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R R Dubielzig

Publications and source records attributed to R R Dubielzig.

At least 19 recordsLinked to original sources
PubMed2006

Lentoid bodies in the avian retina.

In-vitro studies suggest that, in avian retina, lentoid bodies arise from Müller cells or developing neuroretina. This report describes lentoid bodies in adult avian retinas in association with retinal trauma or degeneration. Retinal lentoids were identified in four birds (three owls and one parrot) in the course of routine diagnostic histopathology. Sections were stained with periodic acid-Schiff for the purposes of descriptive histology, and immunolabelled for a Müller cell marker (glial fibrillary acidic protein; GFAP) and a lens-specific marker (crystallin alpha-A). Intraretinal lentoids of varying size were identified, the constituent cells resembling bladder cells similar to those seen in cataracts. The process of lentoid formation followed a consistent pattern, characterized by progressive Müller cell hypertrophy in damaged areas, culminating in lentoid formation. GFAP immunoreactivity was strongest in Müller cells in the early stages of hypertrophy and receded as Müller cell hypertrophy advanced and lentoids developed. In contrast to GFAP immunoreactivity, crystalline alpha-A labelling increased in distribution and intensity as Müller hypertrophy became more prominent and lentoids were formed. This represents the first report of intraretinal lentoids in birds in vivo. The immunohistochemical data suggest that they arise from Müller cells. Association of lentoids with retinal damage supports the assertion that they arise following disruption of normal cell-cell communication.

Animals↗
PubMed2006

Characterizing a rat Brca2 knockout model.

Evidence exists that BRCA2 carriers may have an elevated risk of breast, ovarian, colon, prostate, and pancreatic cancer. In general, carriers are defined as individuals with protein truncating mutations within the BRCA2 gene. Many Brca2 knockout lines have been produced and characterized in the mouse. We previously produced a rat Brca2 knockout strain in which there is a nonsense mutation in exon 11 between BRC repeats 2 and 3, and a truncated protein is produced. Interestingly, while such a mutation in homozygous mice would lead to limited survival of approximately 3 months, the Brca2-/- rats are 100% viable and the vast majority live to over 1 year of age. Brca2-/- rats show a phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in the Brca2-/- rats is due to a failure of homologous chromosome synapsis. Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs. The establishment of the rat Brca2 knockout model provides a means to study the role of Brca2 in increasing cancer susceptibility and inducing a novel ocular phenotype not previously associated with this gene.

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PubMed2005

Telomerase activity with concurrent loss of cell cycle regulation in feline post-traumatic ocular sarcomas.

Paraffin wax-embedded ocular globes of cats with post-traumatic ocular sarcomas were examined for the presence of TERT, the active subunit of telomerase. The latter is a ribonucleoprotein complex essential for immortalization and expressed by most malignant tumours, germ line cells, lens epithelial cells, and some stem cells. Due to the frequent loss of cell cycle control with the increased expression of telomerase activity, post-traumatic ocular sarcomas were also examined for loss of p16 expression and alterations in p53, the findings being related to mitotic score, tumour grade, and proliferating cell nuclear antigen. These sarcomas expressed telomerase at a high frequency (62.5%); in addition, the majority showed alterations in cell cycle control, as evaluated by lack of p16 immunolabelling (66.7%). Alterations in p53 were the sole mechanism by which cell cycle control was dysregulated in only two tumours expressing TERT (13%). These findings suggest that p16, and not p53, represents the primary mechanism by which post-traumatic ocular sarcomas that express telomerase activity escape cell cycle control.

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PubMed2005

Development of an allogeneic whole-cell tumor vaccine expressing xenogeneic gp100 and its implementation in a phase II clinical trial in canine patients with malignant melanoma.

A xenogeneic melanoma-antigen-enhanced allogeneic tumor cell vaccine (ATCV) is an appealing strategy for anti-cancer immunotherapy due to its relative ease of production, and the theoretical possibility that presentation of a multiplex of antigens along with a xenogeneic antigen would result in cross-reaction between the xenogeneic homologs and self-molecules, breaking tolerance and ultimately resulting in a clinically relevant immune response. In this study, we evaluated the efficacy of such a strategy using a xenogeneic melanoma differentiation antigen, human glycoprotein 100 (hgp100) in the context of a phase II clinical trial utilizing spontaneously arising melanoma in pet dogs. Our results demonstrate that the approach was well tolerated and resulted in an overall response rate (complete and partial response) of 17% and a tumor control rate (complete and partial response and stable disease of >6 weeks duration) of 35%. Dogs that had evidence of tumor control had significantly longer survival times than dogs that did not experience control. Delayed type hypersensitivity (DTH) to 17CM98 canine melanoma cells used in the whole cell vaccine was enhanced by ATCV and correlated with clinical response. In vitro cytotoxicity was enhanced by ATCV, but did not correlate with clinical response. Additionally, anti-hgp100 antibodies were elicited in response to ATCV in the majority of patients tested; however, this also did not correlate with clinical response. This approach, along with further elucidation of the mechanisms of tumor protection after xenogeneic immunization, may allow the development of more rational vaccines. This trial also further demonstrates the utility of spontaneous tumors in companion animals as a valid translational model for the evaluation of novel vaccine therapies.

Animals↗
PubMed2005

Aberrant p53 expression in feline vaccine-associated sarcomas and correlation with prognosis.

Eighty spontaneously occurring feline vaccine-associated sarcomas (VAS) were evaluated to determine the immunohistochemical expression of the tumor suppressor gene p53. Sixty-five of 80 VAS (81%) exhibited positive immunoreactivity with Mab240, a murine monoclonal antibody that specifically recognizes mutated p53. Only 44 of 81 tumors (55%) were positive with rabbit polyclonal antibody CM-1. CM-1 often yielded nonspecific staining of nonneoplastic tissues. Nonspecific staining was greatly reduced or absent with Mab240. Cytoplasmic staining for p53 was a consistent pattern of VAS, occurring in 44% of tumors evaluated. Cats with tumors that exhibited cytoplasmic p53 had significantly shorter time to tumor recurrence compared to those cats with tumors that exhibited nuclear p53 staining (P = 0.0284), but no significant difference in survival outcome was observed. Immunohistochemical detection of p53 offers a prognostic tool for VAS, and, because abnormal p53 expression appears to be a common feature of feline VAS, molecular targeting of mutant p53, may offer a promising new therapeutic opportunity for this cancer.

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PubMed2003

Feline intraocular tumors may arise from transformation of lens epithelium.

Feline ocular sarcomas are malignant intraocular neoplasms that are frequently associated with a history of ocular trauma. They usually present as fibrosarcomas, but some have both epithelial and mesenchymal features. The purpose of this study was to determine the cell of origin of a subset of feline intraocular sarcomas that display a mixed epithelial-mesenchymal phenotype, with elaboration of basement membrane-type matrix. We examined the morphology and histochemical and immunohistochemical phenotypes of nine feline intraocular sarcomas. Immunohistochemistry and in situ hybridization were performed to detect expression of crystallin alpha A. In addition, tumors were examined for expression of vimentin, cytokeratin, smooth muscle actin, desmin, melan A, neural cell adhesion molecule, S-100, glial fibrillary acidic protein, nerve growth factor receptor, and collagen type IV. Animals ranged from 7 to 17 years of age--no breed or sex predilection for tumor occurrence was present. Tumors were characterized by mixed epithelial and mesenchymal phenotypes, both of which elaborated basement membrane-type material and expressed vimentin highly. On the basis of collagen type IV and crystallin alpha A immunopositivity, we established that three of nine tumors were of lens epithelial origin. Expression of desmin and smooth muscle actin identified one tumor as a leiomyosarcoma. The remainder were undifferentiated sarcomas of myofibroblastic origin. This is the first report of lens epithelial neoplasia in clinical material from any species. The history and morphologic features of feline ocular sarcomas are reminiscent of feline vaccine-induced sarcomas. These tumors may share pathophysiologic similarities unique to this species.

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PubMed2002

Cats differ from mink and ferrets in their response to commercial vaccines: a histologic comparison of early vaccine reactions.

Early histologic changes in lesions at vaccine sites were compared in cats, mink, and ferrets. Twenty-four 4-month-old cats, 20 4-month-old mink, and 20 12-month-old ferrets were vaccinated with three rabies virus vaccines, two feline leukemia virus vaccines, alum adjuvant, and saline. Injection sites were excised at selected time points up to 21 days postvaccination. Histologic examination of the tissue revealed significant differences among the cats, mink, and ferrets in the local response to the commercial vaccines. When compared with ferrets and mink, cats had more lymphocytes in response to all three rabies vaccines. Production of fibroblasts, collagen, and macrophages differed among the three killed aluminum-adjuvanted vaccines in cats but did not differ significantly in mink or ferrets. Cats produced fewer binucleate cells than did mink or ferrets in response to the two adjuvanted leukemia virus vaccines. Differences seen in early tissue response of cats to commercial vaccines may be related to the increased predisposition of cats to vaccine-associated sarcomas.

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PubMed2001

A case of Peters' anomaly in a springer spaniel.

An 8-week-old springer spaniel presented with a large central corneal opacity of the left globe, which was accompanied by cords of tissue spanning from the iris collarette to the posterior cornea. A posterior cortical cataract was noted in the right eye. At the owner's request the puppy was humanely destroyed, and a necropsy was performed. Upon sectioning the left globe in the vertical plane, a circle of pigmented strands of tissue was observed spanning the anterior chamber from the iris to the posterior aspect of the cornea. The right globe appeared normal when inspected grossly. Histologically, a membrane of pigmented tissue covered the posterior aspect of the broad central corneal leukoma of the left globe. This membrane and the cords traversing the anterior chamber were composed of vascular uveal tissue. Descemet's membrane and the corneal endothelium were reduced or absent in the zone of corneal opacity. Other than the changes associated with cataract, the right globe was histologically normal. The clinical and histological findings in the left globe were identical with those described for Peters>> anomaly in human beings.

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PubMed2001

Multiple epulides in 13 cats.

Epulides account for 0-7.8% of tumors in surveys of feline oral neoplasms. A review of the literature revealed no reports of multiple epulides in cats. Multiple, concurrent epulides were diagnosed microscopically in 13 cats. Fibromatous and ossifying epulides were diagnosed in 11 of 13 cats and fibromatous epulides were diagnosed in 2 of 13 cats. Microscopically, these epulides were nonencapsulated, well-vascularized, infiltrative, highly cellular neoplasms that expanded the gingiva and were composed of haphazardly arranged, spindle-shaped to stellate cells amid a dense, collagenous stroma. Osseous foci were a feature in the fibromatous and ossifying epulides. The mitotic rate was low and there was marked hyperplasia of the overlying gingiva with a prominent downgrowth of epithelial cords. These tumors recurred in 8 of 13 cats following surgical excision. While uncommon, multiple epulides in cats have a high incidence of recurrence but do not appear to have metastatic potential.

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PubMed2000

Idiopathic or mesothelioma-related pericardial effusion: clinical findings and survival in 17 dogs studied retrospectively.

This retrospective study compares the clinical signs and diagnostic findings of 17 canine patients with histopathological diagnoses of idiopathic pericardial effusion (IPE) or pericardial mesothelioma (MS) in order to identify differences in clinical findings or survival times that might aid in premortem differentiation of these disease conditions. Based on this series of cases, clinical signs, physical examination findings and results of non-invasive diagnostic testing are insufficient to differentiate MS from IPE with confidence unless a discrete pericardial or intrapericardial mass can be identified. Surgical biopsy may be misleading if large amounts of highly reactive and invasive mesothelial cells are seen. Recurrence of significant amounts of pleural effusion within 120 days of pericardiectomy may increase the likelihood that MS is the cause of pericardial effusion in cases in which other causes have been excluded. Survival longer than 120 days postpericardiectomy without chemotherapeutic intervention is associated with a decreased probability of the condition being MS.

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PubMed1999

Immunopathology of pineal glands from horses with uveitis.

PURPOSE: Pinealitis accompanying uveitis is well established in laboratory models of experimental autoimmune uveoretinitis. In naturally occurring uveitis, pinealitis has been demonstrated in the pineal gland from a mare with active uveitis and is suspected in some human uveitides. We have evaluated pineal glands from horses with various stages of uveitis for signs of immunopathology accompanying spontaneous uveitis. METHODS: Pineal glands from 10 horses with uveitis and from 13 horses without uveitis were evaluated for histochemical (H&E, collagen) and immunohistochemical (MHC class II antigen expression, infiltration of T and B lymphocytes, and glial fibrillary acidic protein (GFAP) and vimentin upregulation) evidence of inflammation. RESULTS: Septal areas of pineal glands from horses with uveitis had clusters of MHC class II antigen-expressing cells, T lymphocytes, and enhanced collagen deposition. These changes were not as readily observed in pineal glands from horses without uveitis. B lymphocytes were detected only in the pineal gland from the one mare with active uveitis in which T and B lymphocytes were organized into follicles. No differences in GFAP or vimentin immunoreactivity were noted in pineal glands from horses with or without uveitis. CONCLUSIONS: These pineal gland changes suggest that the pinealitis associated with equine uveitis is transient just as the uveitis of these horses is recurrent. Study of pineal glands from horses with clinically documented uveitis allows demonstration of subtle pineal changes associated with natural uveitis. Similar changes would be difficult to document in human patient populations.

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PubMed1999

Adjuvant therapy for melanoma in dogs: results of randomized clinical trials using surgery, liposome-encapsulated muramyl tripeptide, and granulocyte macrophage colony-stimulating factor.

Spontaneous canine oral melanoma (COM) is a highly metastatic cancer, resistant to chemotherapy, and can serve as a model for cancer immunotherapy. Liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) can activate the tumoricidal activity of the monocyte-macrophage system following i.v. injection. The objective of these studies was to evaluate the therapeutic effectiveness of L-MTP-PE administered alone and combined with recombinant canine granulocyte macrophage colony-stimulating factor (rcGM-CSF) in dogs undergoing surgery for oral melanoma. Ninety-eight dogs with histologically confirmed, clinically staged, oral melanoma were entered into two randomized, double-blind, surgical adjuvant trials. In trial 1, 50 dogs were stratified based on clinical stage and randomized to once a week L-MTP-PE or lipid equivalent (control). When all of the clinical stages were combined, no difference in disease-free survival or in survival time (ST) were detected. However, within stage I, dogs receiving L-MTP-PE had a significant increase in ST compared with control, with 80% of the dogs treated with L-MTP-PE still alive at >2 years. Within each stage II and stage III, there was no difference detected between the treatment groups. In trial 2, 48 dogs were stratified on the basis of clinical stage and extent of surgery (simple resection or radical excision), treated with L-MTP-PE two times a week, and randomized to rcGM-CSF or saline (placebo) given s.c. daily for 9 weeks. Within each stage and when all of the stages were combined, there was no difference between the treatment groups. In both studies, stage I COM is associated with a better prognosis. No effect on survival was observed with regard to tumor location in the oral cavity, sex, type/extent of surgery, or age. In a subset of dogs tested, pulmonary alveolar macrophage cytotoxicity was enhanced with combined rcGM-CSF and L-MTP-PE but not in dogs treated with L-MTP-PE alone. The present study indicates that after surgery, L-MTP-PE administered alone or combined with rcGM-CSF showed no significant antitumor activity in treating advanced stage COM. In early stage COM, L-MTP-PE was shown to result in a prolongation of ST. Furthermore, this study provides additional rationale for the use of the dog model for human malignant melanoma.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1998

Development of human granulocyte-macrophage colony-stimulating factor-transfected tumor cell vaccines for the treatment of spontaneous canine cancer.

Cytokine gene-engineered tumor vaccines are currently an area of intense investigation in both basic research and clinical medicine. Our efforts to utilize tumor vaccines in an immunotherapeutic manner involve canines with spontaneous tumors. We hypothesized that canine tumor cells, transfected with human granulocyte-macrophage colony-stimulating factor (hGM-CSF) cDNA in a plasmid vector, would prove nontoxic following intradermal administration, generate biologically relevant levels of protein, effect local histological changes at the sites of vaccination, and create a systemic antitumor response. Sixteen tumor-bearing dogs were admitted to a study of ex vivo gene therapy. Tumor tissue was surgically removed, enzymatically and mechanically dissociated, irradiated, transfected, and intradermally injected back into the patients. The dogs were vaccinated with primary autologous tumor cells transfected with hGM-CSF or a reporter control gene. hGM-CSF protein was detected (0.07 to 14.15 ng/vaccination site) at 24 hr postinjection and dramatic histological changes were observed, characterized by neutrophil and macrophage infiltration at the sites of injection of hGM-CSF-transfected tumor cells. This was in stark contrast to the lesser neutrophilic and eosinophilic infiltrates found at control vaccination sites. Objective evidence of an antitumor response was observed in three animals. These data, in a large animal translational model of spontaneous tumors, demonstrate in vivo biological activity of hGM-CSF-transfected autologous tumor cell vaccines.

Animals↗
PubMed1998

Orbital lymphosarcoma associated with reticuloendotheliosis virus in a peafowl.

Lymphosarcoma associated with infection by avian reticuloendotheliosis virus was diagnosed in an Indian peafowl with exophthalmia and exposure keratitis. Exenteration of the orbit was complicated by a profound oculocardiac reflex and extensive hemorrhage during surgery. Orbital bleeding was controlled by direct pressure, electrocautery, topical administration of bovine thrombin, and application of sterile gelatin sponges and oxidized regenerated cellulose. A blood transfusion was also performed. In addition to describing methods of handling intraoperative complications of orbital exenteration in birds, to the authors' knowledge, this is the first report to describe an association of reticuloendotheliosis virus, which more commonly affects poultry, with lymphosarcoma in an Indian peafowl.

Animals↗
PubMed1998

Photoreceptor cell death by apoptosis in dogs with sudden acquired retinal degeneration syndrome.

OBJECTIVE: To examine the role of apoptosis in retinal photoreceptor degeneration in dogs with sudden acquired retinal degeneration syndrome (SARDS). SAMPLE POPULATION: Retinas from 3 dogs with SARDS and from 2 clinically normal adult dogs. PROCEDURE: Apoptosis was identified by in situ end-labeling and observation of characteristic morphologic changes by light microscopy. RESULTS: The degree of photoreceptor degeneration varied with duration of vision loss in SARDS-affected eyes. The retina of all 3 SARDS-affected eyes had numerous (34, 61, and 70) apoptotic nuclei per section that were overwhelmingly located in the outer nuclear layer. Apoptotic nuclei were not detected, or were rare in similarly sized retinal sections from normal dogs. Inflammation was not an important feature of SARDS. CONCLUSIONS: Apoptosis appears to be at least 1 mechanism of photoreceptor cell death in dogs with SARDS. CLINICAL RELEVANCE: Because apoptosis appears to be a final common pathway in many retinal degeneration syndromes, future treatment strategies that control apoptosis in other diseases may be applicable to dogs with SARDS. Halting this pathway may allow some photoreceptors to survive and, perhaps, preserve vision.

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PubMed1997

Sodium toxicity and pathology associated with exposure of waterfowl to hypersaline playa lakes of southeast New Mexico.

Cause of mortality was studied in waterfowl in hypersaline playa lakes of southeast New Mexico during spring and fall migration. Mortality was not common in wild ducks resting on the playas during good weather. However, when birds remained on the lakes for prolonged periods of time, such as during experimental trials and stormy weather, a heavy layer of salt precipitated on their feathers. Sodium toxicity was the cause of death for all experimental mallards housed on playa water and for 50% of the wild waterfowl found moribund or dead during the spring of 1995. Gross lesions included heavy salt precipitation on the feathers, ocular lens opacities, deeply congested brains, and dilated, thin-walled, fluid-filled cloacae. Microscopic lesions in the more severely affected birds included liquefaction of ocular lens cortex with lens fiber swelling and multifocal to diffuse ulcerative conjunctivitis with severe granulocytic inflammation, edema, and granulocytic vasculitis resulting in thrombosis. Inflammation similar to that seen in the conjunctiva occasionally involved the mucosa of the mouth, pharynx, nasal turbinates, cloaca, and bursa. Transcorneal movement of water in response to the hypersaline conditions on the playa lakes or direct contact with salt crystals could induce anterior segment dehydration of the aqueous humor and increased osmotic pressure on the lens, leading to cataract formation.

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