Mesenchymal stem cell-based therapy for ischemic stroke

Ischemic stroke represents a major, worldwide health burden with increasing incidence. Patients affected by ischemic strokes currently have few clinically approved treatment options available. Most currently approved treatments for ischemic stroke have narrow therapeutic windows, severely limiting the number of patients able to be treated. Mesenchymal stem cells represent a promising novel treatment for ischemic stroke. Numerous studies have demonstrated that mesenchymal stem cells functionally improve outcomes in rodent models of ischemic stroke. Recent studies have also shown that exosomes secreted by mesenchymal stem cells mediate much of this effect. In the present review, we summarize the current literature on the use of mesenchymal stem cells to treat ischemic stroke. Further studies investigating the mechanisms underlying mesenchymal stem cells tissue healing effects are warranted and would be of benefit to the field

How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse

Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model

Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice.

Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions

Méningiome en plaque sphéno-orbitaire: à propos d’un cas avec revue de la littérature

Le méningiome intra osseux est une variété des méningiomes ectopiques dans lequel les cellules méningothéliales envahissent la paroi osseuse et entraînent une hyperostose. Le méningiome en plaque, variante macroscopique des méningiomes intra osseux, est une tumeur rare et survient fréquemment au niveau de la région sphéno-orbitaire ce qui le confond avec les tumeurs osseuses primitives. Nous rapportons le cas d'une patiente de 50 ans qui présente une exophtalmie avec cécité unilatérale gauche d'installation progressive depuis un an. L'examen trouve une exophtalmie axile, indolore et non réductible ainsi qu'une limitation de la motilité oculaire dans tous les sens du regard. La palpation montre une masse temporale gauche dure et adhérente à l'os. L'examen du fond d'oeil trouve un oedème papillaire gauche. Le scanner montre une lésion ostéocondensante temporo-sphéno-orbitaire gauche avec envahissement locorégional. Le diagnostic préopératoire fut une tumeur osseuse essentiellement maligne primitive ou secondaire. L'étude histologique a révélée un méningiome meningothélial de type en plaque. La patiente a bénéficié d'une exérèse avec reconstruction chirurgicale. Aucune récidive n'a été notée après 1 an de recul

Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton’s tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2′-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro–B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

Assessment of soil trace metal contamination of an uncontrolled landfill and its vicinity: the case of the city of ‘Targuist’ (Northern Morocco)

This study aims to assess, for the first time, soil Trace Metal Elements (TME) contamination level in an uncontrolled landfill and its vicinity of 'Targuist' (town in northern Morocco). Soil samples were collected at two depths (20 and 40cm) from 16 sampling sites. Samples were characterized for their physicochemical parameters (pH, electrical conductivity (EC), organic matter (OM) and total organic carbon (TOC)) and for their TME (copper (Cu), zinc (Zn), cadmium (Cd) and chromium (Cr)) using atomic absorption spectroscopy (ASS). The results show no significant differences between soils sampled at 20cm or 40cm depths regarding the tested parameters. While significant differences between sampling sites In landfill and Out landfill is observed particularly regarding pH, CaCO3, TOC, and Cd. Overall, our results show that soil physicochemical properties follow a spatial variability with decreasing values moving away from the landfill. Regarding TME soil contents, our results show contamination levels in most of the sampling sites of the study area. Furthermore, the total TME concentrations in soils vary according to the type of the studied metal and to the sampling site. Zn, Cu and Cd show significant positive correlations with pH. However, Cd has no correlation with any other trace elements or soil physicochemical properties. Meanwhile, Cr shows a significant negative correlation with Zn and Cu. OM, TOC, CaCO3 and EC are strongly and positively correlated. These results are well illustrated in the outcomes of the Principal Components Analysis and Hierarchical Cluster Analysis

Genotype x Environment interaction for quality traits in durum wheat cultivars adapted to different environments

The quality traits of durum wheat are important for the utilization by the industries. These traits may be influenced by genotype and interaction of genotype and environment (GxE). To evaluate the effects of genotype, environment and genotype x environment interaction on quality traits such as vitreousness, SDS sedimentation test, yellow pigment index, protein content and test weight, twelve Moroccan durum wheat cultivars representing a range of agronomic adaptation were tested in five locations representing a range of environments in three growing seasons. The results indicated significant effects of genotype, environment and GxE for all the quality traits. The extent of these effects differed; for SDSsedimentation volumes, yellow pigment and test weight, the component of variation due to genotype was larger than due to the environment, indicating the greater influence of genotypes on these traits. However, for vitreousness and protein content, the effect of environment was higher than the effect due to genotypes. Thus, these traits are controlled greatly by environmental effects than genetics. The variation due to GxE was higher than that of genotype for vitreousness and test weight, indicating high GxE interaction effect and less genotypic stability for these traits. For protein content, where the environmental effect was greater than that of genotype and GxE effect, multiple environmental trials are necessary in order to determine protein content of a cultivar. For other traits,  preliminary evaluations can be done in one environment and good performing ones can be selected for multiple environmental trials

Tuberculose uro-génitale : A propos de 95 cas

Objectif: Préciser les aspects cliniques, iconographiques et thérapeutiques de la tuberculose urogénitale. Patients et méthodes: D’avril 1992 à avril 2007, 95 patients atteints de tuberculose uro-génitale ont été vus. Il s’agissait de 53 hommes et 42 femmes âgés de 18 à 72 ans. Tous nos malades ont bénéficié d’un interrogatoire, avec recherche des antécédents de tuberculose extra urinaire, d’un examen clinique, d’une créatinémie, d’une urographie intra veineuse (UIV), d’une échographie et/ou tomodensitométrie, de la recherche du bacille de Koch (BK) dans les urines, d’un ECBU, d’une cystoscopie, et d’une analyse histologique des fragments biopsiques et/ou de la pièce d’exérèse. Résultats: Le diagnostic était basé sur un faisceau d’arguments cliniques, bactériologiques et radiologiques. L’irritation vésicale représentait la manifestation clinique la plus fréquente (51,5%). L’atteinte génitale isolée était présente chez 17,8% des patients. 16,8% de nos malades avaient une insuffisance rénale inaugurale (créatinine moyenne de 24 mg/l). La recherche de BK a été réalisée chez tous les patients et n’a été positive que dans 9,4% des cas. Les anomalies à l’UIV concernaient 86% des malades avec un rein muet dans 42% des cas. On a traité tous nos patients par une chimiothérapie antibacillaire associée à la chirurgie (85,2%) et/ou à des manoeuvres endo-urologiques (20%). Avec un recul moyen de 3 ans (extrêmes allant de 1 à 9 ans), la plupart de nos patients ont bien évolué sous traitement. L’amélioration clinique a été spectaculaire avec disparition des signes cliniques chez 88% des patients. La fonction rénale a été normalisée chez 70% des cas. Conclusion: La tuberculose reste une maladie grave par son évolution latente et le diagnostic tardif. L’amélioration de son pronostic passe par la prévention et par une bonne prise en charge diagnostique et thérapeutique.Mots clés : Tuberculose uro-génitale, diagnostic, traitemen