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Synthesis of substituted 2-aminoimidazoles via Pd-catalyzed alkyne carboamination reactions. Application to the synthesis of preclathridine natural products.
Org. Lett.
PUBLISHED: 09-08-2014
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A new method for the synthesis of 2-aminoimidazole products is described. The heterocyclic products are generated in good yields via Pd-catalyzed carboamination reactions of N-propargyl guanidines and aryl triflates. This methodology generates both a C-N and C-C bond during the annulation step and facilitates the rapid construction of 2-aminoimidazole products with different aryl groups. The utility of this methodology was demonstrated in the total synthesis of preclathridine A, preclathridine B, and dorimidazole B from a single intermediate.
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Monolithic NPG nanoparticles with large surface area, tunable plasmonics, and high-density internal hot-spots.
Nanoscale
PUBLISHED: 06-14-2014
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Plasmonic metal nanostructures have shown great potential in sensing, photovoltaics, imaging and biomedicine, principally due to the enhancement of local electric field by light-excited surface plasmons, i.e., collective oscillation of conduction band electrons. Thin films of nanoporous gold have received a great deal of interest due to the unique 3-dimensional bicontinuous nanostructures with high specific surface area. However, in the form of semi-infinite thin films, nanoporous gold exhibits weak plasmonic extinction and little tunability in the plasmon resonance, because the pore size is much smaller than the wavelength of light. Here we show that by making nanoporous gold in the form of disks of sub-wavelength diameter and sub-100 nm thickness, these limitations can be overcome. Nanoporous gold disks not only possess large specific surface area but also high-density, internal plasmonic "hot-spots" with impressive electric field enhancement, which greatly promotes plasmon-matter interactions as evidenced by spectral shifts in the surface plasmon resonance. In addition, the plasmonic resonance of nanoporous gold disks can be easily tuned from 900 to 1850 nm by changing the disk diameter from 300 to 700 nm. Furthermore, nanoporous gold disks can be fabricated as either bound on a surface or as non-aggregating colloidal suspension with high stability.
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Stereocontrolled synthesis of bicyclic sulfamides via Pd-catalyzed alkene carboamination reactions. Control of 1,3-asymmetric induction by manipulating mechanistic pathways.
Org. Lett.
PUBLISHED: 06-11-2014
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A new annulation strategy for the synthesis of trans-bicyclic sulfamides is described. The Pd-catalyzed alkene carboamination reactions of 2-allyl and cis-2,5-diallyl pyrrolidinyl sulfamides with aryl and alkenyl triflates afford the fused bicyclic compounds in good yields and with good diastereoselectivity (up to 13:1 dr). Importantly, by employing reaction conditions that favor an anti-aminopalladation mechanism, the relative stereochemistry between the C3 and C4a stereocenters of the products is reversed relative to related Pd-catalyzed carboamination reactions that proceed via syn-aminopalladation.
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Adeno-associated virus serotypes 1, 8, and 9 share conserved mechanisms for anterograde and retrograde axonal transport.
Hum. Gene Ther.
PUBLISHED: 05-02-2014
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Adeno-associated virus (AAV) vectors often undergo long-distance axonal transport after brain injection. This leads to transduction of brain regions distal to the injection site, although the extent of axonal transport and distal transduction varies widely among AAV serotypes. The mechanisms driving this variability are poorly understood. This is a critical problem for applications that require focal gene expression within a specific brain region, and also impedes the utilization of vector transport for applications requiring widespread delivery of transgene to the brain. Here, we compared AAV serotypes 1 and 9, which frequently demonstrate distal transduction, with serotype 8, which rarely spreads beyond the injection site. To examine directional AAV transport in vitro, we used a microfluidic chamber to apply dye-labeled AAV to the axon termini or to the cell bodies of primary rat embryonic cortical neurons. All three serotypes were actively transported along axons, with transport characterized by high velocities and prolonged runs in both the anterograde and retrograde directions. Coinfection with pairs of serotypes indicated that AAV1, 8, and 9 share the same intracellular compartments for axonal transport. In vivo, both AAV8 and 9 demonstrated anterograde and retrograde transport within a nonreciprocal circuit after injection into adult mouse brain, with highly similar distributions of distal transduction. However, in mass-cultured neurons, we found that AAV1 was more frequently transported than AAV8 or 9, and that the frequency of AAV9 transport could be enhanced by increasing receptor availability. Thus, while these serotypes share conserved mechanisms for axonal transport both in vitro and in vivo, the frequency of transport can vary among serotypes, and axonal transport can be markedly increased by enhancing vector uptake. This suggests that variability in distal transduction in vivo likely results from differential uptake at the plasma membrane, rather than fundamental differences in transport mechanisms among AAV serotypes.
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Synthesis of substituted tetrahydroindoloisoquinoline derivatives via intramolecular Pd-catalyzed alkene carboamination reactions.
J. Org. Chem.
PUBLISHED: 04-11-2014
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Intramolecular Pd-catalyzed alkene carboamination reactions of substituted 2-allyl-N-(2-bromobenzyl)anilines are described. The substrates for these reactions are generated in two steps from readily available 2-allylanilines and 2-bromobenzaldehyde derivatives. The transformations afford substituted tetrahydroindoloisoquinolines, an uncommon class of fused bicyclic heterocycles, in good yield. The mechanism of these transformations is described, and a model that accounts for the observed product stereochemistry is proposed.
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High-resolution magnetic resonance microscopy and diffusion tensor imaging to assess brain structural abnormalities in the murine mucopolysaccharidosis VII model.
J. Neuropathol. Exp. Neurol.
PUBLISHED: 02-25-2014
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High-resolution microscopic magnetic resonance imaging (?MRI) and diffusion tensor imaging (DTI) were performed to characterize brain structural abnormalities in a mouse model of mucopolysaccharidosis type VII (MPS VII). Microscopic magnetic resonance imaging demonstrated a decrease in the volume of anterior commissure and corpus callosum and a slight increase in the volume of the hippocampus in MPS VII versus wild-type mice. Diffusion tensor imaging indices were analyzed in gray and white matter. In vivo and ex vivo DTI demonstrated significantly reduced fractional anisotropy in the anterior commissure, corpus callosum, external capsule, and hippocampus in MPS VII versus control brains. Significantly increased mean diffusivity was also found in the anterior commissure and corpus callosum from ex vivo DTI. Significantly reduced linear anisotropy was observed from the hippocampus from in vivo DTI, whereas significantly decreased planar anisotropy and spherical anisotropy were observed in the external capsule from only ex vivo DTI. There were corresponding morphologic differences in the brains of MPS VII mice by hematoxylin and eosin staining. Luxol fast blue staining demonstrated less intense staining of the corpus callosum and external capsule; myelin abnormalities in the corpus callosum were also demonstrated quantitatively in toluidine blue-stained sections and confirmed by electron microscopy. These results demonstrate the potential for ?MRI and DTI for quantitative assessment of brain pathology in murine models of brain diseases.
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Influence of catalyst structure and reaction conditions on anti- versus syn-aminopalladation pathways in Pd-catalyzed alkene carboamination reactions of N-allylsulfamides.
Chemistry
PUBLISHED: 02-19-2014
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The Pd-catalyzed coupling of N-allylsulfamides with aryl and alkenyl triflates to afford cyclic sulfamide products is described. In contrast to other known Pd-catalyzed alkene carboamination reactions, these transformations may be selectively induced to occur by way of either anti- or syn-aminopalladation mechanistic pathways by modifying the catalyst structure and reaction conditions.
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Synthesis of cyclic guanidines via Pd-catalyzed alkene carboamination.
Org. Lett.
PUBLISHED: 10-22-2013
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A new approach to the synthesis of substituted 5-membered cyclic guanidines is described. Palladium-catalyzed alkene carboamination reactions between acyclic N-allyl guanidines and aryl or alkenyl halides provide these products in good yield. This method allows access to a number of different cyclic guanidine derivatives in only two steps from readily available allylic amines.
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Long-distance Axonal Transport of AAV9 Is Driven by Dynein and Kinesin-2 and Is Trafficked in a Highly Motile Rab7-positive Compartment.
Mol. Ther.
PUBLISHED: 07-09-2013
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Adeno-associated virus (AAV) vectors can move along axonal pathways after brain injection, resulting in transduction of distal brain regions. This can enhance the spread of therapeutic gene transfer and improve treatment of neurogenetic disorders that require global correction. To better understand the underlying cellular mechanisms that drive AAV trafficking in neurons, we investigated the axonal transport of dye-conjugated AAV9, utilizing microfluidic primary neuron cultures that isolate cell bodies from axon termini and permit independent analysis of retrograde and anterograde axonal transport. After entry, AAV was trafficked into nonmotile early and recycling endosomes, exocytic vesicles, and a retrograde-directed late endosome/lysosome compartment. Rab7-positive late endosomes/lysosomes that contained AAV were highly motile, exhibiting faster retrograde velocities and less pausing than Rab7-positive endosomes without virus. Inhibitor experiments indicated that the retrograde transport of AAV within these endosomes is driven by cytoplasmic dynein and requires Rab7 function, whereas anterograde transport of AAV is driven by kinesin-2 and exhibits unusually rapid velocities. Furthermore, increasing AAV9 uptake by neuraminidase treatment significantly enhanced virus transport in both directions. These findings provide novel insights into AAV trafficking within neurons, which should enhance progress toward the utilization of AAV for improved distribution of transgene delivery within the brain.Molecular Therapy (2013); doi:10.1038/mt.2013.237.
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Synthesis of Substituted 3-Hydroxy-2-Furanone Derivatives via an Unusual Enolate Wittig Rearrangement/Alkylative Cyclization Sequence.
Org. Lett.
PUBLISHED: 06-11-2013
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Treatment of methyl O-(alkynylmethyl) glycolate derivatives with dialkylboron triflates and Hünigs base leads to the formation of highly substituted 3-hydroxy-2-furanone derivatives. The transformations appear to proceed via an unusual mechanism involving initial 2,3-Wittig rearrangement of a boron ester enolate followed by an alkylative cyclization reaction that leads to incorporation of an alkyl group from the boron reagent into the product.
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Transplantation of CD15-enriched murine neural stem cells increases total engraftment and shifts differentiation toward the oligodendrocyte lineage.
Stem Cells Transl Med
PUBLISHED: 05-16-2013
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Neural stem cell (NSC) transplantation is a promising therapeutic approach for neurological diseases. However, only a limited number of cells can be transplanted into the brain, resulting in relatively low levels of engraftment. This study investigated the potential of using a cell surface marker to enrich a primary NSC population to increase stable engraftment in the recipient brain. NSCs were enriched from the neonatal mouse forebrain using anti-CD15 (Lewis X antigen, or SSEA-1) in a "gentle" fluorescence-activated cell sorting protocol, which yielded >98% CD15-positive cells. The CD15-positive cells differentiated into neurons, astrocytes, and oligodendrocytes in vitro, after withdrawal of growth factors, demonstrating multipotentiality. CD15-positive cells were expanded in vitro and injected bilaterally into the ventricles of neonatal mice. Cells from enriched and unenriched donor populations were found throughout the neuraxis, in both neurogenic and non-neurogenic regions. Total engraftment was similar at 7 days postinjection, but by 28 days postinjection, after brain organogenesis was complete, the survival of donor cells was significantly increased in CD15-enriched grafts over the unenriched cell grafts. The engrafted cells were heterogeneous in morphology and differentiated into all three neural lineages. Furthermore, in the CD15-enriched grafts, there was a significant shift toward differentiation into oligodendrocytes. This strategy may allow better delivery of therapeutic cells to the developing central nervous system and may be particularly useful for treating diseases involving white matter lesions.
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Progress in gene therapy for neurological disorders.
Nat Rev Neurol
PUBLISHED: 04-23-2013
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Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy.
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Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length neurokinin-1 receptor.
J. Neurovirol.
PUBLISHED: 04-16-2013
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The associations between the neurokinin-1 receptor (NK-1R), substance P (SP), and HIV-1 were investigated in neurosphere-derived cultures of microglial-depleted human fetal brain cells (HFBC). Full-length NK-1R was identified in HFBC cultures. SP treatment of the HFBC increased intracellular calcium mobilization and decreased electrical impedance, both of which were blocked by the NK-1R antagonist aprepitant. SP treatment of HIV-1-infected HFBC upregulated HIV-1 expression. These data show that human neural cells grown from neurospheres express functional full length NK-1R that is responsive to SP, and that SP enhanced HIV-1 infection in HBFC.
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Hypervitaminosis D in guinea pigs with ?-mannosidosis.
Comp. Med.
PUBLISHED: 04-16-2013
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A colony of guinea pigs (n = 9) with ?-mannosidosis was fed a pelleted commercial laboratory guinea pig diet. Over 2 mo, all 9 guinea pigs unexpectedly showed anorexia and weight loss (11.7% to 30.0% of baseline weight), and 3 animals demonstrated transient polyuria and polydipsia. Blood chemistry panels in these 3 guinea pigs revealed high-normal total calcium, high-normal phosphate, and high ALP. Urine specific gravity was dilute (1.003, 1.009, 1.013) in the 3 animals tested. Postmortem examination of 7 animals that were euthanized after failing to respond to supportive care revealed renal interstitial fibrosis with tubular mineralization, soft tissue mineralization in multiple organs, hepatic lipidosis, and pneumonia. Analysis of the pelleted diet revealed that it had been formulated with a vitamin D3 content of more than 150 times the normal concentration. Ionized calcium and 25-hydroxyvitamin D values were both high in serum saved from 2 euthanized animals, confirming the diagnosis of hypervitaminosis D. This report discusses the clinical signs, blood chemistry results, and gross and histologic findings of hypervitaminosis D in a colony of guinea pigs. When unexpected signs occur colony-wide, dietary differentials should be investigated at an early time point.
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A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 04-03-2013
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Barringtons nucleus, in the pons, regulates micturition through spinal projections to preganglionic parasympathetic neurons. The stress neuropeptide CRF is prominent in these projections and has an inhibitory influence. Social stress in rats causes urinary retention and abnormal urodynamics resembling those produced by partial bladder outlet obstruction (pBOO), and this is associated with CRF upregulation in Barringtons nucleus. Here, we examined the role of CRF in social stress- and pBOO-induced urodynamic dysfunction by assessing the ability of a CRF? receptor antagonist to alter these effects. Male rats exposed to repeated resident-intruder stress were administered vehicle or a CRF? antagonist (NBI-30775) daily prior to the stress. Urodynamic function was recorded in the unanesthetized state 72 h after the final stress. NBI-30775 prevented the increased intermicturition interval, micturition volume, and bladder capacity produced by social stress, but not the increase in CRF expression in Barringtons nucleus neurons. The urinary dysfunction was also partly prevented by shRNA targeting of CRF in Barringtons nucleus, suggesting that stress-induced urinary dysfunction results, in part, from CRF upregulation in Barringtons nucleus and enhanced postsynaptic effects in the spinal cord. Finally, NBI-30775 improved urodynamic function of rats that had pBOO of 2-wk duration when administered daily during the second week but did not block the increase in CRF expression in Barringtons nucleus neurons. These findings implicate a role for Barringtons nucleus CRF in stress- and pBOO-induced urodynamic changes and suggest that CRF? antagonists may be useful therapeutic agents for the treatment of urinary dysfunction.
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Engraftment of nonintegrating neural stem cells differentially perturbs cortical activity in a dose-dependent manner.
Mol. Ther.
PUBLISHED: 02-18-2013
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Neural stem cell (NSC) therapy represents a potentially powerful approach for gene transfer in the diseased central nervous system. However, transplanted primary, embryonic stem cell- and induced pluripotent stem cell-derived NSCs generate largely undifferentiated progeny. Understanding how physiologically immature cells influence host activity is critical to evaluating the therapeutic utility of NSCs. Earlier inquiries were limited to single-cell recordings and did not address the emergent properties of neuronal ensembles. To interrogate cortical networks post-transplant, we used voltage sensitive dye imaging in mouse neocortical brain slices, which permits high temporal resolution analysis of neural activity. Although moderate NSC engraftment largely preserved host physiology, subtle defects in the activation properties of synaptic inputs were induced. High-density engraftment severely dampened cortical excitability, markedly reducing the amplitude, spatial extent, and velocity of propagating synaptic potentials in layers 2-6. These global effects may be mediated by specific disruptions in excitatory network structure in deep layers. We propose that depletion of endogenous cells in engrafted neocortex contributes to circuit alterations. Our data provide the first evidence that nonintegrating cells cause differential host impairment as a function of engrafted load. Moreover, they emphasize the necessity for efficient differentiation methods and proper controls for engraftment effects that interfere with the benefits of NSC therapy.Molecular Therapy (2013); 21 12, 2258-2267. doi:10.1038/mt.2013.163.
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Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates.
Nanoscale
PUBLISHED: 01-22-2013
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Monolithic hierarchical nanoporous gold disks, 500 nm in diameter, 75 nm in thickness and 3.5 nm in pore radius, have been fabricated by hybrid processes. A surface-enhanced Raman scattering enhancement factor of at least 10(8) has been obtained on individual disks using benzenethiol self-assembled monolayer with 785 nm laser excitation.
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Synthesis of chromans via Pd-catalyzed alkene carboetherification reactions.
Chem. Commun. (Camb.)
PUBLISHED: 11-24-2011
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A new method for the construction of 2-substituted and 2,2-disubstituted chromans via Pd-catalyzed carboetherification reactions between aryl/alkenyl halides and 2-(but-3-en-1-yl)phenols is described. These reactions effect formation of a C-O bond and a C-C bond to afford the chroman products in good yield, and also provide stereoselective access to tricyclic chroman derivatives.
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Local anesthetic systemic toxicity: update on mechanisms and treatment.
Curr Opin Anaesthesiol
PUBLISHED: 08-16-2011
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With increases in use of regional anesthesia, local anesthetic systemic toxicity (LAST) has been a topic of interest and debate. Despite many years of research, the exact cause and best treatment of LAST (particularly local anesthetic cardiotoxicity) remain unclear. This review will summarize what is known and what remains uncertain about LAST and its treatment, including information published in the past 12-18 months.
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Stereoselective synthesis of substituted 1,3-oxazolidines via Pd-catalyzed carboamination reactions of O-vinyl-1,2-amino alcohols.
Org. Lett.
PUBLISHED: 08-03-2011
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The stereoselective synthesis of 2,4- and 2,5-disubstituted 1,3-oxazolidines is accomplished via Pd-catalyzed carboamination of O-vinyl-1,2-amino alcohol derivatives. The transformations generate cis-disubstituted products with good to excellent diastereoselectivity, and enantiomerically enriched substrates are converted without loss of optical purity. In addition to yielding synthetically useful products that are difficult to generate with existing methods, these transformations illustrate that electron-rich enol ethers are viable substrates for alkene carboamination processes.
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Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey.
Sci Transl Med
PUBLISHED: 06-24-2011
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Gene therapy is emerging as a therapeutic modality for treating disorders of the retina. Photoreceptor cells are the primary cell type affected in many inherited diseases of retinal degeneration. Successfully treating these diseases with gene therapy requires the identification of efficient and safe targeting vectors that can transduce photoreceptor cells. One serotype of adeno-associated virus, AAV2, has been used successfully in clinical trials to treat a form of congenital blindness that requires transduction of the supporting cells of the retina in the retinal pigment epithelium (RPE). Here, we determined the dose required to achieve targeting of AAV2 and AAV8 vectors to photoreceptors in nonhuman primates. Transgene expression in animals injected subretinally with various doses of AAV2 or AAV8 vectors carrying a green fluorescent protein transgene was correlated with surgical, clinical, and immunological observations. Both AAV2 and AAV8 demonstrated efficient transduction of RPE, but AAV8 was markedly better at targeting photoreceptor cells. These preclinical results provide guidance for optimal vector and dose selection in future human gene therapy trials to treat retinal diseases caused by loss of photoreceptors.
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Colonoscopic perforation leading to a diagnosis of Ehlers Danlos syndrome type IV: a case report and review of the literature.
J Med Case Rep
PUBLISHED: 06-23-2011
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Colonoscopic perforation is a rare but serious complication of colonoscopy. Factors known to increase the risk of perforation include colonic strictures, extensive diverticulosis, and friable tissues. We describe the case of a man who was found to have perforation of the sigmoid colon secondary to an undiagnosed connective tissue disorder (Ehlers-Danlos syndrome type IV) while undergoing surveillance for hereditary non-polyposis colorectal cancer.
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Cascade intramolecular N-arylation/intermolecular carboamination reactions for the construction of tricyclic heterocycles.
Org. Lett.
PUBLISHED: 05-23-2011
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A new method for the stereoselective synthesis of tetrahydropyrroloindoles and hexahydropyrroloquinolines of general structure 8 is described. These products are formed through cascade Pd-catalyzed coupling reactions between aryl chlorides and unsaturated amine substrates 5. A single catalyst effects an intramolecular N-arylation reaction followed by an intermolecular alkene carboamination reaction to generate two rings, three bonds, and one stereocenter with good chemoselectivity, diastereoselectivity, and chemical yield.
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Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives.
Org. Lett.
PUBLISHED: 05-11-2011
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The synthesis of tropane derivatives via intramolecular Pd-catalyzed alkene difunctionalization reactions is described. Enantiopure N-aryl-?-aminoalkenes bearing an aryl or alkenyl halide adjacent to the amino group were converted to benzo- or cycloalkenyl-fused tropane products in good yield and with no loss of enantiopurity.
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Enantioconvergent synthesis of (+)-aphanorphine via asymmetric Pd-catalyzed alkene carboamination.
Org. Lett.
PUBLISHED: 05-10-2011
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A concise asymmetric synthesis of (+)-aphanorphine has been achieved via a new enantioconvergent strategy. A racemic ?-aminoalkene derivative is transformed into a 1:1 mixture of enantiomerically enriched diastereomers using an asymmetric Pd-catalyzed carboamination. This mixture is then converted to an enantiomerically enriched protected aphanorphine derivative by a Friedel-Crafts reaction, which generates a quaternary all-carbon stereocenter. The natural product is obtained in three additional steps.
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The changing management of primary mycotic aortic aneurysms.
J. Vasc. Surg.
PUBLISHED: 03-31-2011
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The objective of this study is to examine contemporary management of primary mycotic aortic aneurysms in a single center. We have previously reported the management of mycotic aortic aneurysms in 15 patients between 1991 and 2001, and we hypothesized that management would change in the light of the evolution of endovascular aortic repair.
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Synthesis of saturated 1,4-benzodiazepines via Pd-catalyzed carboamination reactions.
Org. Lett.
PUBLISHED: 03-29-2011
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A new synthesis of 1,4-benzodiazepines and 1,4-benzodiazepin-5-ones is reported. The Pd-catalyzed coupling of N-allyl-2-aminobenzylamine derivatives with aryl bromides affords the heterocyclic products in good yield, and substrates bearing allylic methyl groups are transformed to cis-2,3-disubstituted products with >20:1 dr.
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Asymmetric palladium-catalyzed carboamination reactions for the synthesis of enantiomerically enriched 2-(arylmethyl)- and 2-(alkenylmethyl)pyrrolidines.
J. Am. Chem. Soc.
PUBLISHED: 08-20-2010
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The enantioselective synthesis of 2-(arylmethyl)- and 2-(alkenylmethyl)pyrrolidine derivatives via Pd-catalyzed alkene carboamination reactions is described. These transformations generate enantiomerically enriched products with up to 94% ee from readily available alkenyl or aryl bromides and N-boc-pent-4-enylamines. The application of this method to a concise asymmetric synthesis of (-)-tylophorine is also discussed.
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Pd-catalyzed carboamination of oxazolidin-2-ones: a stereoselective route to trans-2,5-disubstituted pyrrolidines.
Org. Lett.
PUBLISHED: 04-22-2010
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Palladium-catalyzed carboamination reactions between aryl bromides and 4-(but-3-enyl)-substituted oxazolidin-2-ones are described. These transformations afford bicyclic oxazolidin-2-one derivatives that can be converted to trans-2,5-disubstituted pyrrolidines in one step. The starting materials are easily prepared from amino acid precursors, and products that contain up to three stereocenters are generated with >20:1 dr.
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Intramolecular alkene aminopalladation reactions of (dppf)Pd(Ar)[N(Ar(1))(CH(2))(3)CH=CH(2)] complexes. insertion of unactivated alkenes into Pd-N bonds.
J. Am. Chem. Soc.
PUBLISHED: 04-20-2010
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The synthesis of (dppf)Pd(C(6)H(4)-p-F)[N(Ar(1))(CH(2))(3)CH horizontal lineCH(2)] complexes (3), which are thought to be intermediates in Pd-catalyzed alkene carboamination reactions, is described. These complexes undergo syn-migratory insertion of the alkene into the Pd-N bond to yield observable (dppf)palladium(aryl)(pyrrolidin-2-yl-methyl) complexes 6. Reductive elimination from 6 provides 2-benzylpyrrolidine derivatives 4. The rates of conversion of 3 to 6 (k(1)) and 6 to 4 (k(2)) were measured and are within 1 order of magnitude of each other. The syn-migratory insertion stereochemistry was confirmed through a deuterium labeling experiment. These are the first examples of syn-migratory insertions of unactivated alkenes into Pd-N bonds of well-defined complexes.
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Use of aryl chlorides as electrophiles in Pd-catalyzed alkene difunctionalization reactions.
J. Org. Chem.
PUBLISHED: 03-20-2010
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The development of conditions that allow use of inexpensive aryl chlorides as electrophiles in Pd-catalyzed alkene carboamination and carboetherification reactions is described. A catalyst composed of Pd(OAc)(2) and S-Phos minimizes N-arylation of the substrate and prevents formation of mixtures of regioisomeric products. A number of heterocycles, including pyrrolidines, isoxazolidines, tetrahydrofurans, and pyrazolidines, are efficiently generated with this method.
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Highly diastereoselective Pd-catalyzed carboetherification reactions of acyclic internal alkenes. Stereoselective synthesis of polysubstituted tetrahydrofurans.
Org. Lett.
PUBLISHED: 02-23-2010
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A highly diastereoselective synthesis of substituted tetrahydrofurans bearing stereocenters at C2 and C1 via Pd-catalyzed carboetherification reactions of acyclic internal alkenes is described. Use of an improved catalyst composed of Pd(2)(dba)(3)/S-Phos provides products with up to >20:1 dr. The stereoselective preparation of tetrahydrofurans containing three stereocenters, including a molecule structurally related to simplakidine A, is also reported.
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Synthesis of polycyclic nitrogen heterocycles via alkene aminopalladation/carbopalladation cascade reactions.
Org. Lett.
PUBLISHED: 02-10-2010
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A new method for the synthesis of tricyclic nitrogen heterocycles from N,2-diallylaniline derivatives is described. These transformations proceed via sequential alkene aminopalladation of an intermediate L(n)Pd(Ar)(NRR) species followed by alkene carbopalladation of the resulting L(n)Pd(Ar)(R) complex. Both alkene insertion steps occur in preference to C-N or C-C bond-forming reductive elimination. An unusual 1,3-palladium shift occurs when 2-Allyl-N-(2-vinylphenyl)aniline is employed as substrate, which yields a tetracyclic molecule with three contiguous stereocenters.
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Asymmetric tandem Wittig rearrangement/Mannich reactions.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 02-01-2010
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The choice is yours: a highly stereoselective synthesis of ?-alkyl-?-hydroxy-?-amino esters is accomplished through a tandem Wittig-rearrangement/Mannich reaction sequence. Transformations of N-benzyl or N-Boc imines proceed with high selectivity for formation of syn-amino alcohol derivatives, whereas N-Boc-2-(phenylsulfonyl)amines generate anti-amino alcohol products. Auxiliary cleavage (transesterification or reduction) yields enantiomerically enriched products with up to 96 % ee.
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Palladium-catalyzed alkene carboamination reactions for the synthesis of substituted piperazines.
Tetrahedron
PUBLISHED: 09-30-2009
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A strategy for the stereoselective preparation of enantiomerically enriched cis-2,6-disubstituted piperazines from amino acid precursors is described. The target compounds are generated in 95-99% ee with good to excellent levels of diastereoselectivity (usually 14:1 to >20:1) using Pd-catalyzed carboamination reactions between aryl or alkenyl halides and substituted ethylenediamine derivatives to form the heterocyclic rings. The synthesis requires only 4-5 steps from commercially available amino acids, and allows for the modular construction of piperazines bearing different substituents at N(1), N(4), C(2), and C(6). The use of this strategy for the construction of 2,3-disubstituted piperazines, fused bicyclic piperazines, and tetrahydroquinoxalines is also reported. In addition, the mechanism of the key carboamination reactions are discussed, and new models that predict and explain the stereochemical outcome of these transformations are presented.
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Asymmetric tandem wittig rearrangement/Aldol reactions.
J. Am. Chem. Soc.
PUBLISHED: 08-15-2009
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A new method for the asymmetric synthesis of alpha-alkyl-alpha,beta-dihydroxy esters that involves tandem Wittig rearrangement/aldol reactions of O-benzyl- or O-allylglycolate esters derived from 2-phenylcyclohexanol is described. This sequence constructs two C-C bonds and two stereocenters, one of which is quaternary, to afford syn diol products with excellent stereocontrol. Cleavage of the chiral auxiliary affords enantiomerically enriched products with up to 95% ee. The application of this method to the preparation of a key intermediate in the synthesis of the antifungal agent alternaric acid is also described.
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New strategy for the synthesis of substituted morpholines.
J. Org. Chem.
PUBLISHED: 06-02-2009
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A four-step synthesis of cis-3,5-disubstituted morpholines from enantiomerically pure amino alcohols is described. The key step in the synthesis is a Pd-catalyzed carboamination reaction between a substituted ethanolamine derivative and an aryl or alkenyl bromide. The morpholine products are generated as single stereoisomers in moderate to good yield. This strategy also provides access to fused bicyclic morpholines as well as 2,3- and 2,5-disubstituted products.
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Recurrent cystic adventitial disease of the iliofemoral artery.
Ann Vasc Surg
PUBLISHED: 05-24-2009
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We present the case of a 39-year-old man with recurrence of intermittent claudication 4 years after successful Dacron patch repair of the right common femoral artery for cystic adventitial disease. Magnetic resonance angiography results were inconclusive, while conventional angiography demonstrated 90% stenosis of the right common femoral artery. The patient underwent excision and replacement of the affected artery with PTFE and was asymptomatic at 6-month follow-up. In recurrent cystic adventitial disease, excision and replacement of the affected artery with a prosthetic interposition graft provides a successful outcome with minimal chance of recurrence.
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Synthesis of fused-ring and attached-ring bis-tetrahydrofurans via Pd-catalyzed carboetherification.
Org. Lett.
PUBLISHED: 05-08-2009
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A five step-synthesis of fused bis-tetrahydrofurans and attached bis-tetrahydrofurans from butadiene diepoxide is described. Two sequential Pd-catalyzed carboetherification reactions between protected 1,2-diols and aryl/alkenyl bromides, each of which form both a C-O bond and a C-C bond, are used to generate the heterocyclic rings with >20:1 dr. Installation of different R(1) and R(2) groups is achieved in a straightforward fashion through use of different aryl or alkenyl bromide coupling partners.
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Influence of hydroxylamine conformation on stereocontrol in Pd-catalyzed isoxazolidine-forming reactions.
J. Org. Chem.
PUBLISHED: 02-26-2009
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Palladium-catalyzed carboamination reactions between N-Boc-O-(but-3-enyl)hydroxylamine derivatives and aryl or alkenyl bromides afford cis-3,5- and trans-4,5-disubstituted isoxazolidines in good yield with up to >20:1 dr. The diastereoselectivity observed in the formation of cis-3,5-disubstituted isoxazolidines is superior to selectivities typically obtained in other transformations, such as 1,3-dipolar cycloaddition reactions, that provide these products. In addition, the stereocontrol in the C-N bond-forming Pd-catalyzed carboamination reactions of N-Boc-O-(but-3-enyl)hydroxylamines is significantly higher than that of related C-O bond-forming carboetherification reactions of N-benzyl-N-(but-3-enyl)hydroxylamine derivatives. This is likely due to a stereoelectronic preference for cyclization via transition states in which the Boc group is placed in a perpendicular orientation relative to the plane of the developing ring, which derives from the conformational equilibria of substituted hydroxylamines.
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Recent Developments in Pd-Catalyzed Alkene Aminoarylation Reactions for the Synthesis of Nitrogen Heterocycles.
Synthesis (Stuttg)
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This short review describes new developments in Pd-catalyzed aminoarylation reactions between aryl halides and alkenes bearing pendant nitrogen nucleophiles. These transformations provide a novel and powerful method for accessing numerous 3-, 5-, 6-, and 7-membered nitrogen heterocycles.
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Postnatal neural precursor cell regions in the rostral subventricular zone, hippocampal subgranular zone and cerebellum of the dog (Canis lupus familiaris).
Histochem. Cell Biol.
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Identification of neural stem and progenitor cells (NPCs) in vitro and in vivo is essential to the use of developmental and disease models of neurogenesis. The dog is a valuable large animal model for multiple neurodegenerative diseases and is more closely matched to humans than rodents with respect to brain organization and complexity. It is therefore important to determine whether immunohistochemical markers associated with NPCs in humans and rodents are also appropriate for the dog. The NPC markers CD15, CD133, nestin, GFAP and phosphacan (DSD-1) were evaluated in situ in the canine rostral telencephalon, hippocampal dentate gyrus, and cerebellum at different postnatal time-points. Positive staining results were interpreted in the context of region and cellular morphology. Our results showed that neurospheres and cells within the rostral subventricular zone (SVZ), dentate gyrus subgranular zone (SGZ), and white matter tracts of the cerebellum were immunopositive for CD15, nestin and GFAP. Neurospheres and the cerebellum were immunonegative for CD133, whereas CD133 staining was present in the postnatal rostral SVZ. Anti-phosphacan antibody staining delineated the neurogenic niches of the rostral lateral ventricle SVZ and the hippocampal SGZ. Positive staining for phosphacan was also noted in white matter tracts of the cerebellum and within the Purkinje layer. Our results showed that in the dog these markers were associated with regions shown to be neurogenic in rodents and primates.
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Synthesis of enantiomerically enriched imidazolidin-2-ones through asymmetric palladium-catalyzed alkene carboamination reactions.
Angew. Chem. Int. Ed. Engl.
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Positive water effect: A catalyst composed of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and (S)-Siphos-PE is effective for the enantioselective coupling of N-allyl ureas with aryl bromides to afford 4-substituted imidazolidin-2-ones. Added water leads to significantly improved enantioselectivities with electron-poor aryl halide substrates. It is suggested that the C-C bond-forming reductive elimination is the enantiodetermining step in these reactions.
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Overexpression of corticotropin-releasing factor in Barringtons nucleus neurons by adeno-associated viral transduction: effects on bladder function and behavior.
Eur. J. Neurosci.
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The stress-related neuropeptide, corticotropin-releasing factor (CRF), is prominent in neurons of the pontine micturition center, Barringtons nucleus. These neurons co-innervate spinal preganglionic neurons that control the bladder, and locus coeruleus (LC) neurons that provide norepinephrine innervation throughout the brain. Adeno-associated viral (AAV) vector-mediated transfer of CRF cDNA was used to increase CRF expression in Barringtons nucleus neurons and investigate the impact of a gain of function in Barringtons nucleus spinal and LC projections. AAV transfer of the reverse CRF cDNA sequence served as the control. Bladder urodynamics and behavior were assessed 4 weeks after vector injection into Barringtons nucleus. Rats with bilateral injections of AAV-CRF cDNA into Barringtons nucleus had immunohistochemical evidence of CRF overexpression in neurons and transport to the spinal cord and LC. The bladder : body weight ratio was greater and micturition pressure was less in these rats compared with controls, consistent with an inhibitory influence on bladder function. Other indices of urodynamic function were not altered. CRF innervation of the LC was increased in rats with bilateral Barringtons nucleus injections of AAV-CRF cDNA, and this was associated with increased burying behavior, an endpoint of LC activation by CRF. The results provide immunohistochemical evidence for viral vector-induced CRF overexpression in Barringtons nucleus neurons and underscore the ability of AAV vector-mediated transfer to increase CRF function in selective circuits. The findings support an inhibitory influence of CRF in Barringtons nucleus regulation of the bladder and an excitatory influence on the brain norepinephrine system that translates to behavioral activation.
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Expanding the use of simulation in open vascular surgical training.
J. Vasc. Surg.
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Simulation technology has a well-defined role in nonmedical professions such as aviation and over the last two decades has permeated medical training. The most successful surgical simulation is in the fields of laparoscopic and endovascular surgery. These two-dimensional scenarios, as in the aviation industry, lend themselves to simulation. Open simulators have been met with more resistance than their laparoscopic counterparts because of the difficulties in simulating the three-dimensional field. Engaging in persistent practice is what makes the expert and all trainees should aspire to this. Without knowing, all surgical trainees have engaged in deliberate practice when first learning to tie surgical knots. This deliberate practice should be used in all aspects of vascular surgical practice, and it is no longer acceptable to perform procedures such as arterial anastomoses for the first time on patients. Simulators exist for all aspects of vascular surgical training and vary in complexity and price. Some of these simulators are suitable for use at home or in a skills laboratory whereas others are more suitable for use in a specialized skills center. Training on these simulators can be offered at a local level or at a regional level in the skills center. Where surgical procedures are not commonly performed or expertise is required for a new innovation, it is more appropriate to have national or internationally based workshops under the auspices of surgical boards or societies. Simulation of crisis management, well known in aviation, has also been applied to vascular surgical practice and can offer benefit to senior trainees even when their performance on a noncrisis simulator has reached a plateau. This article identifies the areas where simulation in open vascular surgery can benefit the trainee.
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Dysregulation of gene expression in a lysosomal storage disease varies between brain regions implicating unexpected mechanisms of neuropathology.
PLoS ONE
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The characteristic neurological feature of many neurogenetic diseases is intellectual disability. Although specific neuropathological features have been described, the mechanisms by which specific gene defects lead to cognitive impairment remain obscure. To gain insight into abnormal functions occurring secondary to a single gene defect, whole transcriptome analysis was used to identify molecular and cellular pathways that are dysregulated in the brain in a mouse model of a lysosomal storage disorder (LSD) (mucopolysaccharidosis [MPS] VII). We assayed multiple anatomical regions separately, in a large cohort of normal and diseased mice, which greatly increased the number of significant changes that could be detected compared to past studies in LSD models. We found that patterns of aberrant gene expression and involvement of multiple molecular and cellular systems varied significantly between brain regions. A number of changes revealed unexpected system and process alterations, such as up-regulation of the immune system with few inflammatory changes (a significant difference from the closely related MPS IIIb model), down-regulation of major oligodendrocyte genes even though white matter changes are not a feature histopathologically, and a plethora of developmental gene changes. The involvement of multiple neural systems indicates that the mechanisms of neuropathology in this type of disease are much broader than previously appreciated. In addition, the variation in gene dysregulation between brain regions indicates that different neuropathologic mechanisms may predominate within different regions of a diseased brain caused by a single gene mutation.
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The midterm experience of tapered stent grafts in the endovascular management of iliac artery aneurysms with unfavorable anatomy.
Vasc Endovascular Surg
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We report our experience and the midterm results of a modern technique for endovascular management of isolated iliac artery aneurysms (IAAs) with unfavorable neck anatomy, which involves the inversion of an iliac leg of a Zenith stent graft. Patients who underwent endovascular IAA repair from 2002 to 2010 were reviewed. A total of 12 patients, with a mean age of 77.6 years, underwent endovascular repair of 13 IAAs. Mean size of the aneurysms was 54.6 mm (range 34-133 mm). Mean proximal neck diameter was 18 mm (range 15-22 mm). In 7 patients, the length of the proximal neck was <15 mm (10-14 mm). Only 1 patient developed thrombosis of the stent graft immediately after the operation. Patients were followed up for a mean of 31.5 months (range 18-72 months). Our midterm results demonstrate the durability of this technique in the management of iliac aneurysms with unfavorable anatomy.
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