Hybrid approach to intrapancreatic inferior pancreaticoduodenal aneurysm repair.

Pancreaticoduodenal artery aneurysms (PDAAs) are an extremely rare visceral artery aneurysm subtype, usually managed by endovascular techniques. We report the case of a 57-year-old man with an intrapancreatic, inferior PDAA abutting the superior mesenteric artery (SMA). This location, in relation to the SMA, risks SMA thrombosis using an endovascular-only approach.

Computational fluid dynamics modeling of intracranial aneurysms: qualitative comparison with cerebral angiography.

Rationale And Objective: The purpose of this study is to determine whether computational fluid dynamics modeling can correctly predict the location of the major intra-aneurysmal flow structures that can be identified by conventional angiography.

Materials And Methods: Patient-specific models of three cerebral aneurysms were constructed from three-dimensional rotational angiography images and computational fluid dynamic simulations performed. Using these velocity fields, contrast transport was simulated and visualizations constructed to provide a "virtual" angiogram.

Human embryonic stem cells and gene therapy.

Human embryonic stem cells (hESCs) theoretically represent an unlimited supply of normal differentiated cells to engineer diseased tissues to regain normal function. However, before hESCs can be useful as human therapeutics, technologies must be developed to provide them with the specific signals required to differentiate in a controlled fashion, to regulate and/or shut down the growth of hESCs and their progeny once they have been transferred to the recipient, and to circumvent the recognition of non-autologous hESC-derived cells as foreign. In the context that gene therapy technologies represent strategies to deliver biological signals to address all of these challenges, this review sets out a framework for combined gene transfer/hESC therapies.

Correction of a murine model of von Willebrand disease by gene transfer.

von Willebrand disease (VWD), the most common inherited bleeding disorder in the U.S. population, is caused by defects in the expression and processing of von Willebrand factor (VWF), a blood glycoprotein required for normal hemostasis that mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet glycoproteins and to constituents of exposed connective tissue.

Characterization of cerebral aneurysms for assessing risk of rupture by using patient-specific computational hemodynamics models.

Background And Purpose: Hemodynamic factors are thought to play an important role in the initiation, growth, and rupture of cerebral aneurysms. This report describes a pilot clinical study of the association between intra-aneurysmal hemodynamic characteristics from computational fluid dynamic models and the rupture of cerebral aneurysms.

Methods: A total of 62 patient-specific models of cerebral aneurysms were constructed from 3D angiography images.

Protective immunity against alpha-cobratoxin following a single administration of a genetic vaccine encoding a non-toxic cobratoxin variant.

Venomous snakebites result in almost 125,000 deaths per year worldwide. We present a new paradigm for the development of vaccines to protect against snakebite, using knowledge of the structure and action of specific toxins combined with a gene-based strategy to deliver a toxin gene modified to render it non-toxic while maintaining its three-dimensional structure and hence its ability to function as an immunogen. As a model for this approach, we developed a genetic vaccine to protect against alpha-cobratoxin (CTX), a potent, post-synaptic neurotoxin that is the major toxic component of the venom of Naja kaouthia, the monocellate cobra.

Deletions in L-type calcium channel alpha1 subunit testicular transcripts correlate with testicular cadmium and apoptosis in infertile men with varicoceles.

Objective: To identify and understand predictors of successful varicocelectomy.

Design: Examination of testicular L-type voltage-dependent calcium channel (L-VDCC) mRNAs and proteins in testis biopsies and comparison of presence and absence of various mRNAs with testicular cadmium levels, with apoptosis, and with sperm count change after varicocelectomy.

Setting: University clinical urology practice and research laboratories.

Gene transfer-mediated pre-mRNA segmental trans-splicing as a strategy to deliver intracellular toxins for cancer therapy.

Virus-mediated transfer of genes coding for intracellular toxins holds promise for cancer therapy, but the inherent toxicity of such vectors make them a risk to normal tissues and a challenge to produce due to the intrinsic dilemma that expression of toxin molecules kills producer cells. We employed pre-mRNA segmental trans-splicing (STS), in which two engineered DNA fragments coding for 5' "donor" and 3' "acceptor" segments of a toxin gene, respectively, are expressed by viral vectors. When co-delivered to target cells, the two vectors generate two toxin pre-mRNA fragments which are spliced by the target cell machinery to produce functional mRNA and toxin.

Dopamine D4 receptor gene and attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder is a prevalent disorder characterized by hyperactivity, impulsivity, and attentional dysfunction. It is familial and heritable. Its pathophysiology is thought to involve an abnormality of the brain's dopaminergic neurotransmitter system.

Genetic medicine at the RNA level: modifications of the genetic repertoire for therapeutic purposes by pre-mRNA trans-splicing.

Gene therapy is conventionally carried out by transferring genetic material to the target cell where the exogenous gene is expressed using the endogenous transcription and translation machinery in parallel with the target cell genome. This review focuses on a new paradigm of gene therapy, the use of trans-splicing to modify the genetic repertoire at the pre-mRNA level to treat genetic and acquired disorders. Therapeutic trans-splicing can be used to alter coding domains, to create novel fusion proteins, to direct gene products to various cellular compartments, and to overcome some of the limitations to vector-derived gene transfer technology, including gene therapy with large genes or with genes coding for toxic proteins.

Trans-splicing repair of CD40 ligand deficiency results in naturally regulated correction of a mouse model of hyper-IgM X-linked immunodeficiency.

X-linked immunodeficiency with hyper-IgM (HIGM1), characterized by failure of immunoglobulin isotype switching, is caused by mutations of the CD40 ligand (CD40L), which is normally expressed on activated CD4(+) T cells. As constitutive expression of CD40L induces lymphomas, we corrected the mutation while preserving the natural regulation of CD40L using pre-mRNA trans-splicing. Bone marrow from mice lacking CD40L was modified with a lentivirus trans-splicer encoding the normal CD40L exons 2-5 and was administered to syngenic CD40L-knockout mice.

In vivo trans-splicing of 5' and 3' segments of pre-mRNA directed by corresponding DNA sequences delivered by gene transfer.

We have developed a new paradigm of in vivo gene transfer termed "segmental trans-splicing" (STS), in which individual "donor" and "acceptor" DNA sequences, delivered in vitro or in vivo, generate pre-mRNAs with 5' and 3' splice signals, respectively, and complementary hybridization domains through which the two pre-mRNAs interact, facilitating trans-splicing of the two mRNA fragments. To demonstrate STS, we used alpha-cobratoxin, a neurotoxin that binds irreversibly to postsynaptic nicotinic acetylcholine receptors. Cells or animals receiving both donor and acceptor plasmids, but neither plasmid alone, yielded RT-PCR products with the correct sequence of mature alpha-cobratoxin mRNA, suggesting that trans-splicing had occurred.

Adenovirus E4 gene promotes selective endothelial cell survival and angiogenesis via activation of the vascular endothelial-cadherin/Akt signaling pathway.

The early 4 region (E4) of the adenoviral vectors (AdE4(+)) prolongs human endothelial cell (EC) survival and alters the angiogenic response, although the mechanisms for the EC-specific, AdE4(+)-mediated effects remain unknown. We hypothesized that AdE4(+) modulates EC survival through activation of the vascular endothelial (VE)-cadherin/Akt pathway. Here, we showed that AdE4(+), but not AdE4(-) vectors, selectively stimulated phosphorylation of both Akt at Ser(473) and Src kinase in ECs.

Green fluorescent protein selectively induces HSP70-mediated up-regulation of COX-2 expression in endothelial cells.

Reporter genes, including green fluorescent protein (GFP), have been used to monitor the expression of transgenes introduced into vascular cells by gene transfer vectors. Here, we demonstrate that GFP by itself can selectively induce expression of certain genes in endothelial cells. Elevation of the cytoplasmic concentration of GFP in endothelial cells, specifically, resulted in a robust upregulation of heat shock protein 70 (HSP70).

Intraoperative MR systems. Midfield approaches.

Intraoperative MR imaging provides an unrestricted view of intracranial structures and lesions that has revolutionized the way that neurosurgery is performed in the authors' institution. Intraoperative imaging allows the practitioner to update and adjust the approach to intracranial lesions continuously. With this system, important anatomic and vascular structures can be successfully avoided; boundaries of low-grade tumors can be accurately defined, and foci of possible higher grade within these lesions can be identified; foci of high-grade astrocytomas can be differentiated from radiated brain; hyperacute hemorrhage or infarction during and after procedures can be determined; and the possible communication of cystic collections with CSF can be ascertained.

Feasibility of gene therapy for late neuronal ceroid lipofuscinosis.

Late infantile neuronal ceroid lipofuscinosis is a progressive childhood neurodegenerative disorder characterized by intracellular accumulation of autofluorescent material resembling lipofuscin in neuronal cells. This report summarizes the new therapies under consideration for late infantile neuronal ceroid lipofuscinosis, with a focus on strategies for in vivo gene therapy for the retinal and central nervous system manifestations of the disease.

Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line.

We investigated whether the efficacy of fenretinide (HPR) against ovarian tumours may be limited by induction of resistance. The human ovarian carcinoma cell line A2780, which is sensitive to a pharmacologically achievable HPR concentration (IC(50)= 1 microM), became 10-fold more resistant after exposure to increasing HPR concentrations. The cells (A2780/HPR) did not show cross-resistance to the synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and were not sensitive, similarly to the parent line, to all-trans-retinoic acid, 13-cis-retinoic acid or N-(4-methoxyphenyl)retinamide.

Serial intraoperative magnetic resonance imaging of brain shift.

Objective: A major shortcoming of image-guided navigational systems is the use of preoperatively acquired image data, which does not account for intraoperative changes in brain morphology. The occurrence of these surgically induced volumetric deformations ("brain shift") has been well established. Maximal measurements for surface and midline shifts have been reported.

Evaluation of two current generation enzyme immunoassays and an improved isolation-based assay for the rapid detection and isolation of rotavirus from stool.

Background: Rapid and accurate rotavirus testing is important in decisions involving patient care and management. Quality assurance testing needs to be periodically performed, especially among widely used assays having a direct impact on patient care.

Objectives: To evaluate the current generation Kallestad Pathfinder Direct antigen Detection system (PTH), and the widely used Rotaclone(R) Rotavirus EIA Diagnostic Kit (RTC), in comparison with an improved cell culture amplification-antigen detection (CCA-Ag) isolation-based assay.

Rheolytic thrombectomy of the occluded internal carotid artery in the setting of acute ischemic stroke.

Background And Purpose: Acute thromboembolic stroke complicated by ipsilateral carotid occlusion may present both mechanical and inflow-related barriers to effective intracranial thrombolysis. We sought to review our experience with a novel method of mechanical thrombectomy, in such cases, using the Possis AngioJet system, a rheolytic thrombectomy device.

Methods: A review of our interventional neuroradiology database revealed three patients in whom an occluded cervical internal carotid artery was encountered during endovascular treatment for acute stroke and in whom thrombectomy was attempted, using the 5F Possis AngioJet thrombectomy catheter.

Intra-operative MR guidance during trans-sphenoidal pituitary resection: preliminary results.

The use of intra-operative MR image guidance has the potential to improve the precision, extent, and safety of trans-sphenoidal pituitary resections. The trans-sphenoidal approach to pituitary surgery has been performed for some time (1--3). Until now these surgeries have relied on direct visualization without the aid of image guidance.

Intraoperative diffusion imaging on a 0.5 Tesla interventional scanner.

Intraoperative line scan diffusion imaging (LSDI) on a 0.5 Tesla interventional MRI was performed during neurosurgery in three patients. Diffusion trace images were obtained in acute ischemic cases.

Silent thromboembolic events associated with the treatment of unruptured cerebral aneurysms by use of Guglielmi detachable coils: prospective study applying diffusion-weighted imaging.

Background And Purpose: Aneurysm embolization using Guglielmi detachable coils (GDC) is gaining increasing acceptance as a viable alternative to surgery in the treatment of cerebral aneurysms. Although recent reports describe a significant rate of symptomatic thromboembolic complications with GDC use, many of the neurologic deficits are transient. We sought to determine the incidence of silent thromboembolic events with the use of diffusion-weighted imaging and to correlate radiologic findings with the results of neurologic examinations.