereditary character of the urinary lithiasis was 28.6years (3months-63years). The average delay between the onset of the lithiasis disease and the etiological diagnosis was 8years (0-42years). We noted 31 cases of cystinuria, 18 cases of primary hyperoxaluria type 1 with two mutations (I244T in 14 cases, 33-34 Insc in 23 cases) and 11 cases of renal tubulopathy. Fourteen patients were affected with chronic renal failure, of which five were in the end-stage renal disease. Crystalluria was positive in 62% of cases. The morpho-constitutional analysis of stones was performed in 37 cases and it contributed to the diagnosis in 29 cases. After an average follow-up of 16years, we noted normal renal function in 42 cases, chronic renal failure in 7 cases, hemodialysis in 10 cases all with primary hyperoxaluria and transplantation in 1 case. CONCLUSION: The etiological diagnosis of hereditary urinary lithiasis in our study was made with considerable delay. Cystinuria was the most frequent etiology and primary hyperoxaluria was the most serious affection. LEVEL OF EVIDENCE: 4.

[Epigenetics' implication in autism spectrum disorders: A review]. / Implication de l'épigénétique dans les troubles du spectre autistique : revue de la littérature.

BACKGROUND: The etiology of autism spectrum disorders (ASD) is complex and multifactorial, and the roles of genetic and environmental factors in its emergence have been well documented. Current research tends to indicate that these two factors act in a synergistic manner. The processes underlying this interaction are still poorly known, but epigenetic modifications could be the mediator in the gene/environment interface. The epigenetic mechanisms have been implicated in susceptibility to stress and also in the pathogenesis of psychiatric disorders including depression and schizophrenia. Currently, several studies focus on the consideration of the etiological role of epigenetic regulation in ASD. OBJECT: The object of this review is to present a summary of current knowledge of an epigenetic hypothesis in ASD, outlining the recent findings in this field. METHODS: Using Pubmed, we did a systematic review of the literature researching words such as: autism spectrum disorders, epigenetics, DNA methylation and histone modification. RESULTS: Epigenetic refers to the molecular process modulating gene expression without changes in the DNA sequence. The most studied epigenetic mechanisms are those that alter the chromatin structure including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. In ASD several arguments support the epigenetic hypothesis. In fact, there is a frequent association between ASD and genetic diseases whose epigenetic etiologies are recognized. A disturbance in the expression of genes involved in the epigenetic regulation has also been described in this disorder. Some studies have demonstrated changes in the DNA methylation of several autism candidate genes including the gene encoding the oxytocin receptor (OXTR), the RELN and the SHANK3 genes. Beyond the analysis of candidate genes, recent epigenome-wide association studies have investigated the methylation level of several other genes and showed hypomethylation of the whole DNA in brain and blood samples of autistic patients. The changes in epigenetic marks following exposure to environmental factors known as autism risk factors are also discussed in many reports. They include nutritional (vitamin D and folate) and toxic (sodium valproate, bisphenol A) factors. Despite a considerable contribution to understanding the complexity of ASD etiology, the epigenetic studies suffer from numerous methodological biases that limit the scope of their results and make their interpretation difficult. The cell samples used in the psychiatric studies are mostly from the post-mortem tissue of the central nervous system, and factors that might change the epigenome (age, gender, treatments received…) are not taken into account. The use of blood and buccal epithelium samples raises in turn the question as to whether the epigenome of these cells reflects that of the nerve cells. DNA methylation can also be influenced by cell subcomposition variability, transcriptional variability and by DNA sequence variants. CONCLUSION: These recent discoveries in epigenetics are the beginnings of an etiopathogenic research revolution in neurodevelopmental disorders. The conceptualization of epigenetic processes is in its early stages and despite its limited means will help integrate disparate data factors previously involved in autism. It could also be the target for the development of new therapeutic modalities.

Systematic review and meta-analysis: full- vs. half-dose anti-microbials in clarithromycin-based regimens for Helicobacter pylori eradication.

BACKGROUND: Half-dose regimens may be equally effective but associated with diminished adverse events (AE) than standard-dose regimens. AIM: To assess efficacy and safety of full- vs. half-dose clarithromycin in the treatment of H. pylori. METHODS: Medline, EMBASE and PubMed databases were searched for randomised controlled trials (RCTs) that meet eligibility criteria. Only parallel group RCTs with ≥ 2 arms were eligible. Studies comparing triple, quadruple or sequential therapy for 7-14 days were selected. Regimens had to contain the same drug combination, differing only in dosage; the comparison of full- vs. half-dose clarithromycin was required, regardless if other drugs were dose-reduced or not. Data extraction was performed for primary outcome [eradication by intent-to-treat (ITT) and per-protocol (PP) analyses] and secondary outcome (AE). RESULTS: A total of 1622 articles were identified, of which 19 studies were eligible. Overall, eradication was achieved in 82.5% of half-dose (n = 2115) vs. 83.4% of full-dose recipients (n = 2109) on ITT (87.1% vs. 88.4% on PP respectively). Pooled relative risk in the half- vs. full-dose regimen was 0.98 (95% CI: 0.95-1.02) on ITT and 0.99 (95% CI: 0.97-1.01) on PP by the random effects model. Heterogeneity was significant (chi-squared statistic P = 0.05, I(2) = 37%). AE were reported in 29.3% of half- vs. 44.0% of full-dose recipients [pooled RR 0.67 (95% CI: 0.60-0.75)]. Pre-planned subgroup analyses of dose modification, sample size, study origin and treatment duration, as well as sensitivity analysis showed no significant differences between arms. CONCLUSION: A half-dose clarithromycin-based regimen is equally effective yet better tolerated than its full-dose counterpart in the treatment of H. pylori.

The experience of a Tunisian referral centre in prenatal diagnosis of Xeroderma pigmentosum.

AIMS: Xeroderma pigmentosum (XP, OMIM 278700-278780) is one of the most severe genodermatoses and is relatively frequent in Tunisia. In the absence of any therapy and to better manage the disease, we aimed to develop a molecular tool for DNA-based prenatal diagnosis. METHODS: Six consanguineous Tunisian XP families (4 XP-A and 2 XP-C) have benefited from a prenatal diagnosis. Screening for mutations was performed by direct sequencing, while maternal-foetal contamination was checked by genotyping. RESULTS: Among the 7 prenatal diagnoses, 4 foetuses were heterozygous for the screened mutation. Exclusion of contamination by maternal cells was checked. Mutations were detected at a homozygous state in the remaining cases, and the parents decided to terminate pregnancy. CONCLUSION: Our study illustrates the implementation of prenatal diagnosis for better health support of XP in Tunisia.

Characterizing the surface quality and droplet interface shape for microarray plates.

The variation in the surface quality of microarray plates was examined by measuring the contact angles of 480 droplets on five microarray plates. It was found that the measured contact angle did not accurately predict the droplet shape for moderate Bond numbers (~0.5 ≤ N(B) ≤ 5). By defining an apparent contact angle using the ratio of the contact radius to the height, the variance in the predicted interface shape decreased by greater than a factor of 3 for both local and globally averaged characteristics. The error in the predicted droplet height was also reduced by 3 orders of magnitude.

SMG1 and NIK regulate apoptosis induced by Smac mimetic compounds.

Smac mimetic compounds (SMCs) are experimental small molecules that induce tumour necrosis factor alpha (TNFα)-dependent cancer cell death by targeting the inhibitor of apoptosis proteins. However, many cancer cell lines are resistant to SMC-mediated apoptosis despite the presence of TNFα. To add insight into the mechanism of SMC-resistance, we used functional siRNA-based kinomic and focused chemical screens and identified suppressor of morphogenesis in genitalia-1 (SMG1) and NF-κB-inducing kinase (NIK) as novel protective factors. Both SMG1 and NIK prevent SMC-mediated apoptosis likely by maintaining FLICE inhibitory protein (c-FLIP) levels to suppress caspase-8 activation. In SMC-resistant cells, the accumulation of NIK upon SMC treatment enhanced the activity of both the classical and alternative nuclear factor-κB pathways, and increased c-FLIP mRNA levels. In parallel, persistent SMG1 expression in SMC-resistant cells repressed SMC-mediated TNFα-induced JNK activation and c-FLIP levels were sustained. Importantly, SMC-resistance is overcome by depleting NIK and SMG1, which appear to facilitate the downregulation of c-FLIP in response to SMC and TNFα treatment, leading to caspase-8-dependent apoptosis. Collectively, these data show that SMG1 and NIK function as critical repressors of SMC-mediated apoptosis by potentially converging on the regulation of c-FLIP metabolism.

[Polymorphisms of the UDP-glucuronosyltransferase 1-A1 gene in Tunisian population]. / Polymorphismes alleliques du gene UDP-glucuronosyltransferase 1A1 dans une population Tunisienne.

The UDP-glucuronosyltransferase 1A1 gene that encode the enzyme UGT1A1 responsible for glucuronidation undergoes several variations that may affect the enzymatic activity or expression and which are the cause of metabolic disorders related to the glucuronidation of bilirubin, such as Gilbert's syndrome and Crigler Najjar's syndrome. Among the most common variations, there is the repeat polymorphism A (TA) n TAA in TATA box and biallelic mutation G211A in exon 1. We consider in this work to determine their frequencies in a healthy population. The polymorphism A (TA) n TAA showed that genotype [TA7/TA7] was described as being associated with Gilbert's syndrome and was encountered in 11% of the population studied. This percentage is close to the value described in the Caucasian population, estimated at 10%. Concerning the polymorphism G211A, our results show that the mutated allele is encountered in 15.7% of our study population. This frequency differs greatly from that reported for Caucasians and Afro-Americans but it is similar to that perceived at the Japanese. All these results suggest that the Tunisian population appears to be heterogeneous view UGT1A1 gene mutation status. Regarding the origins and distribution of such polymorphisms in our population, the study reveals a high haplotypic haplotype (TA) 6-G considered ancestral. The comparison of the haplotype structure generally leads to the development of a hypothetical tree of the origin and spread of different haplotypes.

An empirically validated analytical model of droplet dynamics in electrowetting on dielectric devices.

Explicit analytical models that describe the capillary force on confined droplets actuated in electrowetting on dielectric devices and the reduction in that force by contact angle hysteresis as a function of the three-dimensional shape of the droplet interface are presented. These models are used to develop an analytical model for the transient position and velocity of the droplet. An order of magnitude analysis showed that droplet motion could be modeled using the driving capillary force opposed by contact angle hysteresis, wall shear, and contact line friction. Droplet dynamics were found to be a function of gap height, droplet radius, surface tension, fluid density, the initial and deformed contact angles, contact angle hysteresis, and friction coefficients pertaining to viscous wall friction and contact line friction. The first four parameters describe the device geometry and fluid properties; the remaining parameters were determined experimentally. Images of the droplet during motion were used to determine the evolution of the shape, position, and velocity of the droplet with time. Comparisons between the measured and predicted results show that the proposed model provides good accuracy over a range of practical voltages and droplet aspect ratios.

[Late revelation of homocysteinuria: clinical, biological and progressive aspects]. / Homocystéinurie à révélation tardive : aspect clinique, biologique et évolutif.

UNLABELLED: Homocysteinuria is a metabolic disorder with defect in genes encoding for methionine metabolism enzymes. The clinical features consist in: ophthalmic, neurological, orthopedic and vascular manifestations. It is generally diagnosed in childhood. Vascular involvements characterize adult's forms. We report one case. OBSERVATION: A 26-year-old man, who has lentis ectopia and a recent epilepsy, was hospitalized for deep vein thrombosis. Regarding the marfanoid phenotype and the high level homocysteinemia (231 micromol/L), homocysteinuria was suspected. Amino acid chromatography and reduced CBS activity were used to confirm the diagnosis. Vitamin enriched diet with vitamin B6 and folates has reduced slightly the homocysteine level. CONCLUSION: Homocysteinuria must be diagnosed early since a simple vitamin supply could ameliorate prognosis and decrease complications.

Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation.

The cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2) proteins have been implicated in the activation of NF-kappaB by TNFalpha; however, genetic deletion of either cIAP1 or 2 did not support a physiologically relevant role, perhaps because of functional redundancy. To address this, we used combined genetic and siRNA knockdown approaches and report that cIAP1 and 2 are indeed critical, yet redundant, regulators of NF-kappaB activation upon TNFalpha treatment. Whereas NF-kappaB was properly activated by TNFalpha in cultured and primary cells deficient in either cIAP1 or 2, removal of both cIAPs severely blunted its activation. After treatment with TNFalpha, cIAP1 and 2 were rapidly recruited to the TNF receptor 1, along with the adapter protein TNF receptor associated factor 2. Importantly, either cIAP1 or 2 was required for proper TNF receptor 1 signalosome function. In their combined absence, polyubiquitination of receptor interacting protein 1, an upstream event necessary for NF-kappaB signaling, was attenuated. As a result, phosphorylation of the inhibitor of kappaB kinase beta was diminished, and signal transduction was severely blunted. Consequently, cells missing both cIAP1 and 2 were sensitized to TNFalpha-mediated apoptosis. Collectively, these data demonstrate that either cIAP1 or 2 is required for proper Rip1 polyubiquitination and NF-kappaB activation upon TNFalpha treatment.

[Growth hormone deficiency and pituitary stalk interruption in Fanconi anemia]. / Déficit en GH par interruption de la tige pituitaire dans l'anémie de Fanconi.

Fanconi anemia is a rare disorder inherited by recessive autosomic transmission belonging to the group of chromosomal instability syndromes. It is characterized by progressively developing medullary aplasia, various congenital malformations and especially a high risk of cancer, particularly acute myeloblastic leukemia and certain solid tumors. The association is quite common in patients with endocrine disease which constitutes an additional factor of morbidity and must be diagnosed and treated. We report a case of Fanconi anemia revealed by severe delay in statural growth and primary amenorrhea with a 21-year-old girl. The diagnosis was suggested by asymptomatic pancytopenia caused by a medullary hypoplasia and confirmed by a cytogenetic investigation using cross-linking agents that showed a large number of chromosomal breaks. Hormonal exploration revealed hypopituitarism with complete growth hormone (GH) deficiency and hypogonadotrophic hypogonadism caused by interruption of the pituitary stalk. The aim of this case report is to illustrate the importance of early exploration of retarded growth which, in some patients, can reveal potentially serious, and treatable, disease.

Gene frequencies of human neutrophil antigens in the Tunisian blood donors and Berbers.

Human neutrophil antigens play an important role in provoking immune neutropenia and transfusion-reactions. The aim of this study was to determine granulocyte-specific antigens on the neutrophil Fc gamma receptor IIIb (Fc gamma RIIIb, CD16b), namely, the HNA-1a(NA1) and HNA-1b(NA2) antigens and their gene frequencies in Tunisian blood donors and Berbers. One hundred and ninety-nine unrelated healthy Tunisian blood donors and Berbers were typed for HNA-1a and HNA-1b(NA1 and NA2), using polymerase chain reaction with sequence-specific primers (PCR-SSP). In 24 granulocyte samples, the HNA-1a and HNA-1b phenotypes was additionally determined by the granulocyte immunofluorescence test (GIFT) and correlated with the genotyping results. A subsequent analysis of the genotyping study showed that, the HNA-1a and HNA-1b gene frequencies observed, were 0.342 and 0.658 for Berbers, and 0.311 and 0.668 for blood donors, respectively. In the genotyping study conducted, it was determined that the HNA-1a and HNA-1b gene frequencies observed in Tunisian blood donors and Berbers are similar to those previously reported in other white populations.

[Epidemiologic data in renal lithiasis in adults]. / Données épidémiologiques de la lithiase rénale chez l'adulte.

The morpho-costitutional analysis of 574 urinary lithiasis emitted by tunisean adults permitted to define an épidemiology's profile. This resemble to the épidemiology's profile of under-developed conry: Amore raised frequency of the renal lithiasis at the man than at the woman with a sec ratio of 2.4. An average age of +14 years with a peak to 4th decade in 2 sexes. The upper localitation of the calculi is founded in 94% cases. The fréquency of the relapses, the mode of expulsion and the size of calculi are différent of those published in the litérature. Probably because the time of study which last 4 years is too short, so it don't enable us to find a result like the literature. The surgery is the mode of most fréquent élimination (51%). This s dû to the présence great size calculi in our popûlation and to the récent introduction of the lithotritie in our country.

Development of an occupational illness and injury surveillance database for the electric energy sector.

Currently available occupational injury and illness data for electric energy companies provide only overall summary rates. Specific information about types of injury or illnesses, rates by occupational or work environments, and injury costs and severity are generally not readily available. Relevant data such as personnel and claims information are frequently not integrated into a comprehensive health and safety surveillance system suitable for epidemiologic and health and safety research purposes. Epidemiological methods are valuable for identifying key risk factors for work-related injuries and illnesses and assessing their magnitude, as well establishing priorities for health and safety research. Application of such methods can result in long-term reductions in injury and illness rates and their attendant costs. Aggregation of relevant health and safety data across companies improves statistical power for the assessment of rare (yet costly) injuries or illness or specific at-risk subgroups within the electric energy sector. A pilot occupational injury and illness database has been developed that can incorporate and standardize data across a spectrum of companies of differing sizes and configurations. In illustrative data analyses, injury trends were summarized by company size, occupation, and demographic factors, among others. Trends observed in these illustrative analyses were consistent with results previously reported in the epidemiological literature, however, results are considered preliminary pending development of the full database. This study shows that development of a standardized surveillance occupational injury and illness database across companies with different database configurations is feasible. This database will ultimately provide a stable and accurate occupational health and safety assessment tool not currently available for this sector.

Refined 2.7 centimorgan locus in Xp21.3-22.1 for a nonspecific X-linked mental retardation gene (MRX54).

Nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which mental retardation (MR) appears to be the only consistent manifestation. A large genetic interval of assignment obtained on individual families by linkage analysis, genetic, heterogeneity, and phenotypic variability usually are major obstacles to fine-map and identify the related disease genes. Here we report on a large Tunisian family (MRX54) with an MRX condition. X-linked recessive inheritance is strongly suggested by the segregation of MR through seven unaffected carrier females to 14 affected males in two generations. Two-point linkage analysis demonstrated significant linkage between the disorder and several markers in Xp21.3-22.1 (maximum LOD score Zmax = 3.56, recombination fraction 0 = 0 at DXS1202), which was confirmed by multipoint linkage analyses. Recombinant events observed with the flanking markers DXS989 and DXS1218 delineate a refined locus of approximately 2.7 cM in accordance with the physical distance between these two markers. The small interval of assignment observed in this family overlaps not only with nine large MRX loci previously reported in Xp21.3-22.1 but also with two inherited microdeletions in Xp21.3-22.1 involved in nonspecific MR. Although the involvement of several genes located in the Xp21.3-22.1 region cannot be ruled out, data reported in this study could be used as a starting point for the search of such gene(s).