[Blood groups and bladder cancer].
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Biomedical subjects
Publications and source records attributed to L H Liu.
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When applied topically to the skin of rabbits in vivo, sulfur mustard (SM), the vesicant used in World War I, produced a slowly developing inflammatory response, which peaked in size at 1 and 2 days, ulcerated within 3 days, and reepithelialized by 10 days. Histologically, basophils and polymorphonuclear leukocytes (PMNs) were common in both early and late lesions, and the crust over the ulcers was composed of dead epidermal cells, fibrin, and large numbers of PMNs. Healing occurred under the crust by migration of epidermal cells from the margins of the lesions and from the hair follicles. In organ culture, the lesion explants survived well, and reepithelialization even took place. Their excellent survival enabled us to compare the life spans of the infiltrating leukocytes within an inflammatory site. PMNs within the explants began disappearing during the first day of culture, and almost all had disappeared by 3 days. In contrast, over half of the basophils and the mononuclear cells within the explants were still present after 3 days of culture. The 1-, 2-, 3-, 6-, and 10-day (1.0-sq cm) SM lesion biopsies showed a 30-45% increase in weight (when compared with normal skin), presumably due to the extravasation of serum proteins and the fluids retained by them. When the biopsies were organ-cultured for 3 days, the 1-, 2-, and 3-day lesions lost weight, and the 6- and 10-day lesions (and normal skin) gained weight. These weight differences were not due to the amount of unbound protein extractable into the culture fluids, because both the early lesions and the late lesions contained about the same amount of unbound protein. The most likely explanation for these weight differences is that the newly formed ground substances of late lesions absorbed culture fluid, because the ground substance had changed from the sol state of acute inflammation (in which it was extractable) back to its normal gel state (in which it was not extractable). The unbound protein extractable into the culture fluids was mostly of serum origin. This protein averaged 1.9 mg for 1.0 sq cm normal skin explants (with a mean weight of 215 mg), and 6.4 mg for 1-day SM lesions (with a mean weight of 313 mg). Because rabbit serum contains about 60 mg protein/ml, these figures indicate that normal skin contained about 15% (unbound) serum by weight.(ABSTRACT TRUNCATED AT 400 WORDS)
Administration of a hematoporphyrin derivative (HpD) followed by photoradiation with red light completely or partially destroyed Greene hamster melanoma developed in the anterior chamber of rabbit eyes. Tumor-bearing eyes were divided into two groups. Twenty-two eyes received an HpD injection followed by exposure to red light from a slide projector with a 500-W quartz halogen lamp and a red filter (intensity to the tumor was about 4.0 mW/sq cm). In the control group (six eyes), eyes were exposed either to red light only or to HpD injection only. Local complications after therapy included edema and congestion of the conjunctiva, clouding of the cornea, and hemorrhage on the iris surface. The HpD itself has no cytotoxic effect, is preferentially retained in tumor cells, and causes a destructive photodynamic effect as a result of the production of cytotoxic singlet oxygen in the tumor. Accordingly, it may be a safe and potentially therapeutic procedure in the treatment of uveal melanoma.
Uveal Greene melanoma was produced in the anterior chamber of 47 eyes in 29 rabbits. One group of rabbits was untreated and served as controls. One group was treated with carmustine (1,3-bis(2-chloroethyl)-1-nitro-sourea; BCNU) intravenously and one group was treated with BCNU both intravenously and locally via an implanted silicone device. Tumor specimens were studied histopathologically with light and electron microscopy. Compared with controls, the treated tumors were smaller, more necrotic, and contained more spindle-shaped cells intermingled with inflammatory cells. Changes were particularly striking in the combined-treatment group. Treated tumors of both groups also showed less invasion into surrounding ocular tissues. Morphologic changes after treatment included the development of numerous degenerative tumor cells with calcium deposition, fragmentation of nuclei, degeneration of mitochondria, accumulation of fat droplets, and disorganization of cytoplasm. These changes may indicate that the drug, particularly following combined delivery, has a cytotoxic effect directly on the tumor cells.
We studied the morphology of metastatic tumors in three rabbits with implanted choroidal Greene melanoma. The tumor-bearing eyes were perforated and destroyed by the expanding tumors 10 to 12 weeks after implantation. The animals then lost body weight and became cachectic; they were suspected of having metastases and were sacrificed. The interval between the destruction of the eye and the discovery of metastases was 1 to 14 weeks. Widespread metastases involved the liver, lungs, kidneys, and subcutaneous tissue, with the greatest number of tumors in the liver and lungs. Histopathologic findings in the metastases and primary tumors were identical. This model may be considered appropriate for study of human uveal melanoma because (1) the biological behavior is similar to that of human uveal melanoma, (2) the primary and metastatic tumors are histologically similar, and (3) the large size of the rabbit's eye facilitates observation and manipulation.
Sustained release of carmustine (1,3-bis[2-chloroethyl]-1-nitrosourea, or BCNU) via an episcleral implanted silicone device was used to treat Greene hamster melanoma implanted in the anterior chamber of rabbit eyes. Group 1 animals received carmustine intravenously; group 2 received the drug by local sustained release via an episcleral implanted silicone device; group 3 received the drug by both local sustained release and intravenous injection (a total dosage more than twice that in group 1); and group 4 was not treated. The effectiveness of the various administration routes was compared by clinical observation of tumour size and systemic and local toxic reactions, and by histopathological examination. Carmustine delayed the growth of Greene melanoma in all 3 treated groups, but was most effective when a lower dose of the drug administered intravenously was combined with an additional higher dose administered by local sustained release. Local side effects included corneal clouding and conjunctival oedema and congestion at the early stage of local drug delivery via the episcleral implanted device.
Miconazole nitrate is a broad-spectrum antimycotic agent with low systemic and ocular toxicity. Since this drug does not adequately penetrate the vitreous cavity by topical, subconjunctival, or intravenous routes, we determined whether it can be given intravitreously for fungal endophthalmitis. Retinal and lens toxicity studies were carried out in 40 rabbits and three owl monkeys. Results showed that both miconazole and its vehicle produced toxic damage to the retina and crystalline lens in concentrations of 100 micrograms or greater. Concentrations of 10 to 80 micrograms caused mild to moderate retinal necrosis in some rabbit eyes. In monkey eyes, these concentrations did not cause significant histopathologic or electroretinographic changes. We believe that clinical use of this drug in doses not to exceed 40 micrograms may be justified in desperate cases of fungal endophthalmitis.
The release rates of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an anticancer drug, from various kinds of silicone and silicone-nylon implantable and refillable devices were investigated in vitro. The devices were made with different surface areas and wall thicknesses. The relation of the release rate at steady state to the surface area and the relation of the release rate per unit surface area to the wall thickness were determined. The relationship among the release rate, the surface area, and the wall thickness was analyzed using the multiple regression method, and is represented on a three-dimensional graph. The multiple regression equation predicts the release rate from the surface area and the wall thickness; the release rate can also be read from a nomogram that is presented.
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A substrain of Greene hamster melanoma adapted to grow in the choroid of the rabbit eye is shown to have the tendency to metastasize. Twenty-one normal rabbits were studied for the effects of vascular inoculation of a tumor cell suspension prepared from this choroidal melanoma, and two rabbits were used for long-term observation of the natural untreated course of the choroidal melanoma. In both groups, metastases to the liver, lung, kidney, and other organs were demonstrated.
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), an anticancer drug, was assayed in the aqueous and vitreous of rabbits after intravenous injection, subconjunctival injection, and topical application. Pharmacokinetic parameters were calculated from the time-course curves. The penetration into aqueous and vitreous across the blood-aqueous barrier and the blood-retinal barrier after intravenous injection was related to the anatomic dimensions of the eye (the volume of tissue involved and the surface area through which BCNU diffuses). To evaluate the three routes of administration, the area under the time-course curve was calculated from the simulated time-course curve. The results suggest that topical application of BCNU is the best and subconjunctival injection the second best route for treating an iris tumor, and that intravenous injection is the best route for choroidal and retinal tumors.
We evaluated the tolerance of ocular tissues to topical application of the anticancer agent 1,3 bis(2-chloroethyl)-1-nitrosourea (carmustine, BCNU) in eight normal rabbit eyes. Early changes in the anterior ocular structures, including moderate to severe chemosis, lid swelling, and superficial punctate keratitis with epithelial defect and corneal edema, occurred within the first 36 hours. These changes subsided gradually following administration of Cortisporin ointment (polymyxin B-bacitracin-neomycin-hydrocortisone) in the eyes that received 1.0 mg of BCNU per day. In one of the two eyes given the 3.0-mg dose, corneal clouding with interstitial vascularization was still present 40 days after drug administration, despite Cortisporin treatment.
The instrument consists of a high-speed air turbine driven cutter combined with a pressure-regulated infusion system and a peristaltic pump evacuation system. The tool has an exposure control to vary the axial position of the cutter relative to its housing. The entire unit is controlled and powered by compressed air. A foot pedal start and stops all suction and cutting functions. The intraocular pressure is controlled by a flow-compensating pressure regulator that balances out the inflow system pressure drop and thereby provides essentially constant intraocular pressure.
The NASA-McGannon cataract fragmentor, a newly designed mechanical phacofragmentor powered by compressed air, was tested on 100 eyes of old rabbits and on 50 dark brown nuclei of human cataracts that were implanted in the anterior chambers of rabbit eyes after the lenses had been removed. It was possible to eliminate the eddy current in the anterior chamber, reduce the requirement for infusion, and reduce the time of fragmentation both for rabbit lenses and for implanted hard nuclei of human cataracts. Iatrogenic damage to the iris and posterior capsule of the lens was noted in the early cases but not in the later ones, as the operators became more skillful in manipulating the instrument.
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The production and release of granulocytes and macrophages, crucial elements of the host defense system, are significantly impaired after burn injury and sepsis. Prostaglandin E2 (PGE2) is known to be myelosuppressive. We hypothesized that the macrophages contributed to myelopoietic suppression by means of increased PGE2 production, which is induced by thermal injury and sepsis. In this study, peritoneal macrophages were elicited at day 3 from normal mice and from mice who underwent a 15% total body surface area dorsal scald burn with or without Pseudomonas aeruginosa burn wound infection. The macrophages were incubated with or without endotoxin and with or without PGE2 polyclonal antiserum (anti-PGE2) for 18 hours. Macrophage supernatants were then used in co-cultures of bone marrow cells in a clonogenic assay of granulocyte-macrophage colony-forming cells (GM-CFCs) to determine the effect of burn wound infection on the alteration of the proliferative status of the GM-CFCs. Burn wound infection and endotoxin both caused marked reductions in GM-CFC growth in culture (20%-40% as compared with normal, P < .05-.01). The inhibition of GM-CFC growth induced by burn, burn plus infection, or endotoxin was significantly reversed by the addition of anti-PGE2 to the cultures (30%-40% increase in GM-CFC colony growth as compared with cultures without anti-PGE2). These results suggest that PGE2 is a key mediator in the gram-negative sepsis-induced macrophage suppression of granulocyte and macrophage production. The ability of anti-PGE2 to neutralize PGE2 activity may provide a useful means of mitigating myeloid depression that follows postburn sepsis.
Recent studies have demonstrated that neutrophils have the capacity to produce a variety of cytokines after stimulation. The synthesis and release of prostaglandin E2 (PGE2) via the cyclooxygenase (COX) pathway has been reported to occur in activated neutrophils. In the present study, we sought to determine the status of COX protein synthesis and PGE2 production in murine neutrophils after burn injury. The effect of burn injury on neutrophil COX and PGE2 response to infection or lipopolysaccharide (LPS) was also examined. Peritoneal neutrophils were obtained from BDF1 mice at 4, 18, 24, and 36 hours after a 15% TBSA full-thickness scald burn or sham burn. We found that neutrophils from healthy mice express a low level of COX-2 protein. Neutrophil COX-2 protein expression in burn animals was significantly increased at 4 hours and dramatically decreased at 36 hours after burn injury. Animals 36 hours after burn and topically infected with Pseudomonas Aeruginosa had neutrophil COX-2 expression almost identical to burn injury only. Neutrophils harvested from healthy mice cocultured with LPS (1 microg/ml) had a marked induction of COX-2 protein. Neutrophils 24 hours after burn were unresponsive to LPS-stimulated COX-2 enhancement. COX-1 protein was strongly expressed constitutively and not affected further by burn injury or LPS. The production of PGE2 corresponded with the changes in COX-2 expression for all groups of mice. Our data suggested that neutrophils express both COX-1 and COX-2 and produce PGE2. The effects of burn injury on neutrophil COX-2 protein synthesis and PGE2 production suggest that after burn there is a time-dependent response. Insights into not only the global cellular response to injury and infection but also temporal nature of the response are important in the development of the therapeutic treatment strategies for burn patients.