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Biomedical subjects

Justine R Smith

Publications and source records attributed to Justine R Smith.

At least 19 recordsLinked to original sources
PubMed2006

Primary treatment of acute retinal necrosis with oral antiviral therapy.

PURPOSE: To explore the possibility of oral antiviral therapy in lieu of intravenous acyclovir for treating acute retinal necrosis (ARN), a necrotizing retinopathy caused by herpes simplex virus type 1 or 2 or by varicella zoster virus. DESIGN: Retrospective, interventional, small case series. PARTICIPANTS: Four patients (6 eyes). METHODS: Patients were treated with oral antiviral therapy. Medications included valacyclovir (1 g 3 times daily), oral famciclovir (500 mg 3 times daily), and topical and oral corticosteroids. MAIN OUTCOME MEASURES: Improvement of symptoms, including photophobia, blurred vision, ocular discomfort, and floaters; increase in visual acuity; and resolution of vitreitis, retinitis, and retinal vasculitis, where present. RESULTS: Symptoms and visual acuity improved within 2 weeks to 1 month in 3 of 4 patients (75%) treated with oral antiviral medication. One patient required surgical treatment for asymptomatic retinal detachment after 3 weeks of treatment; retinal detachment in the fellow eye was repaired 2 months later. Duration of antiviral therapy ranged from 5 weeks to 3 months. CONCLUSIONS: For 4 patients with relatively indolent cases of ARN, oral antiviral therapy alone was effective in eliminating signs and symptoms of the disease. In particular, oral valacyclovir and famciclovir appeared to be effective, although further study is necessary to determine whether these drugs are as effective as intravenous acyclovir for initial treatment of ARN.

2-Aminopurine↗
PubMed2006

Ocular coherence tomography in acute posterior multifocal placoid pigment epitheliopathy.

The authors report a case of typical acute posterior multifocal placoid pigment epitheliopathy in which an ocular coherence tomographic scan was performed through an acute lesion and then repeated through the same lesion 12 months later. The initial ocular coherence tomographic scan showed marked anterior displacement of both neuroretina and outer reflective band. A subsequent ocular coherence tomographic scan revealed resolution of the prior displacement, increased reflectance of the outer reflective band and mild disruption of the outer retinal layers. These findings are consistent with a primary choroiditis.

Acute Disease↗
PubMed2005

Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma.

Standardized guidelines for the baseline evaluation and response assessment of primary CNS lymphoma (PCNSL) are critical to ensure comparability among clinical trials for newly diagnosed patients. The relative rarity of this tumor precludes rapid completion of large-scale phase III trials and, therefore, our reliance on the results of well-designed phase II trials is critical. To formulate this recommendation, an international group of experts representing hematologic oncology, medical oncology, neuro-oncology, neurology, radiation oncology, neurosurgery, and ophthalmology met to review current standards of reporting and to formulate a consensus opinion regarding minimum baseline evaluation and common standards for assessing response to therapy. The response guidelines were based on the results of neuroimaging, corticosteroid use, ophthalmologic examination, and CSF cytology. A critical issue that requires additional study is the optimal method to assess the neurocognitive impact of therapy and address the quality of life of PCNSL survivors. We hope that these guidelines will improve communication among investigators and comparability among clinical trials in a way that will allow us to develop better therapies for patients.

Central Nervous System Neoplasms↗
PubMed2005

A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes.

OBJECTIVE: Infliximab, a monoclonal antibody against tumor necrosis factor alpha, is approved by the US Food and Drug Administration for treatment of numerous autoimmune disorders. We conducted a prospective, open-label phase 2 clinical trial to assess the effectiveness of infliximab in treating refractory autoimmune uveitis. METHODS: We prospectively enrolled 23 patients from the uveitis clinic of the Casey Eye Institute, Portland, Ore, into this trial. All patients meeting eligibility criteria received 3 infliximab infusions at weeks 0, 2, and 6. Clinical success was ascertained at week 10. Patients meeting initial criteria for success received an infusion at week 14 and every 8 weeks thereafter, with dose escalation permitted for breakthrough inflammation, and underwent outcome measurements at week 50. RESULTS: All patients underwent outcome assessment at week 10. Eighteen (78%) of these subjects met criteria for clinical success at this time. Success was judged by the composite clinical end point of visual acuity, control of intraocular inflammation, ability to taper concomitant medication therapy, and improvement in inflammatory signs on fluorescein angiography and/or ocular coherence tomography. Successful grading required improvement in at least 1 of 4 subcomponents and worsening in none. Seven of 14 patients enrolled for 1 year continued infliximab therapy and maintained their successful grading. Five did not complete 1 year of treatment because of significant adverse events, and 2 terminated treatment early for reasons unrelated to the study. Serious adverse events that were potentially related to infliximab included pulmonary embolus, congestive heart failure, lupus-like reaction in 2, and vitreous hemorrhage in 2 patients. Antinuclear antibodies developed in 15 of 20 enrolled patients receiving 3 or more infusions. CONCLUSIONS: Infliximab was an effective short-term immunosuppressive agent in most of the patients, with 18 of 23 meeting criteria for clinical success at week 10. Infliximab was effective in the long term in all patients able to complete 50 weeks of therapy. Although some patients achieved clear benefit, the rate of serious toxic effects was unexpectedly high. Further long-term studies are warranted to determine the safety and efficacy of infliximab in treating intraocular inflammation.

Adolescent↗
PubMed2005

A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease.

OBJECTIVE: Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS: Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS: As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION: This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.

Acute Disease↗
PubMed2005

B-Cells in ocular adnexal lymphoproliferative lesions express B-cell attracting chemokine 1 (CXCL13).

PURPOSE: The homeostatic chemokine, B cell attracting chemokine 1 (CXCL13), has been implicated in the pathogenesis of lymphocyte-mediated diseases. We investigated the cellular expression of this chemokine in the spectrum of ocular adnexal lymphoproliferative lesions. DESIGN: Laboratory investigation. METHODS: CXCL13 expression in paraffin-embedded adnexal biopsy specimens was determined by indirect immunohistochemistry with antigen retrieval. RESULTS: In 15 of 16 biopsy specimens, including reactive lymphoid hyperplasia (n = 7), atypical lymphoid hyperplasia (n = 3), and B cell lymphoma (n = 6), CXCL13 was detected. CD20-positive B-cells, as well as dendritic cells and endothelial cells, expressed the chemokine. CONCLUSIONS: B-cells in ocular adnexal lymphoproliferative lesions demonstrate expression of CXCL13, a chemokine that may participate in tumor pathogenesis and is a potential target for novel therapies.

Antibodies, Monoclonal↗
PubMed2005

Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated virus in experimental autoimmune uveoretinitis.

Members of the adeno-associated virus (AAV) family are good candidates for the treatment of ocular diseases because of their relative lack of pathogenicity. We studied the effect of intraocular injection of AAV2-viral IL-10 (vIL-10) on retinal S-antigen-induced experimental autoimmune uveoretinitis (EAU) in Lewis rats. We demonstrated that AAV2/2-GFP injected into the vitreous body transduced the iris and ciliary body, or anterior uvea, and the retina. We showed that intravitreal injection of the AAV2/2-tetON-vIL-10 construct achieved detectable levels of vIL-10 mRNA and protein within the eye and was effective in protecting the rat retina against destruction. This protection was dependent on the level of vIL-10 present in the aqueous humor/ vitreous body. Intravitreal injection of the same construct encased within an AAV5 shell, AAV2/5-tetONvIL- 10, did not confer any degree of protection. It appeared that the AAV2/5 vectors did not transduce the anterior uvea, the site at which inflammatory cells first localize in EAU, nor the ganglion cell layer; induced low expression of vIL-10 mRNA; and did not achieve detectable levels of transgene expression in the aqueous humor/vitreous body. Local treatment with AAV2/2-tetON-vIL-10 did not dampen the systemic immune response, as determined by S-antigen-specific lymphocyte proliferation. Our results show that local intravitreal injection of AAV2/2 is an effective means by which to deliver immunoregulatory molecules into the eye during uveitis, a chronic human ocular disease.

Animals↗
PubMed2005

Expression of immunoglobulin transcription factors in primary intraocular lymphoma and primary central nervous system lymphoma.

PURPOSE: Several B-cell-associated transcription factors and their coactivators, including BCL-6, BSAP/PAX5, BOB.1/OBF.1, Oct.2, MUM1/IRF4, and PU.1, have been detected in peripheral B-cell lymphomas. There are limited data on their expression in centrally located lymphoid neoplasms, such as primary intraocular lymphoma (PIOL) or primary central nervous system lymphoma (PCNSL). PIOL is a rare non-Hodgkin lymphoma, considered a subtype of PCNSL. Both are usually diffuse, large B-cell lymphoma (DLBCL), rarely manifest outside the CNS, and carry a poor prognosis. METHODS: Tissue biopsy specimens were examined from eight cases of PIOL and 42 cases of HIV-negative PCNSL, as well as 50 cases of peripheral DLBCL, for the above-mentioned transcription factors and for immunoglobulin heavy and light chains, using immunohistochemistry. RESULTS: Immunoglobulin expression was demonstrated in 46 (92%) of 50 cases of PIOL/PCNSL but in only 27 (54%) of 50 cases of peripheral DLBCL. Positivity for BOB.1/OBF.1 and Oct.2 was observed in all immunoglobulin-expressing PIOL and PCNSL. BSAP/PAX5 expression occurred in 98% of PIOL/PCNSL, and MUM1/IRF4 immunoreactivity in 45 (90%) of 50 of these cases. PU.1 expression was observed in only 10% of the PIOL/PCNSL group in contrast to 23 (46%) of 50 peripheral DLBCLs. Aberrant coexpression of MUM1/IRF4, PAX5, MUM1/IRF4, and BCL-6 was observed in most PIOLs/PCNSLs. CONCLUSIONS: These data provide further support to the notion that peripheral and centrally located DLBCLs differ in clinical, immunophenotypic, and genotypic features, despite their similar morphologic characteristics. PIOL and PCNSL tumor cells are most likely to be derived from mature B-cells that have undergone the germinal center reaction.

Central Nervous System Neoplasms↗
PubMed2005

Management of sight-threatening uveitis: new therapeutic options.

Over the past 2 decades therapy for the treatment of intraocular inflammation (uveitis) has developed into a highly differentiated approach with an increasing number of drug options. This paper primarily summarises literature from the past 5 years (2000 to May 2004), gives an update on systemic immunosuppressive therapy for non-infectious uveitis and speculates about new developments that could become relevant in the near future for the treatment of uveitis patients. The spectrum of immunosuppressive drugs has been notably expanded by tumor necrosis factor inhibitors, but with some limitations to uveitis. Behcet's disease is an example of uveitis where a multisystem disorder can affect the eye very severely. This clinical example has been used to investigate the utility of many different types of immunosuppressive therapies and the clinical approach is extensively discussed in this review. An accompanying table summarises the proposed mode of action, standard dosage, common adverse effects, as well as estimated cost of current treatment options.

Adrenal Cortex Hormones↗
PubMed2005

Retisert (Bausch & Lomb/Control Delivery Systems).

Retisert (Envision TD), a sustained release intraocular implant containing fluocinolone acetonide, has been developed and launched in the US by Bausch & Lomb and Control Delivery Systems for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.

Animals↗
PubMed2004

In vivo confocal microscopy of keratic precipitates.

OBJECTIVE: To evaluate the heterogeneity of keratic precipitates (KP) in varying subtypes of uveitis by in vivo confocal microscopy (IVCM). METHODS: The KP were viewed with a scanning confocal microscope in patients (n = 33) who sought care at a tertiary referral uveitis service for immune-mediated and infectious forms of uveitis, including HLA-B27-associated uveitis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, juvenile chronic arthritis, Fuchs heterochromic iridocyclitis, cytomegalovirus retinitis, herpes zoster ophthalmicus, ocular toxoplasmosis, and idiopathic uveitis. Images were captured and digitalized in real time. RESULTS: Forty-two eyes of 33 patients were examined in this study. Patient age ranged from 22 to 84 years, with a mean age of 49.4 years. Seventeen (52%) of the patients were women, and 16 patients (48%) were men. The KP ranged in diameter from 10 to 350 mum. We observed the following absolute and speculative outcomes: KP are markedly heterogeneous and variable as documented by IVCM; KP in individual patients are consistent throughout the cornea; the morphologic features of KP change across time; infectious vs noninfectious causes of uveitis seem to be readily distinguishable by using IVCM; and KP may have consistency for specific disease states and therefore may have diagnostic importance. CONCLUSIONS: To our knowledge, this is the first time that IVCM has been used to describe the architecture and heterogeneity of KP in uveitis. Such observations reveal a heterogeneity that could not be appreciated by conventional slitlamp microscopy and may have diagnostic relevance.

Adult↗
PubMed2004

Prevalent use of complementary and alternative medicine by patients with inflammatory eye disease.

AIM: To study complementary and alternative medicine (CAM) use in patients who suffer from inflammatory eye disease. METHODS: Current and previous use of CAM was determined by face-to-face interviews of consecutive patients attending a university-based tertiary-referral inflammatory eye disease clinic during a 3-month period. Additional sociodemographic and clinical information was obtained by review of clinical records. RESULTS: Of the 89 eligible patients who were interviewed, 37 (42%) reported using CAM for the specific purpose of improving their eye condition. Most commonly used CAM included vitamin preparations (n = 13), herbal medicines (n = 10), prayer (n = 15) and acupuncture (n = 9). Multiple forms of CAM were used by one third of patients. Female gender (p = 0.05), a higher rating of occupational prestige (p = 0.05) and the diagnosis of uveitis rather than another form of inflammatory eye disease (p = 0.04) were significantly associated with reporting of current or past use of CAM. Most patients who used CAM considered that these therapies were benefiting their ocular condition, and few adverse events were reported. Sixteen percent of patients cited physician resources as a source for therapeutic information about CAM. CONCLUSIONS: Use of CAM is common among patients with inflammatory eye diseases. Because CAM may influence the course of disease, cause adverse effects, and interact with conventional immunosuppressive treatment, physicians should routinely question patients with these diagnoses regarding the use of such therapies.

Adolescent↗
PubMed2004

Susceptibility of retinal vascular endothelium to infection with Toxoplasma gondii tachyzoites.

PURPOSE: Retinochoroidal infection with the protozoan parasite Toxoplasma gondii is the most common cause of posterior uveitis worldwide. Tachyzoites spread throughout the body through the blood stream and lymphatics, but preferentially encyst in the eye and other parts of the central nervous system (CNS). It is unknown whether T. gondii penetrates the CNS selectively or whether these sites of immune privilege have limited capacity to eradicate the parasite. METHODS: Human vascular endothelial cell lines, including retinal (three lines from three different donors), aortic, umbilical vein, and dermal microvascular endothelium, as well as human foreskin fibroblasts, were grown to confluence in 24-well plates. Cells were incubated with RH-strain T. gondii tachyzoites in the presence of [(3)H]-uracil. Trichloroacetic acid-insoluble radioactivity was measured as an index of T. gondii proliferation, because tachyzoites, but not human cells, incorporate uracil directly through pyrimidine salvage. RESULTS: Tachyzoites showed higher [(3)H]-uracil incorporation after incubation with retinal vascular endothelial cells in comparison with aortic (55% more), umbilical vein (33% more) and dermal (34% more) endothelial cells. In eight separate assays, significantly greater radioactivity was measured for tachyzoites cultured with retinal versus other cell subtypes (P < 0.05), except for one assay in which differences reached only borderline significance (P <or= 0.07). In contrast, experiments comparing different retinal endothelial lines revealed no difference between any pair. Growth of the tachyzoites was approximately 2.8-fold higher in retinal endothelium than in foreskin fibroblasts, the cell subtype often used to investigate processes of T. gondii infection. CONCLUSIONS: Enhanced susceptibility of retinal vascular endothelium to infection by T. gondii tachyzoites may explain, at least in part, preferential localization of T. gondii to the retina. Susceptibility may relate to preferential binding of tachyzoites to the retinal vascular endothelial surface, relative ease of penetration into the cell, rate of replication within the cell and/or cell response to infection.

Adolescent↗
PubMed2003

Arthritis and uveitis in children. A pediatric rheumatology perspective.

PURPOSE: We describe important characteristics of the chronic arthritides of childhood associated with anterior uveitis. DESIGN: Literature review and commentary based on the investigators' experiences. METHOD: A review of pertinent publications provides a background of current understanding of those forms of childhood arthritis that are of interest to ophthalmologists caring for children. Recommendations regarding screening for asymptomatic anterior uveitis in this patient group are reviewed, and current advances in therapy are noted. A new classification of childhood arthritis is compared with existing classifications. RESULTS: Uveitis complicates several forms of juvenile idiopathic arthritis (oligoarthritis, rheumatoid factor-negative polyarthritis, psoriatic arthritis, and enthesitis-related arthritis). Uveitis is a complication in up to 30% of children with chronic arthritis, particularly in those with oligoarticular disease. CONCLUSIONS: Visual prognosis is guarded for children with chronic arthritis and uveitis. Surveillance and early therapy are important factors for ensuring a good outcome.

Arthritis, Juvenile↗
PubMed2003

Uveitis in patients with sarcoidosis is not associated with mutations in NOD2 (CARD15).

PURPOSE: Mutations in NOD2 are responsible for Blau syndrome, a systemic disease triad involving the uvea, joints, and skin. NOD2 mutations are also associated with Crohn disease. Both Blau syndrome and Crohn disease involve granulomatous inflammation and uveitis, as does sarcoidosis. We sought to determine if NOD2 mutations were present in patients with sarcoidosis, especially those with uveitis. METHODS: NOD2 gene exons were sequenced from DNA obtained from sarcoidosis patients. The diagnoses of sarcoidosis and uveitis were verified from clinical records. RESULTS: NOD2 polymorphisms were found in 26 patients with sarcoidosis (13 with uveitis). There was no significant difference in allele frequencies between patients with and without uveitis. CONCLUSIONS: Despite the strikingly similar pathologies of Blau syndrome and sarcoidosis, no mutations were found to be associated with sarcoidosis in a group of patients, regardless of the presence of uveitis.

Adult↗
PubMed2003

Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome.

PURPOSE: To identify genetic markers for the tubulointerstitial nephritis and uveitis (TINU) syndrome by using human leukocyte antigen (HLA) genotyping. METHODS: Eighteen patients who had TINU syndrome were evaluated at three institutions. Typing of class I and II genes was performed by using DNA-based techniques. RESULTS: Significant associations were found with HLA-B14 (6/18 patients, 33.3%; control subjects, 5.5%; P = 0.0003; relative risk [RR] = 8.5), HLA-DQA1*01 (17/18 patients, 94.4%; control subjects, 46.6%, P = 0.0001; RR = 19.5), HLA-DQA1*0101 (14/18 patients, 77.8%; control subjects 22.2%; P < 0.0001; RR = 12.2), HLA-DQB1*05 (14/18 patients, 77.8%; control subjects 17.7%; P < 0.0001; RR = 16.3), HLA-DQB1*0501 (13/18 patients, 72.2%; control subjects 12.9%; P < 0.0001; RR = 17.6), HLA-DRB1*01 (14/18 patients, 77.8%; control subjects, 12.1%; P < 0.0001; RR = 25.5), and HLA-DRB1*0102 (13/18 patients, 72.2%; control subjects, 1.6%; P < 0.0001, RR = 167.1). The HLA haplotype most frequently identified in the study patients was HLA-DQA1*01/DQB1*05/DRB1*01 (13/18 patients, 72.2%). CONCLUSIONS: TINU syndrome is strongly associated with HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01. The association with HLA-DRB1*0102 is one of the highest reported for any disease. Because these genes are in linkage disequilibrium, the role of the individual alleles is difficult to assess. Based on the results of the present study and on previously reported HLA associations in patients with TINU syndrome, the alphabeta dimer encoded by HLA-DQA1*01/DQB1*05 may be particularly important in conferring risk for development of this disease.

Adolescent↗
PubMed2003

Visualization of cell death in vivo during murine endotoxin-induced uveitis.

PURPOSE: To develop a technology to image cell death in the eye of a live mouse and to apply that technology to characterize the role of apoptosis and necrosis in the evolution of endotoxin-induced uveitis (EIU), a standard model of intraocular inflammation. METHODS: To induce EIU, 250 ng Escherichia coli 055:B5 lipopolysaccharide was injected into the vitreous body of BALB/c mice. At 0, 6, 10, 16, 20, 24, 48, 72, and 96 hours and on day 7 after endotoxin injection, annexin V and propidium iodide were injected into the anterior chamber of these mice, and labeled cells were observed by using intravital epifluorescence video microscopy. Iris and corneal wholemounts isolated from the mice were also evaluated with standard and confocal fluorescence microscopy. TUNEL staining was performed on iris wholemounts taken from additional mice similarly injected with endotoxin, to confirm the in vivo results. RESULTS: Uveitis was induced in all the mice that received an endotoxin injection. The percentages of annexin V(+) propidium(-) cells, annexin V(+) propidium(+) cells, and annexin V(-) propidium(+) cells in the iris tissues visible by intravital microscopy were comparable to those observed by TUNEL staining in vitro. In addition, intravital microscopy allowed observation of labeled cells in the aqueous humor and on the surface of the lens. Both the number and the pattern of labeled cells changed dramatically over time. The cells stained with annexin V had a variety of morphologies, including small and round, round with a lobulated or a kidney-shaped nucleus, dendriform, and irregular. CONCLUSIONS: A technique was developed to image cell death in the anterior segment of the eye in vivo and used to demonstrate that the number and proportion of early apoptotic (annexin V(+) propidium(-)) and late apoptotic or necrotic (annexin V(+) propidium(+) and annexin V(-) propidium(+)) cells change over the course of EIU. A variety of inflammatory cells and resident cells undergo apoptosis, or possibly necrosis, which may contribute to the rapid resolution of EIU. This in vivo technique will be a valuable tool for future studies on the resolution of ocular inflammation.

Animals↗