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Biomedical subjects

John T Flynn

Publications and source records attributed to John T Flynn.

15 recordsLinked to original sources
PubMed2006

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.

Adolescent↗
PubMed2006

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.

Humans↗
PubMed2006

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.

Birth Weight↗
PubMed2006

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.

Cryotherapy↗
PubMed2005

Selective thromboxane A2 synthase inhibition by OKY-046 prevents cardiopulmonary dysfunction after ovine smoke inhalation injury.

BACKGROUND: Because thromboxane A2 is implicated in the pathophysiology of acute lung injury, the aim of this study was to evaluate the effects of selective thromboxane A2 synthase inhibition on cardiopulmonary function in the experimental setting of severe smoke inhalation injury. METHODS: Sixteen adult sheep were operatively instrumented for chronic study. The injured intervention group was treated with the selective thromboxane A2 synthase inhibitor OKY-046, whereas the injured control group received only the vehicle (n = 8 each). RESULTS: The progressive increase in thromboxane B2 lung lymph concentrations in control animals was associated with increased transvascular fluid flux, augmented resistances in the pulmonary and systemic circulation, and a reciprocal decrease in cardiac output. In addition, end-systolic pressure-diameter relation and maximum +dp/dt were markedly depressed as compared with baseline (24 h: 14.3 +/- 0.9 vs. 8.9 +/- 0.5 mmHg/mm and 2,120 +/- 50 vs. 1,915 +/- 40 mmHg/s, respectively; each P < 0.05). Infusion of OKY-046 significantly inhibited pulmonary thromboxane B2 delivery, attenuated the early increase in pulmonary vascular resistance, and blocked the increase in systemic vascular resistance. In addition, OKY-046 blunted and delayed the decrease in cardiac output and maintained end-systolic pressure-diameter relation, +dp/dt, and lung lymph flow at baseline values. CONCLUSIONS: These findings suggest that selective thromboxane A2 synthase inhibition may represent a goal-directed therapeutic approach to alleviate cardiovascular and pulmonary dysfunction in the setting of smoke inhalation injury.

6-Ketoprostaglandin F1 alpha↗
PubMed2005

Assessment of image-based technology: impact of referral cutoff on accuracy and reliability of remote retinopathy of prematurity diagnosis.

Telemedicine has potential to improve the delivery, quality, and accessibility of ophthalmic care for infants with Retinopathy of Prematurity (ROP). Using a telemedicine screening strategy, three potential diagnostic cutoffs may be used to define disease that warrants ophthalmologic referral: presence of any ROP, presence of moderate ("type-2 prethreshold") ROP, or presence of severe ROP requiring treatment. This study examines the relationship between accuracy and reliability of diagnosis by three masked ophthalmologist graders at each of these diagnostic cutoffs. The sensitivity, specificity, inter-grader reliability, and intra-grader reliability showed significant variation depending on the diagnostic cutoff, with best results at cutoffs of type-2 prethreshold ROP or treatment-requiring ROP. Before the large-scale adoption of telemedicine for image-based screening of diseases such as ROP, standards defining clinically-relevant referral cutoffs must be established, and diagnostic accuracy and reliability at these cutoffs must be characterized.

Atlases as Topic↗
PubMed2004

Incidence of retinopathy of prematurity from 1996 to 2000: analysis of a comprehensive New York state patient database.

OBJECTIVE: To determine the current incidence of retinopathy of prematurity (ROP) in New York state. DESIGN: Population-based cohort study. PARTICIPANTS: Newborn infants (15 691) with initial hospital length of stay >28 days and date of discharge from January 1, 1996, to December 31, 2000. Subjects were identified from the New York Statewide Planning and Research Cooperative System (SPARCS) database, which contains information about every patient hospitalized in New York during this period. METHODS: Demographic and clinical information about eligible infants was abstracted by searching the SPARCS database. Patients with a discharge diagnosis of ROP or who underwent laser retinal photocoagulation, scleral buckle, or pars plana vitrectomy were identified by searching for appropriate discharge and procedure codes. Incidence of ROP in the study population was determined and analyzed on the basis of birth weight. MAIN OUTCOME MEASURES: Incidence of any ROP, laser photocoagulation, scleral buckle, and pars plana vitrectomy in study population. RESULTS: On the basis of SPARCS coding, the overall incidence of any ROP among all newborn infants in New York state during the study period was 0.2% (2284 of 1 167 427), or 1 in 511. The incidence of any ROP in the study population of newborns with initial hospital length of stay >28 days was 20.3% (2152 of 10 596) among infants with birth weight <1500 g and 27.3% (1839 of 6745) among infants with birth weight <1200 g. Among study patients with any ROP, the proportion who underwent laser photocoagulation during initial hospital stay was 9.5% (218 of 2284), and the proportion who underwent scleral buckle or vitrectomy surgery was 0.5% (12 of 2284). Seventeen study newborns with birth weight > or =2000 g had a discharge diagnosis of ROP, although none of these patients required laser or incisional surgery during hospitalization. CONCLUSIONS: This study involves the largest known cohort of newborns that has been analyzed for ROP. The incidence of ROP in this study is lower than results from previous multicenter clinical trials. However, the diagnosis of ROP in 17 study newborns with birth weight > or =2000 g deserves further investigation and may have implications for ROP screening protocols.

Birth Weight↗
PubMed2004

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.

Adolescent↗
PubMed2004

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.

Animals↗
PubMed2004

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.

Adult↗
PubMed2003

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.

Acute Disease↗
PubMed2002

Telephotoscreening to detect retinopathy of prematurity: preliminary study of the optimum time to employ digital fundus camera imaging to detect ROP.

PURPOSE: Labor-intensive screening of infants in the neonatal intensive care units is the only way presently to detect retinopathy of prematurity (ROP). Our purpose is to determine if RetCam 120 images (Massie Research Laboratories, Inc, Dublin, Calif), acquired by a neonatal nurse, can be used to screen for ROP by performing 2 screening sessions, at 32 to 34 weeks' (examination 1) and 38 to 40 weeks' (examination 2) postconceptional age. METHODS: RetCam examinations were performed by a nurse on infants at examination 1 and examination 2 intervals. At the same time, an examination was performed by an experienced ophthalmologist. Masked readers evaluated the digital images for the presence of ROP and, if ROP was present, estimated the risk of that eye progressing to prethreshold or threshold disease. The data were compared to the eye's clinical course. RESULTS: A total of 46 eyes were assessed at examination 1 and 50 eyes at examination 2 from July 1, 1999, to December 15, 1999. For detecting ROP, the sensitivity and specificity were 46% and 100% for examination 1 and 76% and 100% for examination 2. Sensitivity and specificity of predicting prethreshold was 64% and 97%, respectively, for examination 1 and 2. Sensitivity for predicting ROP threshold at examination 1 was 0% (only 1 photo was available for grading of sensitivity) and specificity for predicting ROP threshold at examination 1 was 95%. At examination 2, sensitivity and specificity were 100%. CONCLUSION: The RetCam examination had insufficient sensitivity to be recommended as a substitute for indirect ophthalmoscopy in screening for ROP. Reasons for low sensitivity are the technical limitation of the camera design itself, which creates difficulty in photographing the peripheral retina in small eyes, and the need for a lid speculum better adapted to the contact camera optical system design. Both of these issues are being addressed as part of an ongoing project to study the feasibility of employing telemetry of digital fundus images from remote, underserved neonatal intensive care units to ophthalmologists capable of diagnosing ROP.

Diagnostic Techniques, Ophthalmological↗
PubMedDate not supplied

Toward a miniaturized fundus camera.

Retinopathy of prematurity (ROP) describes a pathological development of the retina in prematurely born children. In order to prevent severe permanent damage to the eye and enable timely treatment, the fundus of the eye in such children has to be examined according to established procedures. For these examinations, our miniaturized fundus camera is intended to allow the acquisition of wide-angle digital pictures of the fundus for on-line or off-line diagnosis and documentation. We designed two prototypes of a miniaturized fundus camera, one with graded refractive index (GRIN)-based optics, the other with conventional optics. Two different modes of illumination were compared: transscleral and transpupillary. In both systems, the size and weight of the camera were minimized. The prototypes were tested on young rabbits. The experiments led to the conclusion that the combination of conventional optics with transpupillary illumination yields the best results in terms of overall image quality.

Animals↗