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1.
PLoS One ; 9(10): e111432, 2014.
Article in English | MEDLINE | ID: mdl-25347445

ABSTRACT

Microphthalmia is a severe ocular disorder, and this condition is typically caused by mutations in transcription factors that are involved in eye development. Mice carrying mutations in these transcription factors would be useful tools for defining the mechanisms underlying developmental eye disorders. We discovered a new spontaneous recessive microphthalmos mouse mutant in the Japanese wild-derived inbred strain KOR1/Stm. The homozygous mutant mice were histologically characterized as microphthalmic by the absence of crystallin in the lens, a condition referred to as aphakia. By positional cloning, we identified the nonsense mutation c.444C>A outside the genomic region that encodes the homeodomain of the paired-like homeodomain transcription factor 3 gene (Pitx3) as the mutation responsible for the microphthalmia and aphakia. We examined Pitx3 mRNA expression of mutant mice during embryonic stages using RT-PCR and found that the expression levels are higher than in wild-type mice. Pitx3 over-expression in the lens during developmental stages was also confirmed at the protein level in the microphthalmos mutants via immunohistochemical analyses. Although lens fiber differentiation was not observed in the mutants, strong PITX3 protein signals were observed in the lens vesicles of the mutant lens. Thus, we speculated that abnormal PITX3, which lacks the C-terminus (including the OAR domain) as a result of the nonsense mutation, is expressed in mutant lenses. We showed that the expression of the downstream genes Foxe3, Prox1, and Mip was altered because of the Pitx3 mutation, with large reductions in the lens vesicles in the mutants. Similar profiles were observed by immunohistochemical analysis of these proteins. The expression profiles of crystallins were also altered in the mutants. Therefore, we speculated that the microphthalmos/aphakia in this mutant is caused by the expression of truncated PITX3, resulting in the abnormal expression of downstream targets and lens fiber proteins.


Subject(s)
Aphakia/genetics , Codon, Nonsense , Homeodomain Proteins/metabolism , Lens, Crystalline/metabolism , Microphthalmos/genetics , Transcription Factors/metabolism , Animals , Aphakia/metabolism , Aquaporins/genetics , Aquaporins/metabolism , Crystallins/genetics , Crystallins/metabolism , Eye Proteins/genetics , Eye Proteins/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Homeodomain Proteins/genetics , Lens, Crystalline/growth & development , Mice , Mice, Inbred C57BL , Microphthalmos/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
2.
Acta Ophthalmol ; 89(5): e417-22, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21595861

ABSTRACT

PURPOSE: To compare limbal and pars plana silicone oil removal (SOR) in aphakic eyes and to evaluate the acute effect of silicone oil flow to the corneal endothelium. METHODS: Sixteen aphakic patients with silicone oil endotamponade requiring SOR were recruited for this prospective study and randomly scheduled for limbal or pars plana SOR. The central corneal thickness (CCT), visual acuity (VA) and intraocular pressure were measured preoperatively, on the first postoperative day and 4 months after surgery. Endothelial cell density (ECD) was measured preoperatively and at the end of follow-up. The in vitro study was performed on ten enucleated porcine eyes. Corneoscleral discs were prepared and fixed on artificial anterior chamber followed by 2.5-mm limbal incision and 5-ml silicone oil injection in six cases and 5 ml balanced salt solution (BSS) in four cases. RESULTS: The ECD decreased by 239.2 ± 86.7 (13.9%) and 86.7 ± 22.4 cells/mm(2) (5%) after limbal (n = 8) and pars plana SOR (n = 8), respectively (p < 0.001 for both). The difference between the groups was significant (p < 0.001). A significant increase in CCT and corresponding decrease in VA was noted on the first postoperative day using both procedures. At the end of follow-up, the CCT and VA were comparable to initial values. Postoperative hypotony (≤6 mmHg) was observed more frequently after limbal SOR. In the experiment, lamellar abrasions of corneal endothelium were observed after silicone oil injection, whereas no changes were observed after BSS injection. CONCLUSION: Limbal SOR causes more considerable damage to the corneal endothelium than the pars plana approach because of mechanical abrasion.


Subject(s)
Aphakia/surgery , Endotamponade/adverse effects , Limbus Corneae/surgery , Pars Planitis/surgery , Silicone Oils/adverse effects , Adult , Aged , Animals , Aphakia/metabolism , Cell Count , Endotamponade/methods , Endothelium, Corneal/drug effects , Endothelium, Corneal/metabolism , Endothelium, Corneal/pathology , Female , Humans , Male , Middle Aged , Postoperative Complications/etiology , Postoperative Complications/pathology , Prospective Studies , Silicone Oils/pharmacokinetics , Stress, Mechanical , Swine , Swine, Miniature
3.
Hum Mol Genet ; 20(7): 1315-23, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21233129

ABSTRACT

Aphakia (lack of lens) is a rare human congenital disorder with its genetic etiology largely unknown. Even in model organisms, very few mutations are known to result in such a drastic ocular defect. In this study, we have shown that homozygous deletion of Nf1, the Ras GTPase gene underlying human neurofibromatosis type 1 syndrome, causes lens dysgenesis in mouse. Although early lens specification proceeded normally in Nf1 mutants, lens induction was disrupted due to deficient cell proliferation. Further analysis showed that extracellular signal-regulated kinase (ERK) signaling was initially elevated in the invaginating lens placode, but by the lens vesicle stage, ERK phosphorylation was significantly reduced. Only after intraperitoneal treatment of U0126, an inhibitor of ERK phosphorylation, was lens development restored in Nf1 mutants. Hyperactive Ras-mitogen-activated protein kinase (MAPK) signaling is known to cause neuro-cardiofacial-cutaneous (NCFC) syndromes in humans. As a member of NCFC family genes, Nf1 represents the first example that attenuation of Ras-MAPK kinase signaling pathway is essential for normal lens development.


Subject(s)
Cell Proliferation , Extracellular Signal-Regulated MAP Kinases/metabolism , Eye Proteins/metabolism , Lens, Crystalline/embryology , MAP Kinase Signaling System/physiology , Neurofibromin 1/metabolism , Animals , Aphakia/congenital , Aphakia/genetics , Aphakia/metabolism , Extracellular Signal-Regulated MAP Kinases/genetics , Eye Proteins/genetics , Gene Deletion , Humans , Lens, Crystalline/cytology , Mice , Mice, Mutant Strains , Neurofibromin 1/genetics , Phosphorylation/physiology
4.
Proc Natl Acad Sci U S A ; 108(2): 840-5, 2011 Jan 11.
Article in English | MEDLINE | ID: mdl-21187382

ABSTRACT

Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID.


Subject(s)
Cholinergic Fibers/metabolism , Dyskinesias/metabolism , Gene Expression Regulation , Levodopa/metabolism , Neurons/metabolism , Parkinson Disease/metabolism , Adenosine A2 Receptor Antagonists/chemistry , Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/pharmacology , Animals , Aphakia/metabolism , Choline O-Acetyltransferase/metabolism , Disease Models, Animal , Dopamine/genetics , Homeodomain Proteins/genetics , Mice , Mice, Transgenic , Phosphorylation , Transcription Factors/genetics
5.
Neuroscience ; 166(2): 391-6, 2010 Mar 17.
Article in English | MEDLINE | ID: mdl-20026251

ABSTRACT

The dorsal (A9) and ventral striatum (A10) of the midbrain mediate many of the effects of psychoactive drugs that alter emotion, cognition, and motor activity within the contexts of therapy or abuse. Although transgenic and knockout technologies have enabled development of genetic models to dissect contributions of specific dopamine (DA) receptor subtypes to psychoactive drug effects, few models exist that can distinguish contributions of A9 versus A10 circuits. Pitx3 is a transcription factor enriched in DA neurons. Aphakia (ak) mice deficient in Pitx3 show selective loss of nigrostriatal DA, while other DA pathways are relatively spared, and therefore could be a useful tool for investigating the role of this subclass of DA projections. We investigated the effects of stimulants amphetamine, apomorphine, and MK-801 and the antipsychotic drug haloperidol on behavior in ak mice. Whereas wild-type mice showed the characteristic locomotor hyperactivity in response to amphetamine (5 mg/kg) and apomorphine (4 mg/kg), these drugs caused a paradoxical suppression of locomotor hyperactivity in ak mice. MK-801 (0.2 mg/kg) induced hyperactivity was maintained in both wt and ak mice. Additionally, mutant but not wild-type mice were insensitive to the cataleptic effects of haloperidol (1 mg/kg). These studies indicate that the nigrostriatal DA circuit plays a critical role in maintaining normal responsiveness to psychotropic drugs that either stimulate or block DA neurotransmission. We propose that ak mice may represent a valuable genetic model not only to study Parkinson's disease, but also to dissect the pathophysiologic and pharmacotherapuetic mechanisms of other DA-mediated disorders such as attention-deficit hyperactivity disorder, drug abuse and schizophrenia.


Subject(s)
Behavior, Animal/drug effects , Catalepsy/chemically induced , Corpus Striatum/drug effects , Dopamine/metabolism , Homeodomain Proteins/genetics , Motor Activity/drug effects , Neurons/drug effects , Transcription Factors/genetics , Amphetamine/pharmacology , Analysis of Variance , Animals , Aphakia/genetics , Aphakia/metabolism , Apomorphine/pharmacology , Behavior, Animal/physiology , Catalepsy/genetics , Corpus Striatum/metabolism , Dizocilpine Maleate/pharmacology , Dopamine/genetics , Dopamine Agents/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Mice , Mice, Knockout , Motor Activity/genetics , Neurons/metabolism , Time Factors
6.
Dev Dyn ; 238(9): 2193-201, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19334279

ABSTRACT

The transcription factor Pitx3 is critical for lens formation. Deletions in the promoter of this gene cause abnormal lens development in the aphakia (ak) mouse mutant, which has only rudimentary lenses. In this study, we investigated the role of Pitx3 in lens development and differentiation. We found that reduced expression of Pitx3 leads to changes in the proliferation, differentiation and survival of lens cells. The genetic interactions between Pitx3 and Foxe3 were investigated, as these two transcription factors are expressed at the same time in lens development and their absence has similar consequences for lens development. We found no evidence that these two genes genetically interact. In general, our study shows that the abnormal phenotype of the ak lenses is not due to just one molecular pathway, rather in the absence of Pitx3 expression multiple aspects of lens development are disrupted.


Subject(s)
Homeodomain Proteins/physiology , Lens, Crystalline/embryology , Lens, Crystalline/metabolism , Transcription Factors/physiology , Animals , Aphakia/embryology , Aphakia/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/physiology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Immunohistochemistry , In Situ Hybridization , Mice , Mice, Mutant Strains , Transcription Factors/genetics , Transcription Factors/metabolism
7.
Neurobiol Dis ; 31(3): 406-12, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18573342

ABSTRACT

Disorders of the basal ganglia such as Parkinson's disease (PD) and Huntington's disease are commonly thought of primarily as motor disorders; however, the cognitive symptoms of these diseases such as executive dysfunction, learning, memory and attention deficits are prominent and often more disabling than the hallmark motor symptoms. Cognitive features of PD are often neglected in preclinical studies of PD, likely due to the lack of available animal models to study them. Aphakia mice, which are deficient in the transcription factor Pitx3, model the selective nigrostriatal DA loss in PD. Here we report that aphakia mice are impaired in striatum-dependent cognitive tasks including rotarod learning, T-maze and inhibitory avoidance tasks, but not the striatum-independent social transmission of food preference task. These results suggest that some neuropsychiatric symptoms in PD are related to the pathophysiology of the disease rather than stress associated with disease burden, or medications used to treat PD. Furthermore aphakia mice may be used as a novel model of non-motor symptoms in PD.


Subject(s)
Cognition Disorders/physiopathology , Corpus Striatum/physiopathology , Learning Disabilities/genetics , Memory Disorders/genetics , Parkinson Disease/physiopathology , Transcription Factors/deficiency , Animals , Aphakia/genetics , Aphakia/metabolism , Aphakia/physiopathology , Avoidance Learning/physiology , Cognition Disorders/genetics , Disease Models, Animal , Dopamine/metabolism , Feeding Behavior/physiology , Genetic Predisposition to Disease/genetics , Homeodomain Proteins/genetics , Learning Disabilities/metabolism , Learning Disabilities/physiopathology , Male , Maze Learning/physiology , Memory Disorders/metabolism , Memory Disorders/physiopathology , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Parkinson Disease/complications , Social Behavior , Transcription Factors/genetics
8.
Brain Res ; 1185: 283-92, 2007 Dec 14.
Article in English | MEDLINE | ID: mdl-17949697

ABSTRACT

Like humans with Parkinson's disease (PD), the ak mouse lacks the majority of the substantia nigra pars compacta (SNc) and experiences striatal denervation. The purpose of this study was to test whether motor abnormalities in the ak mouse progress over time, and whether motor function could be associated with temporal alterations in the striatal transcriptome. Ak and wt mice (28 to 180 days old) were tested using paradigms sensitive to nigrostriatal dysfunction. Results were analyzed using a linear mixed model. Ak mice significantly underperformed wt controls in rotarod, balance beam, string test, pole test and cotton shred tests at all ages examined. Motor performance in ak mice remained constant over the first 6 months of life, with the exception of the cotton shred test, in which ak mice exhibited marginal decline in performance. Dorsal striatal semi-quantitative RT-PCR for 19 dopaminergic, cholinergic, glutaminergic and catabolic genes was performed in 1- and 6-month-old groups of ak and wt mice. Preproenkephalin levels in ak mice were elevated in both age groups. Drd1, 3 and 4 levels declined over time, in contrast to increasing Drd2 expression. Additional findings included decreased Chrnalpha6 expression and elevated VGluT1 expression at both time points in ak mice and elevated AchE expression in young ak mice only. Results confirm that motor ability does not decline significantly for the first 6 months of life in ak mice. Their striatal gene expression patterns are consistent with dopaminergic denervation, and change over time, despite relatively unaltered motor performance.


Subject(s)
Aphakia/genetics , Aphakia/metabolism , Corpus Striatum/metabolism , Gene Expression Regulation/genetics , Movement Disorders/genetics , Age Factors , Animals , Behavior, Animal/physiology , Body Weight , Female , Male , Mice , Mice, Transgenic , Movement Disorders/physiopathology , Nerve Tissue Proteins/metabolism , Nesting Behavior/physiology , Psychomotor Performance/physiology , Rotarod Performance Test
9.
Development ; 134(8): 1455-63, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17344231

ABSTRACT

The recent identification of a mutation in Foxe3 that causes congenital primary aphakia in humans marks an important milestone. Congenital primary aphakia is a rare developmental disease in which the lens does not form. Previously, Foxe3 had been shown to play a crucial role in vertebrate lens formation and this gene is one of the earliest integrators of several signaling pathways that cooperate to form a lens. In this review, we highlight recent advances that have led to a better understanding of the developmental processes and gene regulatory networks involved in lens development and disease.


Subject(s)
Eye Diseases, Hereditary/genetics , Forkhead Transcription Factors/physiology , Lens, Crystalline/embryology , Animals , Aphakia/congenital , Aphakia/genetics , Aphakia/metabolism , Eye Diseases, Hereditary/metabolism , Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/genetics , Gene Expression Regulation, Developmental , Humans , Lens, Crystalline/metabolism , Mutation , Xenopus Proteins/biosynthesis , Xenopus Proteins/genetics
10.
Mol Vis ; 11: 36-49, 2005 Jan 13.
Article in English | MEDLINE | ID: mdl-15660023

ABSTRACT

PURPOSE: We hypothesize that remodeling of the scleral extracellular matrix, involving collagen and proteoglycan synthesis and turnover, is a key process involved in ocular growth. Decreased axial elongation is observed following neonatal removal of the crystalline lens in a rhesus monkey model of congenital cataract. We wanted to determine changes in gene expression in the operated and companion eye following lensectomy, especially for extracellular matrix in the sclera. METHODS: Between 4 and 7 days of age, infant monkeys underwent surgical removal of the lens from the right eye. Axial lengths of the operated and unmanipulated fellow eyes were measured and when interocular differences of >0.4 mm were achieved, monkeys were sacrificed and RNA was isolated from sclera. In order to determine changes in scleral gene expression in aphakic versus control eyes, we used Clontech's Atlas Gene Array (Human Cancer Array version 1.2) hybridized with total RNA from three monkeys. RESULTS: Atlas Gene Array analysis demonstrated differential expression of several genes in the operated versus the unmanipulated eye. Most notably, there was a statistically significant increase in expression of several extracellular matrix (ECM) genes including: aggrecan, decorin, biglycan, several collagens, and tenascin in the RNA from the sclera of the aphakic eyes when compared to the unmanipulated eyes. Genes for several matrix metalloproteinases (MMPs) showed no significant change following lens removal although there was a trend towards decreased expression. There were also statistically significant changes in the pattern of gene expression in the operated eye relative to the unmanipulated eye for cell adhesion, cell cycle, apoptosis, and cytoskeleton transcripts. CONCLUSIONS: Our results suggest that removal of the crystalline lens alters gene expression in the sclera with a prominent upregulation of ECM transcripts. These data support recent evidence that remodeling of the ECM composition of the sclera may be an important regulator of ocular growth.


Subject(s)
Aphakia/metabolism , Eye Proteins/genetics , Eye/growth & development , Gene Expression Regulation , Sclera/metabolism , Animals , Animals, Newborn , Extracellular Matrix/physiology , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Eye Proteins/metabolism , Gene Expression Profiling , Lens, Crystalline/surgery , Macaca mulatta , Oligonucleotide Array Sequence Analysis , RNA/isolation & purification , RNA, Messenger/metabolism , Up-Regulation
11.
Arch Ophthalmol ; 116(6): 781-4, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9639448

ABSTRACT

OBJECTIVE: To determine the effect of age on the retardation of axial elongation in neonatal monkey eyes following the extraction of the crystalline lens. METHODS: A monocular lensectomy was performed on 4 rhesus monkeys when they were 4 days, 2 weeks, 7.5 months, and 1 year of age. Longitudinal measurements of axial lengths and keratometry readings were made. RESULTS: The aphakic eye was 1.7 mm shorter than the unmanipulated fellow eye in the monkey undergoing surgery at 4 days of age and 1.1 mm shorter in the monkey undergoing surgery at 2 weeks of age. However, the aphakic eyes were only 0.2 mm and 0.1 mm shorter than their unmanipulated fellow eyes, respectively, in the monkeys undergoing surgery at 7.5 months and 1 year of age. CONCLUSIONS: The retardation of axial elongation following a lensectomy in infantile monkey eyes is age dependent. Little effect is observed in monkeys aged 7.5 months or older.


Subject(s)
Aging/physiology , Eye/growth & development , Lens, Crystalline/surgery , Animals , Aphakia/etiology , Aphakia/metabolism , Eye/anatomy & histology , Lenses, Intraocular , Macaca mulatta , Myopia/prevention & control
12.
Graefes Arch Clin Exp Ophthalmol ; 236(4): 305-11, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9561366

ABSTRACT

BACKGROUND: Transforming growth factor-beta 2 (TGF-beta 2) is a pluripotent cytokine which has been suggested to play a number of roles in ocular physiologic and pathologic states. Intraocular fluid (i.o.f.) levels of TGF-beta 2 are quite high. Although the sources of ocular TGF-beta are not completely defined, the retinal pigment epithelium, the epithelium of the ciliary body and trabecular meshwork cells all secrete it. In this study we utilized canine lens and rabbit ciliary pigmented epithelial cell cultures to quantitate the in vitro secretion of TGF-beta 2. In addition, the effects of aphakia or the presence of cataractous lenses on IOF TGF-beta 2 levels were determined. METHODS: Lens and ciliary body epithelial cell culture supernatants and aqueous humors were assayed for total TGF-beta 2 levels by ELISA and bioassay. RESULTS: TGF-beta 2 accumulated in the media bathing lens epithelial cell cultures (0.7 +/- 0.03 ng/ml at day 2) and ciliary pigmented epithelial cell cultures (0.8 +/- 0.06 ng/ml at day 2) in a time-dependent manner. Surprisingly, aqueous humor from aphakic rabbit eyes contained significantly higher levels of TGF-beta 2 than their contralateral phakic controls. Furthermore, aqueous humor from canine eyes with cataracts also contained significantly higher levels of TGF-beta 2 than normal eyes. CONCLUSIONS: These results suggest that the lens secretes TGF-beta 2 and that the presence and status of the lens may influence IOF TGF-beta 2 levels.


Subject(s)
Aqueous Humor/metabolism , Lens, Crystalline/metabolism , Transforming Growth Factor beta/metabolism , Animals , Aphakia/etiology , Aphakia/metabolism , Aphakia/pathology , Biological Assay , Cataract/etiology , Cataract/metabolism , Cataract/pathology , Cells, Cultured , Ciliary Body/cytology , Ciliary Body/metabolism , Disease Models, Animal , Dogs , Enzyme-Linked Immunosorbent Assay , Female , Lens, Crystalline/cytology , Male , Pigment Epithelium of Eye/cytology , Pigment Epithelium of Eye/metabolism , Rabbits
13.
J Ocul Pharmacol Ther ; 13(5): 445-59, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9326726

ABSTRACT

The majority of eyes that receive drug therapy exhibit some form of pathophysiological degradation. Two common pathophysiological states are retinal inflammation, which results in breakdown of the blood-retinal barrier, and aphakia. The purpose of this study was to examine the effects of aphakia and changes in retinal permeability and vitreous diffusivity on drug distribution in the vitreous humor of the human eye. The study was performed using a finite element model that accurately accounts for the vitreous geometry and boundary conditions. Intravitreal injection is the most common method for treating posterior segment disorders; therefore, this administration method was simulated using the models. Elimination from aphakic and phakic eyes was compared for four extreme injection locations and for two retinal permeabilities. When the retinal permeability was fixed at 5.0 x 10(-5) cm/s, increasing the drug diffusivity through the vitreous from 5.4 to 10(-7) to 2.4 x 10(-5) cm2/s decreased the half-life of drug from 64 hours to 2.7 hours. When the drug diffusivity was fixed at 5.6 x 10(-6) cm2/s, increasing the retinal permeability of the drug from 1.0 x 10(-7) to 1.0 x 10(-4) cm/s decreased the half-life of drug from 44 to 7 hours. Therefore, drug diffusivity and retinal permeability are key factors that influence elimination from the vitreous, and must be considered, particularly if the blood retinal barrier has been compromised. Faster drug elimination was observed in aphakic eyes than in phakic eyes, especially for drugs with a low retinal permeability and injected close to the lens capsule. Injection position is also important if the drug is injected in close proximity to a primary elimination barrier.


Subject(s)
Aphakia/metabolism , Vitreous Body/metabolism , Capillary Permeability/physiology , Computer Simulation , Diffusion , Half-Life , Humans , Injections
14.
Acta Ophthalmol Scand ; 75(5): 516-9, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9469547

ABSTRACT

PURPOSE: To search for changes in the presence and distribution of the cell-adhesion-related HNK-1 carbohydrate epitope after cataract extraction. METHODS: Twenty-five pseudophakic and two aphakic human autopsy eyes and, for comparison, one anterior subcapsular cataract obtained at surgery were studied with monoclonal antibodies (MAbs) HNK-1 and NC-1 to the HNK-1 epitope using the avidin-biotinylated peroxidase complex method. RESULTS: MAbs to the HNK-1 epitope constantly immunolabelled the inner connective tissue layer of the ciliary body in all pseudophakic and aphakic eyes studied. The distribution of the immunoreaction was similar to that reported for normal eyes. They also labelled the extracellular matrix in each of 18 plaques of secondary cataract on the posterior capsule, in each of 13 plaques at the rim of the capsular bag, and in the anterior subcapsular cataract. Bladder cells in each of 16 Soemmering's rings remained unlabelled. CONCLUSION: The distribution of the HNK-1 epitope in the ciliary body does not appreciably change after cataract extraction, although the accommodative demand of the eye is altered. Its presence in an anterior subcapsular cataract suggests that the epitope may be locally produced by lens epithelial cells also in secondary cataract. The epitope is associated with cell adhesion and migration, both of which may play a role in the pathogenesis of secondary cataract.


Subject(s)
Aphakia/metabolism , CD57 Antigens/metabolism , Cataract/metabolism , Epitopes/metabolism , Lens Capsule, Crystalline/metabolism , Pseudophakia/metabolism , Aged , Aged, 80 and over , Antibodies, Monoclonal , Aphakia/pathology , Cataract/etiology , Ciliary Body/metabolism , Ciliary Body/pathology , Connective Tissue/metabolism , Connective Tissue/pathology , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Female , Humans , Immunoenzyme Techniques , Lens Capsule, Crystalline/pathology , Male , Middle Aged , Pseudophakia/pathology
15.
Am J Ophthalmol ; 122(5): 684-9, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8909208

ABSTRACT

PURPOSE: To determine the penetration of gentamicin and amikacin into the rabbit vitreous cavity after their intravenous administration. METHODS: Gentamicin (1.6 mg/kg every 8 hours) and amikacin (6 mg/kg every 12 hours) were administered intravenously to 25 rabbits that had previously had the lens and vitreous removed from 43 eyes. For each drug, ocular inflammation was induced in one group of eyes by injection of heat-killed Staphylococcus epidermidis, while the other group was maintained as a control. Samples from the vitreous cavity were taken at regular intervals for 72 hours after beginning the intravenous medications and were analyzed for drug concentrations. RESULTS: The maximum intravitreal concentration +/- SD achieved for gentamicin was 1.8 +/- 0.5 microgram/ml. The maximum intravitreal concentration for amikacin was 8.5 +/- 3.2 micrograms/ml. Inflamed eyes demonstrated higher concentrations than did those without inflammation. CONCLUSIONS: In a rabbit model with conditions optimized to enhance penetration of antimicrobials into the vitreous cavity after intravenous administration, neither gentamicin nor amikacin penetrated sufficiently to reach potentially therapeutic concentrations consistently for either Pseudomonas or S epidermidis organisms.


Subject(s)
Amikacin/pharmacokinetics , Anti-Bacterial Agents/pharmacokinetics , Gentamicins/pharmacokinetics , Vitreous Body/metabolism , Amikacin/administration & dosage , Animals , Anti-Bacterial Agents/administration & dosage , Aphakia/metabolism , Biological Availability , Eye Infections, Bacterial/etiology , Eye Infections, Bacterial/metabolism , Gentamicins/administration & dosage , Injections, Intravenous , Lens, Crystalline/surgery , Rabbits , Staphylococcal Infections/etiology , Staphylococcal Infections/metabolism , Staphylococcus epidermidis , Uveitis/metabolism , Uveitis/microbiology , Vitrectomy
16.
Am J Ophthalmol ; 115(6): 770-4, 1993 Jun 15.
Article in English | MEDLINE | ID: mdl-8506912

ABSTRACT

Intraocular injection of amikacin is increasingly used in the treatment of endophthalmitis. We injected 400 micrograms of amikacin into the vitreous cavity of rabbit eyes to study its pharmacokinetics. Phakic, aphakic, and aphakic vitrectomized eyes were injected, and inflamed eyes were compared to control eyes. Vitreous concentrations were determined at two, eight, 24, and 48 hours, and clearance rates were calculated. Amikacin is cleared considerably more quickly from aphakic (half-life, 14.3 hours) than phakic control eyes (half-life, 25.5 hours) and even more quickly from aphakic vitrectomized eyes (half-life, 7.0 hours). Inflammation substantially increased the rate of clearance in aphakic eyes. In inflamed aphakic and aphakic vitrectomized eyes, vitreous drug levels were equal to or below the minimal inhibitory concentration for most organisms considered sensitive to amikacin at 24 hours. Supplementation of intraocular antibiotics may therefore be required in clinical settings.


Subject(s)
Amikacin/pharmacokinetics , Aphakia/metabolism , Endophthalmitis/metabolism , Vitrectomy , Vitreous Body/metabolism , Animals , Disease Models, Animal , Half-Life , Injections , Lens, Crystalline/metabolism , Rabbits
17.
Nippon Ganka Gakkai Zasshi ; 96(1): 67-73, 1992 Jan.
Article in Japanese | MEDLINE | ID: mdl-1553876

ABSTRACT

The amounts of interleukin-1 beta (IL-1 beta) (by enzyme linked immunosorbent assay (ELISA) using anti-rabbit recombinant IL-1 beta (rIL-1 beta) antibody) and total protein content (by Bradford's method) were assayed in the aphakic and pseudophakic aqueous humor in 24 eyes of 16 rabbits. Posterior chamber intraocular lenses were examined scanning electron microscopically and immunohistochemically. The amount of detected IL-1 beta was 10.79 +/- 4.67 ng/ml (mean +/- SD) in the pseudophakic eyes 3 days postoperatively, 10.12 +/- 3.96 ng/ml in the pseudophakic eyes and 3.94 +/- 0.86 ng/ml in the aphakic eyes 7 days postoperatively. A significantly higher amounts (p less than 0.001) of IL-1 beta were detected in the pseudophakic eyes compared with the aphakic eyes at 7 days postoperatively. The amount of IL-1 beta varied in each rabbit 1 month postoperatively. In total protein content in the aqueous humor, pseudophakic eyes showed significantly higher compared with the aphakic eyes at 7 days (pseudophakic eyes: 29.7 +/- 11.7 mg/ml, aphakic eyes: 8.58 +/- 6.90 mg/ml, p less than 0.05) and 1 month (pseudophakic eyes: 8.30 +/- 1.21 mg/ml, aphakic eyes: 2.10 +/- 0.309 mg/ml, p less than 0.001) postoperative. Scanning electron microscopic study showed that small round cells, spindle-shaped cells and giant cells could be observed on the surface of intraocular lenses. All of these types of cells showed positive staining of IL-1 beta immunohistochemically. These results suggest that IL-1 beta might be an inflammatory mediator in eyes with lens extraction, especially pseudophakic eyes.


Subject(s)
Aphakia/metabolism , Aqueous Humor/metabolism , Interleukin-1/metabolism , Lenses, Intraocular , Peptide Fragments/metabolism , Animals , Enzyme-Linked Immunosorbent Assay , Eye Proteins/metabolism , Interleukin-1beta , Rabbits
18.
Ophthalmic Res ; 24(3): 150-4, 1992.
Article in English | MEDLINE | ID: mdl-1407956

ABSTRACT

The concentration of ceftazidime was determined in the aqueous humor and the vitreous body of normal, vitrectomized and aphakic/vitrectomized eyes and in the serum of albino rabbits 1 h after intravenous injection of 100 mg/kg ceftazidime. The intravitreal ceftazidime concentration was low (0.1-0.2 microgram/ml) in normal eyes 1 h after intravenous injection, and high (8.7 +/- 8.5 micrograms/ml) in vitrectomized and aphakic/vitrectomized eyes when injected immediately after surgery. The ceftazidime concentration was also determined in the aqueous humor and the vitreous body of normal eyes and in the serum of albino rabbits 3, 6, 12, 24 and 48 h after intravitreal injection of 200 micrograms. The intravitreal ceftazidime concentration after intravitreal injection decreased exponentially for 12 h (half-life about 7.4 h). It decreased more slowly thereafter and remained at 13.0 micrograms/ml (mean) even 48 h after injection. This concentration exceeded the minimum inhibitory concentrations against common gram-positive and gram-negative organisms causing endophthalmitis.


Subject(s)
Aqueous Humor/metabolism , Ceftazidime/pharmacokinetics , Vitreous Body/metabolism , Animals , Aphakia/metabolism , Ceftazidime/administration & dosage , Injections, Intravenous , Rabbits , Vitrectomy
19.
Acta Ophthalmol (Copenh) ; 69(1): 45-9, 1991 Feb.
Article in English | MEDLINE | ID: mdl-2028767

ABSTRACT

Fifty mcg of gentamicin was combined with saline or with 0.8% sodium hyaluronate and injected into the vitreous cavity of rabbit eyes with moderate to severe Staphylococcus aureus endophthalmitis. Endophthalmitis was controlled in 9 of 10 eyes. There was no evidence of toxicity with either treatment regimen. Although the clearance study demonstrated statistical differences at all time points studied, the half-lives of both treatment regimens were similar (3.3 h for aqueous gentamicin and 3.6 h for sodium hyaluronate/gentamicin). These results suggest that the vitreous played a role in keeping the aqueous gentamicin in the eye for a longer time, as similar half-lives were shown with both types of treatment. Thus, if a vitrectomy has to be done for the treatment of endophthalmitis, as much as possible of the vitreous should be left in situ to maintain the drug for longer periods in the eye. Also, if it is necessary to remove all vitreous during vitrectomy, it may be more effective to administer the drug with sodium hyaluronate so as to prolong its action inside the eye.


Subject(s)
Endophthalmitis/drug therapy , Gentamicins/administration & dosage , Animals , Aphakia/metabolism , Drug Carriers , Gentamicins/pharmacokinetics , Gentamicins/toxicity , Hyaluronic Acid , Rabbits , Retina/drug effects , Staphylococcus aureus/drug effects , Vitrectomy , Vitreous Body/drug effects , Vitreous Body/metabolism
20.
Cornea ; 9(3): 249-53, 1990 Jul.
Article in English | MEDLINE | ID: mdl-2373019

ABSTRACT

Intraocular lens (IOL) insertion is now the standard method of aphakic correction in this country. Previous studies have shown that an IOL can activate the alternative complement system of normal human serum in vitro, thereby generating peptides capable of stimulating inflammation that can result in visual morbidity in pseudophakic eyes. The objective of the present study was to determine if human aqueous humor (AH) levels of total protein, total C3, and C3a cleavage products (activated C3) are influenced by an IOL in pseudophakic eyes as compared with phakic and aphakic eyes. AH from five diagnostic categories was examined: cataract, posterior capsulotomy-IOL, Fuchs' endothelial dystrophy with corneal edema, aphakic bullous keratopathy, and pseudophakic bullous keratopathy. The results of this study do not support the hypothesis that IOLs affect AH protein and complement levels. Statistically, there was no significant difference in AH protein levels when pseudophakic eyes were compared with phakic and aphakic eyes. No significant difference in C3a levels was demonstrated between pseudophakic and phakic eyes, whereas aphakic eyes had significant higher levels than those with pseudophakia. There were significantly greater levels of protein, C3, and C3a in eyes with edematous corneas versus those with clear corneas. Although these studies are difficult to interpret, AH levels of these substances appear to be more related to dysfunctional corneal endothelium and corneal edema than to the presence of an IOL.


Subject(s)
Aqueous Humor/metabolism , Complement C3/metabolism , Complement C3a/metabolism , Eye Proteins/metabolism , Lenses, Intraocular , Aphakia/metabolism , Aphakia/surgery , Aphakia, Postcataract/metabolism , Aphakia, Postcataract/surgery , Cataract Extraction , Corneal Diseases/metabolism , Corneal Diseases/surgery , Humans , Immunoelectrophoresis , Radioimmunoassay
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