Clinical features and magnesium levels: Novel insights in 15q11.2 BP1-BP2 copy number variants.

BACKGROUND: Investigating copy number variations (CNVs) such as microdeletions or microduplications can significantly contribute to discover the aetiology of neurodevelopmental disorders. 15q11.2 genomic region, including NIPA1 and NIPA2 genes, contains a recurrent but rare CNV, flanked by the break points BP1 and BP2. Both BP1-BP2 microdeletion and microduplication have been associated with intellectual disability (ID), neuropsychiatric/behavioural disturbances and mild clinical features, even if with incomplete penetrance and variable expressivity. The pathogenic role of this CNV is quite unclear though. Unknown variants in other DNA regions and parent-of-origin effect (POE) are some of the mechanisms that have been proposed as an explanation of the wide phenotypic variability. As NIPA1 and NIPA2 encode for proteins that mediate magnesium (Mg2+ ) metabolism, it has been suggested that urinary Mg2+ levels could potentially represent informative and affordable biomarkers for a rapid screening of 15q11.2 duplications or deletions. Furthermore, magnesium supplementation has been proposed as possible therapeutic strategy. METHODS: Thirty one children with ID and/or other neurodevelopmental disorders carrying either a duplication or a deletion in 15q11.2 BP1-BP2 region have been recruited. When available, blood samples from parents have been analysed to identify the CNV origin. All participants underwent family and medical data collection, physical examination and neuropsychiatric assessment. Electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) scan were performed in 15 children. In addition, 11 families agreed to participate to the assessment of blood and urinary Mg2+ levels. RESULTS: We observed a highly variable phenotypic spectrum of developmental issues encompassing ID in most subjects as well as a variety of behavioural disorders such as autism and attention-deficit disorder/attention-deficit hyperactivity disorder. Dysmorphic traits and malformations were detected only in a minority of the participants, and no clear association with growth anomalies was found. Abnormal brain MRI and/or EEG were reported respectively in 64% and 92% of the subjects. Inheritance assessment highlighted an excess of duplication of maternal origin, while cardiac alterations were detected only in children with 15q11.2 CNV inherited from the father. We found great variability in Mg2+ urinary values, without correlation with 15q11.2 copy numbers. However, the variance of urinary Mg2+ levels largely increases in individuals with 15q11.2 deletion/duplication. CONCLUSIONS: This study provides further evidence that 15q11.2 BP1-BP2 CNV is associated with a broad spectrum of neurodevelopmental disorders and POE might be an explanation for clinical variability. However, some issues may question the real impact of 15q11.2 CNV on the phenotype in the carriers: DNA sequencing could be useful to exclude other pathogenic gene mutations. Our results do not support the possibility that urinary Mg2+ levels can be used as biomarkers to screen children with neurodevelopmental disorders for 15q11.2 duplication/deletion. However, there are evidences of correlations between 15q11.2 BP1-BP2 CNV and Mg2+ metabolism and future studies may pave the way to new therapeutic options.

Juniperanol: First total synthesis and evaluation in Type 2 Diabetes disease.

The first total synthesis of juniperanol, the tricyclic sesquiterpenoid enantiomer of α-cedrol is described. The synthesis relies on stereoselective gold-catalyzed Ohloff-type propargylic ester rearrangement performed on a 10 g scale, and a carbocationic cascade in the presence of acetyl methanesulfonate. The ability of juniperanol to interfere in glucose processes in different cell types is described.

[CTX-M-15-producing Klebsiella pneumoniae: a change in the epidemiology of ESBL]. / Klebsiella pneumoniae CTX-M-15: vers une modification de l'épidémiologie des ß-lactamases à spectre étendu.

Klebsiella pneumoniae is frequently involved in nosocomial outbreaks worldwide. High level of resistance is common for these bacteria leading to reduce antibiotic treatments and prolonged hospital stay for patients. Resistance determinants are often located on plasmids. During the 1980-1990s, ESBL encoding genes belonged to the TEM and SHV type. From the early 2000s, a new trend was observed with ESBL of the CTX-M type being increasingly described in K. pneumoniae, and more particularly CTX-M-15.

A comparison of the compressive strength of various distal locking screw options in the treatment of tibia fractures with intramedullary nails.

Treatment of distal metaphyseal tibia fractures is often challenging. Newer tibial intramedullary (IM) nails are designed with a wider variety of distal locking options to offer greater stability in treating these fractures. In this study we attempted to determine the most biomechanically stable number and configuration of distal locking screws when treating distal metaphyseal tibia fractures with IM nails. A transverse osteotomy was created 4 cm from the tibial plafond in identical composite saw bones models (Type 43A fracture) as well as in human cadaveric bones. Each specimen was nailed using a tibial nail (Stryker T2). Distal locking was performed in one of the three configurations: (a) Group I: two screws in the medial lateral (ML) direction; (b) Group II: one ML screw and one screw in the anterior posterior (AP) direction; (c) Group 111: two ML screws and one AP screw. The specimens were then mounted onto a uniaxial material testing machine (Instron) and tested in compression. Our results showed that there was no statistical difference in the load-carrying capacity of Group 1 and Group II. This suggests that the treating surgeon can choose either of these two configurations depending on the wound or other considerations without sacrificing the compressive load-carrying capacity of the IM nail fixation. The load-carrying capacity of the Group III samples with these locking screws was higher than those of Group I & II, although this difference was not statistically significant. This work is being continued to compare the load-carrying capacity of the bone samples with the cortical thickness of bone. We also plan to examine the relationship between the load-carrying capacity of these surgical constructs with the bone mineral density of the metaphysis of these tibial specimens.

VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans.

Tumor angiogenesis depends on the vascular endothelial growth factor (VEGF), which exists in multiple splicing isoforms, including the most abundant VEGF165 and VEGF121. We have previously shown that the differential capacity of these two VEGF isoforms to bind Neuropilin-1 accounts for their diverse ability to recruit Nrp1-expressing monocytes (NEMs), resulting in a different arteriogenic potential. Here we measure the expression of VEGF165 and VEGF121 in human cancer and their influence on tumor growth and vascularization. We measured the expression levels of VEGF165 and VEGF121 in human colorectal cancer and found that VEGF121 was more expressed than VEGF165, particularly in patients with extensive lymph node infiltration. Overexpressing either VEGF165 or VEGF121 in a cancer mouse model, we observed that the former decreased, whereas the latter increased tumor growth. In both clinical and experimental tumors, VEGF165 expression resulted in the recruitment of NEMs, paralleled by maturation of the tumor vascular network. Finally, hypoxia induced a shift toward the VEGF165 isoform in the central core of human cancers, as well as in various types of cultured cells. These results demonstrate that the two VEGF splicing isoforms are differentially expressed in colorectal cancers, exerting opposite effects on tumor growth and vessel maturation.

[Carbapenemases in enterobacteriaceae]. / Les carbapénèmases des entérobactéries.

Carbapenem-hydrolyzing beta-lactamases are the most powerful mechanism of resistance to carbapenems. Carbapenemases have been reported extensively worldwide now in Enterobacteriaceae. Carbapenemases of the KPC type have been reported first from the USA in Klebsiella pneumoniae, then worldwide with a marked endemicity in Israel and Greece. Metallo-enzymes (VIM, IMP…) have been also reported internationnaly with high prevalence in Southern Europe and Asia. OXA-48 which is one of the latest carbapenemases reported differs structurally from the other carbapenemases and have been identified mostly from Mediterranean countries. These carbapenemase genes are mostly plasmid located in K. pneumoniae from nosocomial origin. They have been also identified as a source of community-acquired infections. Carbapenemase producers are also multidrug resistant explaining the difficulty to treat infections. Detection of infected patients and carriers remain difficult which may explain an underlying spread with dramatic therapeutic consequences.