bluuebunny/crossref_metadata_2025_split huggingface dataset:
An inventory of shedding data from clinical gene therapy trials
Authors: Schenk‐Braat Ellen A. M. , van Mierlo Marjolein M. K. B. , Wagemaker Gerard , Bangma Chris H. , Kaptein Leonie C. M. 
Published: September 2007

AbstractViruses are the most commonly used vectors for clinical gene therapy. The risk of dissemination of a viral vector into the environment via excreta from the treated patient, a phenomenon called shedding, is a major safety concern for the environment. Despite the significant number of clinical gene therapy trials that have been conducted worldwide, there is currently no overview of actual shedding data available. In this article, an inventory of shedding data obtained from a total of 100 publications on clinical gene therapy trials using retroviral, adenoviral, adeno‐associated viral and pox viral vectors is presented. In addition, the experimental set‐up for shedding analysis including the assays used and biological materials tested is summarized. The collected data based on the analysis of 1619 patients in total demonstrate that shedding of these vectors occurs in practice, mainly determined by the type of vector and the route of vector administration. Due to the use of non‐quantitative assays, the lack of information on assay sensitivity in most publications, and the fact that assay sensitivity is expressed in various ways, general conclusions cannot be made as to the level of vector shedding. The evaluation of the potential impact and consequences of the observations is complicated by the high degree of variety in the experimental design of shedding analysis between trials. This inventory can be supportive to clinical gene therapy investigators for the establishment of an evidence‐based risk assessment to be included in a clinical protocol application, as well as to national regulatory authorities for the ongoing development of regulatory guidelines regarding gene therapy. Copyright © 2007 John Wiley & Sons, Ltd.
PGE2 receptor EP1 renders dopaminergic neurons selectively vulnerable to low‐level oxidative stress and direct PGE2 neurotoxicity
Authors: Carrasco Emilce , Casper Diana , Werner Peter 
Published: September 2007

AbstractOxidative stress and increased cyclooxygenase‐2 (COX‐2) activity are both implicated in the loss of dopaminergic neurons from the substantia nigra (SN) in idiopathic Parkinson's disease (PD). Prostaglandin E2 (PGE2) is one of the key products of COX‐2 activity and PGE2 production is increased in PD. However, little is known about its role in the selective death of dopaminergic neurons. Previously, we showed that oxidative stress evoked by low concentrations of 6‐hydroxydopamine (6‐OHDA) was selective for dopaminergic neurons in culture and fully dependent on COX‐2 activity. We postulated that this loss was mediated by PGE2 acting through its receptors, EP1, EP2, EP3, and EP4. Using double‐label immunohistochemistry for specific EP receptors and tyrosine hydroxylase (TH), we identified EP1 and EP2 receptors on dopaminergic neurons in rat SN. EP2 receptors were also found in non‐dopaminergic neurons of this nucleus, as were EP3 receptors, whereas the EP4 receptor was absent. PGE2, 16‐phenyl tetranor PGE2 (a stable synthetic analogue), and 17‐phenyl trinor PGE2 (an EP1 receptor–selective agonist) were significantly toxic to dopaminergic cells at nanomolar concentrations; EP2‐ and EP3‐selective agonists were not. We challenged dopaminergic neurons in embryonic rat mesencephalic primary neuronal cultures and tested whether these receptors mediate selective 6‐OHDA toxicity. The nonselective EP1–3 receptor antagonist AH‐6809 and two selective EP1 antagonists, SC‐19220 and SC‐51089, completely prevented the 40%–50% loss of dopaminergic neurons caused by exposure to 5 μM 6‐OHDA. Together, these results strongly implicate PGE2 activation of EP1 receptors as a mediator of selective toxicity in this model of dopaminergic cell loss. © 2007 Wiley‐Liss, Inc.
Novel culture strategy for human stem cell proliferation and neuronal differentiation
Authors: Serra Margarida , Leite Sofia B. , Brito Catarina , Costa Júlia , Carrondo Manuel J.T. , Alves Paula M. 
Published: September 2007

AbstractEmbryonal carcinoma (EC) stem cells derived from germ cell tumors closely resemble embryonic stem (ES) cells and are valuable tools for the study of embryogenesis. Human pluripotent NT2 cell line, derived from a teratocarcinoma, can be induced to differentiate into neurons (NT2‐N) after retinoic acid treatment. To realize the full potential of stem cells, developing in vitro methods for stem cell proliferation and differentiation is a key challenge. Herein, a novel culture strategy for NT2 neuronal differentiation was developed to expand NT2‐N neurons, reduce the time required for the differentiation process, and increase the final yields of NT2‐N neurons. NT2 cells were cultured as 3D cell aggregates (“neurospheres”) in the presence of retinoic acid, using small‐scale stirred bioreactors; it was possible to obtain a homogeneous neurosphere population, which can be transferred for further neuronal selection onto coated surfaces. This culturing strategy yields higher amounts of NT2‐N neurons with increased purity compared with the amounts routinely obtained with static cultures. Moreover, mechanical and enzymatic methods for neurosphere dissociation were evaluated for their ability to recover neurons, trypsin digestion yielding the best results. Nevertheless, the highest recoveries were obtained when neurospheres were collected directly to treated surfaces without dissociation steps. This novel culture strategy allows drastic improvement in the neuronal differentiation efficiency of NT2 cells, insofar as a fourfold increase was obtained, reducing simultaneously the time needed for the differentiation process. The culture method described herein ensures efficient, reproducible, and scaleable ES cell proliferation and differentiation, contributing to the usefulness of stem cell bioengineering. © 2007 Wiley‐Liss, Inc.
Cellular and molecular characterization of oxidative stress in olfactory epithelium of Harlequin mutant mouse
Authors: Vaishnav Radhika A. , Getchell Marilyn L. , Huang Liping , Hersh Matthew A. , Stromberg Arnold J. , Getchell Thomas V. 
Published: September 2007

AbstractOxidative stress in the olfactory system is a major factor associated with age‐related olfactory impairment, although the mechanisms by which this occurs are not completely understood. The Harlequin mutant mouse (Hq/Y), which carries an X‐linked recessive mutation in the Aifm1 gene, is a model of progressive oxidative stress–induced neurodegeneration in the cerebellum and retina. To determine whether the Hq/Y mutant mouse is a suitable model of oxidative stress–associated olfactory aging, we investigated cellular and molecular changes in the olfactory epithelium (OE) and olfactory bulb (OB) of 6‐month‐old male Hq/Y mice compared to those in sex‐matched littermate controls (+/Y) and in age‐ and sex‐matched C57BL/6 mice. Immunoreactivity for apoptosis‐inducing factor, the protein product of Aifm1, was localized in mature olfactory sensory neurons (mOSNs) in +/Y mice but was rarely detected in Hq/Y mice. Hq/Y mice also exhibited increased lipofuscin autofluorescence and increased immunoreactivity for an oxidative DNA/RNA damage marker in mOSNs and in mitral/tufted cells in the OB and an increased number of cleaved caspase‐3 immunoreactive apoptotic cells in the OE. Microarray analysis demonstrated that Aifm1 expression was down‐regulated by 80% in the OE of Hq/Y mice compared to that in +/Y mice. Most significantly, regulated genes were classified into functional categories of cell signaling/apoptosis/cell cycle, oxidative stress/aging, and cytoskeleton/extracellular matrix/transport‐associated. Analysis with EASE software indicated that the functional categories significantly overrepresented in Hq/Y mice included up‐regulated mitochondrial genes and down‐regulated cytoskeletal organization‐ and neurogenesis‐related genes. Our results strongly support the Hq/Y mutant mouse being a novel model for mechanistic studies of oxidative stress–associated olfactory aging. © 2007 Wiley‐Liss, Inc.
Inhibition of proteoglycan synthesis affects neuronal outgrowth and astrocytic migration in organotypic cultures of fetal ventral mesencephalon
Authors: Berglöf Elisabet , Plantman Stefan , Johansson Saga , Strömberg Ingrid 
Published: September 2007

AbstractGrafting fetal ventral mesencephalon has been utilized to alleviate the symptoms of Parkinson's disease. One obstacle in using this approach is the limited outgrowth from the transplanted dopamine neurons. Thus, it is important to evaluate factors that promote outgrowth from fetal dopamine neurons. Proteoglycans (PGs) are extracellular matrix molecules that modulate neuritic growth. This study was performed to evaluate the role of PGs in dopamine nerve fiber formation in organotypic slice cultures of fetal ventral mesencephalon. Cultures were treated with the PG synthesis inhibitor methyl‐umbelliferyl‐β‐D‐xyloside (β‐xyloside) and analyzed using antibodies against tyrosine hydroxylase (TH) to visualize dopamine neurons, S100β to visualize astrocytes, and neurocan to detect PGs. Two growth patterns of TH‐positive outgrowth were observed: nerve fibers formed in the presence of astrocytes and nerve fibers formed in the absence of astrocytes. Treatment with β‐xyloside significantly reduced the distance of glial‐associated TH‐positive nerve fiber outgrowth but did not affect the length of the non‐glial‐associated nerve fibers. The addition of β‐xyloside shifted the nerve fiber growth pattern from being mostly glial‐guided to being non‐glial‐associated, whereas the total amount of TH protein was not affected. Further, astrocytic migration and proliferation were impaired after β‐xyloside treatment, and levels of non‐intact PG increased. β‐Xyloside treatment changed the distribution of neurocan in astrocytes, from being localized in vesicles to being diffusely immunoreactive in the processes. To conclude, inhibition of PG synthesis affects glial‐associated TH‐positive nerve fiber formation in ventral mesencephalic cultures, which might be an indirect effect of impaired astrocytic migration. © 2007 Wiley‐Liss, Inc.
Mode of cembranoid action on embryonic muscle acetylcholine receptor
Authors: Ulrich H. , Akk G. , Nery A.A. , Trujillo C.A. , Rodriguez A.D. , Eterović V.A. 
Published: September 2007

AbstractThe mechanism of eupalmerin acetate (EUAC) actions on the embryonic muscle nicotinic acetylcholine receptor (nAChR) in BC3H‐1 cells was studied by using whole‐cell and single‐channel patch‐clamp current measurements. With whole‐cell currents, EUAC did not act as an agonist on this receptor. Coapplication of 30 μM EUAC with 50 μM, 100 μM, or 500 μM carbamoylcholine (CCh) reversibly inhibited the current amplitude, whereas, with 20 μM CCh, current was increased above control values in the presence of EUAC. EUAC concentration curves (0.01–40 μM) obtained with 100 μM and 500 μM CCh displayed slope coefficients, nH, significantly smaller than one, suggesting that EUAC bound to several sites with widely differing affinities on the receptor molecule. The apparent rate of receptor desensitization in the presence of EUAC and CCh was either slower than or equal to that obtained with CCh alone. The major finding from single‐channel studies was that EUAC did not affect single‐channel conductance or the ability of CCh to interact with the receptor. Instead, EUAC acted by increasing the channel closing rate constant. The results are not consistent with the competitive model for EUAC inhibition, with the sequential open‐channel block model, or with inhibition by increased desensitization. The data are best accounted for by a model in which EUAC acts by closed‐channel block at low concentrations, by positive modulation at intermediate concentrations, and by negative allosteric modulation of the open channel at high concentrations. © 2007 Wiley‐Liss, Inc.
Histological correlation of diffusion tensor imaging metrics in experimental spinal cord injury
Authors: Herrera Juan J. , Chacko Tessy , Narayana Ponnada A. 
Published: September 2007

AbstractDiffusion tensor imaging (DTI) has the potential to provide important information about the integrity of white matter tracts in injured spinal cord tissue. It is thought that DTI‐based transverse diffusivity (λt) reflects the state of myelin, whereas longitudinal diffusivity (λl) reflects axonal integrity. However, this has not been established in spinal cord injury (SCI). Therefore, we performed quantitative histologic analysis on 4‐ and 8‐week post‐SCI rodent spinal cords that had received a moderately severe injury at the T7 level and correlated the histology with λt and λl measured in vivo. Using antibodies specific to myelin and axonal process (i.e., neurofilament), the percent area of expression was determined in the dorsal, ventral, and lateral white matter from both rostral and caudal regions away from the epicenter of the injury site. The results suggest a positive correlation between λt and demyelination in many but not all regions. However, these studies failed to establish a correlation between λl and axonal damage. These results suggest that caution must be exercised in interpreting the DTI metrics in terms of tissue pathology in SCI. © 2007 Wiley‐Liss, Inc.
Proteomic analysis of embryonic stem cell–derived neural cells exposed to the antidepressant paroxetine
Authors: McHugh Patrick C. , Rogers Geraldine R. , Loudon Barbara , Glubb Dylan M. , Joyce Peter R. , Kennedy Martin A. 
Published: September 2007

AbstractAntidepressant drugs can have significant effects on the mood of a patient suffering from major depression or other disorders. The pharmacological actions of these drugs generally affect the uptake or metabolism of the neurotransmitters serotonin, noradrenalin, and, to a lesser extent, dopamine. However, many aspects of antidepressant action are not understood. We conducted a proteomic analysis in a neuronal cell culture model in an attempt to identify molecules important to the operation of pathways functionally relevant to antidepressant action. The model involved generating cultures containing mixed neural and glial cells by controlled differentiation of mouse embryonic stem cells, followed by exposure to 1 μM paroxetine for 14 days. After antidepressant exposure, we observed increased expression or modification of sepiapterin reductase (SPR), heat shock protein 9A, RAS and EF‐hand domain containing, and protein disulfide isomerase associated 3 and decreased expression or modification of creatine kinase, actin, prohibitin, a T‐cell receptor α chain, defensin‐related cryptdin 5, and the intermediate filament proteins glial fibrillary acidic protein and vimentin. SPR, the most strongly up‐regulated protein observed, controls production of tetrahydrobiopterin, an essential cofactor for the synthesis of many neurotransmitters including serotonin, making it a plausible and intriguing candidate protein for involvement in mood control and antidepressant drug action. SPR and the other proteins identified may represent links to molecular processes of importance to mood dysregulation and control, and their respective genes may be novel candidates for the study of antidepressant pharmacogenetics. © 2007 Wiley‐Liss, Inc.
The use of integra artificial dermis to minimize donor‐site morbidity after suprafascial dissection of the radial forearm flap
Authors: Gravvanis Andreas I. , Tsoutsos Dimosthenis A. , Iconomou Thomais , Gremoutis George 
Published: September 2007

AbstractIn an effort to minimize the radial forearm flap donor‐site morbidity, the flap was elevated using the suprafascial dissection technique, in six patients with various facial defects. The donor site was covered primarily with Integra artificial skin and secondarily with an ultrathin split‐thickness skin graft. The mean time to wound healing of the forearm donor site was 24 days. There were no flap failures, and all flaps healed uneventfully. At the end of the follow‐up, all patients showed normal range of motion of the wrist and the fingers, normal power grip, and power pinch. All patients evaluated the esthetic appearance of the forearm donor site as very good. In conclusion, suprafascial dissection of the forearm flap creates a superior graft recipient site, and the use of Integra artificial dermis is a valuable advancement to further minimize the donor‐site morbidity, resulting in excellent functional and aesthetic outcomes. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.
Selection of recipient vessels in microsurgical free tissue reconstruction of head and neck defects
Authors: Yazar Sukru 
Published: September 2007

AbstractThe development of microsurgical techniques has facilitated proper management of extensive head and neck defects and deformities. Bone or soft tissue can be selected to permit reconstruction with functional and aesthetic results. However, for free tissue transfer to be successful, proper selection of receipient vessels is as essential as the many other factors that affect the final result. In this article selection strategies for recipient vessels for osteocutaneous free flaps, soft tissue free flaps, previously dissected and irradiated areas, recurrent and subsequent secondary reconstructions, simultaneous double free flap transfers in reconstruction of extensive composite head and neck defects, and the selection of recipient veins are reviewed in order to provide an algorithm for the selection of recipient vessels for head and neck reconstruction. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.
Reconstruction of the human median nerve in the forearm with the Neurotube™
Authors: Donoghoe Nicholas , Rosson Gedge D. , Dellon A. Lee 
Published: September 2007

AbstractReconstruction of the median nerve in the forearm traditionally has required multiple interfascicular interposition autologous nerve grafts. Recovery of two‐point discrimination, even in young adults, has been reported rarely. Two patients, aged 43 and 61, are reported with 5‐year follow‐up of median nerve reconstruction in the distal forearm in which multiple interposition bioabsorbable polyglycolic acid conduits (Neurotube™) were used to bridge the 3‐cm nerve defects. Four separate 2.3‐mm diameter, 4.0‐cm long conduits were used in each patient. Sensory re‐education was used for rehabilitation. Each patient recovered two‐point discrimination with good localization in the thumb, index, and middle finger by 2 years after the nerve reconstruction. Both patients recovered abductor pollicis brevis function. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.
Surgical treatment of superimposed nerve compressions in hepatitis C neuropathy
Authors: Rosson Gedge D. , Rodriguez Eduardo D. , Dellon A. Lee 
Published: September 2007

AbstractThe plastic surgeon's usual involvement in patients with hepatitis C is most frequently limited to an inner city population with hand and forearm abscesses from intravenous drug use or to incidences of needle‐stick injury in the operating room when the patient is hepatitis C positive. Hand surgeons and peripheral nerve surgeons often treat patients with underlying neuropathies who have superimposed overlying nerve compressions such as carpal tunnel syndrome. We have applied this experience to a patient with underlying peripheral neuropathy associated with Hepatitis C and clinical evidence of overlying lower extremity nerve compressions. We believe that she is the first successful surgical treatment of peripheral nerve compressions in a patient with hepatitis C—associated neuropathy, documented by noninvasive neurosensory testing. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.
Clinical experience with the nasolabial fold as receptor site in microvascular reconstruction
Authors: Smit Jeroen M. , Hartman ED H. M. , Acosta Rafael 
Published: September 2007

AbstractWe report our experience using the vessels at the nasolabial fold as receptor site in free tissue transfer in head and neck reconstructions; a site that proved more convenient than the submandibulary site in selected cases. Six cases as well as the dissection technique of the nasolabial fold are reported. No complications occurred during or post surgery and in all cases the vessels were of adequate diameter for an end to end anastomosis. The advantages this site offers are discussed. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.
Early reintervention of compromised free flaps improves success rate
Authors: Smit Jeroen M. , Acosta Rafael , Zeebregts Clark J. , Liss Anders G. , Anniko Matti , Hartman ED H. M. 
Published: September 2007

AbstractIntroduction and aim: To develop a protocolized monitor schedule in microvascular free flap reconstruction, we investigated a possible correlation between the outcome and the interval between clamp release and start of revision. Materials and methods: All the charts of patients treated between 2000 and 2006 with a free flap were evaluated. The patients who underwent a flap revision were further analyzed. Results: A total of 608 free flaps were evaluated; 69 of these flaps were revised. Most vascular complications took place within the first 24 h; the latest complication was observed 8 days after surgery. After 6 days post surgery, the number of revisions decreased considerably. With regard to the salvaged flaps the mean time to start the revision was 46.5 h (SD 39). With regard to the failed revisions, the mean time to start the revision was 82.0 h (SD 47). This difference proved significant (P = 0.006). Conclusion: Our data shows that the majority of anastomotic failures occur within the first 24 h. Thereafter, the frequency of failures decreases. We also found that the time between initial reconstruction and start of the salvage procedure influences the outcome of the revision negatively. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.
A modified model of hindlimb osteomyocutaneous flap for the study of tolerance to composite tissue allografts
Authors: Adamson Larry A. , Huang Wei‐Chao , Breidenbach Warren C. , Rahhal Dina , Xu Hong , Huang Yiming , Pidwell Diane J. , Wei Fu‐Chan , Tobin Gordon , Ildstad Suzanne T. 
Published: September 2007

AbstractComposite tissue allotransplantation (CTA) is the new frontier in transplantation. More than 25 hand allograft transplants have been performed worldwide, and the feasibility has been well established. The classical experimental model of CTA involves rat orthotopic hindlimb transplantation, a time‐consuming procedure associated with high mortality and morbidity. We describe a rat heterotopic osteomyocutaneous flap that serves as a nonfunctional CTA, allowing the study of tolerance induction to a highly antigenic vascularized allograft of bone, muscle, and skin while minimizing the morbidity and mortality of full hind limb transplantation. In the present studies, we explored whether establishing chimerism by nonmyeloablative conditioning would induce tolerance to CTA. When compared with the classic hind limb transplantation model, these results demonstrate that our heterotopic hind limb flap is less morbid and as an effective experimental model for the study of CTA tolerance. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.