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Jessica B Ciralsky, Kimberly C SippelDepartment of Ophthalmology, Weill Cornell Medical College, New York, NY, USABackground: Stevens-Johnson syndrome is often associated with blinding ocular surface cicatricial sequelae. Recent reports have described markedly improved clinical outcomes with the application of amniotic membrane to the ocular surface during the acute phase. Here we describe the clinical outcome of a patient with acute Stevens-Johnson syndrome and severe ocular surface involvement in whom the evolving medical condition and family consent resulted in amniotic membrane application to each eye at differing intervals from disease onset.Methods: We undertook a retrospective chart review of a woman with Stevens-Johnson syndrome who presented within hours of disease onset. She underwent application of amniotic membrane to the ocular surface of the left eye during the hyperacute phase (

Ana G Alzaga Fernandez,* Nathan M Radcliffe,* Kimberly C Sippel, Mark I Rosenblatt, Priyanka Sood, Christopher E Starr, Jessica B Ciralsky, Donald J D'Amico, Szilárd KissDepartment of Ophthalmology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA*These authors contributed equally to this work and both are considered principal authorsBackground: The purpose of this study was to assess whether the resolution offered by two different, recently commercially available high-resolution, spectral-domain anterior segment optical coherence tomography (AS-OCT) instruments allows for detailed anatomic characterization of the critical device-donor cornea interface in eyes implanted with the Boston type I permanent keratoprosthesis.Methods: Eighteen eyes of 17 patients implanted with the Boston type I keratoprosthesis were included in this retrospective case series. All eyes were quantitatively evaluated using the Cirrus HD-OCT while a subset (five eyes) was also qualitatively imaged using the Spectralis Anterior Segment Module. Images from these instruments were analyzed for evidence of epithelial migration onto the anterior surface of the keratoprosthesis front plate, and presence of a vertical gap between the posterior surface of the front plate and the underlying carrier donor corneal tissue. Quantitative data was obtained utilizing the caliper function on the Cirrus HD-OCT.Results: The mean duration between AS-OCT imaging and keratoprosthesis placement was 29 months. As assessed by the Cirrus HD-OCT, 83% of eyes exhibited epithelial migration over the edge of the front plate. Fifty-six percent of the keratoprosthesis devices displayed good apposition of the device with the carrier corneal donor tissue. When a vertical gap was present (44% of eyes), the mean gap was 40 (range 8–104) microns. The Spectralis Anterior Segment Module also displayed sufficient resolution to allow for similar characterization of the device-donor cornea interface.Conclusion: Spectral-domain AS-OCT permits high resolution imaging of the keratoprosthesis device-donor cornea interface. Both the Cirrus HD-OCT and the Spectralis Anterior Segment module allowed for visualization of epithelial coverage of the device-donor cornea interface, as well as identification of physical gaps. These imaging modalities, by yielding information in regard to integration of the keratoprosthesis with surrounding corneal tissue, may help identify those at risk for keratoprosthesis-related complications, such as extrusion and endophthalmitis, and hence guide clinical management.Keywords: keratoprosthesis, anterior segment optical coherence tomography, epithelialization

Eleventh in a series of exerpts from the book 101 Pearls in Refractive, Cataract, and Corneal Surgery. [ABSTRACT FROM AUTHOR]

Tenth in a series of excerpts from the book 101 Pearls in Refractive, Cataract, and Corneal Surgery. Look for more appearing in OSN throughout the year. [ABSTRACT FROM AUTHOR]

Purpose: To compare the effect of decreased illumination on the rate of postoperative visual recovery, and the incidence of cystoid macular edema (CME) with surgical visualization achieved with a traditional analog operating microscope compared with a 3D digital visualization system., Setting: Ambulatory surgery center, New York., Design: Prospective, randomized, consecutive, single-surgeon series., Methods: Patients undergoing routine cataract surgery were randomized into either (1) visualization through the binoculars of a standard operating microscope ("traditional group") or (2) visualization through a 3D digital visualization system affixed to the same operating microscope ("digital group"). Note was made in each case of light intensity used, light exposure time, cumulative dissipated energy (CDE), femtosecond laser use, preoperative medical and ocular conditions, intraoperative and/or postoperative complications, and preoperative and postoperative visual acuities and optical coherence tomography confirmed CME., Results: The study comprised 118 eyes in the traditional group and 96 eyes in the digital group. There were no differences in preoperative visual acuity, light exposure time, CDE, or femtosecond laser use between groups, but the light intensity used in the digital group was significantly less (19.5% ± 0.5%) than in the traditional group (48.6% ± 0.6%; P < .001). Furthermore, the digital group achieved a better decimal postoperative day 1 visual acuity (0.60 ± 0.03) with less rates of CME (2.1%) when compared with that of the traditional group (0.51 ± 0.02, P = .03; and 9.2%, P = .03), respectively., Conclusions: Visual recovery and CME rates were significantly better in patients who underwent cataract surgery assisted by the 3D digital visualization platform without an increase in complications or surgical time., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS.)

Purpose: To compare the coaxial light intensity required during cataract surgery and rate of postoperative visual recovery, with surgical visualization achieved with a traditional analog operating microscope compared with a 3D digital visualization system., Setting: Weill Cornell Medical Center, New York Presbyterian Hospital, New York, New York., Design: Retrospective, consecutive, single-surgeon series., Methods: Patients undergoing femtosecond laser-assisted cataract surgery were retrospectively grouped into either: (1) visualization using the binoculars of a standard operating microscope (traditional group) or (2) visualization using a 3D digital visualization system affixed to the same operating microscope (digital group). Note was made in each case of light intensity used, light exposure time, intraoperative and/or postoperative complications, and postoperative visual acuities., Results: The study comprised 24 eyes in the traditional group and 27 eyes in the digital group. There were no intraoperative or postoperative complications in either group and no difference in mean light exposure time, but the mean light intensity used in the digital group was significantly less (18.5% ± 1.5%) than that in the traditional group (43.3% ± 3.7%; P < .001). Furthermore, the digital group achieved a postoperative day 1 visual acuity that was within 2 lines of the postoperative month 1 visual acuity a greater percentage of time than that in the traditional group (81.5% of eyes vs 54.2% of eyes; P = .04)., Conclusions: Light intensity was significantly decreased in patients who underwent cataract surgery assisted by the 3D digital visualization platform without an increase in complications or surgical time and possibly with a faster postoperative visual recovery., (Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Purpose: To propose a new treatment paradigm for chemical burns to the eye - in the acute and chronic phases., Methods: Recent laboratory and clinical data on the biology and treatment of chemical burns are analyzed., Results: Corneal blindness from chemical burns can now be successfully treated with a keratoprosthesis, on immediate and intermediate bases. Long term outcomes, however, are hampered by early retinal damage causing glaucoma. New data suggest that rapid diffusion of inflammatory cytokines posteriorly (TNF-α, etc) can severely damage the ganglion cells. Prompt anti-TNF-α treatment is markedly neuroprotective. Long term profound reduction of the intraocular pressure is also vital., Conclusion: A new regimen, in addition to standard treatment, for severe chemical burns is proposed. This involves tumor necrosis factor alpha (TNF-α) inhibition promptly after the accident (primarily for retinal neuroprotection), prophylactic maximal lowering of the intraocular pressure (starting immediately), and keratoprosthesis implantation in a later quiet state.

Purpose: Severe cutaneous adverse reactions to drugs (SCARs) such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS) serve as one of the main reasons for inpatient ophthalmic consultation. Although it is well-recognized that SJS/TEN is associated with severe ocular mucosal inflammation and cicatrizing, potentially blinding, sequelae, this association has not been described in relation to other SCARs. We present a patient fulfilling the diagnostic criteria for probable DRESS/DIHS but not for SJS/TEN, yet exhibiting the severe ocular surface involvement characteristic of SJS/TEN., Methods: Case report., Results: A 64-year-old man presented with bilateral pseudomembranous conjunctivitis and conjunctival denudation (sloughing) in the setting of a maculopapular rash, fever, liver dysfunction, and hematologic abnormalities 1 month after initiating several medications. A skin biopsy was not consistent with SJS/TEN. The patient was diagnosed with probable DRESS/DIHS and treated with high-dose systemic corticosteroids. The ocular surface inflammation was addressed with intensive topical corticosteroid ointment. The pseudomembranes resolved over a 6-week period, but the patient exhibited residual conjunctival scarring of all palpebral surfaces., Conclusions: The development of severe ocular surface mucosal inflammation and denudation with cicatrizing sequelae in a patient carrying a diagnosis of DRESS/DIHS has diagnostic and therapeutic implications for the ophthalmologist. Careful ophthalmic assessment is indicated in any SCAR patient with ophthalmic symptoms, regardless of formal diagnosis. Furthermore, the early therapeutic interventions recently recommended in SJS/TEN to limit the ophthalmic cicatricial sequelae, such as systemic or topical corticosteroids, may be indicated.

Our purpose is to comprehensively review the state of the art with regard to Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with particular attention to improving the management of associated ocular surface complications. SJS and TEN are two ends of a spectrum of immune-mediated disease, characterized in the acute phase by a febrile illness followed by skin and mucous membrane necrosis and detachment. Part I of this review focused on the systemic aspects of SJS/TEN and was published in the January 2016 issue of this journal. The purpose of Part II is to summarize the ocular manifestations and their management through all phases of SJS/TEN, from acute to chronic. We hope this effort will assist ophthalmologists in their management of SJS/TEN, so that patients with this complex and debilitating disease receive the best possible care and experience the most optimal outcomes in their vision and quality of life., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To compare ease of adoption of the BostonSight Prosthetic Replacement of the Ocular Surface Ecosystem device, a custom-fit scleral lens, by patients in different age and diagnosis groups., Methods: In this prospective study, patients were categorized by age as younger than 60 or 60 years and older and by diagnosis as corneal irregularity (CI) or ocular surface disease (OSD). Ease of adoption of the scleral device was assessed by (1) number of devices and visits required to complete the fitting process, (2) time needed for device insertion and removal, (3) adaptation to the device, as assessed by daily wear time and by time needed to achieve full-time wear (defined as 8 hours per day), and (4) patients' subjective rating of ease of device insertion and removal. The length of the fitting process was also assessed., Results: There was no significant difference in the number of devices and visits needed between age group younger than 60 and age group of 60 and older or between CI and OSD groups. Patients in all groups achieved full-time wear in less than 2 weeks. Average wear time per week did not differ significantly between age or diagnosis groups. Similarly, the time needed for daily insertion and removal during the fitting period, as well as patients' subjective rating of ease of device insertion and removal, did not differ between age or diagnosis categories. The length of the fitting process was significantly longer in the OSD group compared with the CI group (P<0.001); however, factors not related to ease of adoption of the scleral device may be responsible for this difference., Conclusions: Patients in both younger and older patient groups adopted the use of a scleral device with equal ease, as did patients in the CI and OSD diagnosis groups.

The intent of this review is to comprehensively appraise the state of the art with regard to Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with particular attention to the ocular surface complications and their management. SJS and TEN represent two ends of a spectrum of immune-mediated, dermatobullous disease, characterized in the acute phase by a febrile illness followed by skin and mucous membrane necrosis and detachment. The widespread keratinocyte death seen in SJS/TEN is rapid and irreversible, and even with early and aggressive intervention, morbidity is severe and mortality not uncommon. We have divided this review into two parts. Part I summarizes the epidemiology and immunopathogenesis of SJS/TEN and discusses systemic therapy and its possible benefits. We hope this review will help the ophthalmologist better understand the mechanisms of disease in SJS/TEN and enhance their care of patients with this complex and often debilitating disease. Part II (April 2016 issue) will focus on ophthalmic manifestations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate continuous wear of a fluid-ventilated, gas-permeable scleral PROSE device using a standardized protocol as treatment for refractory persistent corneal epithelial defects in patients with severe ocular surface disease., Methods: Retrospective review of eight eyes of seven consecutive patients with persistent epithelial defects refractory to traditional therapies. The standardized treatment regimen consisted of: (1) 24-hour-a-day PROSE wear until re-epithelialization was achieved, (2) brief daily device removal, cleaning, disinfection, and reservoir fluid replacement, (3) addition of a benzalkonium chloride (BAK)-free fourth-generation fluoroquinolone antibiotic drop to the reservoir, and (4) transition to long-term, daytime PROSE wear upon re-epithelialization., Results: All eight eyes exhibited resolution of the persistent epithelial defect. No eyes developed microbial keratitis. Four eyes exhibited recurrences; all recurrences promptly responded to reinstitution of continuous wear., Conclusions: Continuous wear of a PROSE device, using a strictly standardized regimen, constitutes an effective, safe treatment option for refractory persistent epithelial defects.

Purpose: The aim of this study was to determine whether long-term wear of a fluid-filled scleral lens alters basal tear production, corneal sensation, corneal nerve density, and corneal nerve morphology in 2 disease categories., Methods: Patients recruited from the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) treatment program at the Weill Cornell Medical College were categorized into 2 groups: distorted corneas (DC) or ocular surface disease (OSD). We measured tear production, central corneal sensation, subbasal nerve density and tortuosity, and stromal nerve thickness before and after long-term wear of the prosthetic device used in PROSE treatment, defined as at least 60 days of wear for a minimum of 8 hours a day., Results: Twenty patients were included in the study. After long-term wear of the prosthetic device, tear production decreased in patients with DC (21.2 ± 8.5 to 10.4 ± 4.6 mm; P < 0.0001) but did not change in patients with OSD (7.5 ± 5.2 to 8.7 ± 7.2 mm; P = 0.71). Corneal sensation increased in the DC group (45.6 ± 9.2 to 55.0 ± 5.6 mm; P < 0.05). There was no significant change in sensation in patients with OSD (45.0 ± 8.7 to 49.1 ± 14.8 mm; P = 0.37). Subbasal nerve density, subbasal nerve tortuosity, and stromal nerve thickness remained unchanged in both DC and OSD groups after long-term wear (P > 0.05)., Conclusions: Patients with DC had significantly reduced basal tear production and increased corneal sensation after long-term wear of the scleral lens, but patients with OSD did not show any changes in tear production or corneal sensation.

Purpose of Review: To review the newer, effective ophthalmologic treatments for acute Stevens-Johnson syndrome (SJS) as well as the emerging treatment options for patients with chronic, severe ocular surface damage from the disease., Recent Findings: Amniotic membrane transplantation (AMT) applied to the eyes and eyelids in the acute phase of SJS can prevent the devastating scarring and visual problems that characterize the chronic phase of the disease. The severity of ocular inflammation in the acute phase does not always correlate to the severity of skin and systemic involvement. Thus, it is crucial that all patients with SJS be evaluated by an ophthalmologist familiar with the current management of the disease, the potential urgency of the situation and the option of AMT. Although challenging, the severe, chronic ocular problems of SJS can be at least partially alleviated with autologous serum drops, mucous membrane grafting to replace scarred tarsal conjunctiva, specialized contact lenses (PROSE), conjunctival replacement surgery (COMET), limbal stem cell transplantation and kerotoprostheses., Summary: Early AMT is an effective treatment of acute SJS. Emerging treatments offer increased hope for those who have already suffered damage from SJS, but emphasis on the prevention of damage in the acute phase is most crucial.

Background: The aim of this work is to characterize a transparent tissue layer partially covering the anterior surface of the type I Boston permanent keratoprosthesis front plate in four patients., Methods: The tissue over the front plate was easily scrolled back as a single transparent layer using a sponge. In two cases, histopathologic analysis was undertaken and immunofluorescent staining with a cytokeratin 3-specific antibody was performed. The relationship of the tissue to the keratoprosthesis device was further characterized using spectral domain high-definition optical coherence tomography (HD-OCT)., Results: Histopathologic analysis revealed the tissue to be non-keratinized squamous epithelium. No goblet cells were seen, suggesting the cells were of corneal, and not conjunctival, epithelial origin. Immunofluorescent staining of all cells was positive for cytokeratin 3, a protein strongly associated with corneal epithelium. The tissue was easily discerned by HD-OCT and was of substantial thickness near the external junction between the keratoprosthesis device and the carrier corneal tissue. In three cases, visual acuity was unaffected by the presence or absence of this tissue. In one case, a prominent tissue margin temporarily obscured the visual axis and reduced visual acuity; this resolved with mechanical central debridement and has not recurred., Conclusions: The transparent tissue layer covering the anterior surface of the type I Boston keratoprosthesis front plate was found to represent non-keratinized squamous epithelium, most likely of corneal epithelial origin. This potentially represents a further step in bio-integration of the keratoprosthesis device. In particular, epithelial coverage of the critical junction between the device and the carrier corneal tissue might serve an important barrier function and further reduce the incidence of infection and extrusion of the type I Boston permanent keratoprosthesis.

Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN), are relatively rare but have high mortality rates. Survivors are frequently afflicted with severe blinding ocular surface diseases. Recent literature in the areas of ophthalmology and dermatology illustrate that the ophthalmologist's role should no longer be considered secondary in the acute management of SJS/TEN. Accurately differentiating SJS or TEN from erythema multiforme majus (EMM) at the onset of the disease is important, because the management approach to these disease entities differs. Systemic cyclosporine and intravenous immunoglobulin have shown some potential as treatments for SJS/TEN, but their efficacies remain controversial. Amniotic membrane transplantation and intravenous corticosteroid pulse therapy at the acute stage have shown promise for preventing late sight-threatening cicatricial complications. An improved staging system for the ocular surface involvement of acute SJS/TEN, as well as better understanding of the underlying destructive pathogenic mechanism, should further improve our ability to predict ocular involvement and develop new therapeutics to abort destructive processes at the acute stage.

Purpose: To describe the results of a novel treatment approach to the acute ophthalmic management of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)., Design: Retrospective interventional case series., Methods: setting: Institutional. study population: Sixteen eyes of 8 patients with acute, biopsy-proven SJS or TEN and significant ophthalmic involvement. interventional procedure(s): Application of amniotic membrane to the ocular surface, either in the operating room or at the bedside, and short-term use of intensive topical corticosteroid medication. main outcome measures: Visual acuity, slit-lamp appearance of the ocular surface, and patients' subjective impression of ocular comfort., Results: Two patients expired during the hospitalization. Mean follow-up time for the surviving patients was 7.7 months. Four surviving patients in whom the entire ocular surface (ie, the cornea, bulbar and palpebral conjunctiva, and eyelid margins) was treated with amniotic membrane retained visual acuities of 20/40 or better and an intact ocular surface. In contrast, the initial 2 patients in the study who were treated with only a Prokera device or unsutured amniotic membrane sheets, leaving the palpebral conjunctiva and eyelid margins uncovered, developed more significant ocular surface abnormalities, and 1 developed a corneal perforation., Conclusions: Amniotic membrane coverage of the ocular surface in its entirety coupled with the use of intensive short-term topical corticosteroids during the acute phase of SJS and TEN is associated with the preservation of good visual acuity and an intact ocular surface. Partial amniotic membrane coverage of the ocular surface may not serve to minimize the cicatrizing ocular sequelae of SJS and TEN as effectively as complete coverage., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

The goal of the present study was to determine the rate of restoration of the corneal epithelial barrier following a superficial keratectomy using a functional assay of tight junction integrity. Adult Sprague-Dawley rats were anesthetized and a 3-mm superficial keratectomy was performed. The eyes were allowed to heal from 4 h to 8 weeks and the rate of epithelial wound closure was determined. To examine the restoration of the barrier function, EZ-Link Sulfo-NHS-LC-Biotin (LC-Biotin) was applied to all eyes, experimental and control, for 15 min at the time of sacrifice. This compound does not penetrate through intact tight junctions. Indirect immunofluorescence was performed with anti-laminin, a marker of basement membrane; fluorescein-conjugated streptavidin to detect the biotinylated marker; and anti-occludin and anti-ZO-1, markers of tight junctions. Epithelial wound closure was observed at 36-42 h after wounding. LC-Biotin did not penetrate the intact epithelium. Upon wounding, LC-Biotin penetrated into the stroma subjacent and slightly peripheral to the wound area. This pattern was present from 4-48 h post-wounding. The area of LC-Biotin localization decreased with time and the functional barrier was restored by 72 h. Occludin and ZO-1 were present at all time points. The number of cell layers expressing these proteins appeared to increase at 48 and 72 h. Continuous laminin localization was not observed until at least 7 days after wounding. Barrier function is restored within 1-1.5 days after epithelial wound closure. The loss of barrier function does not extend beyond the edge of the original wound. The restoration of barrier function does not appear to correlate with reassembly of the basement membrane in this model.

Human amniotic membrane (AM) is composed of three layers: a single epithelial layer, a thick basement membrane, and an avascular stroma. Amniotic membrane has anti-adhesive properties and is felt to promote epithelialization and decrease inflammation, neovascularization, and fibrosis. Amniotic membrane transplantation (AMT) is currently being used for a continuously widening spectrum of ophthalmic indications. Amniotic membrane transplantation has been shown to be effective in the reconstruction of the corneal surface in the setting of persistent epithelial defects, sterile corneal ulcerations, and partial limbal stem cell (LSC) deficiency states, including those secondary to chemical or thermal burns. Amniotic membrane transplantation also has been used in conjunction with limbal stem cell transplantation (LSCT) both in a concurrent fashion as well as in preparation for LSCT. Amniotic membrane transplantation also has been used in place of conjunctival autografting after pterygium excision and to reconstruct the conjunctival surface after removal of conjunctival lesions. Most recently, ex vivo cultivation and expansion of limbal epithelial cells has been performed utilizing AM as a matrix. However, the superiority of AMT over other treatment modalities in many of these settings needs to be substantiated by controlled clinical trials.

Purpose: To establish the DNA sequence of the coding regions of the human arrestin locus and to determine whether defects in this sequence are present among patients with retinitis pigmentosa (RP) or types of stationary night blindness in addition to Oguchi disease., Methods: The human genomic locus encoding arrestin was cloned in bacteriophage and P1 vectors. The sequence of the intron DNA flanking each exon was determined from these clones. Single-strand conformation polymorphism analysis and direct genomic sequencing techniques were used to screen 272 unrelated patients, comprising 177 patients with autosomal dominant RP, 85 with recessive RP, and 10 with stationary night blindness., Results: The arrestin gene is divided into 16 exons ranging in size from 10 bp to 194 bp, with the open reading frame spanning exons 2 through 16. The authors identified several discrepancies between the genomic sequence the authors obtained and the previously published cDNA and genomic sequences. In the set of patients with dominant RP, the authors found one of three heterozygous missense changes (Arg84Cys, Thr125Met, and Val378Ile) in each of four unrelated patients; none of these changes cosegregated with disease in the respective families. In the set of patients with recessive RP, the authors found one of two heterozygous missense changes in each of two unrelated patients with recessive RP (Pro364Leu and Arg384Cys). One of the patients was the offspring of a consanguineous marriage; because the Arg384Cys change in him was heterozygous, it is unlikely to have been the cause of his RP. Cosegregation studies could not be performed on the patient with the Pro364Leu change. The authors confirmed the existence of two previously described polymorphisms (Ile76Val and a multiallelic polymorphism at codon 403), and the authors identified several silent polymorphisms and rare sequence variants. No sequence changes, other than polymorphic changes also found in some patients with RP, were identified in the patients with stationary night blindness., Conclusions: We found no evidence that mutations in arrestin are a cause of RP or stationary night blindness other than Oguchi disease. According to the genomic sequence obtained, a region in exon 8 that has been postulated to represent the site of interaction between arrestin and rhodopsin is 100% conserved between humans and all other mammals studied to date.

Although mosaicism can have important implications for genetic counseling of families with hereditary disorders, information regarding the incidence of mosaicism is available for only a few genetic diseases. Here we describe an evaluation of 156 families with retinoblastoma; the initial oncogenic mutation in the retinoblastoma gene had been identified in these families. In 15 ( approximately 10%) families, we were able to document mosaicism for the initial mutation in the retinoblastoma gene, either in the proband or in one of the proband's parents. The true incidence of mosaicism in this group of 156 families is probably higher than our findings indicate; in some additional families beyond the 15 we identified, mosaicism was likely but could not be proven, because somatic or germ-line DNA from key family members was unavailable. Germ-line DNA from two mosaic fathers was analyzed: in one of these, the mutation was detected in both sperm and leukocyte DNA; in the other, the mutation was detected only in sperm DNA. Our data suggest that mosaicism is more common than is generally appreciated, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations. The possibility of mosaicism should always be considered during the genetic counseling of newly identified families with retinoblastoma. As demonstrated here, genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA.

Oguchi disease is a recessively inherited form of stationary night blindness due to malfunction of the rod photoreceptor mechanism. Patients with this disease show a distinctive golden-brown colour of the fundus that occurs as the retina adapts to light, called the Mizuo phenomenon. Recently a defect in arrestin, a member of the rod phototransduction pathway, was found to cause this disease in some Japanese patients. As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase. This report describes an analysis of the arrestin and rhodopsin kinase genes in three unrelated cases of Oguchi disease. No defects in arrestin were detected, but all three cases had mutations in the rhodopsin kinase gene. Two cases were found to be homozygous for a deletion encompassing exon 5, predicted to lead to a nonfunctional protein. The third case was a compound heterozygote with two allelic mutations, a missense mutation (Val380Asp) affecting a residue in the catalytic domain, and a frameshift mutation (Ser536(4-bp del)) resulting in truncation of the carboxy terminus. Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness.

Activation-induced cell surface molecules are involved in mediating bidirectional T-B lymphocyte signaling that is important in the induction of T or B lymphocyte effector functions. In this regard, T-BAM/CD40-L is an activation-induced CD4+ T cell surface molecule known to be important in inducing B cell effector functions. This report demonstrates that T-BAM/CD40-L molecules on a Jurkat T cell leukemia subclone (D1.1) or nonlymphoid 293 kidney cell transfectants induce B cells or B-CLL cells to express CD80 (B7/BB-1) in a manner that is specifically inhibited by anti-T-BAM/CD40-L mAb 5C8. Because activation-induced B cell surface molecules, such as CD80, deliver costimulatory signals to T cells that augment T cell proliferation, the functional costimulatory capacity of T-BAM/CD40-L-primed B cells and B-CLL cells was studied. T-BAM/CD40-L-primed B cells or B-CLL cells augment the proliferative responses of allogenic T cells. Furthermore, T-BAM/CD40-L priming is specifically inhibited by mAb 5C8. Together, these studies demonstrate that T-BAM/CD40-L induces CD80 expression on resting B cells or B-CLL cells. Moreover, T-BAM/CD40-L signaling enhances B cell costimulatory capacity. These studies suggest that T-BAM/CD40-L molecules not only induce B cell differentiative processes that result in Ab secretion, but also enable B cells to prime Ag-specific T cells for subsequent clonal expansion.