The use of fibrin adhesive in trabeculectomy: a pilot study.
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Aged↗
Biomedical subjects
M Lusky
Publications and source records attributed to M Lusky.
Augmented trabeculectomy in paediatric glaucoma.
AIMS: To report the experience with trabeculectomy augmented with mitomycin C and 5-fluorouracil for the treatment of paediatric glaucoma. METHODS: Retrospective, interventional case series design was used. The sample included 17 children (29 eyes) with primary (19 eyes) or secondary (10 eyes) glaucoma who were treated with augmented trabeculectomy as the primary procedure between 1990 and 2002. Data were collected on age and family history, preoperative and end of follow up intraocular pressure, cup/disc ratio (evaluated by drawing), visual acuity, complications, and post-surgery treatment. RESULTS: Patient age at surgery ranged from 1 month to 8 years; most patients (n = 14, 82.3%) were aged less than 1 year (range 1 month-8 months, mean 3.95 (SD 2.56) months); three patients (17.7%) were aged 3, 5, and 8 years. The duration of follow up was 3-120 months (mean 46 months). Intraocular pressure significantly improved from 21 mm Hg to 60 mm Hg (mean 33.1 (10) mm Hg) before surgery to 6-26 mm Hg (mean 17.1 (6) mm Hg) after, (p <0.0001). There was no significant change in cup/disc ratio: 0.1-0.8 (mean 0.42 (0.26)) before and 0.1-1.0 (mean 0.511 (0.27)) after (p = 0.45). In 22 eyes (75.8%), intraocular pressure was controlled at less than 20 mm Hg and the cup/disc ratio remained stable or improved. The life table success rate for intraocular pressure control remained stable at 86% at the 12, 24, and 36 months and after 48 months decreased to 53%. There was no significant difference in the life table results between primary and secondary glaucoma. 14 eyes (48.2%) had a visual acuity better than 20/120 by the end of follow up. Repeated surgery was necessary in eight eyes (27.5%), and additional antiglaucoma treatment in 13 (44.8%). Complications included retinal detachment 1 year after surgery, choroidal detachment, and blebitis (one eye each). CONCLUSIONS: Augmented trabeculectomy with mitomycin C and 5-fluorouracil may serve as the primary procedure in a selected group of paediatric patients with glaucoma.
Antimetabolites↗
Pupillary block following posterior chamber intraocular lens implantation in adults.
BACKGROUND: Pupillary block rarely occurs after cataract extraction with posterior chamber intraocular lens implantation. METHODS: A series of six patients (seven eyes) treated for pupillary block after posterior chamber intraocular lens implantation between 1990 and 2001 is described; in one eye, the attack occurred after phacoemulsification. RESULTS: The interval between pupillary block development and the cataract surgery ranged from 1 day to 5 years. In all eyes, treatment consisted of neodymium-YAG laser peripheral iridotomy. In four eyes, the laser peripheral iridotomy relieved the block (one procedure in two; two to three procedures in two). One patient was also treated with YAG capsulotomy, and two patients needed additional surgical intervention. CONCLUSION: Despite the rarity of the complication of pupillary block after posterior chamber intraocular lens implantation, physicians should be aware of the sometimes difficult course of recovery after treatment.
Aged↗
Persistent hepatic expression of human apo A-I after transfer with a helper-virus independent adenoviral vector.
Gene transfer with 'gutted' vectors is associated with persistent transgene expression and absence of hepatotoxicity, but the requirement of helper viruses hampers efficient production and leads to contamination of viral batches with these helper-viruses. In the present study, gene transfer with a helper-virus independent E(1)/E(3)/E(4)-deleted adenoviral vector induced persistent expression of human apo A-I (200 +/- 16 mg/dl at day 35, 190 +/- 15 mg/dl at 4 months, 170 +/- 16 mg/dl at 6 months) and stable transgene DNA levels (3.5 +/- 0.60 at day 35, 3.3 +/- 0.39 at 4 months, 3.1 +/- 0.47 mg/dl at 6 months) in C57BL/6 mice in the absence of significant toxicity. The vector contained the 1.5 kb human alpha(1)-antitrypsin promoter in front of the genomic human apo A-I sequence and four copies of the human apo E enhancer (hAAT.gA-I.4xapoE) and was deleted in E(1), E(3) and E(4). Reintroduction of E(4) ORF 3 and E(4) ORF 4 in the viral backbone caused a more than four-fold decline of transgene DNA between day 35 and 4 months after transfer both in wild-type and in C57BL/6 SCID and C57BL/6 Rag-1(-/-) mice, indicating that the effect of E(4) ORF 3 and E(4) ORF 4 is independent of a cellular immune response against viral epitopes. Co-injection of an E(1)-deleted vector containing no expression cassette and the E(1)/E(3)/E(4)-deleted vector containing the hAAT.gA-I.4xapoE expression cassette indicated that E(4) gene products destabilize transgene DNA in trans. Gene transfer with an E(1)/E(3)/E(4)-deleted vector containing only E(4) ORF 3 and the hAAT.gA-I.4xapoE expression cassette was associated with transgene DNA decline, but not with hepatotoxicity, indicating that transgene DNA persistence and hepatotoxicity are dissociated processes. After transfer with E(1)/E(3)/E(4)-deleted vectors containing expression cassettes with a different promoter or a different position of the apo E enhancers, transgene DNA levels were less stable than after transfer with the vector containing hAAT.gA-I.4xapoE, indicating that the expression cassette is an important determinant of episomal stability. In conclusion, gene transfer with an E(1)/E(3)/E(4)-deleted vector containing the hAAT.gA-I.4xapoE expression cassette induces persistent expression of human apo A-I in the absence of hepatotoxicity. Transgene DNA turnover is independent of an adaptive cellular immune response against viral epitopes and of hepatotoxicity. E(1)/E(3)/E(4)-deleted vectors containing transgenes under control of the hAAT promoter in combination with four copies of the human apo E enhancer may be suitable for hepatocyte-specific overexpression of transgenes after gene transfer. doi:10.1038/sj.gt.3301824
Adenoviridae↗
Radioisotopic imaging allows optimization of adenovirus lung deposition for cystic fibrosis gene therapy.
Cystic fibrosis is a common, heriditary disease resulting from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Airway transfer of the CFTR gene is a potential strategy to treat or prevent the lung pathology that is the main cause of morbidity and mortality. Among the vectors used for gene therapy, adenoviruses have shown their ability to transfer the CFTR gene to respiratory epithelial cells, using either instillation or nebulization. Our objective was to characterize the lung deposition of aerosolized adenovirus by quantitative radioisotopic imaging, the only noninvasive technique allowing in vivo quantitation of inhaled drugs. We first labeled an adenovirus expressing human CFTR with the gamma-emitting radioisotope, technetium 99m (99mTc), and determined the best labeling conditions to allow preservation of virus bioactivity. We then administered the radioaerosol to baboons, determined lung regional deposition of 99mTc-labeled adenovirus, and compared the expression of CFTR transcripts 3 and 21 days after inhalation. The expression of vector-encoded mRNA ranged from 4 to 22% with respect to the endogenous CFTR mRNA depending on the lung segments. Moreover, we have developed a model using 99mTc-DTPA (diethylenetriamine pentaacetic acid), which can be used, as an alternative to adenovirus, to determine the profile of lung deposition of the vector. This study demonstrates that scintigraphy is a useful technique to achieve optimization of gene administration to the airways.
Adenoviridae↗
Effects of first generation E1E3-deleted and second generation E1E3E4-deleted/modified adenovirus vectors on human endothelial cell death.
Adenoviral vectors are promising tools for pulmonary vascular gene transfer. In first generation vectors, the viral E4 region is preserved (E4+ Ad), but E4 is deleted in second generation vectors (E4- Ad). These vectors were compared for their toxicity in human endothelial cells in terms of apoptosis and necrosis. Infection with E4+ Ad vectors reduced whereas E4- Ad vectors enhanced apoptosis under normal culture conditions. Furthermore, E4+ Ad protected against apoptosis induced by growth factor deprivation, while E4- Ad enhanced apoptosis triggered by ceramide. Ad vectors containing different E4 open reading frames, alone or in different combinations, showed similar effects to E4- Ad, leaving the viral genes that might be responsible for reducing apoptosis unidentified at the present time. As previously observed with E4+ Ad devoid of transgene, E4+ Ad carrying beta-galactosidase or green fluorescent protein under the control of either the RSV or CMV promoter also reduced apoptosis triggered by growth factor deprivation. In contrast, E4+ Ad containing a CFTR expression cassette did not reduce apoptosis, and E4- Ad with CFFR showed increased toxicity. We conclude that Ad vectors may have important effects on the control of apoptosis in transfected cells, depending on the residual expression of viral genes. This effect can be complicated by the action of transgene expression on cell survival.
Adenoviridae↗
Modulation of the inflammatory properties and hepatotoxicity of recombinant adenovirus vectors by the viral E4 gene products.
Liver toxicity and inflammation were assessed in C57BL/6, CBA, and BALB/c mice injected intravenously with a series of recombinant adenoviruses deleted simultaneously in E1/E3, in E1/E3/E2A, or in E1/E3/E4. All vectors were either devoid of transgenes or carried in E1 the human CFTR cDNA under the control of the CMV promoter. Injection of the E1/E3-deleted vector induced a significant liver dystrophy and inflammatory responses that were accompanied by an increased serum transaminase concentration. The vector toxicity remained elevated on additional deletion of the E2A gene and was further enhanced when hCFTR was expressed. In contrast, additional deletion of E4 led to a reduction in hepatotoxicity, suggesting an active role of E4 gene products in liver injury. However, deletion of E4 also led to a loss of transgene expression. To identify the individual E4 product(s) involved in liver toxicity and in the regulation of transgene expression, a series of isogenic E1/E3-deleted vectors, with or without the hCFTR transgene, and containing various combinations of functional E4 open reading frames (ORFs), were evaluated in vitro and in vivo. We demonstrate that liver injury was markedly reduced with vectors containing either ORF3 alone or ORF3,4 while vectors containing ORF4, ORF6,7 or ORF3,6,7 still displayed elevated hepatotoxicity and inflammatory responses. Moreover, transgene expression was restored when ORF3,4 or ORF3,6,7 was retained in the vector. These results highlight the importance of the E4 gene products in the design of improved in vivo gene transfer vectors.
Adenoviridae↗
Regulation of adenovirus-mediated transgene expression by the viral E4 gene products: requirement for E4 ORF3.
In a previous study we showed that multiple deletions of the adenoviral regulatory E1/E3/E4 or E1/E3/E2A genes did not influence the in vivo persistence of the viral genome or affect the antiviral host immune response (Lusky et al., J. Virol. 72:2022-2032, 1998). In this study, the influence of the adenoviral E4 region on the strength and persistence of transgene expression was evaluated by using as a model system the human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA transcribed from the cytomegalovirus (CMV) promoter. We show that the viral E4 region is indispensable for persistent expression from the CMV promoter in vitro and in vivo, with, however, a tissue-specific modulation of E4 function(s). In the liver, E4 open reading frame 3 (ORF3) was necessary and sufficient to establish and maintain CFTR expression. In addition, the E4 ORF3-dependent activation of transgene expression was enhanced in the presence of either E4 ORF4 or E4 ORF6 and ORF6/7. In the lung, establishment of transgene expression was independent of the E4 gene products but maintenance of stable transgene expression required E4 ORF3 together with either E4 ORF4 or E4 ORF6 and ORF6/7. Nuclear run-on experiments showed that initiation of transcription from the CMV promoter was severely reduced in the absence of E4 functions but could be partially restored in the presence of either ORF3 and ORF4 or ORFs 1 through 4. These results imply a direct involvement of some of the E4-encoded proteins in the transcriptional regulation of heterologous transgenes. We also report that C57BL/6 mice are immunologically weakly responsive to the human CFTR protein. This observation implies that such mice may constitute attractive hosts for the in vivo evaluation of vectors for cystic fibrosis gene therapy.
Adenoviridae↗
[Lowering intraocular pressure in glaucoma--by how much?].
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Glaucoma↗
Intravitreal gas injection for hypotony after cataract surgery.
PURPOSE: To evaluate the efficacy and safety of intravitreal perfluoropropane gas injection to treat hypotony after cataract surgery. SETTING: The ophthalmology department of a major tertiary medical center. METHODS: After uneventful cataract extraction, 5 patients with hypotony due to iridocyclitis, choroidal detachment, and serous retinal detachment were treated with an intravitreal injection of 1.0 cc of perfluoropropane gas. RESULTS: The hypotony, choroidal detachment, and exudative retinal detachment resolved in all 5 patients, and visual acuity improved. No complications were observed. CONCLUSION: Intravitreal gas injection can be used to treat hypotony after cataract surgery in selected patients.
Aged↗
In vitro and in vivo biology of recombinant adenovirus vectors with E1, E1/E2A, or E1/E4 deleted.
Isogenic, E3-deleted adenovirus vectors defective in E1, E1 and E2A, or E1 and E4 were generated in complementation cell lines expressing E1, E1 and E2A, or E1 and E4 and characterized in vitro and in vivo. In the absence of complementation, deletion of both E1 and E2A completely abolished expression of early and late viral genes, while deletion of E1 and E4 impaired expression of viral genes, although at a lower level than the E1/E2A deletion. The in vivo persistence of these three types of vectors was monitored in selected strains of mice with viral genomes devoid of transgenes to exclude any interference by immunogenic transgene-encoded products. Our studies showed no significant differences among the vectors in the short-term maintenance and long-term (4-month) persistence of viral DNA in liver and lung cells of immunocompetent and immunodeficient mice. Furthermore, all vectors induced similar antibody responses and comparable levels of adenovirus-specific cytotoxic T lymphocytes. These results suggest that in the absence of transgenes, the progressive deletion of the adenovirus genome does not extend the in vivo persistence of the transduced cells and does not reduce the antivirus immune response. In addition, our data confirm that, in the absence of transgene expression, mouse cellular immunity to viral antigens plays a minor role in the progressive elimination of the virus genome.
Adenovirus E1 Proteins↗
Gene therapy with recombinant adenovirus vectors: evaluation of the host immune response.
E1, E3-deleted, replication-deficient recombinant adenoviruses are widely studied as vectors for their capacity to transfer therapeutic genes in vivo. They can infect a wide variety of dividing and quiescent cells from different organs and possess a large packaging capacity. One of the major limitations in the use of these vectors for gene therapy is the transient expression of the transgene in vivo and the poor transduction efficiency when re-administered. Despite the deletion of the viral E1 region, low level of early and late viral genes are expressed in vivo. Thus, viral antigens plus those derived from transgene expression in transduced cells contribute to cellular immune responses leading to the destruction of these cells. Production of anti-adenovirus antibodies, the cellular immune response as well as the early non-specific clearance of the vectors, constitute barriers to successful gene therapy. New vectors have been derived with additional deletions in the E2a or the E4 regions. Such second generation vectors were evaluated in vivo. These studies have revealed the complexity of the immune mechanisms elicited by these vectors and the importance of several parameters in these evaluations (i.e. mouse strains, nature of the transgene, route of administration...). In order to inhibit the production of neutralizing antibodies to adenovirus that prevent from further readministration of the vectors, immunosuppressive strategies were undertaken. Treatment regimens with immunosuppressive drugs (cyclophosphamide, FK506) or with monoclonal antibodies that block either the T cell receptor or costimulation pathways allow prolonged transgene expression and/or readministration of adenoviral vectors. In addition, transduction efficiencies may be increased by transiently inhibiting non-specific immune mechanisms that lead to the dramatic early clearance of the vectors. Taken together, these strategies may improve further gene therapy protocols by decreasing the host immune response to adenoviral vectors.
Adenoviruses, Human↗
Clinical dose-regimen studies with latanoprost, a new ocular hypotensive PGF2 alpha analogue.
This review summarizes recent short-term clinical studies evaluating the ocular hypotensive efficacy of different dose-regimens of latanoprost. When tested in ocular hypertensive and glaucoma patients concomitantly treated with timolol, 0.006% latanoprost given only in the evening, was found to be more effective than the same concentration given in the morning and evening. In patients with open angle, pseudoexfoliation and normal tension glaucoma not receiving other treatment, once-daily 0.005% latanoprost monotherapy was more effective than twice-daily 0.0015% latanoprost treatment. No significant differences were found in conjunctival hyperemia, sensory irritation or blood-aqueous barrier permeability between these two treatment regimens. Although the ocular hypotensive efficacy of once-daily application of the lower concentration (0.0015%) latanoprost was not investigated, we would conclude, based on the studies reviewed here, that at a concentration of 0.005%, once-a-day dosing of latanoprost is highly effective in significantly reducing intraocular pressure, causing only minimal, clinically acceptable short-term ocular side effects.
Administration, Topical↗
A comparative study of two dose regimens of latanoprost in patients with elevated intraocular pressure.
OBJECTIVE: The purpose of the study was to determine whether latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor PGF2a-isopropyl ester), a new prostaglandin analogue that has been found effective in reducing intraocular pressure (IOP) in humans, is equally effective at lower concentrations than those currently employed. DESIGN AND PARTICIPANTS: Fifty patients with glaucoma or ocular hypertension were treated in a randomized, crossover, double-masked fashion with 1 drop of latanoprost (50 microg/ml once daily and 15 microg/ml twice daily) in the affected eye(s) for 3 weeks on each concentration. Tonometry was obtained at 8:00, 13:00, and 17:00 hours at baseline (untreated) and after 3 weeks on each concentration. Placebo (a buffer solution of latanoprost eye drop) was administered for complete masking of the study. RESULTS: Mean baseline (untreated) diurnal IOP for the entire sample was 24.7 mmHg. Intraocular pressure was reduced by 6.1 mmHg with latanoprost 15 microg/ml twice daily, and by 7.5 mmHg with 50 microg/ml once daily. Results with both regimens were significant (P < 0.001 each, Student's t-test). However, the 50 microg/ml dose was significantly more effective than the 15 microg/ml dose, with a difference of 1.4 mmHg (P < 0.001, ANOVA). Both dose regimens were well tolerated, with little, predominantly mild, ocular discomfort. The higher dose did not cause more hyperemia at 3 weeks than the lower one, i.e., the lower dose yielded a slightly higher score (1.8 mm) on the visual analogue scale (P < 0.29, ANOVA). CONCLUSIONS: Latanoprost administered at a concentration of 50 microg/ml once daily effectively reduces IOP in patients with elevated IOP. Administration of a lower concentration (15 microg/ml) twice daily is less effective, but still significant.
Adult↗
Ultrasonographic findings of the optic disc in congenital glaucoma.
A 2-month-old female infant with intractable congenital glaucoma and diffuse corneal opacification underwent trabeculectomy with 5-fluorouracil (5-FU) injection in both eyes followed by penetrating keratoplasty (PKP) combined with partial cyclocryotherapy in the right eye. The latter procedure was undertaken despite the B-scan ultrasonographic finding of extensive optic disc cupping in order to provide the infant with some degree of improved visual function. The anatomic and functional results are discussed.
Antimetabolites↗
The effect of topical beta-adrenoceptor blocking agents on pulsatile ocular blood flow.
Thirty-three ocular hypertensive patients (21 with primary open angle glaucoma and 12 glaucoma suspects) were randomly assigned to receive either timolol, levobunolol or betaxolol in one eye. Pulsatile ocular blood flow (POBF) was measured before treatment (baseline) and 2 hours after drop administration. After 1 week of regular twice-daily dosage, POBF was measured again both immediately before and 2 hours after drop instillation. All measurements were made by an investigator masked to treatment. POBF increased by 11% (p = 0.09) at week 0 after levobunolol administration, and by 22% (p = 0.20) at week 1 before drop administration compared with baseline. It dropped by 23% and 25% (p = 0.04 and 0.06, respectively) before and after betaxolol administration at week 1. Although POBF was reduced in the timolol group, this change was not significant. These results can not be explained uniformly by changes in intraocular pressure or blood pressure. The relevance of these measurements to visual function in glaucoma is not known.
Adrenergic beta-Antagonists↗
Late visual field changes following cryotherapy for retinopathy of prematurity stage 3.
AIMS: The correlation between cryoscars and visual field defects following cryoablation was studied. METHODS: A Humphrey 120 full field screening test was performed in 10 children (15 eyes) who were treated by cryotherapy between 10 and 14 years previously for retinopathy of prematurity (ROP) stage 3. RESULTS: In eight eyes treated by cryoablation through 360 degrees in zone I or II, a moderate circumferential peripheral visual field constriction was found. In seven other eyes, cryotreated up to 180 degrees only in the temporal retina (zone III), a nasal field constriction was noted. There was no evidence of late development of retinal tears or retinal detachment. The correlation between the primary cryoapplications, late chorioretinal cryoscars, and the visual field changes was evaluated. CONCLUSION: Late chorioretinal scars following cryotherapy for ROP stage 3 are associated with visual field defects, but as these defects are at the periphery of the visual field they do not cause any subjective derangements 10-14 years after treatment.
Adolescent↗
Induction of structural changes in the bovine papillomavirus type 1 origin of replication by the viral E1 and E2 proteins.
Chemical and enzymatic probing techniques were used to examine the interaction of the bovine papillomavirus type 1 E1 and E2 proteins with the viral origin of replication (ori). E1 was found to generate significant distortions to the structure of ori, as assayed by KMnO4 oxidation of DNA. The primary site of ori distortion was located within and adjacent to the AT-element of the core replicator sequence, although a number of minor structural transitions were also detected. The induction of these structural changes required ATP and appeared to require ATP hydrolysis. E2 was found to decrease the amount of E1 required for ori distortion but did not significantly alter the pattern of structural distortion. In contrast, the presence of E2 resulted in a biphasic mechanism for E1 binding to ori, as assayed by nuclease protection. Under these conditions, E1 bound preferentially to the dyad symmetry region containing the conserved Hpa I site. Higher levels of E1 were required for binding to the adjacent ori AT-rich region. Thus, these data suggest that E2 can order the stepwise binding of E1 to ori.
Adenosine Triphosphate↗