LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome

Background

LMO2 is highly expressed at the most immature stages of lymphopoiesis. In T-lymphocytes, aberrant LMO2 expression beyond those stages leads to T-cell acute lymphoblastic leukemia, while in B cells LMO2 is also expressed in germinal center lymphocytes and diffuse large B-cell lymphomas, where it predicts better clinical outcome. The implication of LMO2 in B-cell acute lymphoblastic leukemia must still be explored.

Design and Methods

We measured LMO2 expression by real time RT-PCR in 247 acute lymphoblastic leukemia patient samples with cytogenetic data (144 of them also with survival and immunophenotypical data) and in normal hematopoietic and lymphoid cells.

Results

B-cell acute lymphoblastic leukemia cases expressed variable levels of LMO2 depending on immunophenotypical and cytogenetic features. Thus, the most immature subtype, pro-B cells, displayed three-fold higher LMO2 expression than pre-B cells, common-CD10+ or mature subtypes. Additionally, cases with TEL-AML1 or MLL rearrangements exhibited two-fold higher LMO2 expression compared to cases with BCR-ABL rearrangements or hyperdyploid karyotype. Clinically, high LMO2 expression correlated with better overall survival in adult patients (5-year survival rate 64.8% (42.5%–87.1%) vs. 25.8% (10.9%–40.7%), P= 0.001) and constituted a favorable independent prognostic factor in B-ALL with normal karyotype: 5-year survival rate 80.3% (66.4%–94.2%) vs. 63.0% (46.1%–79.9%) (P= 0.043).

Conclusions

Our data indicate that LMO2 expression depends on the molecular features and the differentiation stage of B-cell acute lymphoblastic leukemia cells. Furthermore, assessment of LMO2 expression in adult patients with a normal karyotype, a group which lacks molecular prognostic factors, could be of clinical relevance.     

Site‐specific addition of an 18F‐N‐methylaminooxy‐containing prosthetic group to a vinylsulfone modified peptide

Numerous strategies employing prosthetic groups for the radiosynthesis of ¹⁸F‐fluorinated peptides for positron emission tomography have been investigated in recent years. We have previously reported a novel [¹⁸F]prosthetic group bearing the N‐methylaminooxy functionality capable of reacting in a site‐selective manner with peptides functionalized with Michael‐acceptors. In a further extension of this methodology we demonstrate that O‐[2‐(2‐[¹⁸F]fluoroethoxy)ethyl]‐N‐methyl‐N‐hydroxylamine, [¹⁸F]4 , reacts chemoselectively with a vinylsulfone functionalized peptide. The conjugation yields were studied with respect to reaction time, level of radioactivity, peptide concentration and purity of the [¹⁸F]prosthetic group used in the conjugation reaction. Incubation at 70°C gave conjugation yields of around 80% with high radiochemical purity after 70 min at pH 5 in acetate buffer. Copyright © 2009 John Wiley & Sons, Ltd.     

Endoscopic Facet Debridement for the treatment of facet arthritic pain - a novel new technique

Study design: Retrospective, observational, open label.Objective: We investigated the efficacy of facet debridement for the treatment of facet joint pain.Summary of background data: Facet joint disease, often due to degenerative arthritis, is common cause of chronic back pain. In patients that don''t respond to conservative measures, nerve ablation may provide significant improvement. Due to the ability of peripheral nerves to regenerate, ablative techniques of the dorsal nerve roots often provide only temporary relief. In theory, ablation of the nerve end plates in the facet joint capsule should prevent reinnervation.Methods: All patients treated with endoscopic facet debridement at our clinic from 2003-2007 with at least 3 years follow-up were included in the analysis. Primary outcome measure was percent change in facet-related pain as measured by Visual Analog Scale (VAS) score at final follow-up visit.Results: A total of 174 people (77 women, 97 men; mean age 64, range 22-89) were included. Location of facet pain was cervical in 45, thoracic in 15, and lumbar in 114 patients. At final follow-up, 77%, 73%, and 68% of patients with cervical, thoracic, or lumbar disease, respectively, showed at least 50% improvement in pain. Mean operating time per joint was 17 minutes (range, 10-42). Mean blood loss was 40 ml (range, 10-100). Complications included suture failure in two patients, requiring reclosure of the incision. No infection or nerve damage beyond what was intended occurred.Conclusions: Our results demonstrate a comparable efficacy of endoscopic facet debridement compared to radiofrequency ablation of the dorsal nerve branch, with durable results. Large scale, randomized trials are warranted to further evaluate the relative efficacy of this surgical treatment in patients with facet joint disease.     

Collaboration between general hospitals and community health services in the care of suicide attempters in Norway: a longitudinal study

Background  

The aim of this paper was to study the collaboration between emergency departments (EDs) in general hospitals and community health services (CHS) in Norway when providing psychosocial care and aftercare to patients treated in EDs following a suicide attempt. We wanted to explore the extent to which quality indicators at the hospital level measured in 1999 and 2006 could predict the presence or absence of a chain of care structure in the CHS in 2006.     

Human and mouse cortical astrocytes differ in aquaporin‐4 polarization toward microvessels

Aquaporin‐4 (AQP4), the predominant water channel in the brain, is expressed in astrocytes and ependymal cells. In rodents AQP4 is highly polarized to perivascular astrocytic endfeet and loss of AQP4 polarization is associated with disease. The present study was undertaken to compare the expression pattern of AQP4 in human and mouse cortical astrocytes. Cortical tissue specimens were sampled from 11 individuals undergoing neurosurgery wherein brain tissue was removed as part of the procedure, and compared with cortical tissue from 5 adult wild‐type mice processed similarly. The tissue samples were immersion‐fixed and prepared for AQP4 immunogold electron microscopy, allowing quantitative assessment of AQP4's subcellular distribution. In mouse we found that AQP4 water channels were prominently clustered around vessels, being 5 to 10‐fold more abundant in astrocytic endfoot membranes facing the capillary endothelium than in parenchymal astrocytic membranes. In contrast, AQP4 was markedly less polarized in human astrocytes, being only two to three‐fold enriched in astrocytic endfoot membranes adjacent to capillaries. The lower degree of AQP4 polarization in human subjects (1/3 of that in mice) was mainly due to higher AQP4 expression in parenchymal astrocytic membranes. We conclude that there are hitherto unrecognized species differences in AQP4 polarization toward microvessels in the cerebral cortex.     

Features of KAT6B-related disorders in a patient with 10q22.1q22.3 deletion

Background: Blepharophimosis is a fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures. It is a rare facial malformation and is considered an important diagnostic feature in dysmorphic analysis. It is likely that many patients with blepharophimosis-mental retardation syndrome have submicroscopic chromosomal rearrangements, and the use of molecular karyotyping can narrow the known blepharophimosis-mental retardation–critical regions or clarify the effect of the haploinsufficiency of the involved genes on the phenotype.

Materials and methods: A female patient presented with bilateral blepharophimosis, ptosis, epicanthus inversus, telecanthus, low-set and small ears, other minor anomalies, hypotonia and psychomotor developmental delay. Metabolic investigations and array CGH analysis were performed. The results of molecular karyotyping were confirmed by real-time PCR analysis.

Results: Molecular karyotyping revealed a 5.2 Mb deletion in the 10q22.1q22.3 region. Real-time PCR analysis of the proband and her parents confirmed the deletion in the proband and revealed its de novo origin.

Conclusions: With ptosis, hypotonia, and developmental delay as the main diagnostic features of our patient, the effect of histone acetyltransferase-encoding KAT6B gene haploinsufficiency was suspected to have a significant role in determining the phenotype. Detailed clinical characterization of the patient provided additional information on the clinical manifestation of the 10q22 deletion.     

Omega‐3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses

Dietary omega‐3 fatty acids accumulate and are actively retained in central nervous system membranes, mainly in synapses, dendrites and photoreceptors. Despite this selective enrichment, their impact on synaptic function and plasticity has not been fully determined at the molecular level. In this study, we explored the impact of omega‐3 fatty acid deficiency on synaptic function in the hippocampus. Dietary omega‐3 fatty acid deficiency for 5 months after weaning led to a 65% reduction in the concentration of docosahexaenoic acid in whole brain synaptosomal phospholipids with no impact on global dopaminergic or serotonergic turnover. We observed reduced concentrations of glutamate receptor subunits, including GluA1, GluA2 and NR2B, and synaptic vesicle proteins synaptophysin and synaptotagmin 1 in hippocampal synaptosomes of omega‐3 fatty acid‐deficient mice as compared to the omega‐3 fatty acid rich group. In contrast, an increased concentration of neuronal inositol 1,4,5‐trisphosphate‐receptor (IP₃‐R) was observed in the deficient group. Furthermore, omega‐3 fatty acid deficiency reduced the long‐term potentiation (LTP) in stratum oriens of the hippocampal CA1 area, but not in stratum radiatum. Thus, omega‐3 fatty acids seem to have specific effects in distinct subsets of glutamatergic synapses, suggesting specific molecular interactions in addition to altering plasma membrane properties on a more global scale.