Corneal biomechanical properties in primary open angle glaucoma and normal tension glaucoma

PURPOSE: To determine and compare the corneal biomechanical properties between eyes with primary open angle glaucoma (POAG) and eyes with normal tension glaucoma (NTG). PATIENTS AND METHODS: Prospective cross-sectional study. Consecutive eligible POAG and NTG patients attending the Glaucoma Clinic had assessment of their corneal biomechanical properties-corneal hysteresis (CH) and corneal resistance factor (CRF)-using the Ocular Response Analyzer by an observer masked to the diagnosis. Exclusion criteria included previous intraocular surgery, corneal pathology, inflammatory connective tissue disease, and refraction of 5-dimensional or over. If both eyes were eligible, then the right eye was used for analysis. The main outcome measures were corneal hysteresis and CRF measurements. Data analysis was performed using the t test and general linear model. RESULTS: Eighty-one patients (80 whites) were analyzed. Forty had NTG, whereas 41 had POAG. Thirty-five were females. There was a statistically significant difference in mean CH (NTG 9.6±1.3 mm Hg; POAG 9.0±1.4 mm Hg; P=0.01), but not in mean CRF (NTG 9.9±1.4; POAG 10.8±1.7; P=0.06). The highest recorded Goldmann applanation intraocular pressure (IOP) was statistically significantly associated with lower CH (P=0.01) and higher CRF (P=0.02). CONCLUSIONS: There was a small but statistically significant difference in the mean CH between POAG and NTG (CH was higher in NTG). The highest recorded Goldmann applanation IOP was also statistically significantly correlated with lower CH and higher CRF, suggesting that alterations to the corneal biomechanical properties may occur as a result of chronic raised IOP in POAG. © 2008 by Lippincott Williams & Wilkins.

The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy

Our recent studies suggest that activation of the wingless-type MMTV integration site (WNT) pathway plays pathogenic roles in diabetic retinopathy and age-related macular degeneration. Here we investigated the causative role of oxidative stress in retinal WNT pathway activation in an experimental model of diabetes.

Tracking down the cause of proteinuria in primary care

Proteinuria originates from the kidney and occurs as a result of injury to either the glomerulus or the renal tubule or both. It is relatively common in the general population with reported point prevalence of up to 8% but the prevalence falls to around 2% on repeated testing. Chronic glomerular injury resulting in proteinuria may be secondary to prolonged duration of diabetes or hypertension. A tubular origin of proteinuria may be associated with inflammation of renal tubules triggered by prescribed drugs or ingested toxins. In the absence of obvious clues to the cause of persistent proteinuria on history or clinical examination it is worthwhile reviewing the patient's prescribed drugs to identify any potentially nephrotoxic agents e.g. NSAIDs. NICE guidelines recommend screening for proteinuria in individuals at higher risk for chronic kidney disease (CKD). These include patients with diabetes, hypertension, cardiovascular disease, connective tissue disorders, a family history of renal disease and those prescribed potentially nephrotoxic drugs. Patients with sudden onset of lower limb oedema and associated proteinuria should have a serum albumin level measured to exclude the nephrotic syndrome. Renal tract ultrasound will measure kidney size, and detect scarring associated with chronic pyelonephritis or prior renal stone disease which can cause proteinuria.

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.

Role of saphenous vein wall in the pathogenesis of primary varicose veins

UNLABELLED: Varicose veins may be due to weakness of the vein wall as a result of structural problems. There are conflicting findings in the literature about these problems especially concerning collagen, elastin and smooth muscle cells content. The aim of this study was to look at the structural abnormalities of varicose veins (with and without valvular incompetence).

MATERIALS AND METHODS: We studied 70 specimens of long saphenous veins from 35 patients (24 with varicose and 11 with normal veins). Two specimens were taken from each vein approximately 3-4 cm from the saphenofemoral junction. Vein specimens were processed for histological and electron microscopic studies. Both qualitative and quantitative analyses were performed to assess the degree of wall changes. Using the image analyzer, contents of collagen, elastin and smooth muscle cells, in addition to intimal and medial thickness, were measured.

RESULTS: Light microscopy revealed significant increase in intimal and medial thickness and collagen content of media and significant decrease in elastin content in varicose veins compared with normal veins. There was no statistical significant difference between varicose veins with and without saphenofemoral valve incompetence. Electron microscopy showed marked degenerative changes in intima and media of varicose veins.

CONCLUSION: The findings in our study supported the theory of primary weakness of the vein wall as a cause of varicosity. This weakness is due to intimal changes, disturbance in the connective tissue components and smooth muscle cells.

Provision of resin bonded bridgework for a patient with microstomia secondary to scleroderma

Scleroderma is a connective tissue disorder that can present with orofacial involvement. A 48 year-old patient presented to Cork University Dental Hospital with concerns about the appearance of her upper central incisor teeth, which had become progressively mobile in recent years. A diagnosis of localised scleroderma had been made a number of years previously by her medical practitioner and the patient reported that her scleroderma-associated microstomia had progressed significantly in recent years. Most reports of this condition advocate the use of sectional impression trays and sectional dentures to replace missing teeth. This report describes the use of resin-bonded bridgework (RBB) and discusses the possible advantages of this treatment option over those already presented in the literature.

Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.

MMP-8 Activity Profiling In GCF Samples

Background: In healthy tissues a family of enzymes known as matrix metalloproteinases (MMPs) play an important role in regulating turnover and metabolism of connective tissue collagen. MMPs have been implicated in a wide variety of pathological conditions including periodontal disease. MMP-8 has been extensively studied in periodontal health and disease using enzyme-linked immunosorbent assay (ELISA). Although ELISA quantifies the presence of the MMP-8 protein, it is not possible to determine enzyme activity using this method. Furthermore, since members of the MMP family have poor substrate sequence specificity, a peptide substrate alone cannot differentiate the activity of MMP-8 from other MMPs that may be present in biological samples. Objectives: In the present study, a method to specifically measure MMP-8 activity in gingival crevicular fluid (GCF) samples was developed. Methods: GCF was collected from healthy patients and those with periodontal disease using Perio paper strips. Samples were stored frozen until required for analysis. A specific MMP-8 antibody was used to coat 96 well microtitre plates to selectively remove MMP-8 from the GCF samples. Following a washing step, the activity of bound MMP-8 was measured over 70 minutes using a fluorogenic (FRET) substrate. Results: GCF from healthy subjects exhibited basal MMP-8 activity but in diseased samples MMP-8 activity was significantly higher. Minimal binding of other recombinant MMPs to the specific MMP-8 antibody was observed in cross-reactivity studies. Conclusion: We show for the first time that MMP-8 activity was significantly increased in GCF from periodontitis sites compared with activity levels in healthy sites. Further studies of MMP-8 activity in GCF samples should improve our understanding of its destructive role in periodontal disease.

Extracellular matrix sub-types and mechanical stretch impact human cardiac fibroblast responses to transforming growth factor beta

Understanding the impact of extracellular matrix sub-types and mechanical stretch on cardiac fibroblast activity is required to help unravel the pathophysiology of myocardial fibrotic diseases. Therefore, the purpose of this study was to investigate pro-fibrotic responses of primary human cardiac fibroblast cells exposed to different extracellular matrix components, including collagen sub-types I, III, IV, VI and laminin. The impact of mechanical cyclical stretch and treatment with transforming growth factor beta 1 (TGFβ1) on collagen 1, collagen 3 and alpha smooth muscle actin mRNA expression on different matrices was assessed using quantitative real-time PCR. Our results revealed that all of the matrices studied not only affected the expression of pro-fibrotic genes in primary human cardiac fibroblast cells at rest but also affected their response to TGFβ1. In addition, differential cellular responses to mechanical cyclical stretch were observed depending on the type of matrix the cells were adhered to. These findings may give insight into the impact of selective pathological deposition of extracellular matrix proteins within different disease states and how these could impact the fibrotic environment.