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Background: Perioperative myocardial injury after noncardiac surgery is associated with postoperative mortality. Heart rate (HR) is an independent risk factor for perioperative myocardial injury. In this pilot trial we tested the feasibility of a randomised, placebo-controlled trial of personalised HR-targeted perioperative ivabradine., Methods: This was a single-centre, randomised, placebo-controlled, double-blind, parallel group, feasibility pilot trial conducted at Geneva University Hospitals. We included patients ≥75 yr old or ≥45 yr old with cardiovascular risk factors planned for intermediate- or high-risk surgery. Patients were randomised to receive ivabradine (2.5, 5.0, or 7.5 mg) or placebo according to their HR, twice daily, from the morning of surgery until postoperative day 2. Primary outcomes were appropriate dosage and blinding success rates., Results: Between October 2020 and January 2022, we randomised 78 patients (recruitment rate of 1.3 patients week -1 ). Some 439 of 444 study drug administrations were adequate (99% appropriate dosage rate). The blinding success rate was 100%. There were 137 (31%) administrations of Pill A (placebo in both groups for HR ≤70 beats min -1 ). Nine (11.5%) patients had a high-sensitive cardiac troponin T elevation ≥14 ng L -1 between any two measurements. The number of bradycardia episodes was eight in the placebo group and nine in the ivabradine group., Conclusions: This pilot study demonstrates the feasibility of, and provides guidance for, a future trial testing the efficacy of personalised perioperative ivabradine. Future studies should include patients at higher risk of cardiac complications., Clinical Trial Registration: NCT04436016., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic., Methods: To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed., Results: Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients., Conclusion: Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD., (© 2023. The Author(s).)

Background: Corpus callosum malformations (CCM) represent one of the most common congenital cerebral malformations with a prevalence of around one for 4000 births. There have been at least 230 reports in the literature concerning 1q43q44 deletions of varying sizes discovered using chromosomal microarrays. This disorder is distinguished by global developmental delay, seizures, hypotonia, corpus callosum defects, and significant craniofacial dysmorphism. In this study, we present a molecular cytogenetic analysis of 2 Tunisian patients with corpus callosum malformations. Patient 1 was a boy of 3 years old who presented psychomotor retardation, microcephaly, behavioral problems, interventricular septal defect, moderate pulmonary stenosis, hypospadias, and total CCA associated with delayed encephalic myelination. Patient 2 was a boy of 9 months. He presented a facial dysmorphia, a psychomotor retardation, an axial hypotonia, a quadri pyramidal syndrome, a micropenis, and HCC associated with decreased volume of the periventricular white matter. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used., Results: Array CGH analysis reveals that patient 1 had the greater deletion size (11,7 Mb) at 1q43. The same region harbors a 2,7 Mb deletion in patient 2. Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. In both patients, the commonly deleted region includes six genes: PLD5, AKT3, ZNF238, HNRNPU, SDCCAG8 and CEP170. Based on the role of the ZNF238 gene in neuronal proliferation, migration, and cortex development, we hypothesized that the common deletion of ZNF238 in both patients seems to be the most responsible for corpus callosum malformations. Its absence may directly cause CCM. In addition, due to their high expression in the brain, PLD5 and FMN2 could modulate in the CCM phenotype., Conclusion: Our findings support and improve the complex genotype-phenotype correlations previously reported in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of several genes related to this pathology., (© 2022. The Author(s).)

Introduction: X-linked recessive ichthyosis (XLI) is a genodermatosis, caused by a deficiency of the steroid sulphatase enzyme encoded by the STS gene (OMIM # 300,747). Adopted XLI molecular diagnosis approaches differ from one laboratory to another depending on available technical facilities. Our work aims to figure out a sound diagnostic strategy for XLI., Patients and Methods: We collected 8 patients with XLI, all males, from 3 unrelated Tunisian families from central Tunisia. Genetic diagnosis was conducted through a large panel of genetic techniques including: Sanger Sequencing, haplotype analysis of STR markers, MLPA analysis, FISH and array CGH., Results: Direct Sanger sequencing of the STS gene showed the same deletion of 13 base pairs within the exon 4 in all patients resulting in a premature stop codon. However, all patients' mothers were not carriers of this variant and no common haplotype flanking STS gene was shared between affected patients. Sequence alignment with reference human genome revealed an unprocessed pseudogene of the STS gene located on the Y chromosome, on which the 13 bp deletion was actually located. STS MLPA analysis identified a deletion of the entire STS gene on X chromosome for all affected patients. This deletion was confirmed by FISH and delineated by array CGH., Conclusion: All our patients shared a deletion of the entire STS gene revealed by MLPA, confirmed by FISH and improved by array CGH. Geneticists must be aware of the presence of pseudogenes that can lead to XLI genetic misdiagnosis., (© 2022. The Author(s).)

We report the influence of treatment time of electrospun chitosan nanofibers (CHT NFs) in dopamine hydrochloride bath (2 mg.mL -1 in 10 mM Tris buffer, pH 8.5) on the extent of the polydopamine (pDA) coating on NFs surface. The reaction was characterized by FTIR and SEM analysis and the cytocompatibility of the scaffolds toward MT3C3-E1 cells was assessed. Biomimetic deposition of hydroxyapatite (HA) in 1.5xSBF batch was investigated by SEM-EDS and XRD. Samples treated in dopamine bath during 2 h promoted the structural stability of NFs in PBS, provided optimal cytocompatibility and induced the in vitro biomineralization from 6 days in 1.5xSBF. The XRD and SEM-EDS investigations confirmed formation of spherical-shaped particles composed of apatitic phase. Finally, this study shows that these NFs-pDA scaffolds prepared in the optimal experimental conditions defined here are promising candidates for application as osteoinductive scaffolds for bone regeneration applied to orthopedic and dental applications., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate quantitative alterations of the choriocapillaris in swept-source optical coherence tomography angiography in diabetic patients., Methods: We included normal patients and diabetic patients with and without diabetic retinopathy (DR), excluding patients with macular edema. Angiograms in 3 × 3 mm were acquired with Plexelite 9000 swept-source optical coherence tomography angiography. Choroidal flow voids were analyzed after removal of projection artifacts. The main evaluation was the correlation between choroidal flow voids area (FVA-CC) and DR stage., Results: A total of 120 eyes of 72 patients were analyzed. There were 17 eyes from healthy subjects, 30 eyes without DR, 22 eyes with minimal nonproliferative DR, 30 eyes with moderate nonproliferative DR, 16 eyes with severe nonproliferative DR, and 5 eyes with proliferative DR (PDR). The percentage of FVA-CC for each group was, respectively, 10.9 ± 3.4%, 14.6 ± 4.8%, 17.6 ± 3.5%, 20.7 ± 5.9%, 19.9 ± 2.9%, and 26.6 ± 4.4%. FVA-CC and DR stage significantly correlated (P < 0.0001). FVA-CC was significantly increased in diabetic patients without DR compared with healthy subjects (P = 0.008)., Conclusion: Diabetes is associated with quantifiable choriocapillaris alterations in swept-source optical coherence tomography angiography. These alterations precede clinical signs of DR and are correlated with DR stage.

The aim was to analyze the variations in macular vascularization on optical coherence tomography angiography (OCTA) according to the presence of intraretinal fluid (IRF) induced by exudative age-related macular degeneration (AMD). We included exudative AMD patients with IRF and/or subretinal fluid (SRF) and age-matched control eyes. All patients underwent a macular 6 × 6 mm swept-source OCTA. The mean perfusion density (MPD) and mean vascular density (MVD) were calculated in the superficial (SCP) and the deep (DCP) capillary plexus at two timepoints: during an episode of exudation (T0) and after its total resorption (T1). A total of 22 eyes in the IRF ± SRF group, 11 eyes in the SRF group and 11 eyes in the healthy group were analyzed. At T0, the IRF ± SRF group showed significantly lower MPD and MVD than healthy eyes in the SCP ( p < 0.001) and DCP ( p < 0.001). At T1, MPD and MVD significantly increased from T0 in the SCP ( p = 0.027 and p = 0.0093) and DCP ( p = 0.013 and p = 0.046) but remained statistically lower than in the healthy eyes. For the SRF group, only the DCP showed significantly lower MPD ( p = 0.012) and MVD ( p = 0.046) in comparison to the healthy eyes at T0. The present study shows that retinal vascular changes do occur in the case of exudative AMD.

The use of dental stem cells has raised many hopes in the development of new treatments for neurodegenerative diseases. According to current statistics, about 1 in 6 people in the world would be affected by a neurological disease. This number continues to increase as the world's population ages, making neurodegenerative diseases probably the one of the major challenges of public health in the 21st century. Neurodegenerative diseases are characterized mainly by a progressive loss of cognitive abilities and patient autonomy related to loss and degeneration of neurons in brain structures. Unfortunately, today, the only treatments available for this type of disease do only relieve the symptoms, they do not treat them, and few clinical trials have been truly convincing to date. Hence, hope lies for these diseases in the development of other therapeutic approaches. As such, dental stem cells could be a promising area of research because of their rapid growth, their great capacity for differentiation into different types of cells (among neuronal ones for some of them) and how easy they can be obtained, without raising ethical issues as for example for embryonic stem cells.

Primary pulmonary lymphoma is a rare entity. Furthermore, simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare condition which is often related to therapeutic complications. We present, to the best of our knowledge, the first case of primary pulmonary mucosa associated lymphoid tissue (MALT) lymphoma revealed by SBSP. A 50-year-old female was diagnosed with organizing pneumonia. One month later, she presented with sudden chest pain and shortness of breath due to SBSP. Bilateral chest tubes were inserted. A scan- guided right lung biopsy led to the diagnosis of primary pulmonary MALT lymphoma. The patient was treated with R-CHOP chemotherapy. The association between lymphoma and pneumothorax is extremely rare, often related to therapeutic toxicity. We report the case of SBSP as the first manifestation of primary pulmonary MALT lymphoma., Competing Interests: The authors declare no competing interests., (Copyright: Asma Migaou et al.)

Background: While Miller-Dieker syndrome critical region deletions are well known delineated anomalies, submicroscopic duplications in this region have recently emerged as a new distinctive syndrome. So far, only few cases have been described overlapping 17p13.3 duplications., Methods: In this study, we report on clinical and cytogenetic characterization of two new cases involving 17p13.3 and 3p26 chromosomal regions in two sisters with familial history of lissencephaly. Fluorescent In Situ Hybridization and array Comparative Genomic Hybridization were performed., Results: A deletion including the critical region of the Miller-Dieker syndrome of at least 2,9 Mb and a duplication of at least 3,6 Mb on the short arm of chromosome 3 were highlighted in one case. The opposite rearrangements, 17p13.3 duplication and 3p deletion, were observed in the second case. This double chromosomal aberration is the result of an adjacent 1:1 meiotic segregation of a maternal reciprocal translocation t(3,17)(p26.2;p13.3)., Conclusions: 17p13.3 and 3p26 deletions have a clear range of phenotypic features while duplications still have an uncertain clinical significance. However, we could suggest that regardless of the type of the rearrangement, the gene dosage and interactions of CNTN4, CNTN6 and CHL1 in the 3p26 and PAFAH1B1, YWHAE in 17p13.3 could result in different clinical spectrums.

Background: Small Supernumerary Marker Chromosomes (sSMC) are rare chromosomal abnormalities, which have abnormal banding arrangement and take many shapes. Several disorders have been correlated with sSMC presence. The aim of this study is to characterize the sSMC derived from chromosome 18 by Fluorescence in situ hybridization (FISH) and Array Comparative Genomic Hybridization (aCGH)., Results: Nine children with dysmorphic features have been investigated. They have these features in common: a triangular face, low-set ears, a large mouth with a thin upper lip, and a horizontal palpebral fissure. Epicanthus and strabismus were present in two patients. In addition, we have noticed microcephaly and mental and/or developmental delay with low birth weight. However, two patients had standard birth weight; one patient had hypospadias; two had skin problems; and three showed different congenital heart defects. One patient had corpus callosum hypoplasia. Systematic karyotype analysis revealed a de novo supernumerary chromosome. Array CGH showed a gain in copy number on the short arm of chromosome 18 in the nine cases. In one case, the sSMC seemed to be in mosaic. The breakpoints of the marker were identified using aCGH and FISH. Thus, the sSMC led to 18p tetrasomy with approximately 14 Mb lengths, between 364344 and 14763575 based on the human genome version 18., Conclusions: These results have been completed by FISH in order to ascertain the shape of the sSMC. Our results confirm the uniqueness and particularity of the iso18p syndrome on the phenotypic as well as on the genetic level., Competing Interests: The local Ethics Board of the University Teaching Hospital Farhat Hached approved the present study (IRB00008931) and written consents were taken from the parents for photo publication.The local Ethics Board approved the present study (IRB00008931) and written consents were taken from the parents for photo publication.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

From 20th century, chitosan, a natural polysaccharide, has received much attention for use in biomedical applications thanks to its remarkable properties, such as biodegradability, biocompatibility, hemostasis and antibacterial activity. Over the last decades, many researchers have attempted to generate new chitosan derivatives-based biomaterials though chemical modifications, especially through sulfonation or sulfation reactions in order to tailor the physicochemical and biochemical properties. Due to the presence of residual amino groups, the generated polyampholytic derivatives are characterized by convenient biological properties, such as antioxidation, antiviral activity, anticoagulation and bone regeneration, expanding their application scope. This paper provides an overview of the strategies used to chemically modify chitosan by introduction of sulfonate groups on chitosan backbone, focusing on various sulfonating or sulfating agents used and substitution regioselectivity, and highlights their applications in biomedical field., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to explore the role of nine microRNAs (miRNAs) in microparticles (MPs) on the efficacy of aerobic exercise in the regulation of inflammation and vascular function in obesity., Methods: Sedentary women with normal weight (n = 6, BMI < 25 kg/m 2 ) and women with obesity (n = 9, BMI > 30 kg/m 2 ) were recruited at F. Hached Hospital (Sousse, Tunisia) and enrolled in an 8-week aerobic program. Vascular function was assessed using laser Doppler flowmetry/iontophoresis, circulating MPs by flow cytometry, miRNAs by real-time polymerase chain reaction, and inflammation by ELISA, before and after exercise., Results: Women with obesity presented with high prevalence of cardiovascular risk factors and a higher circulating MP level compared with healthy subjects. The MP miRNA profile was significantly different in the two groups. Exercise reduced BMI and inflammation in both groups and significantly improved endothelial-dependent response (acetylcholine cutaneous vascular conductance) for healthy subjects, with a trend for women with obesity. Circulating MP level was increased after exercise, and miRNA expression was differentially modulated in both populations. Pearson analysis revealed a correlation between MPs miR-124a and miR150 and adiponectin, TNFα, or IL-6 levels., Conclusions: The relation between MPs and miRNA profile, inflammation, vascular function, and exercise is of particular interest for defining "miRNA biomarker signature" in patients with cardiovascular disease who are potentially susceptible to respond to exercise., (© 2018 The Obesity Society.)

This work firstly aimed to synthesize mono- and di- sulfonic derivatives of chitosan by reductive amination reaction using respectively 2-formyl benzene sulfonic acid and 2,4 formyl benzene sulfonic acid sodium salts. The influence of the reactants molar ratio (R), aryl - substituted amino groups versus chitosan free amino groups, on the degree of substitution (DS) of both sulfonated chitosans was assessed by 1 H NMR, elemental analysis, coupled conductometry-potentiometry analysis and UV spectrometry and FTIR. The influence of pH on sulfonated chitosans' properties in solution were investigated by solubility and zeta potential (ZP) studies, size exclusion chromatography equipped with MALLS detection (SEC-MALLS) and Taylor dispersion analysis (TDA). The polyampholytic character of both series was evidenced and strongly modified the solutions properties compared to chitosan. Then, the anticoagulant properties of mono- and di- sulfonic polymers were investigated by the measurement of the activated partial thromboplastin time (aPTT), Prothrombin-time (PT) and anti-(factor Xa)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Due to progress in medical care, the number of survivors from cancer has increased significantly during recent years and this raises the question of the quality of life (QoL), especially of the many women treated for a breast cancer. This paper focuses on correlations of QoL with anxiety and depression on the one hand and with socio demographic, anatomo-clinical and therapeutic parameters on the other. Methods: In this cross-sectional study, seventy patients were enrolled and filled in two auto-questionnaires, both in validated Arabic versions: The SF-36 for assessment of QoL and the Hospital Anxiety and Depression Scale (HAD-S) for evaluation of anxiety and depression. The statistical approaches used to determine predictive factors were bivariate correlations to determine relationships between quantitative variables, and T-tests and one-way Anova to analyze links between qualitative and quantitative variables. Results: The QoL of patients was altered with an SF-36 mean total score of 54.0 ± 22.7, and the alteration affects the different aspects. The mean scores for anxiety and depression in patients were 6.91 ± 4.72 and 6.24 ± 3.88, respectively. The results of this study suggested an association between the QoL and chemotherapy (p= 0.014) and its adverse effects (p=0.01), as well as anxiety (p= 0.0001) and depressive symptoms (p= 0.0001). Socio-demographic factors, the stage of the cancer, and surgery, radiotherapy or hormone therapy did not appear to have significant effects. Conclusion: The management of breast cancer patients needs a collaborative approach between oncologists, gynecologists, psychologist and psychiatrists., (Creative Commons Attribution License)

Objective: To identify the gene(s) involved in the etiology of premature ovarian insufficiency in a highly consanguineous Tunisian family., Design: Genetic analysis of a large consanguineous family with several affected siblings., Setting: University hospital-based cytogenetics and molecular genetics laboratories., Patient(s): A highly consanguineous Tunisian family with several affected siblings born to healthy second-degree cousins., Intervention(s): None., Main Outcome Measure(s): Targeted exome sequencing was performed by next-generation sequencing for affected family members. Mutations were validated by Sanger sequencing. Functional experiments were performed to explore the deleterious effects of the identified mutation. DNA damage was induced by increasing mitomycin C (MMC) concentrations on cultured peripheral lymphocytes., Result(s): Analysis of the next-generation sequencing data revealed a new homozygous missense mutation in the minichromosome maintenance 8 gene (MCM8).This homozygous mutation (c. 482A>C; p.His161Pro) was predicted to be deleterious and segregated with the disease in the family. MCM8 participates in homologous recombination during meiosis and DNA double-stranded break repair by dimerizing with MCM9. Mcm8 knock out results in an early block in follicle development and small gonads. Given this, we tested the chromosomal breakage repair capacity of homozygous and heterozygous MCM8 p.His161Pro mutation on cultured peripheral lymphocytes exposed to increasing MMC concentrations. We found that chromosomal breakage after MMC exposure was significantly higher in cells from homozygously affected individuals than in those from a healthy control., Conclusion(s): Our findings provide additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.

Objective: To determine the genetic cause of 46,XY primary amenorrhea in three 46,XY girls., Design: Whole exome sequencing., Setting: University cytogenetics center., Patient(s): Three patients with unexplained 46,XY primary amenorrhea were included in the study., Intervention(s): Potentially pathogenic variants were confirmed by Sanger sequencing, and familial segregation was determined where parents' DNA was available., Main Outcome Measure(s): Exome sequencing was performed in the three patients, and the data were analyzed for potentially pathogenic mutations. The functional consequences of mutations were predicted., Result(s): Three novel homozygous nonsense mutations in the luteinizing hormone receptor (LHCGR) gene were identified:c.1573 C→T, p.Gln525Ter, c.1435 C→T p.Arg479Ter, and c.508 C→T, p.Gln170Ter., Conclusion(s): Inactivating mutations of the LHCGR gene may be a more common cause of 46,XY primary amenorrhea than previously considered., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The endothelial nitric oxide synthase (NOS3) has been shown to play a role in the modulation of lipolysis. The goal of this study was to examine the impact of the G894T (rs1799983) and a 27 bp variable number of tandem repeats (VNTR 4a/b) of NOS3 gene on obesity in a sample of the Tunisian population., Research Methods and Procedures: The study included 211 normal weight subjects and 183 obese patients. NOS3 G894T and 4a/b variants were determined by PCR analysis and examined for association with obesity-related traits. The effect of obesity on forearm skin blood flow (FSBF) response to acetylcholine, an endothelium-dependent vasodilator was determined by laser Doppler iontophoresis., Results: In case-control studies, both G894T and 4a/b variants were associated with obesity. A significantly increased risk of obesity was found with the NOS3(G894T) TT genotype (OR:2.62, P=0.04). This association remains significant after adjustments for age and gender (OR: 2.93, P=0.03). A higher risk was also observed for carriers of the G894T allele (OR: 1.72, P=0.001). Stratified analysis by gender revealed that obese men (but not women) had significantly higher frequency of TT genotypes compared to controls (9.9% vs. 2.9%, P=0.01). Carriers of the 4b allele presented a significantly higher risk of obesity than non-carriers even after adjustments for age and gender (OR (95%CI): 1.72 (1.16-2.56), P=0.004). Correlations with anthropometric parameters revealed that carriers of TT and bb genotypes had significantly higher body mass index compared to those homozygous for the G and a alleles (P=0.0004)., Conclusion: This study provides the first evidence for the association of G894T and 4a/b variants with body mass index and the risk of obesity in Tunisians. These polymorphisms did not exhibit, however any significant association with both metabolic traits and vascular function., (Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Objective: To explore the pathophysiological profile of patients who have obesity and to investigate the potential role of circulating microparticles (MPs) in endothelial dysfunction in patients who have obesity., Methods: The inflammatory and oxidative status and the cutaneous microvascular blood flow were characterized in 69 patients with android obesity and 46 subjects with normal weight (controls) by using laser Doppler flowmetry. Circulating MP levels were measured by flow cytometry, and endothelial nitric oxide synthase (eNOS) and NADPH oxidase (NOX) expression in MPs was investigated by Western blotting. MP effect on vascular reactivity was assessed in rat aorta rings., Results: Patients with obesity showed endothelial dysfunction, hyperglycemia, inflammation, and oxidative stress. In controls, low MP levels were positively correlated with normal microvascular function. Western blot analysis revealed reduced eNOS and increased NOX4D expression in MPs from subjects with obesity compared with controls. However, this was not correlated with endothelial dysfunction parameters and did not impair ex vivo endothelium-dependent vasodilation., Conclusions: These results suggest that MPs do not contribute directly to endothelial dysfunction associated with obesity. Conversely, eNOS- and NOX-containing MPs could be involved in the compensatory mechanism of vascular endothelial cells to counteract the pathologic mechanisms underlying endothelial dysfunction., (© 2016 The Obesity Society.)

Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Understanding and targeting cancer cell invasion is an important therapeutic approach. Cell invasion is a complex process that replies on many signaling pathways including the mitogen-activated protein (MAP) kinase (MAPK). In many cell lines, the use of MAPK-targeted drugs proved to be a potential method to inhibit cancer cell motility. In the present study, we use a recombinant anthrax lethal toxin (LeTx), which selectively inhibits the MAPK pathway, in order to target invasion. LeTx proved ineffective on cell survival in astrocytoma (as well as normal cells). However, astrocytoma cells that were treated with LeTx showed a significant decrease in cell motility as seen by wound healing as well as random 2D motility in serum. The cells also showed a decrease in invasion across a collagen matrix. The effect of LeTx on cell migration was mediated though the deregulation of Rho GTPases, which play a role in cell motility. Finally, the effect of LeTx on cell migration and Rho GTPases was mimicked by the inhibition of the MAPK pathway. In this study, we describe for the first time the effect of the LeTx on cancer cell motility and invasion not cell survival making it a potentially selective brain tumor invasion inhibitor.

Infantile Spasms syndrome (ISs) is a characterized by epileptic spasms occurring in clusters with an onset in the first year of life. West syndrome represents a subset of ISs that associates spasms in clusters, a hypsarrhythmia EEG pattern and a developmental arrest or regression. Aetiology of ISs is widely heterogeneous including many genetic causes. Many patients, however, remain without etiological diagnosis, which is critical for prognostic purpose and genetic counselling. In the present study, we performed genetic screening of 73 patients with different types of ISs by array-CGH and molecular analysis of 5 genes: CDKL5, STXBP1, KCNQ2, and GRIN2A, whose mutations cause different types of epileptic encephalopathies, including ISs, as well as MAGI2, which was suggested to be related to a subset of ISs. In total, we found a disease-causing mutation or CNV (Copy Number Variation) in 15% of the patients. These included 6 point mutations found in CDKL5 (n = 3) and STXBP1 (n = 3), 3 microdeletions (10 Mb in 2q24.3, 3.2 Mb in 5q14.3 including the region upstream to MEF2C, and 256 kb in 9q34 disrupting EHMT1), and 2 microduplications (671 kb in 2q24.3 encompassing SCN2A, and 11.93 Mb in Xq28). In addition, we discuss 3 CNVs as potential risk factors, including one 16p12.1 deletion, one intronic deletion of the NEDD4 gene, and one intronic deletion of CALN1 gene. The present findings highlight the efficacy of combined cytogenetic and targeted mutation screening to improve the diagnostic yield in patient with ISs., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Objectives: Rolandic epilepsies (REs) represent the most frequent epilepsy in childhood. Patients may experience cognitive, speech, language, reading, and behavioral issues. The genetic origin of REs has long been debated. The participation of rare copy number variations (CNVs) in the pathophysiology of various human epilepsies has been increasingly recognized. However, no systematic search for microdeletions or microduplications has been reported in RE so far., Methods: Array comparative genomic hybridization (aCGH) and quantitative polymerase chain reaction (qPCR) were used to analyze the genomic status of a series of 47 unrelated RE patients who displayed various types of electroclinical manifestations., Results: Thirty rare CNVs were detected in 21 RE patients. Two CNVs were de novo, 12 were inherited, and 16 were of unknown inheritance. Each CNV was unique to one given patient, except for a 16p11.2 duplication found in two patients. The CNVs of highest interest comprised or disrupted strong candidate or confirmed genes for epileptic and other neurodevelopmental disorders, including BRWD3, GRIN2A, KCNC3, PRKCE, PRRT2, SHANK1, and TSPAN7., Significance: Patients with REs showed rare microdeletions and microduplications with high frequency and heterogeneity. Whereas only a subset of all genomic alterations found here may actually participate in the phenotype, the novel de novo events as well as several inherited CNVs contain or disrupt genes, some of which are likely to influence the emergence, the presentation, or the comorbidity of RE. The future screening of cohorts of larger size will help in detecting more de novo or recurrent events and in appreciating the possible enrichment of specific CNVs in patients with RE., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Colon cancer is a cancer of the epithelial cells lining the colon. It is mainly divided into different stages according to the invasiveness and metastatic ability of the tumor. Many mutations are acquired which leads to the development of this malignancy. These occur in entities that greatly affect the cell cycle, cell signaling pathways and cell motility, which all involve the action of Rho GTPases. The protein of interest in the present study was DLC2, also known as StarD13 or START-GAP2, a GTPase-activating protein (GAP) for Rho and Cdc42. Literature data indicate that this protein is considered a tumor-suppressor in hepatocellular carcinoma. Previous research in our laboratory confirmed StarD13 as a tumor suppressor in astrocytoma and in breast cancer. In the present study, we investigated the role of StarD13 in colon cancer. When overexpressed, StarD13 was found to lead to a decrease in cell proliferation in colon cancer cells. Consistently, knockdown of StarD13 led to an increase in cell proliferation. This showed that, similarly to its role in astrocytoma and breast cancer, StarD13 appears to be a tumor suppressor in colon cancer as well. We also examined the role of StarD13 in cell motility. StarD13 knockdown resulted in the inhibition of 2D cell motility. This was due to the inhibition of Rho; consequently Rac-dependent focal complexes were not formed nor detached for the cells to move forward. However, StarD13 knockdown led to an increase in 3D cell motility. Although StarD13 was indeed a tumor suppressor in our colon cancer cells, as evidenced by its effect on cell proliferation, it was required for cancer cell invasion. The present study further describes the role of StarD13 as a tumor suppressor as well as a Rho GAP.