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Biomedical subjects

Victor M Elner

Publications and source records attributed to Victor M Elner.

At least 19 recordsLinked to original sources
PubMed2006

Periocular necrotizing fasciitis with visual loss pathogenesis and treatment.

OBJECTIVE: To illustrate the role of clinically necessary aggressive subcutaneous debridement with limited excision of necrotic skin in treating necrotizing faciitis, while demonstrating the histopathologic basis of orbital spread and blindness complicating this disorder. DESIGN: Observational retrospective case series. PARTICIPANTS: Seven consecutive patients cared for by the Eye Plastic and Orbital Surgery Services at the University of Michigan and University of Iowa. METHODS: Retrospective review of ocular findings, systemic features, management, outcome, and histopathology of debrided tissue from 7 patients with periocular necrotizing fasciitis. MAIN OUTCOME MEASURES: Patient survival and morbidity. RESULTS: Bilateral involvement was present in 6 of the 7 patients. Five patients suffered ophthalmic or central retinal artery occlusion with loss of vision. All patients underwent extensive debridement of subcutaneous tissue with sparing of overlying nonnecrotic skin and intensive systemic antibiotic therapy. Four patients required unilateral exenteration. After a mean follow-up of 38 months, 6 patients were alive; 1 died perioperatively due to septic shock. Histopathology, not previously described, showed inflammation to spread preferentially along eyelid fibrofatty-fascial tissue planes into the orbit and along orbital fibrous septae, leading to intense perivascular inflammation, thrombosis, and ocular infarction. CONCLUSIONS: Necrotizing fasciitis is a potentially fatal disease that often causes blindness when affecting the periocular region. To reduce morbidity and mortality in severe infections, prompt subcutaneous debridement and limited resection of necrotic skin are usually necessary.

Adult↗
PubMed2006

Differential expression of retinal pigment epithelium (RPE) IP-10 and interleukin-8.

Interferon-gamma induced protein of 10 kDa (IP-10) is a C-X-C chemokine that attracts T lymphocytes and inhibits angiogenesis. In this study, we investigated the expression of IP-10 by human retinal pigment epithelial cells (HRPE) and compared IP-10 expression to that of interleukin-8 (IL-8), which is a leukocytic chemoattractant and pro-angiogenic factor. Cultured HRPE cells were incubated with either IL-1 beta (0.2-20 ng/ml) or tumor necrosis factor (TNF)-alpha (0.2-20 ng/ml) alone or in combination with interferon-gamma (IFN-gamma) (1000 U/ml). HRPE cells were also incubated with: (1) media conditioned by activated human T lymphocytes (CM), or (2) the same CM treated with neutralizing antibodies to IL-1, TNF, and/or IFN-gamma. IL-8 and IP-10 protein levels were measured by ELISA and mRNA levels by Northern blot analysis of HRPE cells. HRPE cells produced very high levels of IP-10 in response to either IL-1 beta/IFN-gamma, TNF-alpha/IFN-gamma or CD3-activated T-lymphocyte CM. The levels of IP-10 were at least tenfold higher (p<.001) than IL-8 measured in the same samples. Neutralizing antibodies to TNF and IFN-gamma, but not to IL-1, abrogated the ability of the CD3-activated T lymphocytes CM to induce HRPE IP-10 (p<.001). HRPE cells produce differential levels of IP-10 and IL-8 in response to various combinations of recombinant and T-lymphocyte-secreted pro-inflammatory cytokines. This may be important in evolving inflammatory and angiogenic ocular responses.

Antibodies↗
PubMed2006

Gene expression profile of human trabecular meshwork cells in response to long-term dexamethasone exposure.

PURPOSE: Topical use of dexamethasone has long been associated with steroid induced-glaucoma, although the mechanism is unknown. We applied a strict filtering of comparative microarray data to more than 18,000 genes to evaluate global gene expression of cultured human trabecular meshwork cells in response to treatment with dexamethasone. METHODS: Three human trabecular meshwork cell primary cultures from nonglaucomatous donors were incubated with and without dexamethasone for 21 days. Relative gene expression was evaluated by analysis of U133A GeneChip and the results validated using quantitative polymerase chain reaction (PCR). RESULTS: Application of strict filtering to include only genes with statistically significant differences in gene expression across all three trabecular meshwork cell cultures produced a list of 1,260 genes. Significant changes in signal level were observed, including 23 upregulated and 18 downregulated genes that changed greater than three fold in each of three cell cultures. Using quantitative PCR we found changes greater than a thousand fold for two genes (SLP1 and SAA2) and changes greater than a hundred fold for another five genes (ANGPTL7, MYOC, SAA1, SERPINA3, and ZBTB16). CONCLUSIONS: Expression changes in trabecular meshwork cells in response to dexamethasone treatment indicate that a group of actins and actin-associated proteins are involved in the development of cross-linked actin networks that form in response to dexamethasone. A trend was identified toward decreased expression of protease genes accompanied by an increased expression of protease inhibitors. Such a trend in nonproteasomal proteolysis conceivably affects gene product levels above the level of transcription. Only two genes, MYOC and IGFBP2, showed significantly elevated expression after dexamethasone treatment in our study and the other three previously published reports of primary culture trabecular meshwork cell gene expression.

Adolescent↗
PubMed2005

Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration.

Age-related macular degeneration (AMD) is a genetically heterogeneous disease that leads to progressive and irreversible vision loss among the elderly. Inflammation, oxidative damage, cholesterol metabolism and/or impaired function of retinal pigment epithelium (RPE) have been implicated in AMD pathogenesis. We examined toll-like receptor 4 (TLR4) as a candidate gene for AMD susceptibility because: (i) the TLR4 gene is located on chromosome 9q32-33, a region exhibiting evidence of linkage to AMD in three independent reports; (ii) the TLR4-D299G variant is associated with reduced risk of atherosclerosis, a chronic inflammatory disease with subendothelial accumulation; (iii) the TLR4 is not only a key mediator of proinflammatory signaling pathways but also linked to regulation of cholesterol efflux and (iv) the TLR4 participates in phagocytosis of photoreceptor outer segments by the RPE. We examined D299G and T399I variants of TLR4 in a sample of 667 unrelated AMD patients and 439 unrelated controls, all of Caucasian ancestry. Multiple logistic regression demonstrated an increased risk of AMD in carriers of the G allele at TLR4 residue 299 (odds ratio=2.65, P=0.025), but lack of an independent effect by T399I variant. TLR4-D299G showed an additive effect on AMD risk (odds ratio=4.13, P=0.002) with allelic variants of apolipoprotein E (APOE) and ATP-binding cassette transporter-1 (ABCA1), two genes involved in cholesterol efflux. Interestingly, the effect of TLR4, APOE and ABCA1 variants on AMD susceptibility was opposite to that of association with atherosclerosis risk. Our data provide evidence of a link between multiple diverse mechanisms underlying AMD pathogenesis.

Aged↗
PubMed2005

Müllerectomy for upper eyelid retraction and lagophthalmos due to facial nerve palsy.

BACKGROUND: Facial nerve palsy often results in symptoms of ocular irritation due to inadequate eyelid closure. Weakened protractor function results in relative upper eyelid retraction and contributes to lagophthalmos. OBJECTIVE: To evaluate the role of müllerectomy in the comprehensive surgical treatment of ocular exposure due to facial nerve palsy. METHODS: Thirty-four patients with chronic facial nerve palsy underwent unilateral transconjunctival removal of Müller muscle and were followed up for an average of 20 months postoperatively. Other procedures were performed to treat lower eyelid retraction, as required. Preoperative and postoperative ocular exposure symptoms, upper eyelid position, lagophthalmos, and keratopathy were compared. RESULTS: Of the 59 preoperative symptoms, 15 (25%) resolved and 39 (66%) improved. Upper eyelid position was lowered by an average of 1.35 mm (P<.001). Lagophthalmos (P = .002) and corneal exposure (P<.001) were significantly improved. Three patients required levator aponeurosis repair, 2 for preexisting dehiscence and 1 for inadvertent aponeurosis transection. CONCLUSION: Müllerectomy is a rapid, safe, and reproducible surgical method for lowering the upper eyelid and reducing ocular exposure symptoms and signs due to chronic facial nerve palsy.

Adolescent↗
PubMed2005

Orbital peripheral T-cell lymphoma in a child.

A 6-year-old boy with known peripheral T-cell lymphoma had progressive left periorbital swelling and CT findings consistent with abscess or necrosis. Biopsy revealed peripheral T-cell lymphoma and associated necrosis involving the lacrimal gland and surrounding orbital tissue. Immunohistochemical and T-cell receptor gene rearrangement studies confirmed the diagnosis. The patient responded to local radiation and systemic chemotherapy. This is the first pathologically confirmed case of orbital peripheral T-cell lymphoma with subpanniculitic features.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Effects of tetrathiomolybdate in a mouse model of retinal neovascularization.

PURPOSE: To determine the effects of tetrathiomolybdate (TM), a copper-chelating agent, on retinal angiogenesis and vascular endothelial growth factor (VEGF) in a mouse model of retinal neovascularization. METHODS: Postnatal day (P)7 C57BL/6N mice were exposed to 75% +/- 2% oxygen for 5 days (P7-P11) and then returned to room air for 5 days (P12-P17) to induce retinal neovascularization. Beginning on P10 or P12, mice received daily intraperitoneal injections of TM or phosphate-buffered saline (PBS; control) through P17. Retinal neovascularization was examined by fluorescein dextran angiography after 5 days in room air and was quantitated histologically by counting the neovascular endothelial cell nuclei anterior to the inner limiting membrane. TM's effects on VEGF expression were measured by ELISA. RESULTS: TM-treated and control animals demonstrated comparable regions of retinal nonperfusion. Retinas from control mice at P17 contained neovascular tufts at the junction between perfused and nonperfused retina. The tufts contained numerous neovascular nuclei. Retinas from mice treated with TM beginning on P10 (2 days before returning to room air), but not P12, demonstrated a 41% reduction in neovascular cell nuclei compared with control mice (P <0.01). The P10-treated mice also demonstrated a 24% reduction of VEGF compared with control animals (P=0.01). CONCLUSIONS: TM significantly inhibits retinal neovascularization and VEGF production in a mouse model of retinal neovascularization.

Angiogenesis Inhibitors↗
PubMed2005

Lacrimal gland involvement in graft-versus-host disease: a murine model.

PURPOSE: To describe lacrimal gland involvement in a murine model of acute graft-versus-host disease (GVHD). METHODS: Histopathologic examination was performed on lacrimal glands of mice affected by GVHD at 1, 2, 4, and 6 weeks after allogeneic bone marrow transplantation (BMT). Histopathologic scoring, based on characteristic GVHD findings in human disease involved evaluation of periductal inflammation, apoptosis, ductal stasis, ductal debris, and fibrosis. CD3, CD4, CD8, CD20, and CD68 antibodies were used to stain leukocyte subsets in GVHD lacrimal gland infiltrates. Lacrimal glands from syngeneic BMT mice were used in control experiments. RESULTS: Patchy periductal inflammation and focal fibrosis were significantly elevated as early as 2 weeks after allogeneic BMT. Histopathologic scoring of lacrimal glands after allogeneic BMT was significantly different at 4 (P = 0.005) and 6 (P < 0.0001) weeks when compared with scores in syngeneic control mice. The leukocytes in lacrimal gland GVHD infiltrates were predominately CD3+ T lymphocytes, most of which were CD8+, with fewer CD4+ cells present. CONCLUSIONS: This study describes the first murine model of lacrimal gland GVHD with features that closely mimic those described in human disease and indicates that lacrimal involvement occurs in acute GVHD.

Acute Disease↗
PubMed2005

TLR4 mediates human retinal pigment epithelial endotoxin binding and cytokine expression.

PURPOSE: It was previously demonstrated that toll-like receptor 4 (TLR4) is involved in species-specific human retinal pigment epithelial (HRPE) photoreceptor outer segment recognition and oxidant production. This study was performed to demonstrate the classical role of TLR4 in HRPE endotoxin (lipopolysaccharide; LPS) binding leading to HRPE proinflammatory cytokine secretion. METHODS: Cultured HRPE cells were examined for TLR4 expression by immunofluorescence, Western blot analysis, and RT-PCR. HRPE cells labeled with fluorescent monoclonal antibodies (mAbs) to TLR4 and its associated adhesion molecule, CD14, were analyzed by real-time microscopy and resonance energy transfer (RET), determining associations of fluorescent LPS, TLR4, and CD14. LPS-induced HRPE secretion of interleukin (IL)-8 was measured with and without specific blocking mAb to TLR4 and CD14. HRPE TLR4 expression was measured after LPS exposure in the presence and absence of blocking antibodies to TLR4 and CD14. RESULTS: All three HRPE cell lines demonstrated constitutive TLR4 expression by immunofluorescence, Western blot analysis, and RT-PCR. Examination of HRPE cells labeled with fluorescent mAb to TLR4, CD14, and LPS demonstrated RET among the three molecules, indicating that LPS-CD14 binding preceded LPS-TLR4 binding and the close association of CD14 and TLR4. LPS-induced IL-8 was significantly reduced (P < 0.05) in the presence of blocking mAb to TLR4 or CD14. Upregulation of HRPE TLR4 gene and protein expression occurred in response to LPS exposure and was inhibited by mAb to TLR4 or CD14. CONCLUSIONS: HRPE TLR4 is a multifunctional molecule that participates in photoreceptor outer segment membrane recognition, oxidant production, LPS recognition, and cytokine production. These roles indicate potential involvement in retinal degenerative and inflammatory processes.

Antibodies, Blocking↗
PubMed2005

Local corticosteroid treatment of eyelid and orbital xanthogranuloma.

PURPOSE: To demonstrate the efficacy of local corticosteroid therapy for the treatment of eyelid and orbital xanthogranuloma in adults. METHODS: We performed a retrospective chart review of six patients receiving local triamcinolone acetonide (40 mg/mL) injections for the treatment of eyelid and orbital xanthogranuloma at the University of Michigan. All patients underwent diagnostic biopsy prior to treatment. The effects of this therapy on symptoms and signs of the disease were assessed. RESULTS: All six patients complained of eyelid swelling or nodularity, and five had yellow discoloration of their eyelids. All lesions involved the eyelids and anterior orbit, and five were present bilaterally. Biopsy revealed necrobiotic xanthogranuloma in four patients and adult-onset xanthogranuloma in two patients. Triamcinolone acetonide was administered intralesionally as series of two to 25 injections. Local control was obtained in all six cases, with the reduction of symptoms and signs of the disease in five cases. Two patients with necrobiotic xanthogranuloma developed non-Hodgkin's lymphoma. Average follow-up of patients whose treatment was not truncated by systemic chemotherapy was 52 months (range, 30 to 86 months). No complications occurred as a result of this treatment. CONCLUSION: Intralesional injection of triamcinolone acetonide is an effective, safe treatment for orbital xanthogranuloma in adults. This modality avoids the side effects associated with systemic corticosteroid or cytotoxic agent therapy.

Adult↗
PubMed2005

TLR4 mediates human retinal pigment epithelial endotoxin binding and cytokine expression.

PURPOSE: We previously demonstrated toll-like receptor 4 (TLR4) to be involved in species-specific human retinal pigment epithelial (HRPE) photoreceptor outer segment recognition and oxidant production. This study was performed to demonstrate the classic role of TLR4 in HRPE endotoxin (lipopolysaccharide [LPS]) binding leading to HRPE proinflammatory cytokine secretion. METHODS: Cultured human HRPE cells were examined for TLR4 expression by immunofluorescence, Western blot analysis, and reverse transcription polymerase chain reaction (RT-PCR). HRPE cells labeled with fluorescent monoclonal antibodies (mAb) to TLR4 and its associated adhesion molecule, CD14, were analyzed by real-time microscopy and resonance energy transfer (RET), determining associations of fluorescent LPS, TLR4, and CD14. LPS-induced HRPE secretion of interleukin-8 (IL-8) was measured with and without specific blocking mAb to TLR4 and CD14. HRPE TLR4 expression was measured after LPS exposure in the presence and absence of blocking antibodies to TLR4 and CD14. RESULTS: All three HRPE cell lines demonstrated constitutive TLR4 expression by immunofluorescence, Western blot analysis, and RT-PCR. Examination of HRPE cells labeled with fluorescent mAb to TLR4, CD14, and LPS demonstrated RET among the three molecules, indicating that LPS-CD14 binding preceded LPS-TLR4 binding and the close association of CD14 and TLR4. LPS-induced IL-8 was significantly reduced (P < .05) in the presence of blocking mAb to TLR4 or CD14. Up-regulation of HRPE TLR4 gene and protein expression occurred in response to LPS exposure and was inhibited by mAb to TLR4 or CD14. CONCLUSION: HRPE TLR4 is a multifunctional molecule that participates in photoreceptor outer segment membrane recognition, oxidant production, LPS recognition, and cytokine production. These roles indicate potential involvement in retinal degenerative and inflammatory processes.

Blotting, Western↗
PubMed2004

Graded full-thickness anterior blepharotomy for upper eyelid retraction.

BACKGROUND: A chief morbidity of Graves eye disease is upper eyelid retraction that results in exposure keratopathy and cosmetic deformity. OBJECTIVE: To assess the efficacy of graded anterior blepharotomy to treat upper eyelid retraction. METHODS: Fifty eyelids of 32 patients with Graves eye disease-associated upper eyelid retraction, causing symptomatic ocular exposure, were treated with graded, transcutaneous, full-thickness, anterior blepharotomy. Preoperative and postoperative ocular exposure symptoms, upper eyelid position, lagophthalmos, and keratopathy were compared. RESULTS: At a mean +/- SD of 8.5 +/- 8.1 months' (range, 2-35 months) follow-up, more than 90% of preoperative symptoms resolved or improved. Upper eyelid position (P<.001), lagophthalmos (P<.001), and keratopathy (P<.01) were significantly improved. Mild contour abnormalities (all </=1 mm) occurred in 7 of 50 eyelids. Eyelid crease recession or asymmetry occurred in 4 of 22 patients with postoperative eyelid crease measurements. Complications of ptosis, wound dehiscence, and a full-thickness hole each occurred once. The mean +/- SD time taken to perform the procedure was 31.5 +/- 8.9 minutes per eyelid. CONCLUSIONS: Graded anterior blepharotomy for upper eyelid retraction is a safe and highly effective surgery for upper eyelid retraction associated with symptomatic Graves eye disease. This technique achieves excellent functional and cosmetic outcomes.

Adult↗
PubMed2004

Human, but not bovine, photoreceptor outer segments prime human retinal pigment epithelial cells for metabolic activation and massive oxidant release in response to lipopolysaccharide and interferon-gamma.

Reactive oxygen metabolites (ROMs) may contribute to several eye diseases, such as age-related macular degeneration, although the underlying mechanisms are unclear. The present study shows that human photoreceptor outer segments (POS) prime human retinal pigment epithelial (RPE) cells for massive ROM release in response to lipopolysaccharide (LPS) and interferon-gamma. However, no ROM priming of human RPE cells is observed for bovine POS. ROM production appears to be linked with underlying metabolic oscillations involving the hexose monophosphate shunt.

Animals↗
PubMed2004

Ex vivo produced human conjunctiva and oral mucosa equivalents grown in a serum-free culture system.

PURPOSE: We sought to develop full-thickness ex vivo produced human conjunctiva and oral mucosa equivalents using a serum-free culture system without a feeder layer and to compare conjunctiva and oral mucosa equivalents to assess their suitability as graft materials for eyelid reconstruction. MATERIALS AND METHODS: Human conjunctival and oral mucosal keratinocytes were cultured, expanded, and seeded onto AlloDerm (LifeCell Corp, Branchburg, NJ), a cadaveric, acellular dermis, to produce ex vivo produced full-thickness mucosa equivalents. Histology of equivalents and their expression of immunoreactive Ki-67, a proliferation marker, and GLUT1, a membrane antigen seen in barrier tissues, were examined at 4, 11, and 18 days after seeding onto AlloDerm. RESULTS: Progressive epithelial stratification was observed on day 4, 11, and 18 conjunctiva and oral mucosa equivalents. Ki-67 immunoreactivity progressively increased with cultured time in both types of equivalent, indicating the continued presence of actively proliferating cells. GLUT1 immunoreactivity, concentrated in the basal keratinocytes of stratified epithelia of both types of equivalents, mimicked native tissue and indicated a high glycolytic state of the basal cells. CONCLUSIONS: Conjunctival and oral mucosal equivalents are similar to native tissue and demonstrate high proliferative and glycolytic states. Due to the similarity to conjunctiva, oral mucosal equivalents may be useful for eyelid reconstruction. Their advantages for surgical reconstruction include 1) ease of obtaining autogenous oral epithelium for expansion in vitro without the possibility of contaminating cellular- or serum-borne biologic agents, 2) growth of intact, confluent epithelia on rigid, transplantable human allogeneic dermis that may be surgically transplanted, and 3) reduced donor site morbidity and surgical time.

Biocompatible Materials↗
PubMed2004

Toll-like receptor 4 (TLR4) of retinal pigment epithelial cells participates in transmembrane signaling in response to photoreceptor outer segments.

Retinal pigment epithelial (RPE) cells mediate the recognition and clearance of effete photoreceptor outer segments (POS), a process central to the maintenance of normal vision. Given the emerging importance of Toll-like receptors (TLRs) in transmembrane signaling in response to invading pathogens as well as endogenous substances, we hypothesized that TLRs are associated with RPE cell management of POS. TLR4 clusters on human RPE cells in response to human, but not bovine, POS. However, TLR4 clustering could be inhibited by saturating concentrations of an inhibitory anti-TLR4 mAb. Furthermore, human POS binding to human RPE cells elicited transmembrane metabolic and calcium signals within RPE cells, which could be blocked by saturating doses of an inhibitory anti-TLR4 mAb. However, the heterologous combination of bovine POS and human RPE did not trigger these signals. The pattern recognition receptor CD36 collected at the POS-RPE cell interface for both homologous and heterologous samples, but human TLR4 only collected at the human POS-human RPE cell interface. Kinetic experiments of human POS binding to human RPE cells revealed that CD36 arrives at the POS-RPE interface followed by TLR4 accumulation within 2 min. Metabolic and calcium signals immediately follow. Similarly, the production of reactive oxygen metabolites (ROMs) was observed for the homologous human system, but not the heterologous bovine POS-human RPE cell system. As (a) the bovine POS/human RPE combination did not elicit TLR4 accumulation, RPE signaling, or ROM release, (b) TLR4 arrives at the POS-RPE cell interface just before signaling, (c) TLR4 blockade with an inhibitory anti-TLR4 mAb inhibited TLR4 clustering, signaling, and ROM release in the human POS-human RPE system, and (d) TLR4 demonstrates similar clustering and signaling responses to POS in confluent RPE monolayers, we suggest that TLR4 of RPE cells participates in transmembrane signaling events that contribute to the management of human POS.

Animals↗
PubMed2004

Double silicone intubation as treatment for persistent congenital nasolacrimal duct obstruction.

PURPOSE: The great majority of children with nasolacrimal duct (NLD) obstruction are successfully treated with probing or conventional silicone tube intubation. A small percentage of patients fail to have their NLD obstruction resolved with these procedures and require dacryocystorhinostomy (DCR). This study was conducted to assess the effectiveness of double bicanalicular silicone intubation with placement of two loops of silicone tubing through the NLD for treatment of persistent NLD obstruction in children as an alternative to DCR. METHODS: Ten eyes of 9 patients with nasolacrimal duct obstruction who had failed conventional therapies and were to otherwise undergo DCR were instead treated with double bicanalicular silicone tube intubation. Resolution of preoperative symptoms and signs of NLD obstruction were assessed. RESULTS: At an average follow-up of 40 +/- 5.6 months, all patients had improvement in symptoms and signs. The mean patient age was 31 +/- 3.2 months. The average duration of intubation was 15 +/- 0.73 months. Eight of 10 eyes had complete resolution of NLD obstruction symptoms. Two of 10 treated eyes had occasional symptoms of mattering with upper respiratory infection and exposure to wind or cold but required no further treatment. Nine of 10 eyes were treated for congenital NLD obstruction. The remaining patient had failed conventional bicanalicular intubation after repair of a traumatic common canalicular avulsion. CONCLUSIONS: Double bicanalicular silicone tube intubation is an effective alternative to DCR in selected children who have failed conventional therapies for NLD obstruction. This treatment obviated DCR in all patients in this study.

Biocompatible Materials↗