Pinguecula and contact lenses.

PURPOSE: To assess the relationship between age and the incidence and severity (determined by a grading system) of pinguecula in contact lens (CL) wearers, and to compare the grade of pinguecula between CL wearers and non-wearers. METHODS: A total of 600 CL wearers (94 wore hard CLs (HCLs) and 506 wore soft CLs (SCLs)) aged 11-60 years and 579 non-wearers aged 10-60 years were enrolled. The age, gender, medical history, ocular history, and grade of pinguecula at two locations (nasal and temporal) were determined in all subjects. RESULTS: There was an age-related increase in the grade of pinguecula among both CL wearers and non-wearers. The grade of pinguecula at the temporal conjunctiva was higher in CL wearers than in non-wearers (P=0.01907), whereas it was higher in HCL wearers than SCL wearers at both the nasal and temporal conjunctiva (P<0.00001 and P<0.00001). CONCLUSIONS: This was the first assessment of the severity of pinguecula in a large consecutive series of CL wearers. Our results suggest that the use of CLs is an important risk factor for pinguecula.

Relationship between refraction and allergic conjunctivitis.

PURPOSE: External allergens are the main causative factor in the pathogenesis of allergic diseases; however, little is known about internal factors such as the biometrical structure of the eye. We investigated the relationship between refractive error and allergic conjunctivitis in order to reveal possible insights into the pathogenesis in 1015 subjects. METHODS: The patients were divided into four groups: contact lens wearers with allergic conjunctivitis (n=73), contact lens wearers without allergic conjunctivitis (n=59), non-contact lens wearers with allergic conjunctivitis (n=224), and non-contact lens wearers without allergic conjunctivitis (n=659). The spherical power, cylindrical power, corneal radius, and minimum and maximum corneal refractive powers were measured in all subjects. RESULTS: In the non-contact lens wearers, the spherical equivalent and spherical power were significantly lower in patients with allergic conjunctivitis than in patients without allergic conjunctivitis (-3.01+/-3.83 D vs-1.36+/-3.08 D, P<0.0001, and -2.64+/-3.63 D vs-1.05+/-2.88 D, P<0.0001, respectively), while there was no significant difference in any of the parameters between the contact lens wearers with and without allergic conjunctivitis. CONCLUSION: Refractive error may be a risk factor for allergic conjunctivitis.

Longitudinal analysis of corneal topography in suspected keratoconus.

AIMS: To examine the incidence of progression of suspected keratoconus to true keratoconus and compare quantitative descriptors of corneal topography between eyes with and without progression. METHODS: 34 eyes with suspected keratoconus were retrospectively reviewed in 34 patients. Their age at the initial examination was 13 to 40 years (24.1 (7.5), mean (SD)), and the follow-up periods ranged from 3 to 10 years (6.0 (2.2) years). Suspected keratoconus was defined as the fellow eye of a clinically apparent keratoconus but that had no slit-lamp signs of keratoconus (Fleischer ring, Vogt striae and Munson sign) with a best spectacle-corrected visual acuity of 20/20 or better. Eyes were monitored for the progression of apparent slit-lamp findings of keratoconus during the follow-up period. Using a Fourier analysis of the corneal topography data, regular astigmatism, asymmetry component and higher-order irregularity component were calculated in the central 3 mm zone. Quantitative descriptors of corneal topography were compared between eyes which progressed to true keratoconus and those which did not. RESULTS: Five eyes (14.7%) progressed to apparent keratoconus from suspected keratoconus (progression group), and 29 eyes did not (non-progression group). On average, it took 5.2 years for the eyes to develop apparent slit-lamp findings of keratoconus. The cumulative incidence of progression by Kaplan-Meier analysis was 21.5% in 6 years. The asymmetry component and regular astigmatism by Fourier analysis at the initial examination were significantly larger in the progression group than in the non-progression group. CONCLUSION: In our retrospective study, approximately 20% of eyes with suspected keratoconus progressed to true keratoconus in 6 years, and these eyes had presented greater asymmetry and regular astigmatism at the initial examination.

Penetrating keratoplasty for bullous keratopathy after trabeculectomy.

PURPOSE: To evaluate the results of penetrating keratoplasty (PK) in eyes with bullous keratopathy having previously undergone trabeculectomy. METHODS: We reviewed medical records of patients that had undergone PK for bullous keratopathy having previously undergone trabeculectomy. A total of 34 eyes in 34 patients were included in the study. As a control group, we reviewed the medical records of 26 eyes in 26 patients that had no history of glaucoma and who had undergone PK for bullous keratopathy in the same period at the same institutes. Kaplan-Meier survival analysis was performed to estimate the cumulative probability of successful intraocular pressure (IOP) control, immune reaction-free graft, and graft survival. RESULTS: Visual acuity improved by more than two lines in 30-34 eyes (88%). Log-rank tests showed a statistically significant difference in the cumulative probability of successful IOP control between eyes with functioning blebs and eyes with non-functioning blebs (P=0.0005), but not between the experimental subjects of 34 eyes and the control group (P=0.198). The log-rank test did not show statistically significant differences in the cumulative probability of immune reaction-free grafts and graft failure between the subjects and the control group and between eyes with functioning blebs and eyes with non-functioning blebs. CONCLUSION: The outcomes for PK in bullous keratopathy are good for patients having previously undergone trabeculectomy. Surgical procedures should be performed before PK in eyes with non-functioning blebs even when IOP is controllable with medication.

A randomised, placebo controlled clinical trial of the aldose reductase inhibitor CT-112 as management of corneal epithelial disorders in diabetic patients.

AIM: To evaluate the efficacy of topical aldose reductase inhibitor CT-112 (5-[3-ethoxy-4-pentyloxyphenyl]-2,4-thiazolidinedione) on corneal epithelial barrier function in diabetic patients. METHODS: This was a prospective, randomised, double masked placebo controlled study. 34 eyes of 34 diabetic patients were randomly assigned treatment with 0.25% eye drops of CT-112 (n = 22) or a placebo (n = 12) four times a day for 8 weeks. Corneal fluorescein staining and corneal sensation were examined before treatment as well as 4 and 8 weeks after administration. Corneal epithelial permeability to fluorescence was measured with an anterior fluorophotometer. RESULTS: Average scores of superficial punctate keratopathy and corneal sensitivity did not differ significantly between the two groups at any time. Whereas average fluorescein concentrations did not differ significantly for the CT-112 and placebo groups before treatment, they did differ significantly 4 and 8 weeks after treatment (4 weeks, p = 0.0327; 8 weeks, p = 0.0143). CONCLUSION: The topical aldose reductase inhibitor, CT-112 improves the corneal epithelial barrier function in diabetic patients.

Allergens in Japanese patients with allergic conjunctivitis in autumn.

PURPOSE: The purpose of the current study is to evaluate the relation between various specific class E immunoglobulins (IgE) in the serum and allergic conjunctivitis in autumn. METHODS: Total IgE and specific IgE to 12 inhalant allergens were measured using the CAP system in 32 patients with allergic conjunctivitis in spring (spring group), 27 patients with allergic conjunctivitis in autumn (autumn group), and 40 healthy volunteers (control group). RESULTS: Specific IgE levels caused by house dust, Dermatophagoides pteronyssinus, and orchard grass were higher in the autumn group than in the spring group. The highest positivity rate for a specific allergen was 51.9% for house dust, followed by D. pteronyssinus(48.1%) in the autumn group, while the highest rate was 68.8 % for cedar pollen, followed by cypress pollen (59.4%) in the spring group. Correlation analysis showed that house dust was significantly correlated with animal epithelia, D. pteronyssinus, acarus, and Alternaria tenuis in the autumn group (P<0.001). CONCLUSIONS: These results suggest that house dust is the main cause of allergic conjunctivitis during autumn. In spring, cypress pollen is the largest cause of allergic conjunctivitis, while indoor allergens such as house dust, animal epithelia, D. pteronyssinus, and acarus are not causative allergens in Japan.

1-Azaadamantanes: pharmacological applications and synthetic approaches.

1-Azaadamantane (1-azatricyclo [3.3.1.1(3,7)]decane) was synthesized in 1953, and the derivatives have been used as rigid models for studies on intramolecular charge transfer phenomena, fluorescence excitation Rydberg states, highly twisted amides, solid electrolyte gas sensors, basicities, and self-organization systems. These structures have also been attracting considerable interest due to their pharmacological activities. The substituted 1-azaadamantanes as conformationally restricted amines have great potential for the therapeutic utilization as anticholinergic agents, serotonergic agents, and squalene synthase inhibitors. However, many steps have been needed for the synthesis of 1-azaadamantanes, and the concise synthetic approaches have been developed. Though double or triple Mannich reactions yield 1-azaadamantanes in moderate yields, the reduction steps are necessary. Our recent research has revealed that trifluoromethanesulfonic anhydride is available for the convenient synthesis of 1-azoniaadamantanes and 1-azaadamantanes without reduction. The new tools for the discovery of novel drugs such as quantitative structure-activity relationship (QSAR) analysis and vibrational circular dichroism (VCD) spectroscopy have also been discussed.

Downward extension of the lacrimal gland under the bulbar conjunctiva after trabeculectomy.

PURPOSE: To describe two cases in which the lacrimal gland was considered to extend downward under the bulbar conjuctiva following trabeculectomy. PATIENTS AND METHODS: We report two patients who complained of epiphora after trabeculectomy. A biopsy was performed on the tissue under the bulbar conjunctiva on the periphery of the bleb of case 1. The anatomical relationship between the holes and the avascular filtering bleb in case 2 was investigated using ultrasound biomicroscopy. RESULTS: In case 1, a biopsy showed the lacrimal gland tissue filtrated with mononuclear cells. In case 2, ultrasound biomicroscopy revealed no connection between the multiple leaking holes and localized filtering bleb. CONCLUSION: Following trabeculectomy at the superior temporal quadrant, we should consider downward extension of the lacrimal gland as a possible source of a patient's complaint of epiphora.

Efficacy of postinfection treatment with anti-Shiga toxin (Stx) 2 humanized monoclonal antibody TMA-15 in mice lethally challenged with Stx-producing Escherichia coli.

Infection with Shiga toxin (Stx)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome. TMA-15 is a humanized monoclonal antibody against Stx2, a major pathogenic factor. In a mouse infection model that used B2F1, a virulent STEC strain, the efficacy of TMA-15 was assessed when it was administered after bacterial and toxin exposure. In this model, a time-course analysis of the serum Stx2 level showed that the toxin was detectable from 24 h after infection. In an evaluation of the time-dependent efficacy, treatment with TMA-15 up to 24 h after infection ameliorated the lethal challenge, although treatment at 48 h showed no efficacy. To determine the effective dose, escalating doses were administered at 24 h after infection. The number of mice that survived after doses of 0, 0.25, 0.5, 1.0, and 2.0 mg/kg were 0/20, 11/20, 17/20, 20/20, and 20/20, respectively. These findings suggest that TMA-15 shows potential for prevention of severe complications associated with STEC infection.

Expression and exon/intron organization of two medaka fish homologs of the mammalian guanylyl cyclase A.

Two cDNA clones (OlGC2 and OlGC7) and their genomic DNA clones encoding medaka fish homologs of mammalian natriuretic peptide receptor/membrane guanylyl cyclase A (GC-A) were isolated, and their complete nucleotide sequences were determined. The open reading frame predicts a protein of 1,063 amino acids for OlGC2 cDNA (4,283 bp), and one of 1,055 amino acids for OlGC7 cDNA (3,721 bp), respectively. Northern blot analyses demonstrated 4.7 kb OlGC2 transcripts in the kidney and gill, and 4.0 kb OlGC7 transcripts in the kidney, brain, and ovary, while RNase protection analyses revealed that both genes are expressed in various adult organs. Both the OlGC2 (about 33.0 kbp) and OlGC7 (about 44.3 kbp) genes consist of 22 exons with an exon/intron organization similar to those of the human GC-A gene (about 16.6 kbp) and medaka fish GC-B homolog gene (OlGC1, about 93 kbp). Intron 4 of OlGC2 contains two repeated sequence (RS) clusters, designated as RS1 (about 1 kbp) and RS2 (about 5 kbp), consisting of nucleotide 5'-AGCCTCTGCTCCTCCTTC-3'. In addition, many identical but variably sized nucleotide sequences were found in introns in OlGC1, OlGC2, OlGC6, and OlGC7. The OlGC2 and OlGC7 genes both have no apparent TATA box in the 5' flanking region upstream of the putative transcription initiation point, but several consensus sequences for cis-regulatory elements, including C/EBP, CREB, NF-IL6, and Sp1 and AP-2, NF-IL6, c-Myb, and Sp1 are present in the 5'-flanking region of OlGC2 and OlGC7, respectively.

Isolation and characterization of acetoacetyl-CoA thiolase gene essential for n-decane assimilation in yeast Yarrowia lipolytica.

Yarrowia lipolytica is a yeast which can utilize n-alkane as a sole carbon source. We isolated a Y. lipolytica peroxisomal acetoacetyl-CoA thiolase gene, PAT1, by complementation of a mutant that cannot utilize n-decane as a sole carbon source. We found that the putative PAT1 product had conserved features of peroxisomal acetoacetyl-CoA thiolase. We showed that the PAT1 disruptant was not able to grow on n-decane, and that n-decane-inducible acetoacetyl-CoA thiolase activity largely depended on PAT1. The original mutant carried a mutation involving the replacement of Gly382 with Glu. This mutation inactivated the ability of PAT1 to complement the defective n-decane utilization of the disruptant. These results indicate that PAT1 encodes peroxisomal acetoacetyl-CoA thiolase and is essential for n-decane utilization in Y. lipolytica.

The critical role of lymph nodes in corneal alloimmunization and graft rejection.

PURPOSE: To elucidate the role of draining cervical lymph nodes (CLNs) in corneal alloimmunity. METHODS: Fully mismatched orthotopic corneal transplantation was performed in BALB/c hosts that had their CLNs excised before transplantation (CLN(-)). Normal hosts (CLN(+)), splenectomized mice (Sp(-)), and those without either CLNs or spleen (CLN(-)/Sp(-)) served as comparison groups. To determine the contribution of CLNs to alloimmunity more directly, CLN(-) mice were reconstituted by grafting LNs from other BALB/c mice to their cervical lymphatic chains, thus deriving CLN(-/+) mice. Tetramethyl rhodamine isothiocyanate's (TRITC) flow to draining CLNs was used as a measure of afferent lymph flow. Graft survival and allospecific delayed-type hypersensitivity (DTH) were used as measures of alloreactivity. RESULTS: Fifty percent of normal control and 12% of Sp(-) hosts accepted the allografts. In contrast, 100% of CLN(-) and 88% of CLN(-)/Sp(-) hosts accepted allografts indefinitely (P < 0.01). Additionally, all CLN(-) hosts failed to demonstrate allospecific DTH (P < 0.001). CLN(-/+) mice reconstituted with LN from naïve animals showed graft survival rates and DTH responses that were indistinguishable from those of naïve CLN(+) mice. Of particular interest, however, is that mice reconstituted with CLNs from hosts with rejected corneal grafts had swift rejection of subsequent corneal grafts and exhibited strong donor-specific DTH. In contrast, mice reconstituted with CLNs from hosts with accepted corneal grafts showed rejection of subsequent corneal grafts in a manner that was indistinguishable from rejection in naïve CLN(+) hosts. CONCLUSIONS: Draining CLNs play a critical role in allosensitization and rejection. In contrast to the spleen, draining CLNs do not appear to play a critical role in tolerance induction in corneal transplantation.

Recurrence of myocarditis presenting as pacing and sensing failure after implantation of a permanent pacemaker at first onset.

A 31-year-old woman was admitted to hospital with loss of consciousness and generalized convulsions. Electrocardiography (ECG) showed complete atrioventricular block (AV block) with a pulse rate of 30 beats/min. Endomyocardial biopsy from the right ventricle showed massive necrosis and degeneration of myocardial cells with extensive infiltration of lymphocytes into the interstitial space. These pathological findings suggested fulminant myocarditis. Following glucocorticoid therapy, the patient became asymptomatic, but the AV block did not resolve completely and a bifocal pacemaker was implanted. However, similar symptoms recurred 7 years later. An ECG showed pacing and sensing failure linked to an increase in the pacing threshold and a decrease in the sensing threshold. Endomyocardial biopsy from the right ventricle again showed interstitial infiltration with lymphocytes and eosinophils. After glucocorticoid therapy, she became asymptomatic once more, and the improvement in the pacing and sensing failure, and cardiomegaly, was satisfactory. This patient represents a very rare case of recurrence of acute myocarditis without progression, as much as 7 years after its first occurrence. Glucocorticoid therapy was still effective in treating the recurrent myocarditis presenting with pacing and sensing failure.

Topical soluble tumor necrosis factor receptor type I suppresses ocular chemokine gene expression and rejection of allogeneic corneal transplants.

OBJECTIVE: To determine the effect of topical soluble tumor necrosis factor receptor type I (sTNFR-I) on survival of murine orthotopic corneal transplants and on ocular chemokine gene expression after corneal transplantation. METHODS: BALB/c mice (N = 50) were used as recipients of multiple minor H-disparate corneal transplants from B10.D2 donors. After orthotopic corneal transplantation, mice were randomized in a masked fashion to receive either topical sTNFR-I or vehicle 3 times daily, and all grafts were evaluated for signs of rejection and neovascularization by slitlamp biomicroscopy for 8 weeks. Ocular chemokine gene expression in sTNFR-I- and vehicle only-treated groups was determined using a multiprobe ribonuclease protection assay. RESULTS: Hosts treated with topical sTNFR-I experienced significantly enhanced corneal allograft survival compared with animals treated with vehicle alone (P =.01). Moreover, postoperative messenger RNA levels of RANTES and macrophage inflammatory protein-1beta in sTNFR-I-treated eyes were substantially suppressed compared with vehicle-treated eyes. Vehicle-treated eyes bearing rejected allografts expressed higher levels of messenger RNA for both chemokines than control eyes bearing accepted allografts. CONCLUSIONS: Topical treatment with sTNFR-I promotes the acceptance of allogeneic corneal transplants and inhibits gene expression of 2 chemokines (RANTES and macrophage inflammatory protein-1beta) associated with corneal graft rejection. CLINICAL RELEVANCE: Our findings support the feasibility of a topical anticytokine strategy as a means of reducing corneal allograft rejection without resorting to the use of potentially toxic immunosuppressive drugs.

IL-6 antagonizes TGF-beta and abolishes immune privilege in eyes with endotoxin-induced uveitis.

PURPOSE: To determine the immunosuppressive status of aqueous humor (AqH) from mouse eyes afflicted with endotoxin-induced uveitis (EIU) and to identify the relevant cytokines responsible for immunomodulatory activity within EIU AqH. METHODS: Bacterial lipopolysaccharide (LPS) was injected into hind footpads of C3H/HeN mice; and AqH, collected at 6, 12, 24, and 48 hours, was evaluated for content of transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and interferon (IFN)-gamma and capacity to suppress anti-CD3-driven T-cell proliferation. Cytokine mRNA expression in iris-ciliary body (I/CB) was analyzed by RNase protection assays. RESULTS: During 6 to 24 hours after LPS injection, total TGF-beta levels in AqH increased even though the fluid lost its capacity to suppress T-cell activation. At this time, AqH contained high levels of IL-6, and I/CB contained high levels of IL-6 mRNA. When IL-6 was neutralized with specific antibodies, inflamed AqH reacquired its capacity to suppress T-cell activation, which correlated with high levels of TGF-beta. Coinjection of IL-6 plus antigen into the anterior chamber of the eye of normal mice prevented antigen-specific anterior chamber-associated immune deviation (ACAID). CONCLUSIONS: LPS-induced intraocular inflammation is associated with local production of IL-6, which robs AqH of its immunosuppressive activity, perhaps by antagonizing TGF-beta. The fact that IL-6 antagonized ACAID induction in normal eyes suggests that strategies to suppress the intraocular synthesis of IL-6 may reduce inflammation and restore ocular immune privilege.

Depression of long term potentiation in gerbil hippocampus following postischemic hypothermia.

To investigate the mechanism of chronic cell death following postischemic hypothermia, the change of N-methyl-D-aspartate receptor (NMDAR) were examined by immunohistochemistry of NMDAR1 and long-term potentiation (LTP) in the CA1 subfield of the gerbil hippocampus. At 1 week following postischemic hypothermia (32 degrees Cx4 h), all CA1 neurons survived; however, immunoreactivity of NMDAR1 increased in neuronal perikarya whereas decreased in dendrites in the CA1 neurons. The abnormality was still observed in remaining CA1 neurons at 1 month after hypothermia. LTP was also significantly depressed at 1 week after hypothermia. These results suggest that some abnormalities in the glutamate receptor may be caused by ischemia; such abnormality would persist in spite of hypothermia treatment, resulting in the depression of LTP.

Clostridium perfringens epsilon toxin causes excessive release of glutamate in the mouse hippocampus.

The mechanism of neurotoxicity of Clostridium perfringens epsilon toxin to the mouse brain was investigated. Intravenous injection in mice with the toxin caused seizure and excited hippocampal neurons. Microdialysis revealed that epsilon toxin induced excessive glutamate release in the hippocampus. Both the seizure and glutamate release were attenuated by prior injection with riluzole, an inhibitor of pre-synaptic glutamate release, suggesting that this toxin enhances glutamate efflux, leading to seizure and hippocampal neuronal damage.