Refractive and corneal astigmatism in white school children in Northern Ireland

To study the prevalence of and relation between refractive and corneal astigmatism in white school children in Northern Ireland and to describe the association between refractive astigmatism and refractive error.

Non-invasive phakometric measurement of corneal and crystalline lens alignment in human eyes

We describe a non-invasive phakometric method for determining corneal axis rotation relative to the visual axis (β) together with crystalline lens axis tilt (α) and decentration (d) relative to the corneal axis. This does not require corneal contact A-scan ultrasonography for the measurement of intraocular surface separations. Theoretical inherent errors of the method, evaluated by ray tracing through schematic eyes incorporating the full range of human ocular component variations, were found to be larger than the measurement errors (β < 0.67°, α < 0.72° and d < 0.08 mm) observed in nine human eyes with known ocular component dimensions. Intersubject variations (mean ± S.D.: β = 6.2 ± 3.4° temporal, α = 0.2 ± 1.8° temporal and d = 0.1 ± 0.1 mm temporal) and repeatability (1.96 × S.D. of difference between repeat readings: β ± 2.0°, α ± 1.8° and d ± 0.2 mm) were studied by measuring the left eyes of 45 subjects (aged 18-42 years, 29 females and 16 males, 15 Caucasians, 29 Indian Asians, one African, refractive error range -7.25 to +1.25 D mean spherical equivalent) on two occasions. © 2005 The College of Optometrists.

A study of the effects of orally administered female hormones on the volume and composition of lacrimal fluid related to the toleration of corneal contact lenses

This study was designed to evaluate the effects of certain orally active contraceptive steroids on the eye, related to the tolerance of a corneal contact lens. An oestrogen, ethinyloestradiol BP. 0.05 mg, a progestogen, norethisterone acetate BP. 2.50 mg and a control tablet (vitamin C, 50 mg) were utilised. The effect of these preparations on corneal curvature, lacrimal fluid volume and protein composition and directly on corneal lens tolerance was monitored in a group of 23 volunteer patients. The progestogen was found to produce a significant (P≥ 0.05) decrease in tear volume as measured by a 3 minute Schirmer test. A smaller volume reduction was observed with ethinyloestradiol. A normal cornea appears unaffected, within the measurement limits available, by the use of either hormone. However, in the presence of a corneal lens, oestrogen was found to induce substantial corneal steepening, indicative of tissue oedema, during the initial 2-3 weeks of medication. Progestogen occasionally produced a similar effect, which could recur with either hormone shortly after the end of the treatment period. A new method of acrylamide gel electrophoresis was developed for examination of the protein concentration and composition of lacrimal fluid. This allowed much greater resolution of microquantities of unconcentrated fluid than anything previously reported. Quantitation by densitometry has permitted the recording of medication and lens-induced changes in the protein pattern. Tear albumin has been shown to differ from serum albumin and to consist of up to 3 subfractions, 7 further protein fractions may also be resolved. The concentration and probable origin of these proteins have been established and the overall effects of hormone administration described. Individual idiosyncratic responses are also discussed. The study has established tbenature of some effects of contraceptive steroids on the anterior eye, and the probable reasons for resultant corneal lens intolerance.

The influence of posterior corneal surface astigmatism on residual astigmatism

It has often been found that corneal astigmatism exceeds the amount exhibited by the eye as a whole. This difference is usually referred to as residual astigmatism. Scrutiny of the studies of corneal astigmatismreveal that what has actually been measured is the astigmatic contributionof the anterior corneal surface alone. This anterior surface is easily measured whereas measurement of the posterior corneal surface is much more difficult. A method was therefore developed to measure the radius and toricity of the posterior corneal surface. The method relies upon photography of the first and second Purkinje images in three fixed meridians. Keratometry, comparison of anterior and posterior corneal Purkinje images and pachometricdata were applied to three meridional analysis equations, allowing the posterior corneal surface to be described in sphero-cylindrical form. Measurements were taken from 80 healthy subjects from two distinct age groups. The first consisted of 60 young subjects, mean age 22.04 years and the second consisted of 20 old subjects, mean age 74.64 years. The young group consisted of 28 myopes, 24 emmetropes and 8 hyperopes. The old group consisted of 6 myopes and 14 hyperopes. There was an equal number of males and females in each group. These groupings allowed the study of the effects of age, ametropia and gender on the posterior corneal toricity. The effect of the posterior corneal surface on residual astigmatism was assessed and was found to cause an overall reduction. This reduction was due primarily to the posterior corneal surface being consistently steeper relative to the anterior surface in the vertical meridian compared to the horizontal meridian.

The relationship between measurement method and corneal structure on apparent intraocular pressure in glaucoma and ocular hypertension

Purpose: To analyse the relationship between measured intraocular pressure (IOP) and central corneal thickness (CCT), corneal hysteresis (CH) and corneal resistance factor (CRF) in ocular hypertension (OHT), primary open-angle (POAG) and normal tension glaucoma (NTG) eyes using multiple tonometry devices. Methods: Right eyes of patients diagnosed with OHT (n=47), normal tension glaucoma (n=17) and POAG (n=50) were assessed, IOP was measured in random order with four devices: Goldmann applanation tonometry (GAT); Pascal(R) dynamic contour tonometer (DCT); Reichert(R) ocular response analyser (ORA); and Tono-Pen(R) XL. CCT was then measured using a hand-held ultrasonic pachymeter. CH and CRF were derived from the air pressure to corneal reflectance relationship of the ORA data. Results: Compared to the GAT, the Tonopen and ORA Goldmann equivalent (IOPg) and corneal compensated (IOPcc) measured higher IOP readings (F=19.351, p<0.001), particularly in NTG (F=12.604, p<0.001). DCT was closest to Goldmann IOP and had the lowest variance. CCT was significantly different (F=8.305, p<0.001) between the 3 conditions as was CH (F=6.854, p=0.002) and CRF (F=19.653, p<0.001). IOPcc measures were not affected by CCT. The DCT was generally not affected by corneal biomechanical factors. Conclusion: This study suggests that as the true pressure of the eye cannot be determined non-invasively, measurements from any tonometer should be interpreted with care, particularly when alterations in the corneal tissue are suspected.

Pre-transplant signal induction for vascularisation in human islets

Human islet transplant success is partially impaired by slow revascularisation. Our study investigated the potential for rotational cell culture (RC) of human islets combined with thiazolidinedione (TZD) stimulation of peroxisome proliferator-activated receptor gamma (PPAR?) to upregulate vascular endothelial growth factor (VEGF) expression in the islets. Four groups of human islets were studied: static culture (SC) with and without 25 mmol/L TZD and RC with and without 25 mmol/L TZD. These were assessed for insulin secretion and soluble VEGF-A release. Both proteins were quantified by enzyme-linked immunosorbent assay (ELISA), supported with qualitative immunofluorescence staining. RC + TZD increased insulin secretion by >20% (p <0.05-0.001) in response to 16.7 mmol/L glucose and 16.7 mmol/L glucose + 10 mmol/L theophylline (G + T). This effect was seen at all time intervals compared with SC and without addition of TZD. Soluble VEGF-A release was significantly augmented by RC and TZD exposure with an increased effect of >30% (p <0.001) at 72 h under both SC and RC conditions. RC supplemented with a TZD enhances and prolongs the release of insulin and soluble VEGF-A by isolated human islets. © 2013 The Author(s).

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims - To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods - The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results - The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)0.35 x EXP (-0.0058 x TPT) x EXP (0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Currently tacrolimus is the mainstay of immunosuppression for most children undergoing liver transplantation (LT). • The clinical use of this agent, however, is complicated by its various adverse effects (mainly nephrotoxicity), its narrow therapeutic-index and considerable pharmacokinetic variability. • The low and variable oral bioavailability of tacrolimus is thought to result from the action of the multidrug efflux-pump P-glycoprotein, encoded by the ABCB1 gene. WHAT THIS STUDY ADDS • A significant association between ABCB1 genetic polymorphisms and tacrolimus-associated nephrotoxicity in paediatric patients following LT is reported for the first time. Genotyping such polymorphisms may have the potential to individualize better initial tacrolimus therapy and enhance drug safety. • The long-term effect of ABCB1 polymorphisms on tacrolimus trough concentrations were investigated up to 5 years post-transplantation. A significant effect of intestinal P-glycoprotein genotypes on tacrolimus pharmacokinetics was found at 3 and 4 years post-transplantation suggesting that the effect is maintained long term. AIMS - The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation. METHODS - Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes. RESULTS - The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (≥30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677->T variant allele also had a significant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were significantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation. CONCLUSIONS - These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post-transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety.

Impact of ATP-binding cassette, subfamily B, member 1 pharmacogenetics on tacrolimus-associated nephrotoxicity and dosage requirements in paediatric patients with liver transplant

Importance of the field: Tacrolimus is the most commonly used immunosuppressive agent following solid-organ transplantation in children. Its clinical use, however, is complicated by side effects (mainly nephrotoxicity), narrow therapeutic index and pharmacokinetic variability which can result in an increased risk of treatment failure or toxicity. Studies examining interindividual differences in the expression of the ABCB1 (ATP-binding cassette, subfamily B, member 1) gene (which encodes the drug transporter, P-gp) and its genetic polymorphisms have attempted to elucidate variations in tacrolimus response and disposition in children. Areas covered in this review: This review explores pharmacogenetic knowledge developed over the last decade regarding the impact of ABCB1 polymorphisms on tacrolimus toxicity and dosage requirements in children. What the reader will gain: A better understanding of the role of ABCB1 genetic polymorphisms (and corresponding haplotypes) and ABCB1 expression levels in various tissues and organs on tacrolimus outcomes in children with liver transplant. Take home message: Pharmacogenetics offers significant potential for optimising tacrolimus use. ABCB1 donor genotypes and ABCB1 expression level in the intestine and leukocytes may be useful in dosage selection. Large prospective studies are, however, required to further explore the potential of genetic testing in identifying children who are at risk of toxicity and to better individualise tacrolimus therapy.

Corneal pachymetry in normal and keratoconic eyes:Orbscan II versus ultrasound

Purpose: To compare corneal thickness measurements using Orbscan II (OII) and ultrasonic (US) pachymetry in normal and in keratoconic eyes. Setting: Eye Department, Heartlands and Solihull NHS Trust, Birmingham, United Kingdom. Methods: Central corneal thickness (CCT) was measured by means of OII and US pachymetry in 1 eye of 72 normal subjects and 36 keratoconus patients. The apical corneal thickness (ACT) in keratoconus patients was also evaluated using each method. The mean of the difference, standard deviation (SD), and 95% limits of agreement (LoA = mean ± 2 SD), with and without applying the default linear correction factor (LCF), were determined for each sample. The Student t test was used to identify significant differences between methods, and the correlation between methods was determined using the Pearson bivariate correlation. Bland-Altman analysis was performed to confirm that the results of the 2 instruments were clinically comparable. Results: In normal eyes, the mean difference (± 95% LoA) in CCT was 1.04 μm ± 68.52 (SD) (P>.05; r = 0.71) when the LCF was used and 46.73 ± 75.40 μm (P = .0001; r = 0.71) without the LCF. In keratoconus patients, the mean difference (± 95% LoA) in CCT between methods was 42.46 ± 66.56 μm (P<.0001: r = 0.85) with the LCF, and 2.51 ± 73.00 μm (P>.05: r = 0.85) without the LCF. The mean difference (± 95% LoA) in ACT for this group was 49.24 ± 60.88 μm (P<.0001: r = 0.89) with the LCF and 12.71 ± 68.14 μm (P = .0077; r = 0.89) when the LCF was not used. Conclusions: This study suggests that OII and US pachymetry provide similar readings for CCT in normal subjects when an LCF is used. In keratoconus patients, OII provides a valid clinical tool for the noninvasive assessment of CCT when the LCF is not applied. © 2004 ASCRS and ESCRS.

Numerical simulation of corneal transport processes

This paper presents a numerical study on the transport of ions and ionic solution in human corneas and the corresponding influences on corneal hydration. The transport equations for each ionic species and ionic solution within the corneal stroma are derived based on the transport processes developed for electrolytic solutions, whereas the transport across epithelial and endothelial membranes is modelled by using phenomenological equations derived from the thermodynamics of irreversible processes. Numerical examples are provided for both human and rabbit corneas, from which some important features are highlighted.

Grading of corneal transparency

Aim: To examine the academic literature on the grading of corneal transparency and to assess the potential use of objective image analysis. Method: Reference databases of academic literature were searched and relevant manuscripts reviewed. Annunziato, Efron (Millennium Edition) and Vistakon-Synoptik corneal oedema grading scale images were analysed objectively for relative intensity, edges detected, variation in intensity and maximum intensity. In addition, corneal oedema was induced in one subject using a low oxygen transmissibility (Dk/t) hydrogel contact lens worn for 3 hours under a light eye patch. Recovery from oedema was monitored over time using ultrasound pachymetry, high and low contrast visual acuity measures, bulbar hyperaemia grading and transparency image analysis of the test and control eyes. Results: Several methods for assessing corneal transparency are described in the academic literature, but none have gained widespread in clinical practice. The change in objective image analysis with printed scale grade was best described by quadratic parametric or sigmoid 3-parameter functions. ‘Pupil image scales’ (Annunziato and Vistakon-Synoptik) were best correlated to average intensity; however, the corneal section scale (Efron) was strongly correlated to variations in intensity. As expected, patching an eye wearing a low Dk/t hydrogel contact lens caused a significant (F=119.2, P<0.001) 14.3% increase in corneal thickness, which gradually recovered under open eye conditions. Corneal section image analysis was the most affected parameter and intensity variation across the slit width, in isolation, was the strongest correlate, accounting for 85.8% of the variance with time following patching, and 88.7% of the variance with corneal thickness. Conclusion: Corneal oedema is best determined objectively by the intensity variation across the width of a corneal section. This can be easily measured using a slit-lamp camera connected to a computer. Oedema due to soft contact lens wear is not easily determined over the pupil area by sclerotic scatter illumination techniques.