Incidence and Early Course of Retinopathy of Prematurity.

In the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (ROP), 4099 infants weighing less than 1251 g at birth underwent sequential ophthalmic examinations, beginning at age 4 to 6 weeks, to monitor the incidence and course of ROP. Overall, 65.8% of the infants developed ROP to some degree; 81.6% for infants of less than 1000 g birth weight. As expected, ROP incidence and severity were higher in lower birth weight and gestational age categories. Black infants appeared less susceptible to ROP, of all severity categories, than nonblack infants. The timing of retinal vascular events correlated more closely with postconceptional age than with postnatal age, implicating the level of maturity more than postnatal environmental influences in governing the timing of these vascular events. These results include the current incidence of various severity stages of ROP found in the United States and provide new. insight into the development of ROP.

Parental perceptions toward digital imaging and telemedicine for retinopathy of prematurity management.

BACKGROUND: Telemedicine is an emerging technology with potential to improve care for retinopathy of prematurity (ROP). This study evaluates parental perceptions about digital imaging and telemedicine for ROP care. METHODS: During a 1-year period, one parent of each infant who underwent wide-field retinal imaging for ROP was given a questionnaire designed to evaluate parental perceptions using a 5-point Likert-type scale. Five items assessed perceptions toward digital retinal imaging, and ten items assessed attitudes toward telemedicine. Construct validity of the questionnaire was examined using factor analysis. Responses were summarized using descriptive and correlational statistics. RESULTS: Forty-two parents participated. Factor analysis extracted two factors explaining 79% of the total variance in digital retinal imaging items (Cronbach's alpha = 0.843), and three factors explaining 63% of the total variance in telemedicine items (Cronbach's alpha = 0.631). Among digital imaging items, the highest mean (+/-SD) score was for "digital pictures of my child's retinopathy should be included in the permanent medical record" (4.4 +/- 0.6), and the lowest was for "digital cameras and computers are reliable" (3.8 +/- 0.8). Among telemedicine items, the highest mean (+/-SD) score was for "technology will improve the quality of medical care for my child" (4.3 +/- 0.6), and the lowest was for "technology will make it harder for a patient and doctor to establish a good relationship" (2.6 +/- 1.1). CONCLUSIONS: Parents reported positive perceptions about telemedical ROP diagnosis, but expressed some preference for face-to-face care. Telemedicine has potential to alter the nature of the patient-physician relationship.

Cellular and molecular origin of circumpapillary dysgenesis of the pigment epithelium.

PURPOSE: We studied clinical phenotyping and TEAD1 expression in mice and humans to gain a better understanding of the primary origin in the pathogenesis of circumpapillary dysgenesis of the pigment epithelium. DESIGN: Observational case series and experimental study. PARTICIPANTS: Three female patients from an affected family were included for phenotypic study. Mice and human tissues were used for biochemistry and immunohistochemistry studies. METHODS: We performed genetic analyses and longitudinal clinical, imaging, and electrophysiologic studies in a 3-generation family. Western blotting and immunohistochemistry were used to detect TEAD1 expression in mice and human retinal tissues. MAIN OUTCOME MEASURES: Autofluorescence and optical coherence tomography (OCT) imaging were compared and reviewed from 3 patients. TEAD1 expression was compared in different tissues from mice and human samples. RESULTS: A point mutation at T1261 in TEAD1 was detected in the mother. Autofluorescence and OCT imaging studies revealed choroid is involved earlier than retinal pigment epithelium (RPE). From immunoblot analysis, we discovered that TEAD1 and its cofactors YAP65 and FOXA2 are expressed in the choroid. Immunohistochemical analysis on frozen sections of mouse retina supports immunoblot results. CONCLUSIONS: The primary cellular origin of circumpapillary dysgenesis of the pigment epithelium is within the choroid instead of the pigment epithelium. The loss of the RPE and photoreceptors in later stages of the disease is a secondary consequence of choroidal degeneration. Studies of the downstream targets of TEAD1 in choroidal cells will provide promising new research opportunities for the development of treatments for choroidal diseases. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Telemedical diagnosis of retinopathy of prematurity intraphysician agreement between ophthalmoscopic examination and image-based interpretation.

OBJECTIVE: To evaluate the intraphysician agreement between ophthalmoscopic examination and image-based telemedical interpretation for retinopathy of prematurity (ROP) diagnosis, when performed by the same expert physician grader. DESIGN: Prospective, nonrandomized, comparative study. PARTICIPANTS: Sixty-seven consecutive premature infants who underwent ROP examination at a major university medical center whose parents consented for participation. METHODS: Infants underwent standard dilated ophthalmoscopy by one of two pediatric ophthalmologists, followed by retinal imaging with a commercially available wide-angle fundus camera by a trained neonatal nurse. Study examinations were performed at 31 to 33 weeks postmenstrual age (PMA) and/or 35 to 37 weeks PMA. Images were uploaded to a Web-based telemedicine system developed by the authors. After a 4- to 12-month period, telemedical interpretations were performed in which each physician graded images from infants upon whom he had initially performed ophthalmoscopic examinations. Diagnoses were classified using an ordinal scale: no ROP, mild ROP, type 2 prethreshold ROP, and treatment-requiring ROP. MAIN OUTCOME MEASURES: Absolute intraphysician agreement and kappa statistic between ophthalmoscopic examination and telemedical interpretation were calculated by eye. All intraphysician discrepancies were reviewed, and underlying causes were classified by eye as no ROP identified by ophthalmoscopic examination, no ROP identified by telemedical interpretation, discrepancy about presence of zone 1 ROP, discrepancy about presence of plus disease, or other discrepancy in classification of ROP stage. RESULTS: Absolute intraphysician agreement between ophthalmoscopic examination and telemedical interpretation was 86.3%. The kappa statistic for intraphysician agreement between examinations ranged from 0.657 (substantial agreement) for diagnosis of treatment-requiring ROP to 0.854 (near-perfect agreement) for diagnosis of mild or worse ROP. Among 206 eye examinations (103 infant examinations), there were 28 (13.6%) intraphysician discrepancies in diagnosis, 8 of which resulted from uncertainty about presence of zone 1 disease and 4 from uncertainty about presence of plus disease. CONCLUSIONS: Intraphysician agreement between ophthalmoscopic examination and telemedical interpretation for ROP was very high. Neither examination modality appeared to have a systematic tendency to overdiagnose or underdiagnose ROP. Diagnosis of zone 1 disease and plus disease were major sources of clinically significant discrepancies.

Celecoxib concentration predicts decrease in prostaglandin E2 concentrations in nipple aspirate fluid from high risk women.

BACKGROUND: Epidemiologic studies suggest that long term low dose celecoxib use significantly lowers breast cancer risk. We previously demonstrated that 400 mg celecoxib taken twice daily for 2 weeks lowered circulating plasma and breast nipple aspirate fluid (NAF) prostaglandin (PG)E2 concentrations in post- but not premenopausal high risk women. We hypothesized that circulating concentrations of celecoxib influenced PGE2 response, and that plasma levels of the drug are influenced by menopausal status. To address these hypotheses, the aims of the study were to determine: 1) if circulating plasma concentrations of celecoxib correlated with the change in plasma or NAF PGE2 concentrations from baseline to end of treatment, and 2) whether menopausal status influenced circulating levels of celecoxib. METHODS: Matched NAF and plasma were collected from 46 high risk women who were administered celecoxib twice daily for two weeks, 20 subjects receiving 200 mg and 26 subjects 400 mg of the agent. NAF and plasma samples were collected before and 2 weeks after taking celecoxib. RESULTS: In women taking 400 mg bid celecoxib, plasma concentrations of the agent correlated inversely with the change in NAF PGE2 levels from pre- to posttreatment. Nonsignificant trends toward higher celecoxib levels were observed in post- compared to premenopausal women. There was a significant decrease in NAF but not plasma PGE2 concentrations in postmenopausal women who took 400 mg celecoxib (p = 0.03). CONCLUSION: In high risk women taking 400 mg celecoxib twice daily, plasma concentrations of celecoxib correlated with downregulation of PGE2 production by breast tissue. Strategies synergistic with celecoxib to downregulate PGE2 are of interest, in order to minimize the celecoxib dose required to have an effect.

uPA is upregulated by high dose celecoxib in women at increased risk of developing breast cancer.

BACKGROUND: While increased urokinase-type plasminogen activator (uPA) expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival. Celecoxib has been shown to have antiangiogenic and antiproliferative properties. We sought to determine if uPA, PA inhibitor (PAI)-1 and prostaglandin (PG)E2 expression in nipple aspirate fluid (NAF) and uPA and PGE2 expression in plasma were altered by celecoxib dose and concentration in women at increased breast cancer risk. METHODS: NAF and plasma samples were collected in women at increased breast cancer risk before and 2 weeks after taking celecoxib 200 or 400 mg twice daily (bid). uPA, PAI-1 and PGE2 were measured before and after intervention. RESULTS: Celecoxib concentrations trended higher in women taking 400 mg (median 1025.0 ng/mL) compared to 200 mg bid (median 227.3 ng/mL), and in post- (534.6 ng/mL) compared to premenopausal (227.3 ng/mL) women. In postmenopausal women treated with the higher (400 mg bid) celecoxib dose, uPA concentrations increased, while PAI-1 and PGE2 decreased. In women taking the higher dose, both PAI-1 (r = -.97, p = .0048) and PGE2 (r = -.69, p = .019) in NAF and uPA in plasma (r = .45, p = .023) were correlated with celecoxib concentrations. CONCLUSION: Celecoxib concentrations after treatment correlate inversely with the change in PAI-1 and PGE2 in the breast and directly with the change in uPA in the circulation. uPA upregulation, in concert with PAI-1 and PGE2 downregulation, may have a cancer preventive effect.

Retinopathy of prematurity management using single-image vs multiple-image telemedicine examinations.

PURPOSE: To compare performance of single-image vs multiple-image telemedicine examinations for retinopathy of prematurity (ROP) diagnosis. DESIGN: Prospective comparative study. METHODS: A total of 248 eyes from 67 consecutive infants underwent wide-angle retinal imaging by a trained neonatal nurse at 31 to 33 weeks and/or 35 to 37 weeks postmenstrual age (PMA) at a single academic institution. Data were uploaded to a web-based telemedicine system and interpreted by three masked retinal specialists. Diagnoses were provided based on single images, and subsequently on multiple images, from both eyes of each infant. Findings were compared to a reference standard of indirect ophthalmoscopy by a pediatric ophthalmologist. Primary outcome measures were recommended follow-up interval, presence of plus disease, presence of type-2 or worse ROP, and presence of visible peripheral ROP. RESULTS: Among the three graders, mean sensitivity/specificity for detection of infants requiring follow-up in less than one week were 0.85/0.93 by single-image examination and 0.91/0.88 by multiple-image examination at 35 to 37 weeks PMA. Mean sensitivity/specificity for detection of infants with type-2 or worse ROP were 0.82/0.95 by single-image examination and 1.00/0.91 by multiple-image examination at 35 to 37 weeks PMA. Mean sensitivity/specificity for detection of plus disease were 1.00/0.86 by single-image examination and 1.00/0.87 by multiple-image examination at 35 to 37 weeks PMA. There were no statistically-significant intragrader differences between accuracy of single-image and multiple-image telemedicine examinations for detection of plus disease. CONCLUSIONS: Single-image and multiple-image telemedicine examinations perform comparably for determination of recommended follow-up interval and detection of plus disease. This may have implications for development of screening protocols, particularly in areas with limited access to ophthalmic care.

Evaluation of a computer-based system for plus disease diagnosis in retinopathy of prematurity.

OBJECTIVE: To measure accuracy and reliability of the computer-based Retinal Image Multiscale Analysis (RISA) system compared with those of recognized retinopathy of prematurity (ROP) experts, for plus disease diagnosis. DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS: Eleven recognized ROP experts and the RISA image analysis system interpreted a set of 20 wide-angle retinal photographs for presence of plus disease. METHODS: All experts used a secure Web site to review independently 20 images for presence of plus disease. Images were also analyzed by measuring individual computer-based system parameters (integrated curvature [IC], diameter, and tortuosity index) for arterioles and venules and by computing linear combinations and logical combinations of those parameters. Performance was compared with a reference standard, defined as the majority vote of experts. MAIN OUTCOME MEASURES: Diagnostic accuracy was measured by calculating sensitivity, specificity, and receiver operating characteristic area under the curve (AUC) for plus disease diagnosis by each expert, and by each computer-based system parameter, compared with the reference standard. Diagnostic agreement was measured by calculating the mean kappa value of each expert compared with all other experts and the mean kappa value of each computer-based system parameter compared with all experts. RESULTS: Among the 11 experts, sensitivity ranged from 0.167 to 1.000, specificity ranged from 0.714 to 1.000, AUC ranged from 0.798 to 1.000, and mean kappa compared with all other experts ranged from 0.288 to 0.689. Among individual computer system parameters, arteriolar IC had the highest diagnostic accuracy, with sensitivity of 1.000; specificity, 0.846; and AUC, 0.962. Arteriolar IC had the highest diagnostic agreement with experts, with a mean kappa value of 0.578. CONCLUSIONS: A computer-based image analysis system has the potential to perform comparably to recognized ROP experts for plus disease diagnosis.

Interexpert agreement of plus disease diagnosis in retinopathy of prematurity.

OBJECTIVE: To measure agreement of plus disease diagnosis among retinopathy of prematurity (ROP) experts. METHODS: A set of 34 wide-angle retinal photographs from infants with ROP was compiled on a secure Web site and was interpreted independently by 22 recognized ROP experts. Diagnostic agreement was analyzed using 3-level (plus, pre-plus, or neither) and 2-level (plus or not plus) categorizations. RESULTS: In the 3-level categorization, all experts agreed on the same diagnosis in 4 of 34 images (12%), and the mean weighted kappa statistic for each expert compared with all others was between 0.21 and 0.40 (fair agreement) for 7 experts (32%) and between 0.41 and 0.60 (moderate agreement) for 15 experts (68%). In the 2-level categorization, all experts who provided a diagnosis agreed in 7 of 34 images (21%), and the mean kappa statistic for each expert compared with all others was between 0 and 0.20 (slight agreement) for 1 expert (5%), between 0.21 and 0.40 (fair agreement) for 3 experts (14%), between 0.41 and 0.60 (moderate agreement) for 12 experts (55%), and between 0.61 and 0.80 (substantial agreement) for 6 experts (27%). CONCLUSIONS: Interexpert agreement of plus disease diagnosis is imperfect. This may have important implications for clinical ROP management, continued refinement of the international ROP classification system, development of computer-based diagnostic algorithms, and implementation of ROP telemedicine systems.

Telemedical retinopathy of prematurity diagnosis: accuracy, reliability, and image quality.

OBJECTIVE: To prospectively measure accuracy, reliability, and image quality of telemedical retinopathy of prematurity (ROP) diagnosis. METHODS: Two-hundred forty-eight eyes from 67 consecutive infants underwent wide-angle retinal imaging by a trained neonatal nurse at 31 to 33 weeks' and/or 35 to 37 weeks' postmenstrual age (PMA) using a standard protocol. Data were uploaded to a Web-based telemedicine system and interpreted by 3 expert retinal specialist graders who provided a diagnosis (no ROP, mild ROP, type 2 prethreshold ROP, treatment-requiring ROP) and an evaluation of image quality for each eye. Findings were compared with a reference standard of indirect ophthalmoscopy by an experienced pediatric ophthalmologist. RESULTS: At 35 to 37 weeks' PMA, sensitivity and specificity for diagnosis of mild or worse ROP were 0.908 and 1.000 for grader A, 0.971 and 1.000 for grader B, and 0.908 and 0.977 for grader C. Sensitivity and specificity for diagnosis of type 2 prethreshold or worse ROP were 1.000 and 0.943 for grader A, 1.000 and 0.930 for grader B, and 1.000 and 0.851 for grader C. At 35 to 37 weeks' PMA, weighted kappa for intergrader reliability was 0.791 to 0.889, and kappa for intragrader reliability for detection of type 2 prethreshold or worse ROP was 0.769 to 1.000. Image technical quality was rated as "adequate" or "possibly adequate" for diagnosis in 93.3% to 100% of eyes. CONCLUSION: A telemedicine system using nurse-captured retinal images has the potential to improve existing shortcomings of ROP management, particularly at later PMAs.

Plus disease in retinopathy of prematurity: pilot study of computer-based and expert diagnosis.

PURPOSE: To measure accuracy of plus disease diagnosis by recognized experts in retinopathy of prematurity (ROP), and to conduct a pilot study examining performance of a computer-based image analysis system, Retinal Image multiScale Analysis (RISA). METHODS: Twenty-two ROP experts independently interpreted a set of 34 wide-angle retinal images for presence of plus disease. A reference standard diagnosis based on expert consensus was defined for each image. Images were analyzed by the computer-based system using individual and linear combinations of system parameters for arterioles and venules: integrated curvature (IC), diameter, and tortuosity index (TI). Sensitivity, specificity, and receiver operating characteristic areas under the curve (AUC) for plus disease diagnosis compared with the reference standard were determined for each expert, as well as for the computer-based system. RESULTS: Expert sensitivity ranged from 0.308 to 1.000, specificity ranged from 0.571 to 1.000, and AUC ranged from 0.784 to 1.000. Among individual computer system parameters, venular IC had highest AUC (0.853). Among all computer system parameters, the linear combination of arteriolar IC, arteriolar TI, venular IC, venular diameter, and venular TI had highest AUC (0.967), which was greater than that of 18 (81.8%) of 22 experts. CONCLUSIONS: Accuracy of ROP experts for plus disease diagnosis is imperfect. A computer-based image analysis system has potential to diagnose plus disease with high accuracy. Further research involving RISA system parameter cut-off values from this study are required to fully validate performance of this computer-based system compared with that of human experts.

Proceedings of the Third International Symposium on Retinopathy of Prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California).

The Third International Symposium on Retinopathy of Prematurity (ROP) was convened with the aim of cross fertilizing the horizons of basic and clinical scientists with an interest in the pathogenesis and management of infants with ROP. Ten speakers in the clinical sciences and ten speakers in the basic sciences were recruited on the basis of their research to provide state of the art talks. The meeting was held November 9, 2003 immediately prior to the American Academy of Ophthalmology meeting; scholarships were provided for outreach to developing countries and young investigators. This review contain the summaries of the 20 platform presentations prepared by the authors and the abstracts of presented posters. Each author was asked to encapsulate the current state of understanding, identify areas of controversy, and make recommendations for future research. The basic science presentations included insights into the development of the human retinal vasculature, animal models for ROP, growth factors that affect normal development and ROP, and promising new therapeutic approaches to treating ROP like VEGF targeting, inhibition of proteases, stem cells, ribozymes to silence genes, and gene therapy to deliver antiangiogenic agents. The clinical presentations included new insights into oxygen management, updates on the CRYO-ROP and ETROP studies, visual function in childhood following ROP, the neural retina in ROP, screening for ROP, management of stage 3 and 4 ROP, ROP in the third world, and the complications of ROP in adult life. The meeting resulted in a penetrating exchange between clinicians and basic scientists, which provided great insights for conference attendees. The effect of preterm delivery on the normal cross-talk of neuroretinal and retinal vascular development is a fertile ground for discovering new understanding of the processes involved both in normal development and in retinal neovascular disorders. The meeting also suggested promising potential therapeutic interventions on the horizon for ROP.

Celecoxib decreases prostaglandin E2 concentrations in nipple aspirate fluid from high risk postmenopausal women and women with breast cancer.

BACKGROUND: Celecoxib inhibits PGE2 production in cancerous tissue. We previously reported that PGE2 levels in nipple aspirate fluid (NAF) and plasma were not decreased in women at increased breast cancer risk who received celecoxib 200 mg twice daily (bid). The endpoints of the current study were to determine if a short course of celecoxib 400 mg bid would decrease PGE2 levels in women 1) at increased breast cancer risk, and 2) with established breast cancer. METHODS: NAF and plasma samples were collected before, 2 weeks after taking celecoxib 400 mg bid, and two weeks after washout from 26 women who were at increased breast cancer risk. From 13 women with newly diagnosed breast cancer, NAF from the incident breast and plasma were collected before and on average 2 weeks after taking celecoxib. Additionally, in nine of the 13 women with breast cancer, NAF was collected from the contralateral breast. RESULTS: No consistent change in NAF or plasma PGE2 levels was noted in high risk premenopausal women. NAF PGE2 levels decreased after celecoxib administration in postmenopausal high risk women (p = 0.02), and in both the NAF (p = 0.02) and plasma (p = 0.03) of women with breast cancer. CONCLUSION: Celecoxib 400 mg bid taken on average for 2 weeks significantly decreased NAF, but not plasma, PGE2 levels in postmenopausal high risk women, and decreased both NAF and plasma PGE2 levels in women with newly diagnosed breast cancer. PGE2 levels may predict celecoxib breast cancer prevention and treatment efficacy. Our observations are preliminary, and larger studies to confirm and extend these findings are warranted.

Accuracy and reliability of remote retinopathy of prematurity diagnosis.

OBJECTIVE: To determine the accuracy and reliability of retinopathy of prematurity (ROP) diagnosis using remote review of digital images by 3 masked ophthalmologist readers. METHODS: An atlas was compiled of 410 retinal photographs from 163 eyes of 64 low-birth-weight infants taken using a wide-angle digital fundus camera. All the images were independently reviewed by 3 readers, and the diagnosis in each eye was classified into 1 of 4 ordinal categories: no ROP, mild ROP, type 2 prethreshold ROP, or ROP requiring treatment. Findings were compared with a reference standard of dilated indirect ophthalmoscopy with scleral depression performed by an experienced pediatric ophthalmologist. RESULTS: Sensitivities/specificities of the diagnosis of any ROP were 0.845/0.910 for the first reader, 0.816/0.955 for the second reader, and 0.864/0.493 for the third reader. Sensitivities/specificities of the diagnosis of ROP requiring treatment were 0.850/0.960 for the first reader, 0.850/0.973 for the second reader, and 0.900/0.953 for the third reader. When ROP was classified into ordinal categories, the overall weighted kappa for interreader reliability was 0.743. Intrareader reliability for detection of low-risk prethreshold ROP or worse was 100% for all readers. CONCLUSION: The accuracy, interreader reliability, and intrareader reliability of remote diagnosis of clinically relevant ROP based on digital imaging are substantial.

Retinopathy of prematurity: two distinct mechanisms that underlie zone 1 and zone 2 disease.

PURPOSE: In its most severe form, retinopathy of prematurity (ROP) is located in posterior retina and affects the smallest, most premature infants. We hypothesize that, depending on whether vasculogenesis (de novo formation of new vessels by transformation of vascular precursor cells (VPCs)) or angiogenesis (budding from existing vessels) is perturbed, it results in significant differences in clinical presentation and therapeutic outcome observed in zone 1 vs zone 2 ROP. DESIGN: The study is a retrospective analysis of the difference in outcome between zones 1 and 2 ROP after cryotherapy and laser therapy. METHODS: A review of the clinical presentation of zones 1 and 2 ROP that correlate this with the topography of formation of human retinal vasculature through vasculogenesis and angiogenesis. RESULTS: Population data on susceptible infants, and outcome statistics of clinical trials are given. Digital images show a correlation between ROP in zone 1 with the region of the retina vascularized through vasculogenesis. CONCLUSION: Zone 1 ROP is correlated with vessel development by vasculogenesis, relative insensitivity to laser/cryotherapy and poorer anatomic and visual outcomes. This suggests that, if the vasculogenic process is perturbed, it results in a distinct clinical presentation, poorer response to therapy, and poorer visual outcome. When the current international classification was developed, knowledge of the processes of human retinal vascular development was incomplete. The work presented here provides a framework for the development of a modification to incorporate these ideas without sacrifice of the essential elements of the international classification of ROP.

OCULAR INVOLVEMENT IN HEMOPHAGOCYTIC SYNDROME: A NOVEL FUNDUSCOPIC MANIFESTATION AND REVIEW OF THE LITERATURE.

PURPOSE: Hemophagocytic syndrome (HS) is a rare disease with a spectrum of ocular findings. The authors report a unique funduscopic presentation of HS in a neonate and a discussion of diagnosis, typical features, management, and outcome. METHODS: Single case report with retrospective analysis of the published literature of patients with HS and ocular findings from 1950 to present using the key terms hemophagocytic, lymphohistiocytosis, ocular, and ophthalmic. Literature search from 1950 to the present was performed through PubMed/MEDLINE and the Cochrane database. Requirement for inclusion was that the article or abstract was written in English. RESULTS: A 4-week-old neonate with HS demonstrated bilateral discrete white dots within the retina, which resolved incompletely over the course of the next months but showed increased pigmentation. CONCLUSION: With so few documented ophthalmic cases of HS in existence, the ocular findings at this point can be seen as diverse and variable. However as more cases are reported, hopefully this will allow for increased recognition of the ophthalmic manifestations and sequelae and in turn lead to improved treatment of this disease.

Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice.

Cyclooxygenase (COX)-2-derived prostaglandins (PGs) are thought to contribute to tumor growth and resistance to radiation therapy. COX-2 protein expression is increased in many tumors including those of the breast. COX-2-derived PGs have been shown to protect cells from radiation damage. This study evaluated the role of COX-2-derived PG in radiation treatment by using the NMF11.2 mammary tumor cell line originally obtained from HER-2/neu mice that overexpress HER-2/neu. We determined whether the effects of the COX-2 inhibitor SC236 on cell growth, radiation-induced PGE2 production and COX expression, cell cycle redistribution, and vascular endothelial growth factor (VEGF) were acting through COX-2-dependent mechanisms. The NMF11.2 cells expressed both COX-1 and COX-2 protein and mRNA. The radiation treatment alone led to a dose-dependent increase in the levels of COX-2 mRNA and COX-2 protein, which was associated with an increase in the production of PGE2 and prostacyclin (PGI2). Treating NMF11.2 cells with high concentrations (20 microM) of SC236 for 48 h reduced the radiation-induced increase in COX-2 activity and also decreased cell growth. SC236 (20 microM) increased the accumulation of the cells in the radiosensitive G2-M phase of the cell cycle. However, a low concentration (5 microM) of SC236 was adequate to reduce COX-2 activity. The lower concentration of SC236 (5 microM) also decreased cell growth after a longer incubation period (96 h) and, in combination with a 2 or 5 Gy dose, led to an accumulation of cells in G2-M phase. Restoring PG to control values in cells treated with 5 microM SC236 prevented the growth inhibition and G2-M cell cycle arrest. Radiation treatment of NMF11.2 cells also increased VEGF protein expression and VEGF secretion in a dose-dependent manner, which was blocked in those cells pretreated with 20 microM SC236 but not in those pretreated with 5 microM SC236. These findings indicate that the COX-2 inhibitor SC236 reduced cell growth and arrested cells in the G2-M phase of the cell cycle by mechanisms that are both dependent and independent of PG production while its effects on VEGF appear to be independent of COX-2.

Hyperlipoproteinemic low-density lipoprotein receptor-deficient mice are more susceptible to sepsis than corresponding wild-type mice.

High circulating concentrations of lipoproteins have been shown to modify the cytokine response and reduce mortality after endotoxin or live bacterial challenge. Sepsis, however, is more complex than endotoxemia, and it is not clear whether elevated plasma lipoproteins will be protective. Previous studies have shown that the low-density-lipoprotein receptor deficient (LDLR-/-) mice with increased circulating LDL are protected against the lethal effects of endotoxemia and Gram-negative infection. We evaluated whether the LDLR-/- mice would be protected against the effects of sepsis induced by cecal ligation and puncture (CLP). Mortality was greater in LDLR-/-mice than in control C57Bl/6J mice. At 120 h after inducing sepsis, 20% of the control mice survived whereas none of theLDLR-/-mice were alive. Prior to inducing sepsis, serum concentrations of amyloid A protein and lipopolysaccharide binding protein (LBP) were significantly elevated in the LDLR-/-mice in comparison to the C57Bl/6J mice. Protein expression of sCD14 was also greater in the serum from the LDLR-/-mice than the C57Bl/6J mice. The elevated serum concentrations of LBP and CD14 were not associated with increases in the levels of liver CD14 mRNA and LBP mRNA. After inducing sepsis, serum concentration of interleukin (IL)-1beta was also significantly higher in LDLR-/-mice than in the control C57Bl/6J mice. These findings indicate that the LDLR-/-mice were more susceptible to the lethal effects of sepsis induced by CLP. The LDLR-/-mice also had higher serum concentrations of baseline, acute phase response proteins, SAA and LBP, and increased production of IL-1beta in response to CLP.

Lack of effect of celecoxib on prostaglandin E2 concentrations in nipple aspirate fluid from women at increased risk of breast cancer.

BACKGROUND: Cyclooxygenase enzymes (COX-1, COX-2, and COX-3) convert arachidonic acid to prostaglandins, prostacyclins, thromboxanes, and other hydroxy fatty acids. Among these, prostaglandin E(2) (PGE(2)) has tumor growth-promoting activity. The COX-2 isoform is the primary enzyme involved in PGE(2) production in cancerous tissue. OBJECTIVE/HYPOTHESIS: We administered the COX-2 inhibitor celecoxib (200 mg b.i.d.) to women at increased breast cancer risk. Our hypothesis was that PGE(2) would be secreted in breast nipple aspirate fluid (NAF), that levels in NAF would be higher than in corresponding plasma, and that celecoxib would decrease PGE(2) levels in NAF (reflecting a decreased breast tissue eicosanoid production) and plasma. SPECIFIC AIM: To determine if PGE(2) concentrations in NAF and plasma decrease after a 2-week course of celecoxib and then return to baseline 2 weeks after stopping the medication (washout). STUDY DESIGN: NAF and plasma were collected before celecoxib treatment, 2 weeks after taking celecoxib, and 2 weeks after washout. Each woman served as her own control. RESULTS: PGE(2) concentrations in NAF and plasma were detectable in samples using two measurement techniques. On average, NAF PGE(2) levels were 81-fold higher in NAF than in matched plasma. Technically, there were differences in PGE(2) concentrations measured in similar fluids depending on the assay technique used (RIA versus chemiluminescence immunoassay). There were no significant decreases in PGE(2) concentrations after celecoxib administration. CONCLUSIONS: PGE(2) can be measured in NAF. PGE(2) levels are concentrated in NAF when compared with matched plasma samples. Celecoxib 200 mg b.i.d. does not appear to significantly decrease PGE(2) concentrations in NAF and plasma.

Impact of family history of high myopia on level and onset of myopia.

PURPOSE: To investigate the impact of a positive family history of high myopia on the level and onset of myopia and its ocular components. METHODS: A cross-sectional study was conducted. The participants (aged 17 to 45 years) were categorized into four groups: normal, mild, moderate, and high myopia. The age of first glasses for myopia was used as the onset of myopia. The impact of the family history on the level and the onset of myopia was quantified. Parental effect on corneal curvature (CC), anterior chamber depth (ACD), and axial length (AXL) was analyzed. RESULTS: The study included 185 normal subjects, 170 mild, 140 moderate, and 392 high myopes. Family history was strongly associated with the probands' status (P < 6 x 10(-12)). When there was >or=1 highly myopic parent, the odds ratios (ORs) of developing mild or moderate myopia were between 2.5 and 3.7 (95% CI: 1.1-6.5) and the ORs of having high myopia were > 5.5 (95% CI: 3.2-12.6). A strong association (P = 2 x 10(-6)) between parental myopic state and the AXL in the subjects was also found, but there was no statistical relationship for ACD or CC. There was an association between high myopia in parents and the onset of myopia in children. Siblings had a weaker association with the level of myopia and had no effect on the onset of myopia. CONCLUSIONS: This study found strong familial effects on the level and onset of myopia even after adjusting for environmental factors. The parental effect on ocular components in their offspring was primarily on AXL.