Retinal manifestations of gastrointestinal conditions.
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Gastrointestinal Diseases↗
Biomedical subjects
L H Young
Publications and source records attributed to L H Young.
Establishment of a rabbit model of extrascleral extension of ocular melanoma.
PURPOSE: To establish an animal model of extrascleral extension of choroidal melanoma. METHODS: Pigmented choroidal tumors were established in nine New Zealand albino rabbit eyes using B16F10 melanoma cell line. The sclerotomy site was not closed in the subgroup of six rabbits where extrascleral extension was desired. For the control group, the sclerotomy site was sutured with 8-0 nylon. Animals were treated with daily injections of cyclosporine and followed by serial fundus examinations, color Doppler imaging, and fundus photography. All tumor-bearing eyes were enucleated at the end of the follow-up period and examined for extrascleral extension. RESULTS: Extrascleral extension of choroidal melanoma occurred in all six animals with open sclerotomy sites. No extrascleral extension was observed in the control group. Color Doppler imaging identified extrascleral extension which was confirmed on gross histology. CONCLUSIONS: Our animal model of extrascleral extension of choroidal melanoma requires minimal surgery to establish, and is reproducible and easy to follow with standard diagnostic equipment.
Animals↗
Immunohistochemical localization of ganciclovir in the human retina.
PURPOSE: To localize ganciclovir in the retina of human eyes treated with intravenous or intravitreal ganciclovir for cytomegalovirus (CMV) retinitis. METHODS: Paraffin-embedded five-micron sections of autopsy eyes were obtained from seven patients as follows: two patients with CMV retinitis treated with intravenous ganciclovir; two patients with CMV retinitis treated with an intravitreal sustained-release ganciclovir device; one patient with CMV retinitis treated with intravenous foscarnet; and two patients with AIDS without CMV retinitis who did not receive any anti-CMV therapy. The paraffin was removed from the sections, and indirect immunofluorescent staining was performed, using an antiserum to ganciclovir. RESULTS: Bright fluorescent staining was noted in the retinal pigment epithelium (RPE) and photoreceptor outer segments of eyes treated with intravenous or intravitreal ganciclovir, but not in eyes treated with foscarnet or without CMV retinitis. In addition, patches of bright fluorescent staining of the internal limiting membrane was noted in eyes treated with intravitreal ganciclovir. CONCLUSIONS: Ganciclovir is detected in the outer retina of patients with CMV retinitis treated with intravenous or intravitreal therapy. The drug is detected also in the internal limiting membrane in eyes treated with the intravitreal sustained-release ganciclovir device.
AIDS-Related Opportunistic Infections↗
Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo.
BACKGROUND: Myocardial ischemia increases heart glucose utilization in vivo. However, whether low-flow ischemia leads to the translocation of glucose transporter (GLUT)-4 and/or GLUT-1 to the sarcolemma in vivo is unknown. METHODS AND RESULTS: In a canine model, we evaluated myocardial glucose metabolism in vivo and the distribution of GLUT-4 and GLUT-1 by use of immunoblotting of sarcolemma and intracellular membranes and immunofluorescence localization with confocal microscopy. In vivo glucose extraction increased fivefold (P < .001) and was associated with net lactate release in the ischemic region. Ischemia led to an increase in the sarcolemma content of both GLUT-4 (15 +/- 2% to 30 +/- 3%, P < .02) and GLUT-1 (41 +/- 4% to 58 +/- 3%, P < .03) compared with the nonischemic region and to a parallel decrease in their intracellular contents. Immunofluorescence demonstrated the presence of both GLUT-4 and GLUT-1 on cardiac myocytes. GLUT-1 had a more prominent cell surface pattern than GLUT-4, which was primarily intracellular in the nonischemic region. However, significant GLUT-4 surface labeling was found in the ischemic region. CONCLUSIONS: Translocation of the insulin-responsive GLUT-4 transporter from an intracellular storage pool to the sarcolemma occurs in vivo during acute low-flow ischemia. GLUT-1 is also present in an intracellular storage pool from which it undergoes translocation to the sarcolemma in response to ischemia. These results indicate that both GLUT-1 and GLUT-4 are important in ischemia-mediated myocardial glucose uptake in vivo.
Animals↗
Flow cytometry analysis of peripheral blood lymphocytes in patients with choroidal melanoma.
PURPOSE: To evaluate peripheral blood lymphocyte subpopulations in patients with choroidal melanoma. METHODS: In this prospective study, peripheral blood lymphocytes of 226 patients afflicted with choroidal melanoma were analyzed by flow cytometry and compared with those of 49 age-matched and gender-matched control subjects. Subpopulations of peripheral blood lymphocytes were further identified by monoclonal antibodies specific to cell-surface markers. Statistical analysis was performed by a Student t test. RESULTS: There was no overall difference between the patients with choroidal melanoma and the control subjects with regard to peripheral blood lymphocyte subpopulations. However, when the patients were divided into subgroups based on their clinical characteristics, differences in natural killer (NK) cell population and activated T cells were noted in two subgroups. Patients with ciliary body involvement showed a statistically significant reduction in NK cells (194 +/- 101 vs 260 +/- 178 per mm3; P = .01). The number of activated T cells in this subgroup of patients was increased but not statistically significantly (7.32 +/- 4.79 vs 6.09 +/- 4.34 per mm3; P = .08). In patients with extrascleral extension, a statistically significant increase in activated T cells was noted (9.84 +/- 7.41 vs 6.25 +/- 4.3 per mm3; P = .02). The NK cells in this subgroup of patients were also reduced, but the reduction did not achieve statistical significance (178 +/- 123 vs 248 +/- 167 per mm3; P = .24). CONCLUSIONS: We noted statistically significant differences in peripheral blood lymphocytes in two subgroups of patients with clinically less favorable choroidal melanoma.
Antigens, CD↗
Digital angiography of experimental choroidal melanomas using benzoporphyrin derivative.
PURPOSE: To examine benzoporphyrin derivative angiography as a modality for studying photosensitizer biodistribution in experimental choroidal melanomas. METHODS: A liposomal preparation of benzoporphyrin derivative was used in this study. Digital benzoporphyrin derivative angiograms were performed in 10 rabbits (six for experimental choroidal melanomas, two for normal choroids, and two for irides) using a Topcon ImageNet H1024 digital imaging system, a Kodak Megaplus video camera, and a Topcon TRC-50-VT fundus camera. Only one eye from each rabbit was used. Filters specifically designed for benzoporphyrin derivative (peak absorption at 580 nm and peak emission at 695 nm) were used. Benzoporphyrin derivative (1 mg/kg) was injected into an ear vein while images of tumor, normal choroid, or iris were being obtained. Follow-up images were obtained during the first 3 hours and at 24 hours after injection. Fluorescence microscopy was performed in all 10 rabbits using 1 mg/kg of benzoporphyrin derivative. Tumor-bearing eyes were enucleated at the same time points that angiograms were performed, and the two sets of results were compared for maximum dye accumulation. RESULTS: Digital angiography demonstrated that maximal benzoporphyrin derivative fluorescence occurred in tumors 15 to 45 minutes after injection. Fluorescence photometry corroborated these results. CONCLUSION: Photosensitizer angiography is a valid modality for determining the optimum treatment time for photodynamic therapy.
Animals↗
Photodynamic therapy of choroidal melanoma.
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Animals↗
Lymphocyte-mediated cytolysis and disease.
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Autoimmune Diseases↗
Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia.
Myocardial regions perfused through a coronary stenosis may cease contracting, but remain viable. Clinical observations suggest that increased glucose utilization may be an adaptive mechanism in such "hibernating" regions. In this study, we used a combination of 13C-NMR spectroscopy, GC-MS analysis, and tissue biochemical measurements to track glucose through intracellular metabolism in intact dogs infused with [1-13C]glucose during a 3-4-h period of acute ischemic hibernation. During low-flow ischemia [3-13C]alanine enrichment was higher, relative to plasma [1-13C]glucose enrichment, in ischemic than in nonischemic regions of the heart, suggesting a greater contribution of exogenous glucose to glycolytic flux in the ischemic region (approximately 72 vs. approximately 28%, P < 0.01). Both the fraction of glycogen synthase present in the physiologically active glucose-6-phosphate-independent form (46 +/- 10 vs. 9 +/- 6%, P < 0.01) and the rate of incorporation of circulating glucose into glycogen (94 +/- 25 vs. 20 +/- 15 nmol/gram/min, P < 0.01) were also greater in ischemic regions. Measurement of steady state [4-13C)glutamate/[3-13C]alanine enrichment ratios demonstrated that glucose-derived pyruvate supported 26-36% of total tricarboxylic acid cycle flux in all regions, however, indicating no preference for glucose over fat as an oxidative substrate in the ischemic myocardium. Thus during sustained regional low-flow ischemia in vivo, the ischemic myocardium increases its utilization of exogenous glucose as a substrate. Upregulation is restricted to cytosolic utilization pathways, however (glycolysis and glycogen synthesis), and fat continues to be the major source of mitochondrial oxidative substrate.
Alanine↗
Therapy for cytomegalovirus retinitis: still no silver lining.
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AIDS-Related Opportunistic Infections↗
Photodynamic therapy of pigmented choroidal melanomas using a liposomal preparation of benzoporphyrin derivative.
OBJECTIVE: To evaluate the effectiveness of photodynamic therapy of pigmented choroidal melanoma using a liposomal preparation of benzoporphyrin derivative monoacid (BPD), verteporfin. DESIGN: Pigmented choroidal melanomas were established in 25 New Zealand albino rabbit eyes. The animals were treated with daily injections of cyclosporine, and tumor growth was monitored with funduscopic examination and ultrasonography. Fifteen minutes after intravenous injection of BPD (2 mg/kg), the tumors were irradiated at 692 nm through an argon-pumped dye laser with the delivered fluence ranging between 40 and 150 J/cm2. Control animals were treated with light only, photosensitizer only, or observation only. Tumor growth was monitored by indirect ophthalmoscopy, fundus photography, fluorescein angiography, and ultrasonography. Histologic examination was performed. RESULTS: Eighteen tumor-bearing rabbits were treated with light and BPD; 16 were followed up for 1 month, and two were killed immediately for histologic examination. Tumors regressed in all eyes treated with 60 J/cm2 or more. With fluence of 40 J/cm2, tumor regrowth was observed in one animal within 10 days of treatment. In the three control groups, all animals showed continuous tumor growth. Histologic examination of the eyes treated with photosensitizer and light immediately after treatment showed prominent vascular occlusion throughout the full thickness of the tumor. One month after treatment, tumor necrosis and infiltration of mononuclear cells and pigment-laden macrophages were the predominant findings. CONCLUSIONS: Photodynamic therapy with BPD may have a role in the treatment of pigmented choroidal melanomas.
Animals↗
Alteration of gene expression in rat mammary tumors induced by N-methyl-N-nitrosourea.
Rodents are susceptible to the effects of chemical carcinogens and have been widely used in the study of mammary-gland carcinogenesis. However, little information is available regarding specific phenotypic changes that occur during mammary-gland carcinogenesis. In this study, subtraction hybridization was used to identify specific genes whose expression in N-methyl-N-nitrosourea (MNU)-induced rat mammary tumors had been altered. mRNA isolated from normal rat mammary tissue and tumors induced by treatment of 50-d-old female rats with MNU (50 mg/kg) was used to produce normal and tumor cDNA libraries. Total inserts prepared from each cDNA library were used to produce a subtracted tumor-normal probe. Differential screening of the tumor library with the subtracted probe and normal cDNA yielded 20 clones that appeared to be differentially expressed. Northern analysis of mRNA isolated from normal mammary tissue and tumor tissue confirmed that four of these clones were differentially expressed. The expression of clones 4 and 15 was greatly increased (13-fold and tenfold, respectively) in most MNU-induced mammary tumors, whereas the expression of clones 10 and 27 was decreased (13-fold and fourfold, respectively). Sequence analysis revealed that clones 15 and 27 were highly homologous to calcyclin and a cDNA isolated from HL-60 cells, respectively. The differential expression of clones 4 and 10 was due to the presence within these clones of retroviral sequences and a fragment of transferrin, respectively. These clones may represent markers useful for studying the development of MNU-induced mammary-gland neoplasias.
Alkylating Agents↗
Photodynamic therapy of pigmented choroidal melanomas of greater than 3-mm thickness.
PURPOSE: The purpose of the study is to determine the effect of photodynamic therapy in the destruction of experimental pigmented choroidal melanomas > or = 3 mm in thickness using a liposomal preparation of benzoporphyrin derivative, verteporfin. METHODS: Pigmented choroidal tumors were established in 32 New Zealand albino rabbit eyes. Animals were treated with daily injections of cyclosporine, and tumor growth was followed by serial fundus examinations and ultrasonography. When a tumor exceeded 3 mm in thickness (tumor height ranged from 3.1-4.6 mm), the authors administered benzoporphyrin derivative intravenously (1 mg/kg) and irradiated the tumor at 692-nm through an argon-pumped dye laser at different total light doses ranging from 60 to 120 J/cm2. Control animals were treated with light or benzoporphyrin derivative only. Each animal then was followed-up for 4 to 6 weeks by fundus photography, fluorescein angiography, and ultrasonography. RESULTS: All animals treated with benzoporphyrin derivative and light at fluences of > or = 80 J/cm2 showed complete tumor arrest. In contrast, both control groups showed continuous tumor growth in all animals with tumors filling most of the vitreous cavity by 3 weeks. Histologic examination results of tumors treated with dye plus light immediately after treatment showed prominent vascular closure. No vascular changes were noted in the control eye treated with light or dye alone. Examination results of the eyes that showed tumor regression after a 4-week follow-up period showed tumor necrosis and extensive infiltration of mononuclear cells and pigment-laden macrophages at the tumor site. CONCLUSIONS: These data suggest that photodynamic therapy may have a role in the management of pigmented choroidal melanomas.
Animals↗
IGF-I stimulation of muscle protein synthesis in the awake rat: permissive role of insulin and amino acids.
Infusion of insulin-like growth factor I (IGF-I) lowers plasma amino acid and insulin concentrations, which may limit the capacity of IGF-I to promote muscle protein synthesis in vivo. We measured heart and skeletal muscle incorporation of continuously infused L-[ring-2,6-3H]phenylalanine in awake postabsorptive rats receiving 4-h intravenous infusions of saline (n = 11), IGF-I (1 microgram.kg-1.min-1) with (n = 10) or without (n = 11) amino acid replacement, or IGF-I with insulin replacement (n = 8). There were no significant increases in muscle protein synthesis during the infusion of IGF-I alone, which was associated with decreases in both plasma insulin (52 +/- 5%, P < 0.001) and amino acids (25 +/- 5%, P < 0.05). When IGF-I was given together with amino acids, protein synthesis was significantly increased in gastrocnemius (4.7 +/- 0.4 vs. 2.5 +/- 0.3%/day, P < 0.001), oblique (4.5 +/- 0.4 vs. 2.8 +/- 0.4%/day, P < 0.05), and soleus (8.8 +/- 0.7 vs. 6.4 +/- 0.3%/day, P < 0.01) and tended to be higher than saline control values in heart (10.9 +/- 0.9 vs. 8.8 +/- 0.7%/day, P = 0.08). Amino acid replacement prevented plasma concentrations from falling and also blunted the decline in plasma insulin (22 +/- 5%, P < 0.01 vs. IGF-I alone). When IGF-I and insulin replacement were given, protein synthesis was increased in heart (13.0 +/- 0.6%/day), gastrocnemius (4.7 +/- 0.4%/day), and oblique (4.5 +/- 0.4%/day) (P < 0.001 for each, compared with saline). We conclude that the action of IGF-I to acutely stimulate muscle protein synthesis in the awake rat is limited by the fall in circulating insulin and/or amino acid concentrations that accompanies IGF-I infusion in vivo and is prevented by co-infusion of insulin or amino acids.
Amino Acids↗
Hyperinsulinemia inhibits myocardial protein degradation in patients with cardiovascular disease and insulin resistance.
BACKGROUND: Insulin resistance, hyperinsulinemia, and myocardial hypertrophy frequently coexist in patients. Whether hyperinsulinemia directly affects myocardial protein metabolism in humans has not been examined, however. To test the hypothesis that hyperinsulinemia is anabolic for human heart protein, we examined the effects of insulin infusion on myocardial protein synthesis, degradation, and net balance in patients with ischemic heart disease. METHODS AND RESULTS: Eleven men (aged 57 +/- 3 years) with coronary artery disease who had fasted for 12 to 16 hours received a constant infusion of insulin (50 mU.m-2.min-1) while plasma concentrations of glucose and amino acids were kept constant. Rates of myocardial protein synthesis, degradation, and net balance were estimated from steady state extraction and isotopic dilution of L-[ring-2,6-3H]phenylalanine across the heart basally and 90 minutes into infusion. Subjects had elevated fasting plasma insulin concentrations (173 +/- 21 pmol/L) and used little exogenous glucose during insulin infusion, suggesting resistance to the effects of insulin on whole-body carbohydrate metabolism. Basally, myocardial protein degradation, as estimated by phenylalanine release (133 +/- 28 nmol/min), exceeded protein synthesis, estimated by phenylalanine uptake (31 +/- 15 nmol/min), resulting in net negative phenylalanine balance (-102 +/- 17 nmol/min). Insulin infusion reduced myocardial protein degradation by 80% but did not affect protein synthesis, returning net phenylalanine balance to neutral. CONCLUSIONS: Acute hyperinsulinemia markedly suppresses myocardial protein degradation in patients with cardiovascular disease who are resistant to its effects on whole-body glucose metabolism. This antiproteolytic action represents a potential mechanism by which hyperinsulinemia could contribute to the development of myocardial hypertrophy in patients with cardiovascular disease.
Amino Acids↗
Photoimmunotherapy of human uveal melanoma cells.
To examine whether tumor-reactive monoclonal antibodies can be used to enhance photodestruction of human uveal melanoma cells, we conjugated photosensitizer chlorin e6 monoethylenediamine monoamide (CMA) with a melanoma-reactive monoclonal antibody IG12 and evaluated the effectiveness of this immunoconjugate (IC) in the destruction of OCM431 human uveal melanoma cells in vitro. RPMI1846 melanoma cells do not react with IC and were used as non-target cells. For control, target and non-target cells were treated with IC or light alone. The effects of IC and free CMA in the destruction of melanoma cells were compared. Cell survival was assessed by a colorimetric assay using tetrazolium salt MTT. Target (OCM431) cells preincubated with IC and irradiated with 5-40 J cm-2 showed light dose-dependent decrease in cell survival. At 40 J cm-2, OCM431 cells preincubated with IC showed only 6 +/- 1.4% viability. Under same treatment, non-target (RPMI1846) cells showed much less phototoxicity; cell survival was 54 +/- 2.1%. Treatment with free CMA and light at 40 J cm-2 showed similar phototoxicity to both target and non-target cells, with cell survival being 24.3 +/- 3.5% and 23.7 +/- 1.5%, respectively. These results show that our IC is effective in causing photodestruction of human uveal melanoma cells in vitro. The phototoxicity is selective and more potent than free CMA.
Antibodies, Monoclonal↗
Photodynamic therapy of pigmented choroidal melanomas.
PURPOSE: To evaluate the effectiveness of photodynamic therapy with chloroaluminum sulfonated phthalocyanine in the treatment of pigmented choroidal melanomas in a rabbit model. METHODS: Pigment containing B16F10 murine melanoma cells were implanted transclerally into the subchoroidal space of 28 immunosuppressed New Zealand albino rabbits. The animals were treated with daily injections of cyclosporine and were followed up until tumors at least 2 mm in height were detected by ultrasonography. Twenty-four hours after the intravenous injection of chloroaluminum sulfonated phthalocyanine (CASPc, 5 mg/kg), tumors were irradiated at 675 nm through an argon-pumped dye laser at estimated total light doses of 25 to 70 J/cm2. Control animals were treated with light only or photosensitizer only. The animals were followed up for 4 1/2 to 8 weeks with regular fundus examinations. RESULTS: Twenty tumor-bearing rabbits were treated with light and dye. The tumor regressed in 12 animals. Five of these animals were followed up for at least 4 1/2 weeks and the other seven for 8 weeks after treatment. At light doses under 40 J/cm2, tumor regrowth was observed in five animals within 10 days of treatment. In all control groups, the tumor-bearing eyes were filled with tumor cells by the third week after implantation. Histologic examination of tumors treated with photosensitizer and light revealed prominent vascular damage early after treatment that resulted in vascular occlusion. Tumor necrosis was evident within 24 hours of treatment. CONCLUSIONS: Results suggest that photodynamic therapy may have a role in the treatment of pigmented choroidal melanomas.
Aluminum↗
Technetium-99m-nitroimidazole (BMS181321): a positive imaging agent for detecting myocardial ischemia.
UNLABELLED: A new technetium-99m-labeled nitroimidazole (BMS181321) has been proposed for positive imaging of myocardial ischemia. METHODS: An in vivo open-chest canine model of partial coronary occlusion and pacing-induced demand ischemia was used to correlate myocardial retention of BMS181321, following an intravenous injection at peak stress, with regional microsphere blood flow. Postmortem measurements of myocardial BMS181321 activity and flow were correlated with in vivo planar and ex vivo SPECT images. Myocardial and hepatic clearance of BMS181321 was derived from ROI analysis of serial planar images. RESULTS: Anaerobic metabolism was documented in the ischemic region by selective venous and arterial sampling for lactate and oxygen consumption. Normalized myocardial BMS181321 activity (165% +/- 42% nonischemic) in the central ischemic region (flow < 0.3 ml/min/gm) was significantly greater than activity in normal regions (p < 0.05). Quantitative circumferential analysis of SPECT images revealed a comparable increase in myocardial BMS181321 activity in the ischemic region. Sixty minutes after injection of BMS181321, liver activity was 423% of ischemic myocardial activity. CONCLUSION: BMS181321 was preferentially retained in ischemic but viable canine myocardium and was inversely related to regional myocardial blood flow. Although enhanced retention of BMS181321 was detectable by ex vivo SPECT imaging, an unfavorable heart-to-liver ratio was observed with in vivo planar imaging which may limit its use in clinical myocardial imaging.
Animals↗