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Biomedical subjects

A C Bird

Publications and source records attributed to A C Bird.

At least 73 records · Page 4Linked to original sources
PubMed2000

TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy.

PURPOSE: Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP-3) gene have previously been identified in patients with Sorsby's fundus dystrophy (SFD). We evaluated the ocular distribution of TIMP-3 and other extracellular constituents in SFD. METHODS: The eyes of an SFD donor with a confirmed TIMP-3 mutation were examined using histologic techniques demonstrating connective tissue, calcium, and lipid. Immunohistochemical analyses were performed using antibodies against TIMP-3, collagen type IV, V, and VI, laminin, fibronectin, elastin, and fibrillin. Electron microscopy also was used. RESULTS: A subretinal pigment epithelium (sub-RPE) deposit similar to that previously described was seen. A morphologically similar but different deposit was present internal to the nonpigmented ciliary epithelium (NPCE). Both deposits contained collagens, elastin, glycosaminoglycans, lipids, and calcium. Immunolabeling of TIMP-3 was found in the basement membrane of the NPCE, Bruch's membrane, and choroidal vessels in normal control subjects. In SFD, immunolabeling of TIMP-3 also was present in the sub-RPE deposit and in the inner portion of the ciliary body deposit. TIMP-3 immunoreactivity was more extensive in the SFD eye. The pattern of elastin immunoreactivity was remarkably similar to that of TIMP-3. Electron microscopy revealed a morphologically altered elastic layer of the Bruch's membrane. CONCLUSIONS: Sub-RPE TIMP-3 immunoreactivity appears more extensive in SFD than in control subjects. There is also a correspondence between TIMP-3 and elastin immunoreactivies, which invites speculation as to a link between the SFD TIMP-3 mutation and altered elastin processing. The accumulation of abnormal material in SFD is more widespread than previously reported. In view of this, SFD might be better termed Sorsby's ocular epitheliopathy.

Aged↗
PubMed2000

Familial cavernous hemangioma: An expanding ocular spectrum.

OBJECTIVE: To describe the clinical and genetic findings in a family with multiple cases of cavernous hemangiomas. DESIGN: Investigational clinical and genetic study in which 3 generations of a family consisting of 12 members were screened with magnetic resonance brain imaging, dilated ophthalmoscopic examination, and cutaneous survey coupled with linkage analysis to determine affected individuals and to better define manifestations of this neuro-oculo-cutaneous syndrome. RESULTS: The proband had multiple cerebral cavernous hemangiomas and a choroidal hemangioma. Her son was found to harbor a retinal cavernous hemangioma. The proband's sister manifested a cerebral cavernous hemangioma, cutaneous hemangiomas, and a presumed choroidal hemangioma; her daughter demonstrated radiological findings suggestive of a cerebral cavernous hemangioma. The father of the proband demonstrated multiple, cutaneous hemangiomas. The remaining family members were free of lesions. The 7q locus could not be excluded as harboring the causative gene. CONCLUSIONS: This family may have a dominantly inherited neuro-oculo-cutaneous condition of cavernous hemangiomas with variable expressivity. The presence of choroidal hemangiomas in this phacomatosis has not been described previously to our knowledge. CLINICAL RELEVANCE: The presence of either retinal cavernous or choroidal hemangioma should alert the physician to search for features suggestive of systemic and familial involvement; either lesion may constitute the ocular component of the neuro-oculo-cutaneous phacomatosis, sometimes referred to as cavernoma multiplex. Arch Ophthalmol. 2000;118:969-973

Adult↗
PubMed2000

RP1 protein truncating mutations predominate at the RP1 adRP locus.

PURPOSE: Recent reports have shown that the autosomal dominant retinitis pigmentosa (adRP) phenotype linked to the pericentric region of chromosome 8 is associated with mutations in a gene designated RP1. Screening of the whole gene in a large cohort of patients has not been undertaken to date. To assess the involvement and character of RP1 mutations in adRP, the gene was screened in a panel of 266 unrelated patients of British origin and a Pakistani family linked to this locus. METHODS: Patients exhibiting the adRP phenotype were screened for mutations in the four exons of the RP1 gene by heteroduplex analysis and direct sequencing. Linkage of the Pakistani family was achieved using microsatellite markers. Polymerase chain reaction (PCR) products were separated by nondenaturing polyacrylamide gel electrophoresis. Alleles were assigned to individuals, which allowed calculation of LOD scores. Microsatellite marker haplotyping was used to determine ancestry of patients carrying the same mutation. RESULTS: In the 266 British patients and 1 Pakistani family analyzed, 21 loss-of-function mutations and 7 amino acid substitutions were identified, some of which may also be disease-causing. The mutations, many of which were deletion or insertion events, were clustered in the 5' end of exon 4. Most mutations resulted in a premature termination codon in the mRNA. Haplotype analysis of nine patients carrying an R677X mutation suggested that these patients are not ancestrally related. CONCLUSIONS: RP1 mutations account for 8% to 10% of the mutations in our cohort of British patients. The most common disease-causing mechanism is deduced to be one involving the presence of a truncated protein. Mutations in RP1 have now been described in adRP patients of four ethnically diverse populations. The different disease haplotype seen in the nine patients carrying the same mutation suggests that this mutation has arisen independently many times, possibly due to a mutation hot spot in this part of the gene.

Cohort Studies↗
PubMed2000

Ultrastructural changes associated with accumulation of inclusion bodies in rat retinal pigment epithelium.

PURPOSE: To determine the structural changes in the retinal pigment epithelium (RPE) and neighboring structures induced by intravitreal injection of a lysosomal protease inhibitor. METHODS: Eleven-week-old Sprague-Dawley rats were injected with 5 microliter of a lysosomal protease inhibitor, E-64 (2.22 microM), intravitreally once and killed at 24 hours, 48 hours, or 7 days later. Others received two or three injections at 48-hour intervals or three daily injections, and killed at 1, 4, and 7 days after the last injection. Eyes were enucleated and retinal tissues were processed for light and electron microscopy. RESULTS: A single injection of E-64 caused only a transient accumulation of phagosome-like and phagolysosome-like inclusion bodies in the RPE. By contrast, repeated injection caused progressive accumulation of these inclusions followed by altered RPE cell conformation, and changes in organelles such as loss of smooth endoplasmic reticulum (SER). This was accompanied by shortening and loss of photoreceptor outer segments without prior dysmorphic changes, alteration of choroidal capillaries, and invasion of Bruch's membrane by fibroblasts and pericytes. Intravitreal injection of vehicle as control induced no structural changes. CONCLUSIONS: E-64 treatment induced structural changes in the outer retina. The causal relationship between accumulation of inclusions in RPE and changes in other subcellular organelles and neighboring cells systems is not clear. However, there are possible explanations: physical disturbance of organelles, particularly SER by inclusions; cellular damage by consequent upon accumulation of A2-E; or, shortage of recycled material due to reduced degradation of phagosomes.

Animals↗
PubMed1999

A fluorescein and indocyanine green angiographic study of choriocapillaris in age-related macular disease.

OBJECTIVE: To examine the phenomenon of a prolonged choroidal filling phase (PCFP) as seen on fluorescein and indocyanine green (ICG) angiography in patients with early age-related macular disease (AMD). METHODS: One hundred eyes of consecutive patients with early AMD were studied. Patchy and slow choroidal filling in early fluorescein and distinct areas of reduced choroidal fluorescence in ICG angiography were interpreted as PCFP. In addition, associated drusen characteristics and the AMD status of the fellow eye were recorded. RESULTS: A PCFP was observed in 26% of eyes using fluorescein and 32% of eyes using ICG angiography, with good concordance between findings using both techniques (K = 0.9). A PCFP was associated with confluent drusen (P = .01), the presence of focal retinal pigment epithelial-atrophic patches in the study eye (P=.005), and geographic atrophy in the fellow eye (P=.03). Other drusen characteristics and the distribution of visual acuity (P = .90) were not different between eyes with and without PCFP. CONCLUSIONS: A PCFP on fluorescein and ICG angiography is a common feature in early AMD. This sign has been interpreted as indicating reduced choroidal perfusion caused by change in diffusional characteristics of Bruch membrane. A PCFP is a clinical marker for diffuse deposits in Bruch membrane and a risk factor for the development of geographic atrophy.

Aged↗
PubMed1999

Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families.

OBJECTIVE: To report the phenotype associated with the codon 172 RDS (gene for retinal degeneration slow) mutation in 11 separate families with an arginine-to-tryptophan substitution with common ancestry, and 1 family with an arginine-to-glutamine transition. PATIENTS: Screening for RDS gene mutations was performed in 400 subjects with autosomal dominant retinal degeneration. Twelve families were identified with a mutation in codon 172. Haplotype analysis was performed. Full ophthalmic evaluation was performed, including electrophysiologic and psychophysical investigation and imaging of autofluorescence using confocal laser scanning ophthalmoscopy. RESULTS: Haplotype analysis demonstrated that the 11 families were ancestrally related. All 12 families showed a common phenotype of macular dysfunction, with the deficit increasing with age. Abnormally high autofluorescence predated loss of visual acuity or visual field changes. Pattern electroretinographic (PERG) findings were affected early in disease. There was high intrafamilial and interfamilial consistency of phenotype. CONCLUSION: These families demonstrate a striking conformity of symptoms and signs. CLINICAL RELEVANCE: In the codon 172 RDS mutation, unlike disease resulting from other RDS mutations, prediction of approximate age of onset and progression of visual deficit is possible. This should assist diagnosis and counseling.

Adolescent↗
PubMed1999

An immunohistochemical study of an autosomal dominant feline rod/cone dysplasia (Rdy cats).

An autosomal dominant, early onset feline model of rod/cone dysplasia has been described. The clinical features, light and electron microscopy, and the electrophysiology were documented. We have now examined in more detail the histopathological and immunohistochemical changes during the early phase of the disease using antibodies against opsin, synaptophysin, glial fibrillary acidic protein (GFAP) and an epithelial marker (MNF118). We have also demonstrated programmed cell death by a modified TUNEL (Terminal deoxynucleotidyl transferase, Uridine triphosphate, Nick End Labelling) technique. In the Rdy cats, there was significant photoreceptor degeneration between 5 and 17 weeks of age. The TUNEL-labeled cell and pyknotic cell counts in the outer nuclear layer peaked at around 9 weeks of age. Accumulation of opsin in the entire outer nuclear layer of the retina was noted with opsin-immunolabeled rod neurite sprouting. There was a reduction in synaptophysin immunoreactivity in the outer plexiform layer. The Muller cells were activated and expressed GFAP. No significant change of immunolabeling of MNF118 was found. These findings closely parallel those seen in human RP.

Animals↗
PubMed1999

[Serous central chorioretinopathy. Acute autofluorescence of the pigment epithelium of the eye].

PURPOSE: The lack of histopathological material has placed limitations on our knowledge on lipofuscin in central serous chorioretinopathy (CSCR). This study was designed to document the pathological changes of the retinal pigment epithelium (RPE) in CSCR using in vivo recording of fundus autofluorescence. METHODS: Fundus autofluorescence was documented in 62 eyes of 44 subjects with CSCR using a laser scanning ophthalmoscope (Zeiss, Oberkochen; excitation wavelength: 488 nm, barrier filter at 521 nm). Images were compared to the respective fundus appearance and fluorescein angiograms. RESULTS: Neurososensory retinal detachments showed diffuse increased autofluorescence corresponding to the detached area. Long-standing lesions showed very irregular autofluorescence with regions greater and less than the background levels of autofluorescence. CONCLUSION: Focal accumulation of autofluorescent material occurs at the level of the RPE in patients with CSCR, relating to variation in metabolic activity of the RPE. This technique may be useful in selecting patients for laser photocoagulation.

Adult↗
PubMed1999

Distribution of pigment epithelium autofluorescence in retinal disease state recorded in vivo and its change over time.

BACKGROUND: Recently a technique of imaging the retinal pigment epithelium (RPE) has been developed that takes advantages of its intrinsic fluorescence derived from lipofuscin. The purpose of this study was to document the distribution of fundus autofluorescence in patients with various retinal diseases and its change over time. METHODS: The intensity and spatial distribution of fundus autofluorescence was documented in 318 eyes from 159 patients with various retinal diseases using a confocal Laser Scanning Ophthalmoscope. Thirty patients with macular dystrophies and 30 with age-related macular disease underwent serial examinations over a period of 1-3 years in order to monitor the changes over time of fundus autofluorescence. RESULTS: Absent autofluorescence corresponded well spatially with outer retinal atrophy in eyes with retinitis pigmentosa and rod-cone dystrophy. Abnormally high background autofluorescence was seen in the macular region in some patients with dominant and recessive retinitis pigmentosa and rod-cone dystrophies. In areas of macular edema fundus autofluorescence was abnormal. Fundus autofluorescence showed changes over time in most of the eyes with retinal diseases studied. CONCLUSION: Fundus autofluorescence allows documentation of areas of photoreceptor cell loss in eyes with retinitis pigmentosa and rod-cone dystrophies. If abnormal high background autofluorescence in the surviving areas occurs only in some patients with retinitis pigmentosa, the technique may serve to distinguish the regional from the diffuse type of disease. Over time, fundus autofluorescence may demonstrate change or may remain stable.

Adolescent↗
PubMed1999

Refined genetic and physical positioning of the gene for Doyne honeycomb retinal dystrophy (DHRD).

Doyne honeycomb retinal dystrophy (DHRD) is a late-onset autosomal dominant disorder that causes degeneration of the retina and can lead to blindness. We have previously assigned DHRD to a 5-cM region of chromosome 2p16 between marker loci D2S2739 and D2S378. Using sequence-tagged sites (STSs), expressed sequence tags (ESTs) and polymorphic markers within the DHRD region, we have identified 18 yeast artificial chromosomes (YACs) encompassing the DHRD locus, spanning approximately 3 Mb. The YAC contig was constructed by STS content mapping of these YACs and incorporates 13 STSs, including four genes and six polymorphic marker loci. We also report the genetic mapping of two families with a dominant drusen phenotype to the DHRD locus, and genetic refinement of the disease locus to a critical interval flanked by microsatellite marker loci D2S2352 and D2S2251, a distance of approximately 700 kb. These studies exclude a number of candidate genes and provide a resource for construction of a transcriptional map of the region, as a prerequisite to identification of the DHRD disease-causing gene and genes for other diseases mapping in the region, such as Malattia leventinese and Carney complex.

Chromosomes, Artificial, Yeast↗
PubMed1999

Fluorescein angiographic abnormalities after prophylactic macular photocoagulation for high-risk age-related maculopathy.

PURPOSE: Initial studies suggest that drusen associated with age-related maculopathy resolve in response to laser photocoagulation; there are conflicting reports regarding whether this treatment might prevent neovascular complications and blindness. The goal of the Drusen Laser Study is to maintain good visual acuity in eyes at the highest risk for neovascular complications of age-related maculopathy. In this report, we alert the ophthalmic community to possible laser-induced complications in patients treated within the context of this clinical trial. METHODS: A double-masked, randomized, controlled clinical trial of prophylactic macular photocoagulation for high-risk age-related maculopathy is in progress. Patients randomly assigned to treatment received a ring-type distribution of 12 light spots of argon laser photocoagulation. Drusen were treated directly only if they were present at the protocol treatment locations. Fluorescein angiography was performed in all patients at yearly review, and at nonprotocol visits if symptoms or clinical examination were suggestive of choroidal neovascularization. RESULTS: Fluorescein angiographic abnormalities suggestive of choroidal neovascularization have been seen in treated eyes only: one patient in the pilot study and six patients in the Drusen Laser Study. No fluorescein angiographic abnormalities were seen in eyes of control subjects. CONCLUSIONS: Laser photocoagulation in high-risk age-related maculopathy may induce choroidal neovascularization and, therefore, is not recommended outside the context of a randomized, controlled clinical trial.

Aged↗
PubMed1999

Ocular abnormalities in Alagille syndrome.

OBJECTIVE: To assess the type and frequency of ocular abnormalities occurring in Alagille syndrome (AS) in a large group of affected patients and their parents and the potential pathogenetic role of fat-soluble vitamin deficiency. DESIGN: Observational case series. PARTICIPANTS: Twenty-two children with AS and 23 of their parents participated. MAIN OUTCOME MEASURES: Participants underwent full ophthalmic examination, including refraction, orthoptic examination, keratometry, slit-lamp examination, and funduscopy. Corneal diameter measurement was performed in a subset of nine and fluorescein angiography in a subset of six. Serum levels of vitamins A and E and cholesterol were measured. RESULTS: The most common ocular abnormalities in patients with AS were posterior embryotoxon (95%), iris abnormalities (45%), diffuse fundus hypopigmentation (57%, a previously unreported finding), speckling of the retinal pigment epithelium (33%), and optic disc anomalies (76%). Microcornea was not associated with large refractive errors, and visual acuity was not significantly affected by these ocular changes. Vitamin levels were normal. Ocular abnormalities including posterior embryotoxon, iris abnormalities, and optic disc or fundus pigmentary changes were detected in one parent in 36% of cases. CONCLUSIONS: Alagille syndrome is associated with a characteristic group of ocular findings without apparent serious functional significance and probably unrelated to fat-soluble vitamin deficiency. Simple ophthalmic examination of children with neonatal cholestatic jaundice and their parents should allow early diagnosis of AS, eliminating the need for extensive and invasive investigations.

Abnormalities, Drug-Induced↗
PubMed1999

A clinical and molecular genetic analysis of solitary ocular angioma.

OBJECTIVES: To determine whether ocular angioma can occur in the absence of von Hippel Lindau (VHL) syndrome, to define the clinical characteristics of sporadic (non-VHL) angioma, and to estimate a prevalence for sporadic ocular angioma. DESIGN AND PARTICIPANTS: A cross-sectional study of a cohort of patients with apparent sporadic ocular angiomatosis recruited from throughout the United Kingdom. INTERVENTION: Clinical details and a family history were obtained for the patients in the cohort. Systematic ocular examination and further systemic screening were performed on the patients and relatives when possible. Leukocyte DNA was examined for VHL germline mutations. MAIN OUTCOME MEASURES: Patients with solitary and typical VHL-like ocular angioma, without clinical and family histories for VHL, were selected as possible sporadic (non-VHL) ocular angioma cases. An estimate of the population prevalence of sporadic (non-VHL) ocular angioma was made from patients presenting in the East Anglian region of the United Kingdom over a 25-year period. RESULTS: From 32 patients referred, 17 had typical solitary ocular angioma and no evidence of other VHL complications in themselves or in family members. All 17 patients were negative for germline VHL mutations. The mean age of presentation was 30.9 years (median, 27.5; range, 3-52); 11 of 17 eyes suffered visual loss and 4 of 17 tumors occurred on the optic disc. The estimated prevalence of non-VHL ocular angioma was 9.0 x 10(-6), 95% confidence interval (CI) = 3.3 - 19 x 10(-6) (1 in 110,000 persons, 95% CI = 1 in 53,000-300,000). CONCLUSIONS: Sporadic ocular angioma can occur in the absence of VHL disease but appears less prevalently than VHL itself. The age of presentation, degree of visual morbidity, complications, morphology, and anatomic location of tumors are similar to those seen in VHL disease.

Adult↗
PubMed1999

A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy.

Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium (RPE). Both loci were mapped to chromosome 2p16-21 (refs 5,6) and this genetic interval has been subsequently narrowed. The importance of these diseases is due in large part to their close phenotypic similarity to age-related macular degeneration (AMD), a disorder with a strong genetic component that accounts for approximately 50% of registered blindness in the Western world. Just as in ML and DHRD, the early hallmark of AMD is the presence of drusen. Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied. This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration. Identification of this mutation may aid in the development of an animal model for drusen, as well as in the identification of other genes involved in human macular degeneration.

Aging↗