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Biomedical subjects

Michael P Clarke

Publications and source records attributed to Michael P Clarke.

12 recordsLinked to original sources
PubMed2006

The use of the Newcastle Control Score in the management of intermittent exotropia.

AIM: To evaluate the use of the Newcastle Control Score (NCS) in the management of intermittent exotropia (X(T)). PARTICIPANTS AND METHODS: Children aged <11 years with X(T) had an assessment of NCS as part of routine management. Other data collected included visual acuity, near and distance alignment with alternating prism cover test and near (Frisby test) and distance stereoacuity (Frisby Davis Distance Stereotest (FD2TM)). Analysis involved correlation between baseline NCS, angle and stereoacuity, examination of change over time and logistic regression to determine predictors of surgery. RESULTS: Baseline data were obtained on 272 children and follow-up data on 157. Mean (SD) age was 4 (1.9) years. Complete NCSs were obtained for all except one child at baseline, and all children at follow-up. At baseline, total NCS and the home control component were correlated with near stereo (r = -0.22, p<0.01 and r = -0.19, p<0.02, respectively), near alignment (r = 0.34, p<0.001 and r = 0.19, p<0.02) and distance alignment (r = 0.30, p<0.001 and r = 0.26, p<0.001). The clinic near control component was correlated with near alignment (r = 0.39, p<0.001), but not near stereoacuity, and the clinic distance control with near alignment (r = 0.16, p<0.02), distance alignment (r = 0.27, p<0.001) and distance stereoacuity (r = -0.25, p<0.03). A high (poor) NCS (> or =4) at the latest follow-up predicted surgery (p<0.001, OR 29.3, 95% CI 6.2 to 138.7). CONCLUSION: The NCS is a useful measure of the clinical severity of X(T), can be used to serially assess improvement or deterioration and is a useful tool for the management of these patients.

Child↗
PubMed2006

Amblyopia.

Results from recent randomised clinical trials in amblyopia should change our approach to screening for and treatment of amblyopia. Based on the current evidence, if one screening session is used, screening at school entry could be the most reasonable time. Clinicians should preferably use age-appropriate LogMAR acuity tests, and treatment should only be considered for children who are clearly not in the typical range for their age. Any substantial refractive error should be corrected before further treatment is considered and the child should be followed in spectacles until no further improvement is recorded, which can take up to 6 months. Parents and carers should then be offered an informed choice between patching and atropine drops. Successful patching regimens can last as little as 1 h or 2 h a day, and successful atropine regimens as little as one drop twice a week. Intense and extended regimens might not be needed in initial therapy.

Amblyopia↗
PubMed2006

The treatment of amblyopia.

Recent studies suggest that children with amblyopia associated with anisometropia, strabismus, or both should be treated initially with best refractive correction until visual acuity is stable. This may take several months, and a proportion of children will achieve equal visual acuity with glasses alone. For residual anisometropic and strabismic amblyopia, the initial choice of patching or atropine should involve the parent and the child. The dose of prescribed patching or atropine may initially be quite modest, such as 2 hours of patching a day or twice weekly atropine. Treatment should be offered to children until at least 12 years of age and possibly to teenagers. Ongoing studies are addressing the role of undertaking near activities while patched and the role of atropine for severe amblyopia and for older amblyopic children. Future studies are needed to investigate the best treatment strategies for residual amblyopia, whether weaning treatment is needed at the end of a course, and how compliance can be enhanced.

Amblyopia↗
PubMed2005

TIMP3 mutation in Sorsby's fundus dystrophy: molecular insights.

Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant disorder that results in degeneration of the macular region of the retina, with onset usually in the fourth to fifth decade of life. It leads to the rapid loss of central vision, often followed by further loss of peripheral vision. SFD shares several pathological features commonly found in the 'wet' or exudative form of age-related macular degeneration (AMD), the most common cause of blindness in the elderly in developed countries. These phenotypic similarities have led to SFD being proposed as an acceptable genetic model for AMD. Whereas AMD appears to have a complex aetiology, with both genetic and environmental factors playing a role, SFD has been shown to be a single-gene disorder, linked to mutations in exon 5 of the tissue inhibitor of metalloproteinases 3 (TIMP3) gene on chromosome 22q12-q13. This review confines itself to a discussion of the known biochemical properties of the wild-type and SFD TIMP3 proteins and attempts to relate these to the pathology encountered in SFD patients. We also discuss briefly how, despite the lack of inherited mutations in the structural gene, the TIMP3 protein might play a role in the onset and progression of AMD.

Animals↗
PubMed2005

Analysis of full length ADAMTS6 transcript reveals alternative splicing and a role for the 5' untranslated region in translational control.

The ADAMTS (A Disintegrin and metalloproteinase with thrombospondin-1 type repeats) family of enzymes have been implicated in turnover of extracellular matrix. We previously showed that levels of ADAMTS6 mRNA in ARPE-19 cells were markedly increased following treatment with tumour necrosis factor alpha (TNFalpha). This study shows that the ADAMTS6 transcript contains unusually large untranslated regions (UTRs) at both the 5' and 3'end. The 5'UTR contains 11 AUG codons upstream of the predicted ADAMTS6 start codon and potently inhibits translation of a downstream reporter gene. However some translation can be restored by truncating the 5'UTR from the 5'end. The 5'UTR was tested for internal ribosome entry site activity using a bicistronic luciferase reporter plasmid, but none was detected. Using the 5' and 3'UTR sequences to screen the GenBank database we identified a full length ADAMTS6 cDNA of 7262 bp. This transcript is alternatively spliced at the 3'end of the open reading frame (ORF), resulting in an extended ORF containing 3 additional tsp-1 type repeats. Quantitative RT-PCR showed that the long and short form of the ADAMTS6 ORF are co-expressed in ARPE-19 cells, but the relative levels of the two forms is modulated by TNFalpha. The region of the transcript encoding the catalytic domain also contains several notable differences compared to the previously published ADAMTS6 cDNA sequence, including a redefinition of the predicted active site motif.

5' Untranslated Regions↗
PubMed2005

Heterozygous mutations of OTX2 cause severe ocular malformations.

Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.

Amino Acid Motifs↗
PubMed2005

Stereoacuity in unilateral visual impairment detected at preschool screening: outcomes from a randomized controlled trial.

PURPOSE: Reduced stereoacuity is commonly found in association with reduced visual acuity or strabismus and may significantly affect neuro-developmental performance. Treatment for reduced visual acuity due to refractive error or amblyopia is believed to result in improved stereoacuity. This study was undertaken to investigate the effect on stereoacuity of treatment for unilateral visual impairment detected at preschool vision screenings, in the setting of a randomized controlled trial. METHODS: Children identified through preschool vision screening were recruited and randomized to one of three groups (no treatment, glasses only, or full treatment with glasses and occlusion) for a period of 12 months, after which full treatment was given when indicated. Logarithm of the minimum angle of resolution (LogMAR) visual acuity and random-dot (Randot; Stereo Optical, Chicago, IL) stereoacuity were assessed at recruitment and at 12- and 18-month follow-ups by an orthoptist masked to group allocation. RESULTS: One hundred seventy-seven children were recruited and randomized, 59 to each group. Comparison of stereoacuities showed an immediate median improvement of 30 seconds of arc in each group from refractive correction. Age significantly affected stereoacuity performance at recruitment (mean age, 4 years) but not at follow-up (mean age, 5 years). Deferring treatment did not affect final stereoacuity. CONCLUSIONS: In this group, stereoacuity improved to a normal level as a result of refractive correction. Children in whom treatment was deferred for 12 months did not demonstrate significantly poorer stereoacuity than those in treatment.

Amblyopia↗
PubMed2003

Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation.

Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.

Abnormalities, Multiple↗
PubMed2003

Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby's fundus dystrophy patients.

Gingival fibroblast cell lines were derived from Sorsby's fundus dystrophy (SFD) patients carrying the S181C TIMP3 and the E139X TIMP3 mutations. These cell lines were grown in culture to study expression of the wild-type and mutant tissue inhibitor of metalloproteinase 3 (TIMP3) alleles from a normal diploid cell type. Firstly, patient cells were found to co-express the wild-type and mutant TIMP3 alleles, S181C TIMP3 or E139X TIMP3, at the mRNA level using restriction fragment length polymorphism (RFLP) analysis. A SpeI RFLP for E139X TIMP3 is described. Low levels of endogenous TIMP3 protein expression were elevated using the natural polysaccharide calcium pentosan polysulfate (CaPPs) in combination with the cytokine IL-1alpha. Immunoblotting detected protein expression from both wild-type and mutant alleles, S181C TIMP3 or E139X TIMP3. S181C TIMP3 from these cells was found to dimerise and retain MMP2 inhibitory activity. To facilitate studies of the E139X TIMP3 protein, the allele was expressed using HighFive insect cells. In this cell type, the E139X TIMP3 was synthesised as a mixture of monomer and dimer. Both monomeric and dimeric E139X TIMP3 protein retained MMP2 inhibitory activity in gelatin zymography. Expression of mutant E139X or S181C TIMP3 protein from a normal diploid patient-derived fibroblast cell had no effect on either MMP2 or MMP9 expression or activation whilst transcribed from their normal promoter context.

Animals↗
PubMed2003

Expression of ADAMTS metalloproteinases in the retinal pigment epithelium derived cell line ARPE-19: transcriptional regulation by TNFalpha.

ADAMTS (A Disintegrin-like And Metalloprotease domain with ThromboSpondin type I motifs) are multidomain proteins with demonstrated metalloproteinase functionality and have potential roles in embryonic development, angiogenesis and cartilage degradation. We present here investigations of ADAMTS expression in an ocular cell type, ARPE-19, with a view to implicating them in retinal matrix turnover. Expression analysis was undertaken using a combination of reverse transcription polymerase chain reaction (RT-PCR) and Northern blotting experiments, which together detected the expression of mRNAs for several ADAMTS proteins, all of which have active site motifs characteristic of matrix metalloproteases (MMPs). These included ADAMTS1, ADAMTS2, ADAMTS3, ADAMTS5, ADAMTS6, ADAMTS7 and ADAMTS9. The expression of mRNA isoforms for ADAMTS7 and ADAMTS9 were also detected. Following stimulation with TNFalpha, ADAMTS1, ADAMTS6 and both ADAMTS9 transcripts expressed in ARPE-19 cells showed a potent upregulation. The expression of ADAMTS genes in ARPE-19 cells and the transcriptional stimulation of some family members by TNFalpha may implicate them in inflammatory eye disease and the compromise of retinal matrix structure, which is evident in age-related macular degeneration (ARMD) and other retinal pathologies.

ADAM Proteins↗
PubMed2003

Improved illumination for the Perkins applanation tonometer.

AIMS: To improve the Perkins tonometer measurements by using an augmented, monochromatic solid-state light source of 470 nm wavelength. METHODS: This prospective study comprised 44 patients of our ophthalmic department who were split into two groups of 21 and 23 patients, and were tested by two independent ophthalmologists. Intraocular pressure (IOP) was measured in both eyes, comparing the instrument with augmented source against the standard Perkins for both observers. A set of three consecutive IOP measurements was recorded on each patient's eye and the time required to make each of them was recorded. The mean of the three IOP values was used in the analyses. RESULTS: For Observer 1, higher values of IOP with our augmented illumination against the standard were recorded, the mean difference of +0.59 mmHg being statistically significant (95% CI, 0.0 to +1.18 mmHg). For Observer 2, the mean difference of -0.22 mmHg was not significant (95% CI, -0.70 to +0.26 mmHg). Measurement times for observers were shorter when using the augmented illumination (Observer 1: mean difference = -2.0 s, S.E. = 1.4 s, CI, +0.8 to -4.9 s; Observer 2: mean difference = -5.0 s, S.E. = 1.3 s, CI, -2.5 to -7.5 s). CONCLUSION: The monochromatic blue light source may improve the performance of IOP measurements with the Perkins instrument under bright room conditions, making them faster and more convenient.

Equipment Design↗