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Biomedical subjects

A Ridgway

Publications and source records attributed to A Ridgway.

17 recordsLinked to original sources
PubMed2001

Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy.

Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Z(max) = 3.72, theta = 0.0). Refinement of the critical region defined a 6-7 cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.

Amino Acid Sequence↗
PubMed2000

Management of pellucid marginal corneal degeneration.

PURPOSE: A retrospective study to ascertain the management of pellucid marginal corneal degeneration (PMCD). METHOD AND RESULTS: Sixteen patients (average age 42.6 years) presented with PMCD. PMCD was bilateral in 13 and unilateral in 3 patients. Eight eyes underwent surgery. Nineteen eyes were managed non-surgically. Surgery involved corneal wedge excision (WE) (6 eyes), penetrating keratoplasty (PK) (3 eyes) and lamellar thermo-keratoplasty (LTK) (1 eye). Immediate pre-operative average visual acuity (VA) was 6/24, 6/10 and 6/60 with an average pre-operative astigmatism of 11.40 D, 9.75 D and 20.5 D for WE, PK and LTK respectively. After an average post-operative follow-up of 57 months, 66 months and 1 year, the average astigmatism was 8.90 D, 4.63 D and 6.00 D with an average final VA of 6/19, 6/15 and 6/6 for WE, PK and LTK respectively. In the nonsurgical group, at presentation, 40% of eyes had a VA of 6/12 or better. After an average follow-up period of 32.3 months, 80% of eyes had a visual acuity of 6/12 or better. Optical correction was achieved with spectacles and or contact lenses. CONCLUSIONS: Surgical correction for PMCD provides poor long-term reduction of astigmatism. Patients with PMCD may be adequately corrected in the long term by the use of scleral fitted gas-permeable contact lenses.

Adult↗
PubMed2000

Centration of donor trephination in human corneal transplantation.

PURPOSE: To develop and evaluate a new method to quantify centration of the trephined donor cornea relative to the limbus. METHODS: After human donor corneas were trephined for penetrating keratoplasty, the remaining corneoscleral discs were stained and subjected to image analysis. The centration of the excised donor cornea relative to the limbus was calculated by measuring their centroids from the "captured" images. RESULTS: Fifty-two corneoscleral discs were analyzed. The average deviation from the centre was 0.32 mm (SD, 0.18 mm). Neither surgeon nor the type of trephine significantly influenced the mean centroid deviation. CONCLUSION: We have developed and evaluated a method to quantify centration of human donor cornea. In a small series, decentration did not correlate significantly with either the surgeon or the trephine.

Cornea↗
PubMed2000

Visual function after penetrating keratoplasty for keratoconus: a prospective longitudinal evaluation.

AIMS: To evaluate visual function and vision specific health status in patients undergoing penetrating keratoplasty for keratoconus. METHODS: A prospective longitudinal study measuring logMAR visual acuity, contrast sensitivity, disability glare, binocular visual field, stereoacuity, and subjective visual function (VF-14) was conducted on 18 patients with keratoconus undergoing penetrating keratoplasty (PK), including six patients who had already had PK in the fellow eye. Data were collected preoperatively and at 3, 9, and 18 months after surgery. RESULTS: Within 3 months of surgery there was significant improvement in aided visual acuity, contrast sensitivity, and stereoacuity (p<0.05); disability glare (p<0.05) no longer had a significant detrimental effect on these variables. VF-14 score improved significantly throughout the postoperative period (p<0.05). There was significant correlation of the VF-14 score with aided visual acuity, binocular visual field, and stereoacuity. Postoperative astigmatism (<4D v >4D) did not affect the VF-14 score significantly. CONCLUSIONS: There is substantial and rapid improvement in visual function and vision specific health status in keratoconic patients as a result of uncomplicated penetrating keratoplasty.

Adult↗
PubMed2000

Developmental changes in patterns of expression of tenascin-C variants in the human cornea.

PURPOSE: To study patterns of expression of alternatively spliced tenascin-C (TN-C) variants believed to mediate cellular activities in human corneal development. METHODS: Serial sections of preterm, neonatal, child, and adult globes with normal anterior segments were labeled with monoclonal antibodies to TN-C. The antibodies included BC-4 and BC-8, which recognize epitopes in conserved domains of TN-C and can thus detect all TN-C variants, and BC-2, alpha-A2, alpha-A3, alpha-IIIB, TN11, and alpha-D, which bind to epitopes in alternatively spliced fibronectin type III repeats of TN-C. Bound antibodies were localized and visualized using an avidin-biotin complex-alkaline phosphatase technique. RESULTS: BC-4 and BC-8 showed similar patterns of staining, widely observed in preterm corneas, less so in neonatal corneas, and restricted to the limbus in the child and adult. BC-2, alpha-A2, alpha-A3, alpha-IIIB, TN11, and alpha-D staining was largely localized in corneal epithelium (preterm and neonatal), limbal epithelium, mast cells, and matrix surrounding limbal vessels (preterm, neonatal, child, and adult). CONCLUSIONS: TN-C may play a role in corneal development and in growth and differentiation of stem cells because it is widely expressed in the preterm cornea, less so in the neonate, and is restricted to the limbus in the child and adult. The differential patterns of expression of TN-C variants in normal corneas (preterm and neonatal), and in the limbus (preterm, neonatal, child, and adult), suggest specific roles played by each variant, and cell type-specific expression of the different variants.

Adult↗
PubMed1999

Inhibition of human immunodeficiency virus type 1 by Tat/Rev-regulated expression of cytosine deaminase, interferon alpha2, or diphtheria toxin compared with inhibition by transdominant Rev.

A retroviral vector was designed to express toxic proteins only in the presence of the HIV-1 Rev and/or Tat protein(s). The design of this vector incorporates an HIV-specific expression cassette that consists of three elements: the U3R region of the HIV-1 IIIB LTR provides the promoter and Tat-responsive element, a modified intron derived from the human c-src gene facilitates the splicing of inserted genes, and the HIV-1 RRE region enhances the transport of unspliced mRNAs. To further limit potential readthrough transcription, the expression cassette was inserted in the reverse transcriptional orientation relative to the retroviral vector LTR. Three different genes, interferon alpha2, diphtheria toxin (DT-A), and cytosine deaminase, were inserted into this vector. Tat and Rev inducibility was demonstrated directly by a >300-fold induction of interferon production and functionally by a decrease in colony-forming units when a Tat and Rev expression vector was titered on HeLa cells harboring the inducible DT-A cassette. The Tat-inducible cytosine deaminase gene was tested in the Sup-T1 T cell line and shown to inhibit HIV-1 production only when engineered cells were grown in the presence of 5-fluorocytosine. To test the ability of this system to inhibit HIV-1 infection in bulk PBL cultures, a series of transduction and challenge experiments was initiated with both the interferon and DT-A vectors. Protection against infection was documented against three HIV strains in PBLs. Last, the interferon and DT-A vectors were compared with a vector encoding a transdominant Rev protein and were shown to mediate equal or greater inhibition of HIV-1.

Blotting, Northern↗
PubMed1996

A rational approach to regulation of gene therapy in Canada.

Gene therapy offers prospects of dramatically improved treatments for and possibly true cures of previously intractable diseases, and has therefore attracted much public interest and hopeful expectation. At the same time, it involves new and exploratory techniques and potential risks to patients. The definition of a drug in the Canadian Food and Drugs Act clearly includes materials used to effect gene therapy and also the products of genetic manipulations. The regulatory framework in Canada is based on risk management. The potential hazards and benefits of gene therapy and similar interventions will be assessed for categorization according to risk and an appropriate level of control, with the additional principle of deriving positions that are harmonized with those of counterpart regulatory agencies.

Advisory Committees↗
PubMed1996

Successful medical therapy of Acanthamoeba keratitis with topical chlorhexidine and propamidine.

INTRODUCTION: Following laboratory studies on new potential chemotherapy for Acanthamoeba keratitis, when chlorhexidine and propamidine provided an additive in vitro effect, a series of 12 patients with culture-proven Acanthamoeba keratitis from three UK centres was monitored during and after therapy. METHODS: In all cases the clinical diagnosis was confirmed by amoebal culture. In some instances identification of the protozoa by direct microscopy of corneal tissue was possible. The medication was provided topically in drop form until the keratitis had resolved. In vitro sensitivity to chlorhexidine and propamidine was performed on all isolates and compared with sensitivity to a range of other drugs used for treatment of the infection. RESULTS: In vitro drug testing confirmed that trophozoites and cysts of all 12 Acanthamoeba isolates were fully sensitive to chlorhexidine and propamidine. Therapy was satisfactory for controlling and eradicating the acanthamoebal infection in all patients. Three patients developed discrete stromal infiltration at the site of infection that resolved 1 week after commencing therapy, with or without use of steroids. Two patients developed a late inflammatory effect in the stromal scar at 6 months, which resolved with steroids. No clinical evidence of chlorhexidine toxicity was found in any patients. CONCLUSIONS: The combination of topical chlorhexidine and propamidine was very effective for treating Acanthamoeba keratitis provided the drugs were continued for a sufficient period. No drug toxicity or resistance of Acanthamoeba isolates was observed in the 12 treated patients.

Acanthamoeba↗
PubMed1987

B-lymphoma induction by reticuloendotheliosis virus: characterization of a mutated chicken syncytial virus provirus involved in c-myc activation.

Nondefective reticuloendotheliosis virus induces chicken bursal lymphoma in a manner similar to that of avian leukosis virus. The provirus integrates in the c-myc locus and uses a promoter insertion mechanism to activate c-myc expression. We cloned a provirus involved in c-myc activation from a B lymphoma. Detailed structural characterization of this clone, including sequence determination, revealed proviral insertion at 512 base pairs preceding the second c-myc exon. The provirus has a deletion of 80% of the viral genes but retains two intact long terminal repeats (LTRs). A segment of the viral env sequence is present in an inverted orientation. Elevated expression of c-myc, apparently directed by the 3' LTR, was detected. However, despite the presence of an intact 5' LTR, no viral transcripts were detected. Thus, the internal proviral rearrangement can affect 5' LTR transcription or stability of the message or both. This finding is in consonance with the view that proviral deletion plays an important role in the induction of bursal lymphomas by nonacute retroviruses.

Animals↗
PubMed1985

Isolation and structural mapping of a human c-src gene homologous to the transforming gene (v-src) of Rous sarcoma virus.

We have utilized a lambda Charon 4A human genomic library to isolate recombinant clones harboring a highly conserved c-src locus containing nucleotide sequences homologous to the transforming gene of Rous sarcoma virus (v-src). Four overlapping clones spanning 24 kilobases of cellular DNA were analyzed by restriction endonuclease mapping. Human c-src sequences homologous to the entire v-src region are present in a 20-kilobase region that contains 11 exons as determined by restriction mapping studies utilizing hybridization to labeled DNA probes representing various subregions of the v-src gene and by preliminary DNA sequencing analyses. A considerable degree of similarity exists between the organization of the human c-src gene and that of the corresponding chicken c-src gene with respect to exon size and number. However, the human c-src locus is larger than the corresponding chicken c-src locus, because many human c-src introns are larger than those of chicken c-src. alu family repetitive sequences are present within several human c-src introns. This locus represents a highly conserved human c-src locus that is detectable in human cellular DNAs from various sources including placenta, HeLa cells, and WI-38 cells.

Avian Sarcoma Viruses↗