106 results on '"Adamian M"'
Search Results
2. Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations
- Author
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Sun, X, Pawlyk, B, Xu, X, Liu, X, Bulgakov, O V, Adamian, M, Sandberg, M A, Khani, S C, Tan, M-H, Smith, A J, Ali, R R, and Li, T
- Published
- 2010
- Full Text
- View/download PDF
3. New recipes for in-stent restenosis: cut, grate, roast, or sandwich the neointima?
- Author
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Di Mario, C, Marsico, F, Adamian, M, Karvouni, E, Albiero, R, and Colombo, A
- Published
- 2000
4. The Impacts of Simulated Microgravity on The Cell Viability and Claudin-1 and Claudin-3 Expression of MCF-7 Breast Cancer Cells.
- Author
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Adamian, M., Hekmat, A., and Hajebrahimi, Z.
- Subjects
BREAST cancer etiology ,CELL survival ,CLAUDINS ,PROTEIN expression ,EPITHELIAL cells ,FLOW cytometry - Abstract
It has been believed that microgravity directly can alter the structure, morphology, and function of biosystems and numerous research have been performed to recognize these alterations. Claudin proteins are the tight junctions' main components. Additionally, they are crucial for the protection of the differentiated state of epithelial cells as well as for cell-cell interaction. This study aimed to explore the probable correlation between the claudin-1 and claudin-3 expression and microgravity condition. Additionally, examined the impacts of microgravity condition on cell morphology and viability. The gene expression in MCF-7 cells were assessed by real-time quantitative RT PCR. Afterward, the morphology and cellular viability of the cells were evaluated by an inverted microscope, MTT assay, and flow cytometry analysis. After 72 h of simulated microgravity, the claudin-1 and claudin-3 expression increased significantly (P<0.05). Also, MCF-7 cells after 72 h exposure to microgravity simulation comprised rounded cells, which were grouped and linked to each other making multicellular spheroids. However, microgravity simulation after 24 or 72 h did not have a remarkable effect on the viability of cells. The consequence of this research lied in the fact that simulated microgravity could not be a direct cure for breast cancer treatment. However, microgravity research can offer a unique in vitro tool to explore biomechanical effects in the biology of cancer. The findings obtained from this investigation can open fascinating research lines in astrobiology, biophysics, and cancer biology and can be utilized to improve survivability and life quality for malignancy patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
5. Development of a lipid-rich, soft plaque in rabbits, monitored by histology and intravascular ultrasound
- Author
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Chiesa, G, Di Mario, C, Colombo, N, Vignati, L, Marchesi, M, Monteggia, E, Parolini, C, Lorenzon, P, Laucello, M, Lorusso, V, Adamian, M, Franceschini, G, Newton, R, and Sirtori, C.R
- Published
- 2001
- Full Text
- View/download PDF
6. The effect of cutting temperature on hole quality when drilling CFRP/metal stack
- Author
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Kolesnyk, V., Zajac, J., Radchenko, S., and Adamian, M.
- Subjects
accuracy ,знос свердла ,hole surface integrity ,drill wear ,cutting temperature ,точність ,пакет вуглепластик/метал - Abstract
The carbon fiber reinforced plastic (CFRP) are widely used in stacks with metals. That allows obtaining components with high strength and reduces weight. Holes’ drilling is a basic operation of CFRP/metal and metal/CFRP stacks machining. The most common problems of CFRP/metal stacks drilling are CFRP delamination, fiber pull – out, thermal degradation and low quality of hole surface. In this study the effect of cut ting temperature on the hole quality was provided. It was experimentally established that drilling of CFRP/metal stack was accompanied with a significant change of cutting temperature in the cutting zone during the transition of drill from CFRP to metal plate. Волокнисті полімерні композиційні матеріали (вуглепластики) широко використовуються в пакетах з металами. Це дозволяє отримати компоненти з високою міцністю, разом з тим забезпечивши зниження ваги. Свердління отворів є основною механічною операцією при обробці пакетів вуглепластик / метал і метал / вуглепластика. Найбільш поширені проблеми механічної обробки пакетів вуглепластик / метал є розшарування вуглепластика, витягування волокон, термічна деструкція і низька якість поверхні отвори. У статті представлено дослідження впливу дію температури різання на якість отворів. Експериментально було встановлено, що свердління пакета вуглепластик / сталь супроводжувався істотною зміною температури різання в зоні різання при переході свердла з вуглепластика до металевої пластини.
- Published
- 2015
7. Readers Report.
- Author
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Jacobs, Steven C., Fridl, Bill, Woodard, Ron, Jurison, Jaak, Montesinos, Diego, Adamian, M. Russ, Warda, Mark, Bamel, David A., McCleery, Robert, and Lemelson, Jerome H.
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LETTERS to the editor ,SMALL business ,MEDICAL care costs ,MEDICAL care ,PRICES ,BUSINESS enterprises - Abstract
Several letters to the editor in response to previous articles are presented including "Health Care Has a Bad Case of Cost Disease" published in the November 15, 1993 issue, "Reality Check" published in the November 15, 1993 issue and "Stuck!: How Companies Cope When They Can't Raise Prices" published in the November 15, 1993 issue.
- Published
- 1993
8. Photoreceptor rescue by an abbreviated human RPGR gene in a murine model of X-linked retinitis pigmentosa
- Author
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Pawlyk, B S, primary, Bulgakov, O V, additional, Sun, X, additional, Adamian, M, additional, Shu, X, additional, Smith, A J, additional, Berson, E L, additional, Ali, R R, additional, Khani, S, additional, Wright, A F, additional, Sandberg, M A, additional, and Li, T, additional
- Published
- 2015
- Full Text
- View/download PDF
9. Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations
- Author
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Sun, X, primary, Pawlyk, B, additional, Xu, X, additional, Liu, X, additional, Bulgakov, O V, additional, Adamian, M, additional, Sandberg, M A, additional, Khani, S C, additional, Tan, M-H, additional, Smith, A J, additional, Ali, R R, additional, and Li, T, additional
- Published
- 2009
- Full Text
- View/download PDF
10. Do multiple prior interventions for in-stent restenosis impact the success of gamma brachytherapy?
- Author
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Ashby, Dale T., primary, Dangas, G., additional, Mehran, R., additional, Lansky, A.J., additional, Adamian, M., additional, Collins, M., additional, Krepps, E., additional, New, G., additional, Moussa, I., additional, Stone, G.W., additional, Roubin, G.S., additional, Iyer, S., additional, Moses, J.W., additional, Leon, M.B., additional, and Teirstein, P.S., additional
- Published
- 2002
- Full Text
- View/download PDF
11. Impact of smoking habit on clinical outcomes after percutaneous coronary intervention
- Author
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Ashby, Dale T., primary, Dangas, G., additional, Farkouh, M., additional, Iakovou, I., additional, Weisz, G., additional, Hjazi, I., additional, Adamian, M., additional, Aymong, E., additional, Mohamed, M., additional, Mehran, R., additional, Stone, G.W., additional, Lansky, A.J., additional, Collins, M., additional, Moses, J., additional, and Leon, M.B., additional
- Published
- 2002
- Full Text
- View/download PDF
12. Photoreceptor rescue by an abbreviated human RPGRgene in a murine model of X-linked retinitis pigmentosa
- Author
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Pawlyk, B S, Bulgakov, O V, Sun, X, Adamian, M, Shu, X, Smith, A J, Berson, E L, Ali, R R, Khani, S, Wright, A F, Sandberg, M A, and Li, T
- Abstract
The X-linked RP3gene codes for the ciliary protein RPGR and accounts for over 10% of inherited retinal degenerations. The critical RPGR-ORF15splice variant contains a highly repetitive purine-rich linker region that renders it unstable and difficult to adapt for gene therapy. To test the hypothesis that the precise length of the linker region is not critical for function, we evaluated whether adeno-associated virus-mediated replacement gene therapy with a human ORF15variant containing in-frame shortening of the linker region could reconstitute RPGR function in vivo. We delivered human RPGR-ORF15replacement genes with deletion of most (314 codons, ‘short form’) or 1/3 (126 codons, ‘long form’) of the linker region to Rpgr nullmice. Human RPGR-ORF15expression was detected post treatment with both forms of ORF15transgenes. However, only the long form correctly localized to the connecting cilia and led to significant functional and morphological rescue of rods and cones. Thus the highly repetitive region of RPGR is functionally important but that moderate shortening of its length, which confers the advantage of added stability, preserves its function. These findings provide a theoretical basis for optimizing replacement gene design in clinical trials for X-linked RP3.
- Published
- 2016
- Full Text
- View/download PDF
13. COGNITIVE APPRAISAL OF THE STABLE CHARACTER OF NEGATIVE EVENTS INTERACTS WITH SES TO INFLUENCE 24-HOUR AMBULATORY BLOOD PRESSURE
- Author
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Grewen, K., primary, Costello, N., additional, Adamian, M., additional, Girdler, S., additional, and Light, K., additional
- Published
- 1999
- Full Text
- View/download PDF
14. OXYTOCIN RELATIONSHIPS TO BLOOD PRESSURE IN BREAST- AND BOTTLE-FEEDING MOTHERS OF INFANTS
- Author
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Smith, T. E., primary, Johns, J. M., additional, Chung, S. H., additional, Adamian, M. S., additional, Hofheimer, J. A., additional, and Light, K. C., additional
- Published
- 1999
- Full Text
- View/download PDF
15. HORMONE REPLACEMENT REDUCES LAB AND 24-HOUR BLOOD PRESSURE IN HYPERTENSIVE POSTMENOPAUSAL WOMEN
- Author
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Adamian, M. S., primary, Girdler, S. S., additional, West, S. G., additional, Grewen, K. M., additional, Chung, S. H., additional, Koo, J., additional, Hinderliter, A., additional, and Light, K. C., additional
- Published
- 1999
- Full Text
- View/download PDF
16. New recipes for in-stent restenosis: cut, grate, roast, or sandwich the neointima?
- Author
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Mario, C Di, Marsice, F, Adamian, M, Karvouni, E, Albiero, R, and Colombo, A
- Published
- 2000
17. Retinal histopathology of an autopsy eye with advanced retinitis pigmentosa in a family with rhodopsin Glu181Lys
- Author
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To, K., Adamian, M., Dryja, T. P., and Berson, E. L.
- Published
- 2000
- Full Text
- View/download PDF
18. Histopathologic and immunohistochemical study of dominant cone degeneration
- Author
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To, K., Adamian, M., Jakobiec, F. A., and Berson, E. L.
- Published
- 1998
- Full Text
- View/download PDF
19. Intravascular ultrasound criteria for the assessment of the functional significance of intermediate coronary artery stenoses and comparison with fractional flow reserve.
- Author
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Briguori, Carlo, Anzuini, Angelo, Airoldi, Flavio, Gimelli, Giorgio, Nishida, Takahiro, Adamian, Milena, Corvaja, Nicola, Di Mario, Carlo, Colombo, Antonio, Briguori, C, Anzuini, A, Airoldi, F, Gimelli, G, Nishida, T, Adamian, M, Corvaja, N, Di Mario, C, and Colombo, A
- Subjects
- *
INTRAVASCULAR ultrasonography , *CORONARY artery stenosis - Abstract
The functional significance of coronary artery stenoses of intermediate severity is important in determining strategy in patient care. Intravascular ultrasound (IVUS) is often used to evaluate coronary stenosis severity. However, at present, few data are available about the role IVUS in the assessment of functional significance of intermediate lesions. Myocardial fractional flow reserve (FFR) <0.75 is a reliable index of a functionally severe coronary stenosis. In 53 lesions we assessed (1) by pressure wire: FFR (index of functional significance), and (2) by IVUS: minimal lumen cross-sectional area (MLA, square millimeters), minimal lumen diameter (MLD, millimeters), lesion length (millimeters), and percent area stenosis at the lesion site. By regression analysis, percent area stenosis and lesion length had a significant inverse correlation with FFR (r = -0.58, p <0.001, r = -0.41, p <0.004, respectively). MLD and MLA showed a significant positive relation with FFR (r = 0.51, p <0.001, r = 0.41, p <0.004, respectively). By using a receiver operating characteristic (ROC) curve, we identified a percent area stenosis > 70% (sensitivity 100%, specificity 68%), a MLD < or = 1.8 mm (sensitivity 100%, specificity 66%), a MLA < or =4.0 mm2 (sensitivity 92%, specificity 56%), and a lesion length of >10 mm (sensitivity 41%, specificity 80%) to be the best cut-off values to fit with a FFR <0.75. The combined evaluation of both percent area stenosis and MLD made the IVUS examination more specific (sensitivity 100%, specificity 76%). In 53 intermediate coronary lesions found by angiography, IVUS area stenosis >70%, MLD < or =1.8 mm, MLA < or =4.0 mm2, and lesion length > 10 mm reliably identified functionally critical intermediate coronary stenoses. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
20. Polytetrafluoroethylene-covered stent for the treatment of narrowings in aorticocoronary saphenous vein grafts.
- Author
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Briguori, Carlo, De Gregorio, Joseph, Briguori, C, De Gregorio, J, Nishida, T, Adamian, M, Albiero, R, Tucci, G, Di Mario, C, and Colombo, A
- Subjects
- *
POLYTEF , *SURGICAL stents , *SAPHENOUS vein , *GRAFT rejection , *SURGERY , *VEIN transplantation , *BIOMEDICAL materials , *CORONARY artery bypass , *MYOCARDIAL infarction , *PROSTHETICS , *SURGICAL complications , *VASCULAR grafts , *DISEASE relapse ,MYOCARDIAL infarction-related mortality ,TREATMENT of surgical complications - Abstract
We compared the outcome of patients with saphenous graft disease treated with polytetrafluoroethylene (PTFE)-covered stents or noncovered stents. Angiographic success was similar; non-Q-wave myocardial infarction was lower in the PTFE group (p = 0.06) and long-term major cardiac events and restenosis rate were similar in the 2 groups. Implantation of PTFE-covered stent in vein graft disease seems to reduce the occurrence of distal embolization. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
21. The Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist: A Joint Statement by the ERAS® and ERAS® USA Societies
- Author
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Elias, K.M., Stone, A.B., McGinigle, K., Tankou, J.I., Scott, M.J., Fawcett, W.J., Demartines, N., Lobo, D.N., Ljungqvist, O., Urman, R.D., ERAS® Society and ERAS® USA, Elias, K., Adamian, M., Bushnell, F., Dagal, A., Engan, C., Marcotte, J., McGinigle, K., Pauksta, N., Pillarisetty, V., and Tankou, J.
- Subjects
Checklist ,Consensus ,Humans ,Perioperative Care ,Research Design/standards ,Research Report/standards - Abstract
Enhanced recovery after surgery (ERAS) programs are multimodal care pathways designed to minimize the physiological and psychological impact of surgery for patients. Increased compliance with ERAS guidelines is associated with improved patient outcomes across surgical types. As ERAS programs have proliferated, an unintentional effect has been significant variation in how ERAS-related studies are reported in the literature. To improve the quality of ERAS reporting, ERAS ® USA and the ERAS ® Society launched an effort to create an instrument to assist authors in manuscript preparation. Criteria to include were selected by a combination of literature review and expert opinion. The final checklist was refined by group consensus. The Societies present the Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist. The tool contains 20 items including best practices for reporting clinical pathways, compliance auditing, and formatting guidelines. The RECOvER Checklist is intended to provide a standardized framework for the reporting of ERAS-related studies. The checklist can also assist reviewers in evaluating the quality of ERAS-related manuscripts. Authors are encouraged to include the RECOvER Checklist when submitting ERAS-related studies to peer-reviewed journals.
- Published
- 2019
22. Does the specific intravascular ultrasound criterion used to optimize stent expansion have an impact on the probability of stent restenosis?
- Author
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Moussa, Issam, Moses, Jeffrey, Moussa, I, Moses, J, Di Mario, C, Albiero, R, De Gregorio, J, Adamian, M, Di Francesco, L, and Colombo, A
- Subjects
- *
INTRAVASCULAR ultrasonography , *SURGICAL stents , *CORONARY artery stenosis - Abstract
Intravascular ultrasound (IVUS) imaging has been used to optimize stent implantation in coronary arteries, but the criteria used were chosen on an empiric basis. The aim of this study was to determine whether any of these criteria have an independent role in predicting the probability of freedom from restenosis. The study population consisted of 425 patients (496 lesions) who underwent angiographically successful IVUS-guided stenting. Five IVUS criteria were studied: (1) intrastent minimal lumen cross-sectional area (ISMLCSA) > or =9 mm2; (2) ISMLCSA (> or =9 mm2 and > or =80% of average reference lumen cross-sectional area [CSA]); (3) ISMLCSA > or =90% of average reference lumen CSA; (4) ISMLCSA > or =90% of distal reference lumen CSA; and (5) ISMLCSA > or =55% of average reference vessel CSA. These criteria were met in 33%, 29%, 68%, 82%, and 69% of lesions, respectively. Angiographic follow-up was performed in 335 of 421 eligible patients (80%) at 5.3 +/- 2.7 months. An absolute ISMLCSA > or =9 mm2 was associated with the lowest restenosis, but this criterion was primarily achieved in large vessels. The only criterion that was associated with higher probability of freedom from restenosis independently from vessel size was an ISMLCSA > or =55% of average reference vessel CSA. Therefore, when IVUS is used to guide stent implantation an effort should be made to achieve the largest lumen safely possible. An ISMLCSA > or =55% of the average reference vessel CSA seems to be the most appropriate criterion in terms of frequency of achievement and in terms of increasing the probability of freedom from restenosis. [ABSTRACT FROM AUTHOR]
- Published
- 1999
- Full Text
- View/download PDF
23. Characteristics of patients with a large discrepancy in coronary artery diameter between quantitative angiography and intravascular ultrasound.
- Author
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Moussa, Issam, Kobayashi, Yoshio, Adamian, Milena, Hirose, Makoto, Di Mario, Carlo, Moses, Jeffrey, Colombo, Antonio, Moussa, I, Kobayashi, Y, Adamian, M, Hirose, M, Di Mario, C, Moses, J, and Colombo, A
- Subjects
- *
HEART diseases , *CARDIOLOGY - Abstract
Discusses the characteristics of patients with a large discrepancy in coronary artery diameter between a quantitative angiography and intravascular ultrasound. Tendency for the quantitative coronary angiography to underestimate vessel size; Evidence showing that the degree of difference is not constant across all patient or lesion subsets.
- Published
- 2001
- Full Text
- View/download PDF
24. Initial Experience and Usage Patterns With the Owlet Smart Sock Monitor in 47,495 Newborns.
- Author
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Dangerfield MI, Ward K, Davidson L, and Adamian M
- Abstract
We report the largest experience, to our knowledge, of home cardiorespiratory monitoring in 47,495 newborns using the novel Owlet Smart Sock (OSS) technology (October 2015 to May 2017). On average, 47,495 newborns were monitored for 6 months, 4.5 d/wk, 9.9 h/d. Continuous readings of oxygen saturation and heart rate were obtained from 39,626 full-term newborns. OSS users were likely first-time parents in their 30s with at least a college degree; 37% had a healthcare professional in the family; and 28% were at or below median income level per the US Census Bureau. "Peace of mind" was the reason to own an OSS in 75%, and 82% of parents followed Safe Sleep Guidelines. A total of 94% of parents reported a better quality of sleep. The fast and continuous pace of device adoption and reported experience suggest excellent parental acceptance of the OSS. Prospective studies are warranted to further evaluate its applications in the high-risk newborn population., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Michelle I. Dangerfield, Luke Davidson, and Milena Adamian are employees of Owlet Care, Inc. Kenneth Ward is a consultant and medical advisor to Owlet Care, Inc, and owns stock options in the company.
- Published
- 2017
- Full Text
- View/download PDF
25. Disruption of the blood-aqueous barrier and lens abnormalities in mice lacking lysyl oxidase-like 1 (LOXL1).
- Author
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Wiggs JL, Pawlyk B, Connolly E, Adamian M, Miller JW, Pasquale LR, Haddadin RI, Grosskreutz CL, Rhee DJ, and Li T
- Subjects
- Animals, Anterior Chamber metabolism, Blood-Aqueous Barrier enzymology, Cataract enzymology, Ciliary Body metabolism, Elastin metabolism, Exfoliation Syndrome enzymology, Fluorescein metabolism, Fluorescein Angiography, Fluorescent Antibody Technique, Indirect, Fluorescent Dyes metabolism, Immunoblotting, Intraocular Pressure, Iris metabolism, Lens, Crystalline enzymology, Mice, Mice, Inbred C57BL, Microscopy, Immunoelectron, Phenotype, Polymerase Chain Reaction, Amino Acid Oxidoreductases genetics, Blood-Aqueous Barrier pathology, Cataract pathology, Exfoliation Syndrome pathology, Gene Expression Regulation, Enzymologic physiology, Lens, Crystalline ultrastructure
- Abstract
Purpose: Exfoliation syndrome (ES) is commonly associated with glaucoma, premature cataracts, and other ocular and systemic pathologies. LOXL1 gene variants are significantly associated with ES; however, the role of the protein in ES development remains unclear. The purpose of this study was to characterize the ocular phenotype in Loxl1(-/-) (null) mice., Methods: Loxl1 null mice and strain-matched controls (C57BL) were evaluated by clinical and histologic analyses., Results: Anterior segment histology showed a pronounced vesiculation of the anterior lens in the null mice. The lesions were subcapsular and in direct apposition with the posterior iris surface. Fluorescein angiography showed increased diffusion of fluorescein into the anterior chamber of the null mice compared with age-matched controls (P = 0.003, two-tailed, unequal variance t-test), suggesting compromise of the blood-aqueous barrier. Intraocular pressure measurements were within the normal range (16.5 ± 2.0 mm Hg) in null mice up to 1 year of age. Immunohistochemistry showed decreased elastin in the iris and ciliary body in the null mouse compared with controls., Conclusions: Elimination of LOXL1 in mice impairs the blood-aqueous humor barrier in the ocular anterior segment and causes lens abnormalities consistent with cataract formation, but does not result in deposition of macromolecular material or glaucoma. These results show that mice lacking LOXL1 have some ES features but that complete disease manifestation requires other factors that could be genetic and/or environmental.
- Published
- 2014
- Full Text
- View/download PDF
26. An overview of epigenetics in nursing.
- Author
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Clark AE, Adamian M, and Taylor JY
- Subjects
- Humans, Education, Nursing organization & administration, Epigenesis, Genetic, Genetics, Medical organization & administration, Nurse's Role, Nursing Process organization & administration, Practice Patterns, Nurses' organization & administration
- Abstract
Epigenetic changes to the genome are biochemical alterations to the DNA that do not change an individual's genome but do change and influence gene expression. The nursing profession is qualified to conduct and integrate epigenetic-focused nursing research into practice. This article discusses current epigenetic nursing research, provides an overview of how epigenetic research relates to nursing practice, makes recommendations, and provides epigenetic online resources for nursing research. An overview of major epigenetic studies in nursing (specific to childbirth studies, preeclampsia, metabolic syndrome, immunotherapy cancer, and pain) is provided, with recommendations on next steps., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
27. Cone-beam computerized tomography evaluation of the maxillary dentoskeletal complex after rapid palatal expansion.
- Author
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Kartalian A, Gohl E, Adamian M, and Enciso R
- Subjects
- Adolescent, Cephalometry, Child, Female, Humans, Imaging, Three-Dimensional methods, Male, Malocclusion therapy, Retrospective Studies, Tooth physiopathology, Tooth Crown anatomy & histology, Alveolar Process diagnostic imaging, Cone-Beam Computed Tomography methods, Maxilla diagnostic imaging, Palatal Expansion Technique, Tooth diagnostic imaging
- Abstract
Introduction: Rapid palatal expansion (RPE) is routinely used to correct transverse deficiencies in the maxilla, but its effects on the dentoalveolus are uncertain. The purpose of this study was to compare measurements made on cone-beam computerized tomography scans between patients with RPE treatment and controls to determine transverse dimension increases and the amounts of alveolar and dental tipping., Methods: Twenty-five patients with posterior crossbite who required RPE treatment and 25 sex- and age-matched controls (no crossbite) were orthodontically treated and received cone-beam computerized tomography scans at the beginning and middle of treatment. Transverse widths and several angulations were measured, and matched paired t tests used., Results: RPE treatment produced a significant increase in all measured transverse dimensions. Analysis of posttreatment angulation changes in the RPE group showed that the alveolus substantially tipped buccally by nearly 5.6° (measured from a horizontal reference, the base of the hard palate). The angulations of the dentition, however, remained constant before and after treatment (<1° of change) in both groups., Conclusions: These data showed no statistically significant amount of relative dental tipping after RPE treatment but significant alveolar tipping compared with the controls., (Copyright © 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
28. Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis.
- Author
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Pawlyk BS, Bulgakov OV, Liu X, Xu X, Adamian M, Sun X, Khani SC, Berson EL, Sandberg MA, and Li T
- Subjects
- Animals, Cytoskeletal Proteins, Disease Models, Animal, Electroretinography, G-Protein-Coupled Receptor Kinase 1 metabolism, Genetic Vectors, Humans, Leber Congenital Amaurosis genetics, Mice, Mice, Inbred C57BL, Promoter Regions, Genetic, Proteins therapeutic use, Retinal Degeneration genetics, Retinal Degeneration therapy, Genetic Therapy, Leber Congenital Amaurosis therapy, Photoreceptor Connecting Cilium metabolism, Proteins genetics
- Abstract
RPGR-interacting protein-1 (RPGRIP1) is localized in the photoreceptor-connecting cilium, where it anchors the RPGR (retinitis pigmentosa GTPase regulator) protein, and its function is essential for photoreceptor maintenance. Genetic defect in RPGRIP1 is a known cause of Leber congenital amaurosis (LCA), a severe, early-onset form of retinal degeneration. We evaluated the efficacy of replacement gene therapy in a murine model of LCA carrying a targeted disruption of RPGRIP1. The replacement construct, packaged in an adeno-associated virus serotype 8 (AAV8) vector, used a rhodopsin kinase gene promoter to drive RPGRIP1 expression. Both promoter and transgene were of human origin. After subretinal delivery of the replacement gene in the mutant mice, human RPGRIP1 was expressed specifically in photoreceptors, localized correctly in the connecting cilia, and restored the normal localization of RPGR. Electroretinogram and histological examinations showed better preservation of rod and cone photoreceptor function and improved photoreceptor survival in the treated eyes. This study demonstrates the efficacy of human gene replacement therapy and validates a gene therapy design for future clinical trials in patients afflicted with this condition. Our results also have therapeutic implications for other forms of retinal degenerations attributable to a ciliary defect.
- Published
- 2010
- Full Text
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29. Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss.
- Author
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Yang J, Liu X, Zhao Y, Adamian M, Pawlyk B, Sun X, McMillan DR, Liberman MC, and Li T
- Subjects
- Animals, Extracellular Matrix Proteins genetics, Membrane Proteins genetics, Mice, Mice, Knockout, Protein Isoforms genetics, Reverse Transcriptase Polymerase Chain Reaction, Extracellular Matrix Proteins physiology, Hearing Loss genetics, Membrane Proteins physiology, Protein Isoforms physiology, Vision Disorders genetics
- Abstract
Mutations in whirlin cause either Usher syndrome type II (USH2), a deafness-blindness disorder, or nonsyndromic deafness. The molecular basis for the variable disease expression is unknown. We show here that only the whirlin long isoform, distinct from a short isoform by virtue of having two N-terminal PDZ domains, is expressed in the retina. Both long and short isoforms are expressed in the inner ear. The N-terminal PDZ domains of the long whirlin isoform mediates the formation of a multi-protein complex that includes usherin and VLGR1, both of which are also implicated in USH2. We localized this USH2 protein complex to the periciliary membrane complex (PMC) in mouse photoreceptors that appears analogous to the frog periciliary ridge complex. The latter is proposed to play a role in photoreceptor protein trafficking through the connecting cilium. Mice carrying a targeted disruption near the N-terminus of whirlin manifest retinal and inner ear defects, reproducing the clinical features of human USH2 disease. This is in contrast to mice with mutations affecting the C-terminal portion of whirlin in which the phenotype is restricted to the inner ear. In mice lacking any one of the USH2 proteins, the normal localization of all USH2 proteins is disrupted, and there is evidence of protein destabilization. Taken together, our findings provide new insights into the pathogenic mechanism of Usher syndrome. First, the three USH2 proteins exist as an obligatory functional complex in vivo, and loss of one USH2 protein is functionally close to loss of all three. Second, defects in the three USH2 proteins share a common pathogenic process, i.e., disruption of the PMC. Third, whirlin mutations that ablate the N-terminal PDZ domains lead to Usher syndrome, but non-syndromic hearing loss will result if they are spared., Competing Interests: The authors have declared that no competing interests exist.
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- 2010
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30. Increased light exposure alleviates one form of photoreceptor degeneration marked by elevated calcium in the dark.
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Liu X, Pawlyk BS, Adamian M, Olshevskaya EV, Dizhoor AM, Makino CL, and Li T
- Subjects
- Animals, Disease Models, Animal, Guanylate Cyclase-Activating Proteins metabolism, Mice, Mice, Mutant Strains, Photoreceptor Cells, Vertebrate metabolism, Photoreceptor Cells, Vertebrate radiation effects, Retina metabolism, Retina physiopathology, Retina radiation effects, Calcium metabolism, Darkness, Photoreceptor Cells, Vertebrate pathology
- Abstract
Background: In one group of gene mutations that cause photoreceptor degeneration in human patients, guanylyl cyclase is overactive in the dark. The ensuing excess opening of cGMP-gated cation channels causes intracellular calcium to rise to toxic levels. The Y99C mutation in guanylate cyclase-activating protein 1 (GCAP1) has been shown to act this way. We determined whether prolonged light exposure, which lowers cGMP levels through activation of phototransduction, might protect photoreceptors in a line of transgenic mice carrying the GCAP1-Y99C., Methodology/principal Findings: We reared cohorts of GCAP1-Y99C transgenic mice under standard cyclic, constant dark and constant light conditions. Mouse eyes were analyzed by histology and by immunofluorescence for GFAP upregulation, a non-specific marker for photoreceptor degeneration. Full-field electroretinograms (ERGs) were recorded to assess retinal function. Consistent with our hypothesis, constant darkness accelerated disease, while continuous lighting arrested photoreceptor degeneration., Conclusions/significance: In contrast to most forms of retinal degeneration, which are exacerbated by increased exposure to ambient light, a subset with mutations that cause overly active guanylyl cyclase and high intracellular calcium benefitted from prolonged light exposure. These findings may have therapeutic implications for patients with these types of genetic defects.
- Published
- 2009
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31. Increased choroidal neovascularization following laser induction in mice lacking lysyl oxidase-like 1.
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Yu HG, Liu X, Kiss S, Connolly E, Gragoudas ES, Michaud NA, Bulgakov OV, Adamian M, DeAngelis MM, Miller JW, Li T, and Kim IK
- Subjects
- Animals, Bruch Membrane ultrastructure, Choroidal Neovascularization etiology, Elastic Tissue ultrastructure, Elastin metabolism, Enzyme-Linked Immunosorbent Assay, Female, Fluorescein Angiography, Fluorescent Antibody Technique, Indirect, Immunoblotting, Male, Matrix Metalloproteinases metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Immunoelectron, Vascular Endothelial Growth Factor A metabolism, Amino Acid Oxidoreductases physiology, Bruch Membrane enzymology, Choroidal Neovascularization enzymology, Choroidal Neovascularization physiopathology, Elastic Tissue enzymology, Laser Coagulation
- Abstract
Purpose: Age-related degradation of the elastic lamina in Bruch's membrane may have a permissive effect on the growth of choroidal neovascularization (CNV). This study investigated the influence of defective elastic fiber maintenance in the development of laser-induced CNV., Methods: A mouse lacking lysyl oxidase-like (LOXL)-1, an enzyme essential for elastin polymerization, was studied. The morphologic characteristics of the elastic lamina within Bruch's membrane were examined in mutant and wild-type (WT) eyes. Laser-induced CNV was evaluated by fluorescein angiography and choroidal flat mounts. Immunohistochemistry for elastin was performed on the CNV lesions, and vascular endothelial growth factor (VEGF) levels were determined by ELISA. Soluble elastin and matrix metalloproteinase (MMPs) levels were also analyzed by immunoblotting., Results: The elastic lamina of Bruch's membrane in the LOXL1-deficient mice was fragmented and less continuous than in the WT controls. The mutant mice showed increased levels of soluble elastin peptides and reduced elastin polymer deposition in neovascular membranes. Significantly larger CNV with greater leakage on fluorescein angiography developed in mutant mice. VEGF levels in the RPE/choroid were higher in the knockout mice on days 7 and 14 after laser (P < 0.05). MT1-MMP (MMP14) was also elevated after laser in the LOXL1 mutant eyes compared to the WT controls., Conclusions: These results show that a systemic defect in elastic fiber deposition affects Bruch's membrane integrity and leads to more aggressive CNV growth. The latter may be partially mediated by abnormal signaling from the accumulation of soluble elastin peptides.
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- 2008
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32. AAV-mediated expression targeting of rod and cone photoreceptors with a human rhodopsin kinase promoter.
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Khani SC, Pawlyk BS, Bulgakov OV, Kasperek E, Young JE, Adamian M, Sun X, Smith AJ, Ali RR, and Li T
- Subjects
- Animals, Gene Targeting, Genetic Vectors, Kidney embryology, Luminescent Agents, Mice, Plasmids, Rats, Retinal Neoplasms genetics, Retinoblastoma genetics, Rod Opsins genetics, Transfection, Transgenes, Tumor Cells, Cultured, Dependovirus genetics, G-Protein-Coupled Receptor Kinase 1 genetics, Gene Expression, Green Fluorescent Proteins genetics, Photoreceptor Cells, Vertebrate metabolism, Promoter Regions, Genetic genetics
- Abstract
Purpose: Gene therapy for retinal degeneration requires well-defined promoters that drive expression in rod and cone photoreceptors. This study was undertaken to develop short, active derivatives of the human rhodopsin kinase (RK) gene promoter for targeting transgene expression in rods and cones. RK, also known as G protein-coupled receptor kinase 1 (GRK1), is a component of the light adaptation pathway expressed in rods and cones., Methods: Human RK (hRK) promoter and its concatemers or derivatives extending into the conserved 5' untranslated region (5'-UTR) were assayed for promoter activity in WERI retinoblastoma or Crx/Sp1-supplemented HEK-293 cells. The derivative displaying the highest activity was linked to a GFP reporter and packaged in a pseudotyped adenoassociated viral vector (AAV2/5). The AAV vector was tested in vivo by subretinal injections in wild-type mice, in the all-cone Nrl(-/-) mice, and in the cone-rich diurnal Nile grass rat (Arvicanthis niloticus). Control eyes received a similar AAV2/5 vector carrying a mouse rod opsin (mOps) promoter-controlled GFP reporter., Results: The hRK promoter with the full 5' untranslated sequence (-112 to +180) was the most active in cell culture. Delivered by the AAV2/5 vector, RK promoter drove GFP expression specifically in photoreceptors. In rods, hRK promoter-mediated expression was as efficient as, but appeared more uniform than, mOps promoter-mediated expression. In cones, the hRK promoter drove expression, whereas the mOps promoter did not., Conclusions: The hRK promoter is active and specific for rod and cone photoreceptors. Because of its small size and proven activity in cones, it is a promoter of choice for somatic gene transfer and gene therapy targeting rods and cones.
- Published
- 2007
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33. [Production of fructooligosaccharide syrup from sucrose in combination with palatinose and trehalose].
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Markosian AA, Abelian LA, Adamian MO, Ekazhev ZD, Akopian ZhI, and Abelian VA
- Subjects
- Aspergillus enzymology, Catalysis, Disaccharides biosynthesis, Gammaproteobacteria enzymology, Intramolecular Transferases metabolism, Isomaltose biosynthesis, Isomaltose analogs & derivatives, Oligosaccharides biosynthesis, Sucrose metabolism, Trehalose metabolism, beta-Fructofuranosidase biosynthesis
- Abstract
The fructofuranosidases (EC 3.2.1.26) of Aspergillus niger St-0018 and A. foetidus St-0194 were used to produce fructooligosaccharides (FOS) under periodic and continuous conditions. The incorporation of cells into calcium alginate gel gave the most efficient immobilized biocatalysts. The feasibility of transforming residual sucrose into palatinose and trehalulose using isomaltulose synthase (EC 5.4.99.11) was demonstrated.
- Published
- 2007
34. Mpp4 is required for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals.
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Yang J, Pawlyk B, Wen XH, Adamian M, Soloviev M, Michaud N, Zhao Y, Sandberg MA, Makino CL, and Li T
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Animals, Disks Large Homolog 4 Protein, Fluorescent Antibody Technique, Gene Deletion, Guanylate Kinases, Homeostasis, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Knockout, Microscopy, Confocal, Microscopy, Electron, Transmission, Microscopy, Immunoelectron, Models, Biological, Multiprotein Complexes metabolism, Plasma Membrane Calcium-Transporting ATPases genetics, Presynaptic Terminals ultrastructure, Protein Binding, Retinal Rod Photoreceptor Cells ultrastructure, Synaptic Transmission genetics, Synaptic Transmission physiology, Two-Hybrid System Techniques, Calcium metabolism, Membrane Proteins physiology, Plasma Membrane Calcium-Transporting ATPases metabolism, Presynaptic Terminals metabolism, Retinal Rod Photoreceptor Cells metabolism
- Abstract
Membrane palmitoylated protein 4 (Mpp4) is a member of the membrane-associated guanylate kinase family. We show that Mpp4 localizes specifically to the plasma membrane of photoreceptor synaptic terminals. Plasma membrane Ca(2+) ATPases (PMCAs), the Ca(2+) extrusion pumps, interact with an Mpp4-dependent presynaptic membrane protein complex that includes Veli3 and PSD95. In mice lacking Mpp4, PMCAs were lost from rod photoreceptor presynaptic membranes. Synaptic ribbons were enlarged, a phenomenon known to correlate with higher Ca(2+). SERCA2 (sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase, type 2), which pumps cytosolic Ca(2+) into intracellular Ca(2+) stores and localizes next to the ribbons, was increased. The distribution of IP(3)RII (InsP(3) receptor, type 2), which releases Ca(2+) from the stores, was shifted away from the synaptic terminals. Synaptic transmission to second-order neurons was maintained but was reduced in amplitude. These data suggest that loss of Mpp4 disrupts a Ca(2+) extrusion mechanism at the presynaptic membranes, with ensuing adaptive responses by the photoreceptor to restore Ca(2+) homeostasis. We propose that Mpp4 organizes a presynaptic protein complex that includes PMCAs and has a role in modulating Ca(2+) homeostasis and synaptic transmission in rod photoreceptors.
- Published
- 2007
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35. Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells.
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Liu X, Bulgakov OV, Darrow KN, Pawlyk B, Adamian M, Liberman MC, and Li T
- Subjects
- Animals, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microscopy, Confocal, Molecular Sequence Data, Retinitis Pigmentosa metabolism, Cochlea growth & development, Extracellular Matrix Proteins physiology, Gene Expression Regulation, Developmental, Hair Cells, Auditory growth & development, Retina growth & development, Retinitis Pigmentosa pathology
- Abstract
Usher syndrome type IIA (USH2A), characterized by progressive photoreceptor degeneration and congenital moderate hearing loss, is the most common subtype of Usher syndrome. In this article, we show that the USH2A protein, also known as usherin, is an exceptionally large ( approximately 600-kDa) matrix protein expressed specifically in retinal photoreceptors and developing cochlear hair cells. In mammalian photoreceptors, usherin is localized to a spatially restricted membrane microdomain at the apical inner segment recess that wraps around the connecting cilia, corresponding to the periciliary ridge complex described for amphibian photoreceptors. In sensory hair cells of the cochlea, it is associated transiently with the hair bundles during postnatal development. Targeted disruption of the Ush2a gene in mice leads to progressive photoreceptor degeneration and a moderate but nonprogressive hearing impairment, mimicking the visual and hearing deficits in USH2A patients. These data suggest that usherin is required for the long-term maintenance of retinal photoreceptors and for the development of cochlear hair cells. We propose a model in which usherin in photoreceptors is tethered via its C terminus to the plasma membrane and its large extracellular domain projecting into the periciliary matrix, where they may interact with the connecting cilium to fulfill important structural or signaling roles.
- Published
- 2007
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36. [Transglycosylation of L-ascorbic acid].
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Markosian AA, Abelian LA, Adamian MO, Akopian ZhI, and Abelian VA
- Subjects
- Bacillus enzymology, Glycosylation, Polysaccharides chemistry, Saccharomyces cerevisiae enzymology, gamma-Cyclodextrins chemistry, Ascorbic Acid chemistry, Glucosyltransferases chemistry, alpha-Glucosidases chemistry
- Abstract
Cyclodextrin glucanotransferases (CGTase, EC 2.4.1.19) produced by mesophilic, thermophilic, and halophilic bacilli, as well as maltase (EC 3.2.1.20) produced by various strains of Saccharomyces cerevisiae have been applied for transglycosylation of L-ascorbic acid using starch, maltodextrin, gamma-cyclodextrin, and maltose as donors of glucosyl residue. The CGTases produced by thermophilic strains are the most efficient. The degree of transglucosylation is more than 60%.
- Published
- 2007
37. Rod and cone opsin mislocalization in an autopsy eye from a carrier of X-linked retinitis pigmentosa with a Gly436Asp mutation in the RPGR gene.
- Author
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Adamian M, Pawlyk BS, Hong DH, and Berson EL
- Subjects
- Aged, Female, Fluorescent Antibody Technique, Indirect, Genetic Diseases, X-Linked genetics, Guanine Nucleotide Exchange Factors genetics, Heterozygote, Humans, Retinitis Pigmentosa genetics, Eye Proteins genetics, Genetic Diseases, X-Linked metabolism, Photoreceptor Cells, Vertebrate metabolism, Point Mutation, Retinitis Pigmentosa metabolism, Rod Opsins metabolism
- Abstract
Purpose: We investigated whether opsin mislocalization occurs in photoreceptors in a female carrier of X-linked retinitis pigmentosa with a Gly436Asp mutation in the retinitis pigmentosa GTPase regulator gene (RPGR)., Design: Histologic findings in autopsy eyes from a carrier were compared with those from a normal female., Methods: Frozen retinal sections from the periphery of one eye of the carrier and the normal were stained with antibodies against either human red or green opsins, blue cone opsin, or rhodopsin and labeled with fluorochrome conjugated secondary antibodies. Cell nuclei were counterstained with Hoechst dye. Fellow eyes were evaluated with light microscopy., Results: Fluorescent labeling showed mislocalized cone and rod opsins in photoreceptor cells only in the carrier. The carrier also showed some loss of photoreceptor nuclei., Conclusions: A defect in trafficking of opsins to outer segments exists in a carrier with the RPGR Gly436Asp mutation.
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- 2006
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38. Sexual behaviours of HIV-seropositive men and women following release from prison.
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Stephenson BL, Wohl DA, McKaig R, Golin CE, Shain L, Adamian M, Emrick C, Strauss RP, Fogel C, and Kaplan AH
- Subjects
- Adult, Female, HIV Seropositivity psychology, HIV Seropositivity transmission, Humans, Male, Middle Aged, Risk Factors, Sexual Partners, HIV Infections transmission, HIV Seropositivity epidemiology, Prisoners, Sexual Behavior physiology
- Abstract
Twenty-five percent of the US HIV-infected population is released from a prison or jail each year. As the extent of risky sexual behaviours after prison release is largely unknown, we interviewed a cohort (n = 64) of HIV-infected, recently released (mean 45 days, SD 28) prisoners about their current sexual risk behaviours. Almost half (47%, n = 64) of the released prisoners reported sexual activity after release, mostly with regular partners. Although 26% (n = 27) reported engaging in unprotected sexual activity with their regular partners, none (n = 4) reported unprotected sex with their non-regular partners. Furthermore, 33% percent (n = 15) of the releasees with regular partners reported engaging in unprotected sex with HIV-seronegative partners. These results suggest that regular partners of HIV-infected prison releasees are at risk of acquiring HIV infection, and secondary risk-reduction strategies are needed for HIV-infected prison releasees.
- Published
- 2006
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39. Rootletin interacts with C-Nap1 and may function as a physical linker between the pair of centrioles/basal bodies in cells.
- Author
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Yang J, Adamian M, and Li T
- Subjects
- Animals, Cell Line, Cell Nucleus ultrastructure, Centrioles metabolism, Chromosomal Proteins, Non-Histone analysis, Chromosomal Proteins, Non-Histone metabolism, Cytoskeletal Proteins analysis, Cytoskeletal Proteins metabolism, Dogs, Interphase, Mice, Microscopy, Confocal, Poly-ADP-Ribose Binding Proteins, Two-Hybrid System Techniques, Centrioles ultrastructure, Chromosomal Proteins, Non-Histone physiology, Cytoskeletal Proteins physiology
- Abstract
Rootletin, a major structural component of the ciliary rootlet, is located at the basal bodies and centrosomes in ciliated and nonciliated cells, respectively. Here we investigated its potential role in the linkage of basal bodies/centrioles and the mechanism involved in such linkages. We show that rootletin interacts with C-Nap1, a protein restricted at the ends of centrioles and functioning in centrosome cohesion in interphase cells. Their interaction in vivo is supported by their colocalization at the basal bodies/centrioles and coordinated association with the centrioles during the cell cycle. Ultrastructural examinations demonstrate that rootletin fibers connect the basal bodies in ciliated cells and are present both at the ends of and in between the pair of centrioles in nonciliated cells. The latter finding stands in contrast with C-Nap1, which is present only at the ends of the centrioles. Transient expression of C-Nap1 fragments dissociated rootletin fibers from the centrioles, resulting in centrosome separation in interphase. Overexpression of rootletin in cells caused multinucleation, micronucleation, and irregularity of nuclear shape and size, indicative of defects in chromosome separation. These data suggest that rootletin may function as a physical linker between the pair of basal bodies/centrioles by binding to C-Nap1.
- Published
- 2006
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40. Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP.
- Author
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Pawlyk BS, Smith AJ, Buch PK, Adamian M, Hong DH, Sandberg MA, Ali RR, and Li T
- Subjects
- Animals, Blindness congenital, Blindness metabolism, Cytoskeletal Proteins, Dependovirus genetics, Disease Models, Animal, Electroretinography, Eye Proteins genetics, Eye Proteins metabolism, Fluorescent Antibody Technique, Indirect, Genetic Vectors, Green Fluorescent Proteins genetics, Mice, Mice, Knockout, Photoreceptor Cells, Vertebrate ultrastructure, Promoter Regions, Genetic, Proteins metabolism, Retinal Degeneration metabolism, Retinal Degeneration pathology, Rod Opsins genetics, Transfection, Blindness therapy, Gene Expression Regulation physiology, Genetic Therapy, Photoreceptor Cells, Vertebrate metabolism, Proteins genetics, Retinal Degeneration therapy
- Abstract
Purpose: Retinitis pigmentosa GTPase regulator (RPGR) is a photoreceptor protein anchored in the connecting cilia by an RPGR-interacting protein (RPGRIP). Loss of RPGRIP causes Leber congenital amaurosis (LCA), a severe form of photoreceptor degeneration. The current study was an investigation of whether somatic gene replacement could rescue degenerating photoreceptors in a murine model of LCA due to a defect in RPGRIP., Methods: An RPGRIP expression cassette, driven by a mouse opsin promoter, was packaged into recombinant adeno-associated virus (AAV). The AAV vector was delivered into the right eyes of RPGRIP(-/-) mice by a single subretinal injection into the superior hemisphere. The left eyes received a saline injection as a control. Full-field electroretinograms (ERGs) were recorded from both eyes at 2, 3, 4, and 5 months after injection. After the final follow-up, retinas were analyzed by immunostaining or by light and electron microscopy., Results: Delivery of the AAV vector led to RPGRIP expression and restoration of normal RPGR localization at the connecting cilia. Photoreceptor preservation was evident by a thicker cell layer and well-developed outer segments in the treated eyes. Rescue was more pronounced in the superior hemisphere coincident with the site of delivery. Functional preservation was demonstrated by ERG., Conclusions: AAV-mediated RPGRIP gene replacement preserves photoreceptor structure and function in a mouse model of LCA, despite ongoing cell loss at the time of intervention. These results indicate that gene replacement therapy may be effective in patients with LCA due to a defect in RPGRIP and suggest that further preclinical development of gene therapy for this disorder is warranted.
- Published
- 2005
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41. The ciliary rootlet maintains long-term stability of sensory cilia.
- Author
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Yang J, Gao J, Adamian M, Wen XH, Pawlyk B, Zhang L, Sanderson MJ, Zuo J, Makino CL, and Li T
- Subjects
- Animals, Centrioles physiology, Cytoskeletal Proteins deficiency, Cytoskeletal Proteins genetics, Kinetics, Lymphocytes cytology, Lymphocytes immunology, Mice, Mutation genetics, Organelles physiology, Photoreceptor Cells, Vertebrate cytology, Photoreceptor Cells, Vertebrate physiology, Retinal Degeneration, Time Factors, Cilia physiology, Cytoskeleton physiology
- Abstract
The striated ciliary rootlet is a prominent cytoskeleton originating from basal bodies of ciliated cells. Although a familiar structure in cell biology, its function has remained unresolved. In this study, we carried out targeted disruption in mice of the gene for rootletin, a component of the rootlet. In the mutant, ciliated cells are devoid of rootlets. Phototransduction and ciliary beating in sensory and motile cilia initially exhibit no apparent functional deficits. However, photoreceptors degenerate over time, and mutant lungs appear prone to pathological changes consistent with insufficient mucociliary clearance. Further analyses revealed a striking fragility at the ciliary base in photoreceptors lacking rootlets. In vitro assays suggest that the rootlet is among the least dynamic of all cytoskeletons and interacts with actin filaments. Thus, a primary function of the rootlet is to provide structural support for the cilium. Inasmuch as photoreceptors elaborate an exceptionally enlarged sensory cilium, they are especially dependent on the rootlet for structural integrity and long-term survival.
- Published
- 2005
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42. A single, abbreviated RPGR-ORF15 variant reconstitutes RPGR function in vivo.
- Author
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Hong DH, Pawlyk BS, Adamian M, Sandberg MA, and Li T
- Subjects
- Animals, Cytoskeletal Proteins, Dependovirus genetics, Electroretinography, Exons genetics, Fluorescent Antibody Technique, Indirect, Genetic Vectors, Glial Fibrillary Acidic Protein metabolism, Guanine Nucleotide Exchange Factors genetics, Immunoblotting, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Open Reading Frames genetics, Proteins metabolism, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa pathology, Rod Opsins metabolism, Transfection, Transgenes, Carrier Proteins genetics, Eye Proteins genetics, Gene Expression Regulation physiology, Photoreceptor Cells, Vertebrate metabolism, Recombinant Fusion Proteins genetics, Retinitis Pigmentosa prevention & control
- Abstract
Purpose: The retinitis pigmentosa GTPase regulator (RPGR) is essential for the maintenance of photoreceptor viability. RPGR is expressed as constitutive and ORF15 variants because of alternative splicing. This study was designed to examine whether the retina-specific ORF15 variant alone could substantially substitute for RPGR function. A further objective was to test whether the highly repetitive purine-rich region of ORF15 could be abbreviated without ablating the function, so as to accommodate RPGR replacement genes in adenoassociated virus (AAV) vectors., Methods: A cDNA representing RPGR-ORF15 but shortened by 654 bp in the repetitive region was placed under the control of a chicken beta-actin (CBA) hybrid promoter. The resultant construct was transfected into mouse embryonic stem cells. Clones expressing the transgene were selected and injected into mouse blastocysts. Transgenic chimeras were crossed with RPGR knockout (KO) mice. Mice expressing the transgene but null for endogenous RPGR (Tg/KO) were studied from 1 month to 18 months of age by light and electron microscopy, immunofluorescence, and electroretinography (ERG). The results were compared with those of wild-type (WT) and RPGR-null control mice., Results: Transgenic RPGR-ORF15 was found in the connecting cilia of rod and cone photoreceptors, at approximately 20% of the WT level. Photoreceptor morphology, cone opsin localization, expression of GFAP (a marker for retinal degeneration) and ERGs were consistent with the transgene exerting substantial rescue of retinal degeneration due to loss of endogenous RPGR., Conclusions: RPGR-ORF15 is the functionally significant variant in photoreceptors. The length of its repetitive region can be reduced while preserving its function. The current findings should facilitate the design of gene replacement therapy for RPGR-null mutations.
- Published
- 2005
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43. Comparison of safety and efficacy between first and second generation of angio-seal closure devices in interventional patients.
- Author
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Lasic Z, Mehran R, Dangas G, Mintz G, Nikolsky E, Tsounias E, Udani PC, Adamian M, Adamian J, Moussa I, Collins M, Stone G, and Moses J
- Subjects
- Adult, Aged, Equipment Safety, Hemostasis, Surgical methods, Humans, Middle Aged, Pilot Projects, Suture Techniques, Treatment Outcome, Angioplasty, Balloon, Coronary, Cardiac Catheterization, Hemostasis, Surgical instrumentation
- Abstract
Arterial closure devices are safe and effective in selected patients, with complication rates similar to or lower than manual compression. The purpose of this study was to compare the safety and efficacy of the first- and new-generation Angio-Seal devices in patients undergoing PCI. This study found that the new Angio-Seal STS Platform device can secure hemostasis after PCI in a safe and effective manner similar to the old device. The new platform is easier for the operator and for the patients.
- Published
- 2004
44. Histologic study of retinitis pigmentosa due to a mutation in the RP13 gene (PRPC8): comparison with rhodopsin Pro23His, Cys110Arg, and Glu181Lys.
- Author
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To K, Adamian M, and Berson EL
- Subjects
- Aged, Aged, 80 and over, Genes, Dominant, Humans, Middle Aged, RNA-Binding Proteins, Carrier Proteins genetics, Mutation, Missense, Photoreceptor Cells, Vertebrate ultrastructure, Retinitis Pigmentosa genetics, Retinitis Pigmentosa pathology, Rhodopsin genetics
- Abstract
Purpose: To evaluate the retina in autopsy eyes from patients over age 60 with autosomal dominant retinitis pigmentosa and a mutation in the RP13 gene (designated as PRPC8, Arg2310Gly), rhodopsin Pro23His, rhodopsin Cys110Arg, or rhodopsin Glu181Lys., Design: Histologic study of the retina., Methods: All eyes were prepared for electron microscopy within 12 hours after death., Results: All eyes showed loss of rod photoreceptors. Remaining cones showed perinuclear membranous swirls, inclusion bodies in the inner segments, and shortened or absent outer segments despite causation by various gene defects., Conclusion: The comparable histologic findings in these four cases suggest a final common pathway leading to photoreceptor cell death in these dominant forms of retinitis pigmentosa.
- Published
- 2004
- Full Text
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45. Dominant, gain-of-function mutant produced by truncation of RPGR.
- Author
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Hong DH, Pawlyk BS, Adamian M, and Li T
- Subjects
- Alternative Splicing genetics, Animals, COS Cells, Electroretinography, Gene Expression Regulation physiology, Genes, Dominant, Genetic Diseases, X-Linked pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Open Reading Frames genetics, Photoreceptor Cells, Vertebrate pathology, RNA, Messenger metabolism, Retinitis Pigmentosa pathology, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Transgenes, Carrier Proteins genetics, Eye Proteins, Genetic Diseases, X-Linked genetics, Retinitis Pigmentosa genetics
- Abstract
Purpose: The retinitis pigmentosa GTPase regulator (RPGR) is essential in the maintenance of photoreceptor viability. Mutations in the X-linked RPGR gene have generally been assumed to be recessive. This study was undertaken to investigate whether certain mutant RPGR alleles may act dominantly., Methods: An RPGR transgene representing the RPGR ORF15 variant was placed under a non-tissue-specific promoter and introduced into transgenic mice. The transgene was crossed into both a wild type (WT) and an RPGR null background. Its expression was analyzed by RT-PCR, immunoblot analysis, and immunofluorescence. Photoreceptor survival was assessed by electroretinography and histology., Results: The RPGR transgene transcript underwent photoreceptor-specific, alternative splicing involving the purine-rich region of the ORF15 exon, generating a shortened mRNA and a premature stop codon. This truncation mutant caused more rapid photoreceptor degeneration than that in the RPGR null (knockout) mutant. The disease course was similar, whether the transgene was coexpressed with WT RPGR or expressed alone in the RPGR null background., Conclusions: Certain truncated forms of RPGR can behave as a dominant, gain-of-function mutant. These data suggest that human RPGR mutations are not necessarily null and some may also act as dominant alleles, leading to a more severe phenotype than a null mutant.
- Published
- 2004
- Full Text
- View/download PDF
46. The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis.
- Author
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Zhao Y, Hong DH, Pawlyk B, Yue G, Adamian M, Grynberg M, Godzik A, and Li T
- Subjects
- Amino Acid Sequence, Animals, COS Cells, Chlorocebus aethiops, Cytoskeletal Proteins, DNA Primers, Exons, Mice, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Morphogenesis genetics, Phenotype, Photoreceptor Cells, Vertebrate physiology, Polymerase Chain Reaction, Proteins metabolism, Recombinant Proteins metabolism, Retinitis Pigmentosa genetics, Saccharomyces cerevisiae genetics, Transfection, Carrier Proteins genetics, Carrier Proteins metabolism, Eye Proteins, Optic Disk embryology, Proteins genetics
- Abstract
Retinitis pigmentosa is a photoreceptor degenerative disease leading to blindness in adulthood. Leber congenital amaurosis (LCA) describes a more severe condition with visual deficit in early childhood. Defects in the retinitis pigmentosa GTPase regulator (RPGR) and an RPGR-interacting protein (RPGRIP) are known causes of retinitis pigmentosa and LCA, respectively. Both proteins localize in the photoreceptor connecting cilium (CC), a thin bridge linking the cell body and the light-sensing outer segment. We show that RPGR is absent in the CC of photoreceptors lacking RPGRIP, but not vice versa. Mice lacking RPGRIP elaborate grossly oversized outer segment disks resembling a cytochalasin D-induced defect and have a more severe disease than mice lacking RPGR. Mice lacking both proteins are phenotypically indistinguishable from mice lacking RPGRIP alone. In vitro, RPGRIP forms homodimer and elongated filaments via interactions involving its coiled-coil and C-terminal domains. We conclude that RPGRIP is a stable polymer in the CC where it tethers RPGR and that RPGR depends on RPGRIP for subcellular localization and normal function. Our data suggest that RPGRIP is also required for disk morphogenesis, putatively by regulating actin cytoskeleton dynamics. The latter hypothesis may be consistent with a distant homology between the C-terminal domain of RPGRIP and an actin-fragmin kinase, predicted by fold recognition algorithms. A defect in RPGRIP encompasses loss of both functions, hence the more severe clinical manifestation as LCA.
- Published
- 2003
- Full Text
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47. Deferoxamine enhances neovascularization and recovery of ischemic skeletal muscle in an experimental sheep model.
- Author
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Chekanov VS, Nikolaychik V, Maternowski MA, Mehran R, Leon MB, Adamian M, Moses J, Dangas G, Kipshidze N, and Akhtar M
- Subjects
- Animals, Deferoxamine administration & dosage, Fibrin Tissue Adhesive, Iron Chelating Agents administration & dosage, Sheep, Deferoxamine therapeutic use, Iron Chelating Agents therapeutic use, Ischemia prevention & control, Muscle, Skeletal blood supply, Neovascularization, Physiologic drug effects
- Abstract
Background: Iron chelators have been reported to interfere with inflammatory cells and possibly enhance vascular growth factor expression. The objective of this study was to investigate the efficacy of the iron chelator deferoxamine mesylate in preventing skeletal muscle ischemia., Methods: The latissimus dorsi muscle (LDM) was mobilized in 20 adult sheep. Two separate pockets were created in each sheep. Autologous fibrin sealant with or without 100 mg/mL of deferoxamine mesylate (10 pockets) was added to the pockets. Deferoxamine mesylate alone was also applied to another 10 pockets, whereas the 10 other pockets served as controls., Results: Conventional, indirect immunofluorescent enface staining showed that in nonmobilized, nonischemic LDM the capillary density was 196 +/- 14 capillaries/mm2 in the distal and 207 +/- 19 capillaries/mm2 in the middle part. After severe ischemic shock (subtotal mobilization), the muscle did not recover completely even after 2 months (149 +/- 15 capillaries/mm2 in the distal part and 177 +/- 16 capillaries/mm2 in the middle part of the LDM). Fibrin application only increased muscle neovascularization. The number of capillaries per mm2 of muscle increased to 250 +/- 25 in the distal part and to 271 +/- 24 in the middle part of the LDM. However, when fibrin was applied with added deferoxamine mesylate, the capillary density increased to 361 +/- 25 capillaries/mm2 in the distal part (p < 0.05 vs fibrin only; controls) and to 401 +/- 20 capillaries/mm2 in the middle part of the LDM (p < 0.05 vs fibrin only and p < 0.001 vs controls). The data are concordant with the blood flow estimation before and after mobilization (severe ischemic shock) in the different parts of the LDM., Conclusions: Local application of deferoxamine mesylate enhances neovascularization and recovery of surgically induced skeletal muscle ischemia in a sheep model.
- Published
- 2003
- Full Text
- View/download PDF
48. Transplantation of autologous endothelial cells induces angiogenesis.
- Author
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Chekanov V, Akhtar M, Tchekanov G, Dangas G, Shehzad MZ, Tio F, Adamian M, Colombo A, Roubin G, Leon MB, Moses JW, and Kipshidze NN
- Subjects
- Animals, Fibrinogen administration & dosage, Immunohistochemistry, Injections, Microscopy, Electron, Myocardial Ischemia physiopathology, Myocardial Ischemia therapy, Myocardium chemistry, Myocardium ultrastructure, Sheep, Thrombin administration & dosage, Transplantation, Autologous, Ventricular Function, Left, Cell Transplantation, Coronary Circulation, Endothelium, Vascular cytology, Neovascularization, Physiologic physiology
- Abstract
This study examined the feasibility and efficacy of autologous endothelial cell (EC) transplantation using a fibrin matrix in the ischemic myocardium of sheep. Four weeks after placing an ameroid constrictor in the circumflex artery of 12 adult sheep, four animals (EC group) were subjected to EC transplantation. In four others (saline [SAL] group) saline with added inactivated cells was injected and four animals served as controls. Eight weeks after treatment the animals were sacrificed to assess histology and ultrastructure. Eight weeks after injection, ventricular function was markedly improved in the EC transplant group, but had deteriorated in the SAL and control groups. Myocardial blood flow was also increased in the EC group. Histology and electron microscopy revealed extensive neovascularization after EC transplantation and improved myocardial appearance. Heterotopic transplantation of EC within a fibrin matrix enhances neovascularization, increases myocardial blood flow, and improves left ventricular function.
- Published
- 2003
- Full Text
- View/download PDF
49. Rootletin, a novel coiled-coil protein, is a structural component of the ciliary rootlet.
- Author
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Yang J, Liu X, Yue G, Adamian M, Bulgakov O, and Li T
- Subjects
- Animals, COS Cells, Cytoskeletal Proteins classification, Cytoskeletal Proteins genetics, Epithelial Cells cytology, Humans, Kinesins, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins metabolism, Models, Biological, Molecular Sequence Data, Recombinant Proteins metabolism, Retina chemistry, Retina cytology, Two-Hybrid System Techniques, Cilia chemistry, Cilia ultrastructure, Cytoskeletal Proteins metabolism, Polymers chemistry
- Abstract
The ciliary rootlet, first recognized over a century ago, is a prominent structure originating from the basal body at the proximal end of a cilium. Despite being the largest cytoskeleton, its structural composition has remained unknown. Here, we report a novel 220-kD protein, designated rootletin, found in the rootlets of ciliated cells. Recombinant rootletin forms detergent-insoluble filaments radiating from the centrioles and resembling rootlets found in vivo. An mAb widely used as a marker for vertebrate rootlets recognizes an epitope in rootletin. Rootletin has a globular head domain and a tail domain consisting of extended coiled-coil structures. Rootletin forms parallel in register homodimers and elongated higher order polymers mediated by the tail domain alone. The head domain may be required for targeting to the basal body and binding to a kinesin light chain. In retinal photoreceptors where rootlets appear particularly robust, rootlets extend from the basal bodies to the synaptic terminals and anchor ER membranes along their length. Our data indicate that rootlets are composed of homopolymeric rootletin protofilaments bundled into variably shaped thick filaments. Thus, rootletin is the long-sought structural component of the ciliary rootlet.
- Published
- 2002
- Full Text
- View/download PDF
50. Histopathologic study of variation in severity of retinitis pigmentosa due to the dominant rhodopsin mutation Pro23His.
- Author
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To K, Adamian M, Dryja TP, and Berson EL
- Subjects
- Aged, Aged, 80 and over, Female, Genes, Dominant, Humans, Photoreceptor Cells, Vertebrate ultrastructure, Point Mutation, Retinitis Pigmentosa genetics, Retinitis Pigmentosa pathology, Rhodopsin genetics
- Abstract
Purpose: To compare histopathologic findings in an autopsy eye of an 87-year-old woman with retinitis pigmentosa and the rhodopsin mutation Pro23His with findings in an autopsy eye of a 77-year-old female relative (first cousin) with retinitis pigmentosa and the same mutation., Design: Histopathologic study., Methods: One eye from each patient was prepared for light and electron microscopy within 5 hours after death. Photoreceptor nuclear counts were performed., Results: Photoreceptor degeneration and intraretinal bone spicule pigmentation were evident in both cases. The younger patient had more extensive photoreceptor loss and more intraretinal pigmentation than her older relative., Conclusion: A marked variation in the extent of retinal degeneration can be seen in two relatives with retinitis pigmentosa and rhodopsin, Pro23His. This study supports the idea that factors other than the primary gene defect are responsible for the severity of this condition.
- Published
- 2002
- Full Text
- View/download PDF
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