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Biomedical subjects

Philip I Murray

Publications and source records attributed to Philip I Murray.

16 recordsLinked to original sources
PubMed2006

Inflammatory mediators of uveitis: cytokines and chemokines.

PURPOSE OF REVIEW: The study of uveitis has been restricted by the difficulty in obtaining sufficient intraocular material from both human disease and experimental models. Recent developments in cytokine and chemokine detection have overcome many of these problems. This review presents a summary of the technologic advances in this area. RECENT FINDINGS: Recent advances in cytokine analysis, in particular multiplexed bead immunoassays, have allowed the measurement of an extensive array of cytokines and chemokines from very small sample volumes. This has revolutionized uveitis research, enabling measurement of a large profile of cytokines and chemokines in intraocular fluid, such as aqueous humour. This allows us to recognize complex patterns of cytokines and chemokines from different forms of uveitis and to examine relationships between different molecules. SUMMARY: The spectrum of proinflammatory cytokines and chemokines known to be implicated in uveitis has increased over recent years. Many of these molecules have also been found in experimental models of disease and may represent attractive therapeutic targets for the future. With recent advances in cytokine detection, an extension of these techniques with a more detailed analysis of different uveitis conditions may provide useful diagnostic and prognostic information for this potentially blinding group of diseases.

Animals↗
PubMed2006

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye.

The prereceptor regulation of glucocorticoids (GCs) by 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1), a bidirectional isozyme that interconverts active (cortisol) and inactive (cortisone) GCs, is an established determinant of GC function in tissues such as liver, adipose and bone. Although the therapeutic use of GCs is abundant in ophthalmic practice, where GC interactions with nuclear receptors modulate gene transcription, the prereceptor regulation of endogenous cortisol is not well described in ocular tissues. Recent descriptive studies have localised 11beta-HSD1 to the human corneal epithelium and non-pigmented epithelium (NPE) of the ciliary body, indicating a link to corneal epithelial physiology and aqueous humour production. In this study, we characterise the functional aspects of the autocrine regulation of GCs in the anterior segment of the rabbit eye. Using our in-house generated primary antibody to human 11beta-HSD1, immunohistochemical analyses were performed on paraffin-embedded sections of whole New Zealand white albino rabbits, (NZWAR) eyes. As in human studies, 11beta-HSD1 was localised to the corneal epithelium and the NPE. No staining was seen in the albino 'pigmented' ciliary epithelium. Specific enzyme assays for oxo-reductase (cortisone-->cortisol) and dehydrogenase (cortisol-->cortisone) activity indicated predominant 11beta-HSD1 oxo-reductase activity from both the intact ciliary body tissue (n=12, median 2.1 pmol/mg per h and range 1.25-2.8 pmol/mg per h; P=0.006) and primary cultures of corneal epithelial cells (n=12, median 3.0 pmol/mg per h and range 1.0-7.4 pmol/mg per h, P=0.008) compared with dehydrogenase activity (median 1.0 pmol/mg per h and range 0.5-2.0 pmol/mg per h; median 0.5 pmol/mg per h and range 0.25-1.9 pmol/mg per h respectively). These findings were supported by expression of 11beta-HSD1 protein as visualised by Western blotting of ciliary body tissue and immunocytochemistry of corneal epithelial cells. Reduction of corneal epithelial cell proliferation was seen after primary cultures were co-incubated with cortisol and cortisone. 11beta-HSD1 activity was not demonstrated in naïve conjunctival fibroblasts or corneal stromal keratocytes. Our results indicate that the distribution of 11beta-HSD1 in the rabbit resembles that of the human eye and activates cortisone to cortisol in both corneal and uveal tissues. The NZWAR provides a suitable in vivo model for the further evaluation of 11beta-HSD1 activity in the eye, especially its role in corneal epithelial and ciliary body physiology.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Chronic non-infectious uveitis in the elderly: epidemiology, pathophysiology and management.

Intraocular inflammatory diseases are collectively known as uveitis. The aetiology of this condition can be diverse, as inflammation may result from direct involvement of the uveal tract or indirect inflammation of adjacent tissues. Uveitis can present challenges to diagnosis and treatment, and is potentially a severe sight-threatening disease. In the elderly, uveitis can present de novo after the age of 60 years or may represent a process earlier in life continuing after the age of 60 years, although many cases will have become quiescent by that time. More recent studies suggest that uveitis presenting after 60 years of age is more common than previously believed. Most cases of uveitis are of unknown aetiology and are classed as idiopathic, although sarcoidosis, ocular ischaemia and birdshot chorioretinopathy are recognised non-infectious causes of uveitis in the elderly. Systemic immunosuppression, with its well known complications, may be required to preserve vision. In this age group, one should always have high suspicion of a masquerade syndrome, particularly a primary CNS non-Hodgkin's lymphoma. With the demographics of the elderly population changing and mean life expectancy increasing, it is important that clinicians are familiar with uveitis as a potential cause of visual impairment in this age group.

Aged↗
PubMed2005

Deep intramuscular methylprednisolone treatment of recurrent scleritis.

PURPOSE: To evaluate the efficacy of deep intramuscular methylprednisolone (IMMP) in the treatment of recurrent scleritis. METHODS: A total of 15 patients with scleritis (12 anterior, 3 pan) underwent IMMP injection deep into the thigh. Thirteen patients were already being treated with oral non-steroidal anti-inflammatory drugs, oral prednisolone, an oral immunosuppressive agent, or a combination of these drugs. A second IMMP injection was given to nine patients, making a total of 24 injections. Follow-up ranged from 4 to 18 months. RESULTS: There was a documented improvement in scleritis after 21/24 (87.3%) injections with a mean duration of improvement of 5.7 months. No patient required the introduction of oral corticosteroid or immunosuppressive agent, and only one patient required an increase in methotrexate to control the disease. No systemic, injection site, or ocular side effects were noted. CONCLUSIONS: Deep IMMP is a safe and effective treatment for scleritis. It ensures compliance, avoids the systemic side effects of oral corticosteroids, and is easily repeatable in the outpatient setting.

Adult↗
PubMed2005

Epstein-Barr Virus DNA quantification: an adjunctive diagnostic marker for AIDS-associated lymphoma.

We report an HIV-positive patient who developed a unilateral retinitis and subsequent intracranial lesions. The finding of Epstein Barr virus (EBV) DNA at a > 1-log greater concentration in the vitreous compared to blood raised the possibility of a primary CNS non-Hodgkin's lymphoma, which was subsequently confirmed on brain biopsy. EBV DNA quantification acted as a diagnostic marker that led to a change in the management of our patient.

Adult↗
PubMed2005

Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis.

PURPOSE: To extensively characterize the complex network of cytokines present in uveitis aqueous humor (AqH), and the relationships between cytokines and the cellular infiltrate. METHODS: AqH from noninflammatory control subjects and patients with idiopathic, Fuchs' heterochromic cyclitis (FHC), and herpes-viral or Behçet's uveitis were analyzed for IL-1beta, -2, -4, -5, -7, -8, -10, -12, -13, -15, TNFalpha, IFNgamma, CCL2 (MCP-1), CCL5 (RANTES), CCL11 (Eotaxin), TGFbeta2, and CXCL12 (SDF-1), using multiplex bead immunoassays. The cellular infiltrate was also determined for each sample. RESULTS: Idiopathic uveitis AqH, compared with noninflammatory controls, was characterized by high levels of IL-6, IL-8, CCL2 and IFNgamma, the levels of which correlated with each other. For IL-6 and IL-8 these levels were proportional to the number of neutrophils present. By contrast, the levels of both TGFbeta2 and CXCL12 decreased in idiopathic uveitis AqH with increasing inflammation. Cluster analysis showed a degree of segregation between noninflammatory and idiopathic uveitis AqH. Further examination using random forest analysis yielded a complete distinction between these two groups. The minimum cytokines required for this classification were IL-6, IL-8, CCL2, IL-13, TNFalpha, and IL-2. CONCLUSIONS: Application of multiplex bead immunoassays has allowed us to identify distinct patterns of cytokines that relate to both clinical disease and the cellular infiltrates present. Bioinformatics analysis allowed identification of cytokines that differentiate idiopathic uveitis from noninflammatory control AqH and are likely to be important for the pathogenesis of uveitis.

Adolescent↗
PubMed2004

Inhibition of T cell apoptosis in the aqueous humor of patients with uveitis by IL-6/soluble IL-6 receptor trans-signaling.

A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common gamma-chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

Adolescent↗
PubMed2004

Topical glucocorticoid therapy directly induces up-regulation of functional CXCR4 on primed T lymphocytes in the aqueous humor of patients with uveitis.

Overexpression of the constitutive chemokine receptor CXCR4 has been shown to contribute to the accumulation of leukocytes at sites of chronic inflammation. Glucocorticoids are widely used to treat inflammatory disorders such as uveitis to considerable effect, yet paradoxically have been reported to increase CXCR4 expression in vitro. We show here that ocular lymphocytes isolated from patients with uveitis who had been treated with topical glucocorticoids expressed highly elevated levels of CXCR4. The up-regulation of CXCR4 could be reproduced in vitro by culture of CD4(+) T cells with aqueous humor (AqH), indicating a role for the ocular microenvironment rather than preferential recruitment of CXCR4(+) cells. Untreated uveitis and noninflammatory AqH up-regulated CXCR4 to a limited extent; this was dependent on TGF-beta2. However, the highest levels of CXCR4 both in vivo and in vitro were found in the glucocorticoid-treated patients. Glucocorticoids appeared to be directly responsible for the induction of CXCR4 in treated patients, as the glucocorticoid receptor antagonist RU38486 inhibited the in vitro up-regulation by AqH from these patients. Dexamethasone selectively up-regulated CXCR4 in vitro, but not any of a wide range of other chemokine receptors. CXCL12, the ligand for CXCR4, was present in AqH under noninflammatory conditions, but the levels were low in untreated uveitis and undetectable in treated uveitis AqH. The importance of these results for the treatment of HIV patients with glucocorticoids is discussed as well as a role for glucocorticoid-induced CXCR4 up-regulation and CXCL12 down-regulation in controlling the migration of lymphocyte populations, resulting in resolution of inflammation.

Administration, Topical↗
PubMed2004

The role of chemokines and their receptors in ocular disease.

The migration and infiltration of cells into the eye whether blood-borne leucocytes, endothelial or epithelial cells occurs in many ocular diseases. Dysregulation of this process is apparent in chronic inflammation, corneal graft rejection, allergic eye disease and other sight-threatening conditions. Under normal and inflammatory conditions, chemokines and their receptors are important contributors to cell migration. To date, 47 chemokines and 19 chemokine receptors have been identified and characterised. In recent years, investigations into the role of chemokines and their receptors in ocular disease have generated an increasing number of publications. In the eye, the best understood action of these molecules has arisen from the study of their ability to control the infiltration of leucocytes in uveitis. However, the involvement of chemokines in angiogenesis in several ocular conditions and in the survival of corneal transplants demonstrates the multifaceted nature of their effects. Interestingly, the constitutive expression of chemokines and their receptors in ocular tissues suggests that certain chemokines have a homeostatic function. In this review, we discuss the nature and function of chemokines in health and disease, and describe the role of chemokines in the pathogenesis of different ocular conditions.

Animals↗
PubMed2003

Expression and distribution of the serum and glucocorticoid regulated kinase and the epithelial sodium channel subunits in the human cornea.

The sodium transporting capacity of the corneal endothelium is vital for preserving corneal transparency, and has traditionally been attributed to the endothelial pump transporting sodium and bicarbonate across the corneal endothelium, maintaining the cornea in a dehydrated state. Recent studies have shown that the enzyme, serum and glucocorticoid regulated kinase isoform 1 (SGK1), plays a pivotal role in the corticosteroid induction of epithelial sodium transport in tissues such as the distal nephron, through activation of the epithelial sodium channels (ENaC). This study was designed to identify whether these elements were present within the human cornea. In situ hybridisation studies were conducted on paraffin embedded sections from six human eyes, using in-house generated cRNA antisense probes for human SGK1 and ENaC subunits (alpha, beta, gamma), and confirmed expression of SGK1 and all ENaC subunits in the corneal endothelial cytoplasm. Although ENaC subunits were not demonstrated in the corneal epithelium, SGK1 mRNA was identified in the nuclear region of central basal cells of the corneal epithelium, and limbal epithelial cells. Minimal chromagen precipitation was seen in the Bowman's membrane, corneal stroma, or Descemet's membrane. Control experiments consisted of no antisense probe, competition of the labelled antisense cRNA probe by a 60-fold excess unlabelled antisense cRNA, and use of labelled sense cRNA probes, revealing minimal or no hybridisation signal throughout the corneal layers. These data define components of the mineralocorticoid regulatory pathways of sodium transport in human corneal endothelium, and provide evidence for an additional mechanism contributing to corneal transparency and the 'metabolic' sodium pump.

Cornea↗
PubMed2003

Serum- and glucocorticoid-regulated kinase isoform-1 and epithelial sodium channel subunits in human ocular ciliary epithelium.

PURPOSE: In peripheral sodium-transporting tissues, the serum- and glucocorticoid-regulated kinase (SGK) isoform-1 is an early corticosteroid target gene in the activation of epithelial sodium channels (ENaCs). Sodium transport across the human ocular nonpigmented and pigmented ciliary epithelial bilayer (NPE-PE) is essential for aqueous humor production, but the expression of SGK1 and ENaC subunits remain to be defined. METHODS: SGK1 and ENaC subunits were evaluated by in situ hybridization and RT-PCR analysis on human NPE-PE sections and an NPE cell line (ODM-2). Northern blot analyses were conducted on ODM-2 cells incubated with dexamethasone (DEX) or aldosterone (ALDO) and RU38486 (a glucocorticoid receptor [GR] antagonist) or RU26752 (a mineralocorticoid receptor [MR] antagonist) or both inhibitors. The affinity of the GRs and MRs for DEX and ALDO was assessed by radioligand-binding assays. RESULTS: Expression of SGK1 and ENaC subunits was confirmed in NPE-PE tissues and ODM-2 cells. Dose-dependent induction of SGK1 mRNA in the ODM-2 cells was demonstrated after incubation with DEX or ALDO. While response to DEX was not inhibited by RU38486 or RU26752, there was a moderate reduction in induction by ALDO in the presence of RU26752 that was completely abolished in the presence of both inhibitors. Specific binding of (3)[H]DEX and (3)[H]ALDO was established, revealing greater expression of GRs than MRs. CONCLUSIONS: The expression of ENaCs within the NPE-PE and corticosteroid regulation of SGK1 through the GR and MR, indicate that this mechanism may be a feature of sodium transport in the human ocular ciliary epithelium.

Aldosterone↗
PubMed2002

ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.

PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.

Administration, Oral↗
PubMed2002

The danger of wearing an anorak.

Campaigns to reduce road traffic accidents have paid little attention to the way headgear could interfere with vision. Binocular visual field measurement was undertaken in six healthy volunteers wearing four different types of anorak. All four anoraks greatly reduced the horizontal and superior field of vision. The anorak producing the worst reduction resulted in a width of vision of 99 degrees and only 15 degrees of vision above eye level, versus 167 degrees and 52 degrees respectively without an anorak. Anorak wearers should turn their heads to look sideways before crossing the road.

Accidents, Traffic↗
PubMedDate not supplied

Primary anti-phospholipid antibody syndrome (APS): current concepts.

Primary anti-phospholipid syndrome (APS) is a thrombophilic state characterized by recurrent arterial and venous thrombosis, recurrent pregnancy loss, and the presence of circulating anti-phospholipid antibodies that may be responsible for thrombophilia and pregnancy morbidity. Ophthalmologic features are present in 15-88% of the patients with primary APS, thus ophthalmologists are one of the first physicians to whom the patient will present. An accurate diagnosis may save the patient from recurrent, potentially life-threatening thrombosis. In the U.S.A., an estimated 35,000 new cases of APS-related venous thrombosis occur each year in a population that is several decades younger than the patient population typically affected by thrombosis. Clinical features, such as chorea, transverse myelitis, cardiac valvular lesions, and accelerated atherosclerosis, are hypothesized to be due to a direct tissue-antibody interaction and cannot be explained purely by thrombosis. The use of recently proposed, well-defined diagnostic criteria, and better standardization of laboratory assays for the anti-phospholipid antibodies should help enable epidemiological surveys to establish the prevalence of these antibodies in patients with thrombosis and in the general population. Diagnosis of APS should be considered in all patients with recurrent systemic or ocular thrombosis in the absence of known risk factors. Several well-designed prospective studies show an increased risk of thrombosis in the presence of medium to high antibody level. With ocular involvement in as many as 88% of APS patients, an ophthalmic assessment should be an integral part of the clinical work-up of any patient with suspected or confirmed APS. The presence of isolated ocular thrombophilia with persistently elevated anti-phospholipid antibodies or lupus coagulant should confirm the diagnosis of APS. Management of these patients must be a multi-disciplinary effort with either a rheumatologist or a hematologist having the overall responsibility for coordinating treatment and monitoring the patient's immune status and anticoagulation. Treatment of isolated ocular thrombophilia in the presence of moderate to high titers of antiphospholipid antibodies should be on the same principles as patients with APS to prevent recurrent ocular or cerebral thrombosis.

Antiphospholipid Syndrome↗