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  • 1
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We have shown that the genetically diabetic mouse (C57BLKS/J-m+/+Leprdb) has a wound healing and neovascularization deficit associated with an inability to recruit endothelial precursor cells (EPCs) to the wound. This may account for a fundamental mechanism in impaired diabetic wound healing. We hypothesized that the adenoviral mediated overexpression of platelet-derived growth factor-B (PDGF-B) would enhance wound healing, improve neovascularization, and recruit EPCs to the epithelial wound in three diabetic mouse models. Eight-mm full-thickness flank wounds were made in db/db, nonobese NOD/Ltj, streptozotocin, and C57BLKS/J mice. Wounds were treated with either 1 × 108 PFU Ad-PDGF-B or Ad LacZ or phosphate buffered saline solution. Wounds harvested at seven days were analyzed for epithelial gap, blood vessel density, granulation tissue area, and EPCs per high powered field. All three diabetic models have a significant wound healing and neovascularization defect compared to C57BLKS/J controls. Adenoviral-PDGF-B treatment significantly enhanced epithelial gap closure in db/db, streptozotocin, and nonobese NOD/Ltj mice as compared to diabetic phosphate buffered saline solution or Ad LacZ controls. A similar increase in the formation of granulation tissue and vessel density was also observed. All three models had reduced levels of GATA-2 positive EPCs in the wound bed that was corrected by the adenoviral mediated gene transfer of PDGF. EPC recruitment was positively correlated with neovascularization and wound healing. Three different diabetic models have a wound healing impairment and a decreased ability to recruit EPCs. The vulnerary effect of adenoviral mediated gene therapy with PDGF-B significantly enhanced wound healing and neovascularization in diabetic wounds. The PDGF-B mediated augmentation of EPC recruitment to the wound bed may be a fundamental mechanism of these results.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Inc
    Wound repair and regeneration 8 (2000), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Most patients with chronic wounds fail to heal in a reasonable period of time. Despite considerable advances in elucidating the molecular basis of wound repair, attempts at developing new therapies have been disappointing. In fact, in the few studies where cytokine growth factors have been efficacious, their effect has been dramatically less than would have been predicted from animal studies. We hypothesize that platelet-derived growth factor-BB, a growth factor associated with wound healing, when produced in large quantities within the wound bed due to adenovirus mediated gene overexpression by the cells of the wound bed will dramatically enhance wound healing. Simply stated, we plan to insure the delivery of the growth factor by using gene therapy techniques so that cells locally involved in the wound healing process will temporarily increase their production of platelet-derived growth factor-BB. We present the first step in the series of human investigations to test this hypothesis which is a phase I clinical trial. Our proposed study is designed to assess local and systemic toxicity, and the feasibility of using the maximum tolerated dose of H5.020CMV.PDGF-b associated with in vivo platelet-derived growth factor-BB gene transduction via an intraulcer injection of H5.020CMV.PDGF-b in patients with a diabetic insensate foot ulcer.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Inc
    Wound repair and regeneration 7 (1999), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Chronic nonhealing wounds represent a large clinical problem resulting in severe disabilities and large healthcare expenditures. Despite the scope of this problem, effective new therapies are lacking. The deficiency of growth factors in chronic wounds has brought attention to the topical application of growth factors, but initial clinical trials have resulted in only modest improvements in healing despite large, repetitive doses. The modest improvement in healing observed in these trials show that growth factors can improve chronic wound healing, but a better means of growth factor delivery is needed. We hypothesized that gene therapy using a recombinant adenoviral vector could be used to induce transgene production directly by cells in the wound. An adenovirus containing the β-galactosidase reporter transgene (Ad-LacZ) was used in the ischemic rabbit ear model to test this hypothesis. Ad-LacZ resulted in efficient transgene delivery to cells participating in the wound healing response, with expression up to 2 weeks. However, wound reepithelialization was impaired in Ad-LacZ treated wounds compared to vehicle control wounds. Adenoviral mediated gene transfer is a promising efficient means of growth factor delivery to chronic wounds. However, selection of the proper transgene with appropriate biologic activity in wound healing may be essential to overcome the potential adverse effects of adenoviral infection.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Fetal fibroblasts are intrinsically different from postnatal fibroblasts. We studied the differences in expression, size, and assembly of pericellular matrices in human fetal and postnatal fibroblasts, as well as the effect of fetal fibroblast-conditioned media as a source of migration stimulating factor on pericellular matrix formation. Fibroblasts in their fifth to fifteenth passages were cultured for 24 hours before analysis. Streptomyces hyaluronidase (0.1 U/ml), monoclonal mouse anti-human CD-44std, or anti-human CD-4 antibodies were added and incubated for 1 hour (at 4° and 37° C) before analysis of the pericellular matrices with the use of a particle exclusion technique. The pericellular matrix/cell body ratio of fetal fibroblasts was significantly larger than that of newborn (p 〈 0.002) and adult (p 〈 0.001) fibroblasts. Hyaluronidase disrupted the pericellular matrices in all three cell lines. Assembly of the pericellular matrices was blocked by anti-human CD-44std antibody but not by anti-human CD-4 antibody at both 4° and 37° C. Incubation of fibroblast cell lines in fetal fibroblast-conditioned media did not increase pericellular matrix/cell body ratio but did increase the percentage of fibroblasts expressing a detectable pericellular matrix in adult (p 〈 0.01), newborn (p 〈 0.001), and fetal (p 〈 0.005) fibroblasts. We conclude that fibroblasts produce hyaluronic acid-dependent pericellular matrices which require interaction with a hyaluronic acid-binding protein for assembly. Large pericellular matrices are one intrinsic factor characterizing a unique fetal fibroblast phenotype.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Inc
    Wound repair and regeneration 8 (2000), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The application of gene transfer strategies to wound healing is not an obvious use of this technology until one considers the important role of cytokines and growth factors in the normal wound healing response. Several gene transfer strategies have been proposed, from in vitro retroviral-mediated gene transfer with autologous transplantation, to in vivo plasmid based gene transfer as retroviral gene transfer. The limitations of these approaches have been efficiency of gene transfer, transgene expression and biologic response. Adenoviral-mediated gene transfer in wound healing is a relatively new application of this vector. The advantage of the adenovirus as a gene transfer vector lies in its ability to transduce nondividing cells of all types at very high efficiency without integration into the host cell's genome. The disadvantage of adenovirus as a vector is the relatively short duration of transgene expression and the inflammatory response it elicits. In the setting of wound healing brief duration of high levels of transgene may be all that is necessary to favorably influence wound healing. Secondly, as wound healing is fundamentally an inflammatory response, the inflammation elicited by the adenovirus may not be detrimental as long as the transgene is a growth factor with significant vulnerary effects such as platelet-derived growth factor-B. This review summarizes the current state of adenoviral-mediated gene transfer in experimental models of impaired wound healing which have laid the groundwork for proposed phase I clinical trials of adenoviral-mediated gene transfer of platelet-derived growth factor-B in chronic venous leg ulcers and chronic nonhealing diabetic foot ulcers. Adenoviral-mediated gene transfer is a useful tool in the study of the role of specific cytokines and growth factors in normal and impaired wound healing. Adenoviral-mediated gene transfer may hold significant promise for clinical application as a means of efficient growth factor delivery in correcting impaired wound healing.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The use of an adenoviral vector as a means of therapeutic protein delivery for the treatment of impaired wound healing is a potentially effective application of current gene transfer techniques. This study was designed to investigate the ability of adenovirus to mediate gene transfer in healing wounds in human skin in vivo. The human skin/severe combined immunodeficient mouse chimera model was used to study both the response of human tissue to adenoviral infection and the nature of the acute inflammatory response. The effects of adenoviral infection and transgene expression on the rate and quality of human wound healing were then investigated. Cell- and species-specific monoclonal antibodies were used to characterize the resident skin cell types participating in wound repair, the inflammatory response, and the proliferative potential of adenovirus-treated compared to control skin. Our studies show that, following wounding, normal skin architecture is restored in the presence of adenoviral infection equivalent to noninfected controls. Despite an increased acute inflammatory response after adenovirus injection, no difference in the healing capabilities of wounded skin was observed, suggesting that adenovirus-mediated gene transfer for growth factor-mediated acceleration of wound healing may be feasible.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-198X
    Keywords: Congenital hydronephrosis ; Fetal surgery ; Vesicoamniotic shunts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This report reviews the management of the fetus with congenital hydronephrosis (CH), a challenging diagnostic and therapeutic problem. Experimental models of obstructive uropathy have produced histologic changes similar to those seen in kidneys of human neonates with congenital hydronephrosis. Relief of obstruction in utero in these models has been shown to prevent some of the dysplastic changes caused by obstruction. These studies have formed the theoretical basis for in utero decompression to restore amniotic fluid dynamics to prevent death from pulmonary hypoplasia, and reverse or arrest dysplastic morphogenesis. The development of prognostic criteria has greatly aided in selection of appropriate fetuses for intervention. These criteria include: (1) Na〈100 mEq/l; (2) Cl〈90 mEq/l; (3) osmolarity 〈210 mosmol; (4) sonographic appearance of the fetal kidneys; (5) amniotic fluid status; (6) urine output at fetal bladder catheterization. All fetuses should have ultrasonography to exclude other anomalies, and karyotype analysis to exclude chromosomal abnormality. If amniotic fluid volume is normal, the pregnancy is followed with serial ultrasound examinations. If oligohydramnios develops, a prognostic evaluation is performed, including fetal bladder catheterization. If the fetus has poor residual renal function, on the basis of prognostic criteria, appropriate counseling may be given. If the fetus has good residual renal function, depending on lung maturity, it can be delivered early for corrective surgery. If diagnosed prior to lung maturity in utero, decompression by either vesicoamniotic shunting or open fetal surgery may be attempted in the highly selected case. Very few fetuses with CH will require in utero decompression, but all benefit from early diagnosis allowing preparation for postnatal care. Open fetal surgery should be considered an experimental therapy until efficacy and safety are established in controlled trials.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Diseases of the colon & rectum 34 (1991), S. 336-338 
    ISSN: 1530-0358
    Keywords: Squamous cell carcinoma ; Anus ; HIV ; AIDS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We retrospectively reviewed six patients with squamous cell carcinoma of the anus (SCCA) and human immunodeficiency virus (HIV) infection treated between 1985 and 1988. All six patients were homosexual men. Five patients had AIDS and one was HIV-positive. The most common symptoms and signs were pain (n=5), mass (n =5), and bleeding (n=5). The average tumor size was 3.2 cm with a range of 1–10 cm. Five tumors were located in the anal canal and one at the anodermal junction. One patient was treated with biopsy alone, one with local excision, one with wide local excision and radiation therapy, and two with diverting colostomy. The average follow-up was 8 months. Of the five AIDS patients, two died, one was transferred to a hospice facility, one was lost to follow-up, and one remains alive 1 year following treatment. The HIV-positive patient died secondary to metastatic SCCA. This group of patients raises the question of a possible association between HIV and SCCA.
    Type of Medium: Electronic Resource
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