BAK1 gene variation and abdominal aortic aneurysms

We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene (BAK1) that codes for an apoptotic‐promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism (SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in “minority” forms within specific nondiseased tissues and be selected for, when intra‐ and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny. Hum Mutat 30:1–5, 2009. © 2009 Wiley‐Liss, Inc.     

Using EMGs and kinematics data to study the take-off technique of experts and novices for a pole vaulting short run-up educational exercise

This study attempts to characterise the electromyographic activity and kinematics exhibited during the performance of take-off for a pole vaulting short run-up educational exercise, for different expertise levels. Two groups (experts and novices) participated in this study. Both groups were asked to execute their take-off technique for that specific exercise. Among the kinematics variables studied, the knee, hip and ankle angles and the hip and knee angular velocities were significantly different. There were also significant differences in the EMG variables, especially in terms of (i) biceps femoris and gastrocnemius lateralis activity at touchdown and (ii) vastus lateralis and gastrocnemius lateralis activity during take-off. During touchdown, the experts tended to increase the stiffness of the take-off leg to decrease braking. Novices exhibited less stiffness in the take-off leg due to their tendency to maintain a tighter knee angle. Novices also transferred less energy forward during take-off due to lack of contraction in the vastus lateralis, which is known to contribute to forward energy transfers. This study highlights the differences in both groups in terms of muscular and angular control according to the studied variables. Such studies of pole vaulting could be useful to help novices to learn expert's technique.     

Ventricular arrhythmias in patients treated with methadone for opioid dependence

Purpose  

Over the last decade, there has been a significant rise in reported cases of methadone induced QT prolongation (QTP) and Torsades de Pointes (TdP) in patients treated for opioid dependence. Optimal management of these patients is challenging.     

Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations and resulting from mutations in two major genes: ENG and ACVRL1. The aim of the present study was to estimate the prevalence of the mutations of ENG and ACVRL1 in HHT, based on the largest series of patients reported so far, recruited through a national network. We previously reported the first mutation screening of both genes, in French HHT patients, using heteroduplex analysis. This previous study, bringing 60 novel mutations, provided a significant improvement to the knowledge of molecular pathology in HHT. However, 32% (n=48) of the patients with a confirmed clinical diagnosis remained without mutation. In these patients, we performed an extensive molecular analysis that included the sequencing of the whole coding sequence, the search for large rearrangements, and screening of the potential 5' regulatory regions. Additionally, due to the lack of large pedigrees suitable for linkage analysis, and since SMAD4 germline mutations have been reported in families with combined HHT and juvenile polyposis, we screened this gene and five other genes involved in the TGF-beta/BMP pathway in the patients without mutation of ENG or ACVRL1. Only a novel SMAD1 non-conservative substitution was found in one patient, changing a poorly conserved methionine to an isoleucin. Twenty-three mutations were found in ACVRL1 and 8 in ENG (including a duplication of exons 4 to 8 and deletions of exons 1 to 3 and 9 to 14). Our results, combined with our previous data, increase the mutation rate to 88% (n=119/136) in French patients with a confirmed clinical diagnosis. Our results also emphasize the higher prevalence of large insertions/deletions in ENG and the predominance of ACVRL1 over ENG mutations.     

Notch/Delta4 interaction in human embryonic liver CD34+ CD38- cells: positive influence on BFU-E production and LTC-IC potential maintenance

We investigated whether Notch signaling pathways have a role in human developmental hematopoiesis. In situ histochemistry analysis revealed that Notch1, 2, and 4 and Notch ligand (Delta1-4, and Jagged1) proteins were not expressed in the yolk sac blood islands, the para-aortic splanchnopleure, the hematopoietic aortic clusters, and at the early stages of embryonic liver hematopoiesis. Notch1-2, and Delta4 were eventually detected in the embryonic liver, from 34 until 38 days postconception. Fluorescence-activated cell sorter analysis showed that first-trimester embryonic liver CD34(+)CD38(low) cells expressed both Notch1 and Notch2. When these cells were cultured on S17 stroma stably expressing Delta4, a 2.6-fold increase in BFU-E number was observed at day 7, as compared with cultures with control stroma, and this effect was maintained for 2 weeks. Importantly, exposure of these cells to Delta4 under these conditions maintained the original frequency and quality of long-term culture-initiating cells (LTC-ICs), while control cultures quickly resulted in the extinction of this LTC-IC potential. Furthermore, short-term exposure of embryonic liver adherent cells to erythropoietin resulted in a dose-dependent increase in Delta4 expression, almost doubling the expression observed with untreated stroma. This suggests that Delta4 has a role in the regulation of hematopoiesis after a hypoxic stress in the fetus.     

GM3 synthase deficiency in non-Amish patients

PurposeBiallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD) responsible for Amish infantile epilepsy syndrome. All Amish patients carry the homozygous p.(Arg288Ter) variant arising from a founder effect. To date only 10 patients from 4 non-Amish families have been reported. Thus, the phenotypical spectrum of GM3SD due to other variants and other genetic backgrounds is still poorly known.MethodsWe collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants resulting in GM3SD.ResultsWe identified 12 families originating from Reunion Island, Ivory Coast, Italy, and Algeria and carrying 6 ST3GAL5 variants, 5 of which were novel. Genealogical investigations and/or haplotype analyses showed that 3 of these variants were founder alleles. Glycosphingolipids quantification in patients’ plasma confirmed the pathogenicity of 4 novel variants. All patients (N = 16), aged 2 to 12 years, had severe to profound intellectual disability, 14 of 16 had a hyperkinetic movement disorder, 11 of 16 had epilepsy and 9 of 16 had microcephaly. Other main features were progressive skin pigmentation anomalies, optic atrophy or pale papillae, and hearing loss.ConclusionThe phenotype of non-Amish patients with GM3SD is similar to the Amish infantile epilepsy syndrome, which suggests that GM3SD is associated with a narrow and severe clinical spectrum.     

Myofibroblastic malignancies

Malignant tumors composed of myofibroblasts are increasingly being recognized, but their existence remains controversial. Currently accepted examples within this category represent spindle cell or pleomorphic neoplasms of the soft tissues with a spectrum of histological grades. Low- and intermediate-grade myofibrosarcomas are fascicular spindle cell neoplasms resembling fibrosarcoma or leiomyosarcoma. They infiltrate deep soft tissue with disproportionate involvement of head and neck sites and can recur locally but infrequently metastasize. They variably express myoid immunohistochemical markers, and their differential diagnosis includes benign myofibroblastic proliferations such as fasciitis and fibromatosis as well as other types of spindle cell sarcoma. High-grade (pleomorphic) myofibrosarcomas are an ultrastructurally defined subset of malignant fibrous histiocytoma, which they resemble in morphology and behavior. Inflammatory myofibroblastic tumor and infantile fibrosarcoma are neoplasms that have myofibroblastic features and have been included in this category, but they have distinctive genetic findings. This article reviews the concept of myofibrosarcoma and describes its variants.