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J T Rosenbaum

Publications and source records attributed to J T Rosenbaum.

At least 19 recordsLinked to original sources
PubMed2004

Lack of association of matrix metalloproteinase 3 (MMP3) genotypes with ankylosing spondylitis susceptibility and severity.

OBJECTIVE: To study the linkage and association of ankylosing spondylitis (AS) with genotypes for matrix metalloproteinase 3 (MMP3), a gene located at chromosome 11q22.3 and lying within the 101-124 cM region observed in a recent genome-wide scan as a region associated with AS susceptibility. METHODS: MMP3 genotypes were examined in 229 pedigrees with AS, 131 sporadic AS cases and 87 Caucasian controls. Eight single-nucleotide polymorphisms (SNPs) were selected and genotyped using Taqman. Non-parametric linkage (NPL) analysis was conducted between the eight MMP3 SNPs and AS using the NPL-all statistic and two-point parametric linkage analysis using GeneHunter Plus. Unrelated AS cases and controls were compared using chi2 statistics, and family-based controls using the transmission disequilibrium test and pedigree disequilibrium test. RESULTS: None of the eight MMP3 SNPs were significantly associated with AS, either using the 131 sporadic cases alone or in analyses which combined these cases with the 226 unrelated affected AS patients derived from the pedigrees. Analysis of linkage disequilibrium (LD) demonstrated that seven of the eight SNPs studied were in strong LD except for rs626750, which is about 6 kb upstream of the 5' end of the gene. No significant linkage was observed using NPL and LODs in the families. No association was seen of any of the MMP3 SNPs with disease severity (defined by patient functioning), as measured either by the Bath Ankylosing Spondylitis Functional Index or the modified Health Assessment Questionnaire. CONCLUSION: These data suggest that MMP3 genotypes are not involved in AS susceptibility or severity.

Adult↗
PubMed2004

Susceptibility to endotoxin induced uveitis is not reduced in mice deficient in BLT1, the high affinity leukotriene B4 receptor.

AIM: To investigate the role of arachidonic acid derived chemotactic factor, LTB(4), in the development of endotoxin induced uveitis (EIU), using mice deficient in the BLT1 gene which encodes the high affinity LTB(4) receptor. METHODS: BLT1 gene deficient and wild type BALB/c mice were injected intravitreally with Escherichia coli 055:B5 lipopolysaccharide (250 ng/2 microl). Number of leukocytes invading the anterior chamber 24 hours later were counted on tissue cross sections. RESULTS: In all mice, EIU was characterised by a polymorphonuclear and mononuclear cell infiltrate. Numbers of infiltrating cells did not differ significantly between control and BLT1 gene knockout mice. CONCLUSION: Chemotactic factors other than LTB(4) are primarily responsible for leukocyte migration into the eye during murine EIU.

Animals↗
PubMed2004

Use of corticosteroid sparing systemic immunosuppression for treatment of corticosteroid dependent optic neuritis not associated with demyelinating disease.

AIM: To describe the authors' experience and that in the published literature regarding the use of corticosteroid sparing systemic immunosuppression for patients with corticosteroid dependent optic neuritis not associated with demyelinating disease. METHODS: The records of 10 patients from the authors' clinical database, and 38 patients from the published literature with corticosteroid dependent optic neuritis, were retrospectively reviewed to determine patient demographics, diagnosis, clinical course, and outcomes. These patients had recrudescence of symptoms, such as decreased vision and pain, with attempted taper of corticosteroid. Many of these patients also suffered side effects from systemic corticosteroid use such as weight gain and uncontrolled hyperglycaemia. Antimetabolites (for example, methotrexate and azathioprine), cyclosporine and/or alkylating agents (for example, cyclophosphamide and chlorambucil) were given to enable taper of corticosteroid while effectively controlling optic neuritis. RESULTS: The study included 43 women and 5 men: 17 patients with systemic lupus erythematosus, 12 patients with sarcoidosis, 3 with other systemic autoimmune diseases, and 16 with no clinically identifiable systemic association. 79% of all patients benefited from the use of systemic immunosuppression in that they had successful corticosteroid taper, control of inflammation, improvement in symptoms, and/or tolerance of adverse effects. Mild toxicity was common and 19% of patients, most often those taking cyclophosphamide, discontinued medication because of adverse effects. 24 of 28 (86%) patients on alkylators benefited clinically, while 20 of 29 (69%) patients on antimetabolites had clinical benefit. CONCLUSION: Systemic immunosuppression may be a safer and more effective treatment alternative to chronic oral corticosteroid use in cases of corticosteroid dependent optic neuritis not associated with demyelinating disease.

Adrenal Cortex Hormones↗
PubMed2004

Neurological concomitants of uveitis.

AIM: To describe the prevalence and types of neurological disease that occur in association with uveitis. METHODS: Retrospective review of medical records of patients attending a tertiary referral uveitis service over a 15 year period. RESULTS: Of 1450 patients with uveitis, 115 (7.9%) had neurological disease that was considered to be causally related to the eye inflammation. The most frequent neurological associations were Vogt-Koyanagi-Harada disease, primary central nervous system lymphoma, multiple sclerosis, and herpes virus infections. CONCLUSIONS: Neurological disease is common among patients attending a uveitis service. The distinctive characteristics of the uveal inflammation may be useful in diagnosing the neurological disease.

Central Nervous System Neoplasms↗
PubMed2004

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Biological Therapy↗
PubMed2003

Cloning, sequencing and expression analysis of the mouse NOD2/CARD15 gene.

BACKGROUND: Mutations in the human NOD2/CARD15 gene have been associated with Crohn's disease and Blau syndrome. The objective of the present study was to clone the murine form of NOD2 and characterize its tissue distribution, function and response to inflammatory stimuli. METHODS: Murine NOD2 was isolated using anchored polymerize chain reaction (PCR). Sequence analysis confirmed the identification of full-length cDNA representing the murine NOD2 gene. Using this sequence to search a Mus musculus supercontig database, NOD2 genomic DNA was identified. NOD2 was transfected into human embryonic kidney (HEK) cells and nuclear factor kappa B (NF-kappaB) activation was measured using a reporter assay. Tissue distribution and changes in transcription in mouse monocytes in response to inflammatory stimuli was determined by real time PCR. RESULTS: The NOD2 gene spans 39 KB and contains 12 coding exons on chromosome 8. Expression of mouse NOD2 into HEK cells resulted in NF-kappaB activation. NOD2 was found to be expressed in all mouse tissues analyzed except skin, with highest levels in lung, thymus and spleen. NOD2 mRNA levels increased greater than two-fold in a monocyte cell line in response to lipopolysaccharide, lipoteichoic acid, interferon-g and tumor necrosis factor-alpha. CONCLUSIONS: Common structural and functional features between human and mouse NOD2 were identified. This should allow for development of relevant animal models to evaluate the role of NOD2 in chronic inflammatory disorders.

Amino Acid Sequence↗
PubMed2002

Simultaneous in vivo imaging of leukocyte migration: heterogeneity among iris, limbus, and choroid vessels.

PURPOSE: Endothelial cells of different vascular systems may express site-specific adhesion molecules to attract leukocyte subsets. This study describes a method to visualize and compare leukocyte-endothelial interactions in three vascular beds within the same eye in mice. METHODS: Digital in vivo fluorescence microscopy was used to record a trans-corneal iris view, a superficial limbus view, and a trans-scleral anterior choroid view of mouse tissue. Uveitis was induced by intravitreal injection of E. coli endotoxin into BALB/c mice. Leukocytes were labeled systemically with SYTO-16 or rhodamine 6G. Leukocyte rolling and sticking were quantified at baseline and 4, 6, and 24 hours after endotoxin injection. RESULTS: In a normal animal, the limbus had 18 times the number of rolling leukocytes and 6 times the number of sticking leukocytes relative to the iris. All three vascular beds were affected by intravitreal injection of endotoxin. Although they each showed increased numbers of rolling and sticking cells, the levels and kinetics of these increases differed. Rolling peaked at 6 hours in the iris (34-fold increase from baseline) and limbus (7-fold increase) but was maximal in the choroid earlier with a 16-fold increase. Sticking was maximal at 4 hours for iris (96-fold increase) and choroid (19-fold increase) but peaked in the limbus at 6 hours (47-fold increase from baseline). CONCLUSIONS: This study demonstrates that leukocyte-endothelial dynamics are not the same in different vascular beds in the normal mouse eye. Furthermore, site-specific differences in responses to intravitreally injected endotoxin, beyond what can be readily explained by differential distribution of endotoxin, were observed. The methodology can be used to test the hypothesis that endothelial cells within the eye have site-specific patterns of adhesion molecule expression.

Animals↗
PubMed2002

Iris nodules associated with infectious uveitis.

BACKGROUND/AIM: Iris nodules are an uncommon clinical sign in uveitis. The diseases most commonly associated with iris nodules and uveitis include sarcoidosis, Vogt-Koyanagi-Harada syndrome, multiple sclerosis, Fuchs' heterochromic iridocyclitis, and metastatic infection. While many of these diseases may be appropriately treated with immunosuppressive medication, the management of infectious uveitis is antimicrobial therapy. Inappropriate immunosuppressive therapy may result in a poor outcome for the patient with an infection. Consequently, cases of uveitis with iris nodules were reviewed to identify clinical features that may help differentiate infection from non-infectious inflammation. METHODS: The clinical database of 1353 consecutive patients evaluated at a tertiary care referral based North American uveitis clinic were retrospectively reviewed to identify cases of infectious uveitis with iris nodules. A Medline search was performed to identify additional cases. From these cases information regarding clinical presentation, diagnosis, treatment, and outcome were collected. RESULTS: Three cases (three eyes) were identified from the authors' own records of infectious uveitis with iris nodules. An additional 25 cases of infectious uveitis with iris nodules were identified in 22 published reports. Analysis of the authors' cases and these reports showed that infectious uveitis with iris nodules was specifically characterised by some or all of the following: (1) creamy, soft appearance to the nodule(s), (2) unilateral disease, (3) persistence or growth of the nodule(s) despite corticosteroid therapy, (4) marked inflammatory response in the anterior chamber and/or vitreous humour, and/or (5) history suggesting a potential source of septic emboli. CONCLUSION: Certain features of the clinical history and examination are useful in the diagnosis of metastatic infection in patients presenting with uveitis and iris nodules.

Adult↗
PubMed2001

Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.

OBJECTIVE: To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. METHODS: Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. RESULTS: Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. CONCLUSION: TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis.

Adolescent↗
PubMed2001

Intraocular in vivo imaging of activated T-lymphocytes expressing green-fluorescent protein after stimulation with endotoxin.

BACKGROUND: Intravital microscopy allows imaging of specific cell populations in vivo. The value of this technique is well established, but would be enhanced if one could distinguish functional states of cells in vivo. Interleukin-2 (IL-2) is expressed upon stimulation of T-cells and is a commonly used marker for T-cell activation. This study tests the use of enhanced green fluorescent protein (GFP) as a reporter gene for interleukin-2 (IL-2) expression in vivo. METHODS: Characterization of mice that have the GFP gene under the control of IL-2 regulatory sequences has previously been published. Uveitis was induced by injection of E. coli endotoxin into the vitreous of these IL-2/GFPki transgenic mice. Four hours later, 3 microg of recombinant mouse IL-2 was injected into the anterior chambers of one group of mice. In vivo imaging of infiltrating cells in the iris stroma was performed with fluorescence microscopy at 6, 24, 48, and 72 h after endotoxin injection. The absolute number of fluorescent cells per mm2 was evaluated. RESULTS: Eyes with endotoxin-induced uveitis had cells that expressed GFP and were identifiable by intravital microscopy. The fluorescent cells were exclusively seen in the subset of cells that had infiltrated the iris stroma or arrested along the vascular endothelium. The number of GFP-positive infiltrating cells in the iris increased from undetectable at baseline to 0.5 cells/mm2 at 6 h and 1.3 cells/mm2 at 72 h. The animals that received endotoxin as well as IL-2 tended to have more GFP-positive cells at the 48-h and 72-h time points, but these differences were not statistically significant CONCLUSIONS: GFP is commonly used as a reporter gene for in vitro expression assays. The results presented here document that transgenic mice with GFP under the control of IL-2 regulatory elements can be used with intravital microscopy for in vivo expression assays that allow detection of activated T-cells at multiple time points within the same animal. This provides a novel method for temporal and spatial studies on the state of cell activation in inflammatory responses.

Animals↗
PubMed2001

A role for methotrexate in the management of non-infectious orbital inflammatory disease.

AIM: To evaluate the clinical usefulness of methotrexate for patients with non-infectious orbital inflammatory disease who fail to respond to systemic corticosteroids and/or orbital irradiation. METHODS: The medical records of patients with non-infectious orbital inflammatory disease who were treated with methotrexate at Oregon Health Sciences University between June 1993 and June 2000 were examined. Methotrexate was administered at a median maximum dose of 20 mg per week (range 15-25 mg per week) in conjunction with folate supplementation. Patients were followed with regular ophthalmic examinations, as well as serum liver enzyme levels and blood cell counts. Clinical signs of regression of the orbital inflammation, visual acuity, dosage and duration of methotrexate therapy, requirement for concurrent corticosteroid administration, and adverse drug reactions were recorded. RESULTS: The study cohort included 14 patients (24 eyes) with diagnoses including non-specific orbital inflammation (n=7), Tolosa-Hunt syndrome (n=1), thyroid orbitopathy (n=3), Wegener's granulomatosis (n=1), sarcoidosis (n=1), and Erdheim-Chester disease (n=1). In all cases, methotrexate was commenced as a corticosteroid sparing agent. 10 patients (71%) completed a 4 month therapeutic trial of methotrexate. Median duration of treatment for the nine (64%) patients who experienced clinical benefit was 25 months (range 10-47 months). Six responders were ultimately able to cease methotrexate, including the single patient who required concurrent long term corticosteroid therapy. Complications included fatigue, gastrointestinal disturbance, hair thinning and mild, reversible serum liver enzyme elevation. Two patients (14%) discontinued treatment because of adverse effects. CONCLUSION: Methotrexate is a well tolerated immunosuppressive medication which may benefit patients with recalcitrant non-infectious orbital inflammatory disease.

Adult↗
PubMed2001

Inhibition of leukocyte sticking and infiltration, but not rolling, by antibodies to ICAM-1 and LFA-1 in murine endotoxin-induced uveitis.

PURPOSE: Cell-adhesion molecules are critical elements in intravascular rolling and sticking of leukocytes during acute inflammation. In this process, selectins are thought to be involved in initial adhesion and rolling, and integrin-Ig superfamily interactions are believed primarily to mediate stronger adhesion and transendothelial migration. This study clarifies the role of two adhesion molecules, intercellular adhesion molecule (ICAM)-1 and leukocyte functional antigen (LFA)-1, in endotoxin-induced uveitis (EIU). METHODS: Intravital microscopy was used to record the movement and location of leukocytes in the irises of mice with uveitis induced by intravitreal injection of 250 ng Escherichia coli endotoxin. Each mouse concurrently received an intraperitoneal injection of monoclonal neutralizing antibodies for ICAM-1, LFA-1, or both or control irrelevant antibodies. RESULTS: Mice treated with endotoxin and control antibodies had an inflammatory response that was clearly present at the 6- and 24-hour time points and was mostly resolved by 48 hours. Mice that received anti-ICAM-1 or anti-LFA-1 had significantly fewer cells infiltrating their irises at 6 and 24 hours. Detailed analysis of the 6-hour time point recordings revealed that neither anti-ICAM-1 nor anti-LFA-1 significantly reduced the number of leukocytes rolling on venule endothelial surfaces, but the treatments reduced the number of firmly adherent cells. CONCLUSIONS: These data confirm previous reports that ICAM-1 and LFA-1 are important mediators of EIU. The dynamic in vivo images clearly support the hypothesis that integrin-mediated cell adhesion is more critical for the firm adhesion of sticking cells than for leukocyte rolling.

Acute Disease↗
PubMed2001

Cell adhesion molecule expression in cultured human iris endothelial cells.

PURPOSE: To develop a method to isolate human iris microvascular endothelial cells (HIECs) for exploring their constitutive and inflammatory agent-modulated expression of intercellular adhesion molecules (ICAM)-1 and -2, vascular cell adhesion molecule (VCAM)-1, and E-selectin. METHODS: Endothelial cells from collagenase-digested irises were isolated on the basis of their expression of platelet endothelial cell adhesion molecule (PECAM)-1, using antibody-coupled magnetic beads. Cells were characterized as endothelial based on morphologic criteria, their expression of PECAM-1 and von Willebrand factor, their uptake of acetylated low-density lipoprotein, and their ability to form capillary-like networks on a synthetic basement membrane. Constitutive and inflammatory agent-modulated expression of ICAM-1 and -2, VCAM-1, and E-selectin was evaluated by the reverse transcription-polymerase chain reaction, enzyme-linked immunocellular assays (ELICAs), Western blot analysis, and functional studies of leukocyte adhesion to HIEC monolayers. RESULTS: HIECs constitutively expressed mRNA and protein for ICAM-1 and -2, but only low to nondetectable levels of VCAM-1 or E-selectin. When stimulated with endotoxin- or tumor necrosis factor (TNF)-alpha, ICAM-1, VCAM-1, and E-selectin were potently and time- and dose-dependently upregulated at both the message and protein levels. By contrast, ICAM-2 message and protein were slowly downregulated by inflammatory agents over time, but nonetheless remained present and functional. Overall, cytokine- or endotoxin-activation of HIECs resulted in enhanced adhesiveness for leukocytes. CONCLUSIONS: ICAM-1, VCAM-1, and E-selectin have been previously implicated in mediating anterior ocular inflammation. This is a report of the selective isolation of HIECs, with a demonstration of differential expression and regulation of these adhesion molecules in them. In addition, this is the first demonstration of the regulated expression of ICAM-2 in any ocular microvascular cells.

Adolescent↗
PubMed2000

Digital video-imaging of leukocyte migration in the iris: intravital microscopy in a physiological model during the onset of endotoxin-induced uveitis.

The process of inflammation is accompanied by an alteration of leukocyte-endothelial dynamics. Reciprocal changes in the endothelium and the white cell permit the leukocyte to relinquish its normal free-flowing state in order to roll, arrest, and emigrate through the endothelium. Although intravital microscopy is an established method to observe this process, the eye has been under-utilized for this purpose. Iris vasculature can be videophotographed without the artifact of trauma. We used rhodamine 6G in vivo staining of leukocytes from BALB/c mice in a model of inflammation induced by intravitreally injected endotoxin. Digital video technology was used to record observations at baseline, 2 h, and 4 h after the endotoxin injection. Off-line analysis of microhemodynamic parameters established that the percentage of venules exhibiting rolling increased significantly from 4% at baseline to 34% at 2 h and 82% at 4 h after endotoxin injection. We found a marked increase in leukocyte arrest within 4 h (601+/-119 cells per mm(2) vs. 2+/-1 cells per mm(2) in control animals). Although shear stress differs minimally between iris arterioles and venules, both rolling and arrest occurred preferentially in venules indicating that shear stress is not the dominant factor for determining cell adhesion. Compared to previous reports on intravital microscopy, our methodology includes refinements or advantages in visualizing cells that have transmigrated as well as the avoidance of surgical trauma. The resolution and quantifiable nature of this technique are such that the methodology can be applied to repetitive observation of leukocyte-endothelial dynamics during an immune response.

Angiography↗
PubMed2000

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE: To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS: A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE: Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS: The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Drug Therapy, Combination↗