Compressed sensing in hyperpolarized 3He Lung MRI

In this work, the application of compressed sensing techniques to the acquisition and reconstruction of hyperpolarized ³He lung MR images was investigated. The sparsity of ³He lung images in the wavelet domain was investigated through simulations based on fully sampled Cartesian two‐dimensional and three‐dimensional ³He lung ventilation images, and the k‐spaces of 2D and 3D images were undersampled randomly and reconstructed by minimizing the L1 norm. The simulation results show that temporal resolution can be readily improved by a factor of 2 for two‐dimensional and 4 to 5 for three‐dimensional ventilation imaging with ³He with the levels of signal to noise ratio (SNR) (～19) typically obtained. The feasibility of producing accurate functional apparent diffusion coefficient (ADC) maps from undersampled data acquired with fewer radiofrequency pulses was also demonstrated, with the preservation of quantitative information (mean ADC_cs ～ mean ADC_full ～ 0.16 cm² sec^?1). Prospective acquisition of 2‐fold undersampled two‐dimensional ³He images with a compressed sensing k‐space pattern was then demonstrated in a healthy volunteer, and the results were compared to the equivalent fully sampled images (SNR_cs = 34, SNR_full = 19). Magn Reson Med 63:1059–1069, 2010. © 2010 Wiley‐Liss, Inc.     

Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder caused by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. We performed molecular characterization in clinically affected probands of 31 HHT families and detected a total of 28 different mutations in the two genes, including four shared by more than one family. Twelve mutations were identified in the ENG gene, six of which were novel and comprised two nonsense mutations in exons 6 and 8, deletions in exons 5 and 11, and splice site mutations in exon 12 and intron 8. Eleven of sixteen mutations identified in the ALK1 gene were novel single base pair substitutions in exons 4, 7, 8, and 9. We also describe the first de novo ALK1 mutation that causes a previously unreported c.1133C>A substitution of a highly conserved residue (p.P378H). The proband and his two daughters, who also carried the familial mutation, all suffered from gastrointestinal (GI) bleeding. In addition, we report seven newly identified polymorphisms and summarize all known ones in both genes.     

Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North‐African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi‐allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North‐African patients. This mutation is estimated to date back at least 1,400–1,750 years ago. The identification of this major allele allowed us to suggest a cost‐effective genetic diagnostic strategy in North‐African patients with PCD.     

Expression of Integrin α6β1 Enhances Tumorigenesis in Glioma Cells

The integrin α6β1 and its main ligand laminin-111 are overexpressed in glioblastoma, as compared with normal brain tissue, suggesting they may be involved in glioblastoma malignancy. To address this question, we stably expressed the α6 integrin subunit in the U87 cell line via retroviral-mediated gene transfer. We show that cell surface expression of the α6β1 integrin led to dramatic changes in tumor U87 cell behavior, both in vitro and in vivo. Nude mice receiving either subcutaneous or intracerebral inoculation of α6β1-expressing cells developed substantially more voluminous tumors than mice injected with control cells. The difference in tumor growth was associated with a marked increase in vascularization in response to α6β1 integrin expression and may also be related to changes in the balance between cell proliferation and survival. Indeed, expression of α6β1 enhanced proliferation and decreased apoptosis of U87 cells both in the tumor and in vitro. Additionally, we demonstrate that α6β1 is implicated in glioblastoma cell migration and invasion and that laminin-111 might mediate dissemination of α6β1-positive cells in vivo. Our results highlight for the first time the considerable role of the integrin α6β1 in glioma progression.Malignant brain tumors have an increasing incidence in both children and adults. In adults, the most common type of primary brain tumor, malignant glioma, is considered as one of the deadliest of human cancers. Despite recent advances in both diagnostic modalities and therapeutic strategies, the 5-year survival rate of less than 3% in patients with glioblastoma is among the lowest for all cancers.¹ Patients with the most malignant histopathological subtype, glioblastoma, carry the worst prognosis, with median survival rate of less than 1 year, despite aggressive surgery associated with adjuvant radiotherapy and chemotherapy.¹ Glioblastoma are characterized by rapidly dividing cells, high degree of vascularity, invasion into normal brain tissue, and an intense resistance to death-inducing stimuli.^2,3 Since integrins, the major family of extracellular matrix (ECM) receptors, are involved in these events, they are one of the most promising molecules to consider for a targeted therapy.Integrins are cell surface transmembrane αβ heterodimers that recognize specific ECM ligands. The combination of α and β subunits, leading to the formation of at least 24 receptors, determines the ligand specificity.⁴ Glioblastoma commonly displays enhanced expression of several integrins along with their ECM ligands: αvβ3 and αvβ5 (tenascin and vitronectin receptors), α5β1 (fibronectin receptor), α2β1 (collagens receptor), and α3β1, α6β4, and α6β1 (laminins receptors).⁵ Numerous studies have focused on the αv integrin family. The integrins αvβ3 and αvβ5 are markers of glioblastoma malignancy⁶ and influence a variety of processes in glioblastoma progression in vivo, including proliferation, apoptosis, and angiogenesis.⁷ Furthermore, cilengitide, an αvβ3 and αvβ5 integrins antagonist, extends mouse survival by delaying the tumor growth^8,9 and is nowadays in clinical trial for recurrent malignant glioma. Two other integrins, α5β1 and α3β1, have been shown to be implicated in glioma cell adhesion and migration in vitro.^10,11 In addition, the use of α5β1 antagonists reduces glioma cell proliferation in vitro,¹⁰ while α3β1 antagonists inhibited glioma invasion in vivo.¹¹The α6 integrin subunit associates with β1 or β4 subunits to form functional heterodimers that selectively bind laminins. The α6β4 integrin is essential for the organization and maintenance of epithelial hemidesmosomes that link the intermediate filaments with the extracellular matrix.¹² The major ligand of α6β4 is the laminin-332, while α6β1 is a well-characterized laminin-111 receptor. Overexpression of α6β1 integrin has been associated with the progression of many epithelial tumors. In particular, induction of α6β1 expression is an early event in hepatocellular carcinogenesis.^13,14 In the same way, during prostate cancer progression α6β1 is continually expressed and found in micrometastases.¹⁵ Expression of α6β1 integrin has also been linked to metastatic potential of melanoma cells,¹⁶ and has been involved in the survival and metastatic potential of human breast carcinoma cells.^17,18 Moreover, in a recent study using the α6-blocking antibody GoH3, Lee et al¹⁹ inhibited angiogenesis and breast carcinoma growth in vivo.Several studies concerning gliomas and the α6β1 ligand laminin-111 have been reported in the literature. Using immunohistochemistry studies, Gingras et al²⁰ showed that α6 integrin was strongly expressed in glioblastoma tissue, whereas it was weakly expressed in normal brain. Previtali et al²¹ confirmed that the expression of α6 was increased in glioblastoma and in other central nervous system tumors, such as meningioma, astrocytoma, and neuroblastoma, when compared with the autologous normal tissue counterpart. In glioblastoma biopsies, laminin-111 is highly expressed on tumor blood vessels, but also within the brain tumor as punctuate deposits and at the tumor invasion front.²² In vitro, glioma cells can both secrete laminin-111 and induce its expression in normal brain tissue.^22,23,24 Moreover, laminin-111 is one of the most permissive substrates for adhesion and migration of glioma cells in vitro.^25,26,27 Additionally, over laminin-111, migrating glioma cells are protected from apoptosis.²⁸ For all these reasons, we hypothesized that laminin-111 and its main receptor α6β1 may contribute to glioblastoma progression.In the present study we investigated the role of integrin α6β1 in glioblastoma malignancy by using U87, a well-characterized glioblastoma cell line. We report that stable expression of α6β1 in this α6-negative cell line leads to enhanced tumor progression and tumor growth in vivo. We demonstrate that α6β1 is pro-angiogenic and acts on the balance between proliferation and apoptosis. Additionally, we show that α6β1 is involved in glioblastoma cell migration and invasion. Our results highlight for the first time the considerable role of integrin α6β1 in the malignant phenotype of glioblastoma cells and demonstrate that the α6β1-expressing cell is an appropriate model for the study of glioblastoma progression.     

Mapping of a novel type III variant of Knobloch syndrome (KNO3) to chromosome 17q11.2

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by ocular abnormalities (myopia and retinal detachment) and occipital encephalocele. The syndrome is clinically and genetically heterogeneous (KNO1, KNO2). Previously germline mutations in COL18A1 (21q22.3) were detected in some families, but in other kindreds linkage to COL18A1 was excluded. We ascertained a large consanguineous family with high myopia, vitreoretinal degeneration and occipital scalp defect with autosomal recessive mode of inheritance. Due to the overlapping clinical presentation of this family with Knobloch syndrome we propose this phenotype as a type III variant of KS (KNO3). A genome wide linkage study using microsatellite markers at 10-20 cM interval revealed linkage to 17q11.2 with a maximum LOD scores 3.40 (theta = 0.00) for markers D17S1307 and D17S1166. Fine mapping defined a 2.67 cM disease region between D17S1307 and D17S798. Mutation analysis of three candidate genes (UNC119, MYO1D, and RAB11FIP4) within the disease region did not identify any disease-associated mutation in affected individuals.     

A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family

Hereditary Spastic Paraplegias (HSP) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by insidiously progressive weakness and spasticity of the lower extremities. We describe a consanguineous Saudi family segregating a complicated form of HSP in an autosomal recessive pattern. The two affected siblings had early onset, cognitive, speech and motor involvement with spasticity of the lower extremities. Their upper extremities were mildly hypertonic. An intronic splice acceptor site mutation in ERLIN2 was found to be responsible for causing this disorder found in this family. ERLIN2 is a mediator of endoplasmic reticulum degradation pathway (ERAD) which helps to remove the aberrant proteins. Our results, in concurrence with previous studies suggest that alteration in ERLIN2 is one of the causes of complicated HSP, thereby increasing the spectrum of known mutations in SPG18.     

Childhood stroke in Eastern Province, KSA: pattern, risk factors, diagnosis and outcome

Background and purpose:  Stroke has been increasingly recognized in children in recent years, but diagnosis and management can be difficult because of the diversity of underlying risk factors, atypical presentation and the absence of a uniform treatment approach. The aim of this study was to examine risk factors, clinical presentation, imaging findings and outcomes of paediatric stroke in Eastern Province, Kingdom of Saudi Arabia (KSA).
Subjects and methods:  We evaluated 25 patients (11 boys and 14 girls) using computerized tomography scan of the brain, magnetic resonance (MR) imaging and MR angiography. Cardiac assessment, haematological tests, immunological tests, infection and metabolic screening were also performed in the patients. After discharge, the patients were monitored regularly in the neurology clinic to detect their outcomes.
Results:  A total of 76% of the patients presented with ischaemic stroke, while the remaining 24% had haemorrhagic stroke. Sickle cell disease (SCD) was the commonest risk factor for stroke (36%) followed by non determinate causes (20%). Seizure was the commonest clinical presentation (54%) followed by haemiplegia (31%) and decreased level of consciousness (30%). Recurrence occurred in SCD patients (80%) and patients with moyamoya disease (20%). Regarding the outcome, long-term deficit was the commonest (44%), while short-term deficit and death were equal (28% each).
Conclusion:  Our study in Eastern Province, KSA, showed agreement with other studies regarding risk factors, clinical presentation, imaging features and outcomes of stroke in children, yet with some points of differences, which are as follows: (1) SCD is the commonest risk factor in our study population, while in Chinese study it was not, (2) The percentage of cardiac disorders as a risk factor in this study was less than that in the European and American studies, and (3) there was relative discrepancy regarding predictors of outcome.