Single versus multiple sites and mechanisms of inhaled anesthetics.
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Anesthetics, Inhalation↗
Biomedical subjects
P J Cohen
Publications and source records attributed to P J Cohen.
CD4+ T-cells from mice immunized to syngeneic sarcomas recognize distinct, non-shared tumor antigens.
We have utilized a newly developed culture system to study the properties of antitumor CD4+ T-cells relevant to the rejection of syngeneic methylcholanthrene sarcomas. Fresh syngeneic dendritic cells prepared from spleen, then pulsed with crude lysates of methylcholanthrene sarcomas, evoke antigen-specific proliferation by CD4+ but not by CD8+ T-cells from tumor-immune mice. Unfractionated splenocytes display similar antigen presenting capacity if they are not irradiated before the pulse with tumor lysate. CD4+ T-cells from mice immunized to individual methylcholanthrene sarcomas proliferate cross-reactively to dendritic cells pulsed with fresh tumor digests, but not to dendritic cells pulsed with cultured tumor cells. This apparent shared recognition of sarcoma lysates was demonstrated to be a result of sensitization to bacterial collagenase during the immunization procedure. Therefore, the murine CD4+ T-cell response to tumor immunization is similar to the CD8+ response in that sensitization occurs predominantly to tumor specific transplantation antigens rather than to shared tumor antigens. Strategies to avoid artefactual tumor cross-recognition by CD4+ T-cells are discussed.
Animals↗
Murine epidermal Langerhans cells and splenic dendritic cells present tumor-associated antigens to primed T cells.
We examined the ability of epidermal Langerhans cells and splenic dendritic cells to present tumor-associated antigens (Ag) to immune T cells. Methylcholanthrene (MCA)-induced subcutaneous fibrosarcomas derived from C57BL/6 mice were used as tumor models. Our data demonstrate that both murine Langerhans cells and splenic dendritic cells have the capacity to present tumor-associated Ag to primed T cells. We found that variously treated tumor preparations (irradiated viable tumor cells, irradiated frozen-stored tumor cells, mitomycin C-treated viable tumor cells, and snap freeze-thawed tumor cell lysates) can be utilized for tumor Ag-pulsing. Primed CD4+ T cells demonstrated in vitro specificity towards their respective tumors and did not cross-react to other syngeneic MCA-induced or non-MCA-induced tumors. The T cell proliferative response critically depended on the presence of immune CD4+ T cells. We discuss the implications of these findings for the adoptive immunotherapy of cancer using immune CD4+ T cells.
Animals↗
Keloidal Kaposi's sarcoma: report of three patients.
Kaposi's sarcoma is a unique neoplasm which has emerged as an important element of AIDS in homosexuals but not in others at high risk for AIDS. The biology of this important tumor may be related to cytokines secreted by HIV-infected cells and/or by Kaposi's sarcoma cells themselves. We report 3 patients with multiple keloid-like tumors. These lesions proved to be Kaposi's sarcoma histologically, yet with a unique keloidal component. This variant has not been described previously. It is possible that cytokines that stimulate Kaposi's sarcoma cell growth may also stimulate proliferation of local fibroblasts to produce this variant.
Acquired Immunodeficiency Syndrome↗
Administration of pentosan polysulfate to patients with human immunodeficiency virus-associated Kaposi's sarcoma.
BACKGROUND: Neovascularization induced by basic fibroblast growth factor (basic FGF) or FGF-like cytokines is thought to play a substantial role in the pathogenesis of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma. Pentosan polysulfate has been shown to inhibit basic FGF and FGF-like dependent tumor growth both in vitro and in vivo. Moreover, it has been found to inhibit the growth of Kaposi's sarcoma-derived spindle cells in vitro. These observations suggested that pentosan polysulfate might be worth exploring as a potential agent for the treatment of Kaposi's sarcoma. PURPOSE: The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose of pentosan polysulfate in patients with HIV-associated Kaposi's sarcoma and whether or not this compound had activity against this neoplasm. METHODS: Sixteen HIV-seropositive patients with Kaposi's sarcoma received pentosan polysulfate via continuous venous infusion for 3-6 weeks and then received a subcutaneous dose three times per week. Three different doses of pentosan polysulfate were administered: 2 mg/kg per day by infusion followed by 2 mg/kg per dose given subcutaneously (six patients), 3 mg/kg per day by infusion followed by 3 mg/kg per dose given subcutaneously (five patients), and 4 mg/kg per day by infusion followed by 4 mg/kg per dose given subcutaneously (five patients). Five of the 16 patients in the study also received injections of 1 mg of pentosan polysulfate into two different lesions two times a week for 3 weeks, followed by intralesional therapy once weekly. After receiving pentosan polysulfate for 6 weeks, patients were administered 100 mg zidovudine (AZT) orally every 4 hours in conjunction with pentosan polysulfate. RESULTS: The maximally tolerated dose of pentosan polysulfate given by continuous venous infusion was found to be 3 mg/kg per day. No patient had an objective clinical antitumor response to either systemic or intralesional pentosan polysulfate administration; however, three patients had stable Kaposi's sarcoma for 3-27 weeks. No statistically significant effect on CD4 cells or serum HIV p24 antigen was noted during pentosan polysulfate administration. Dose-limiting toxic effects were characterized by anticoagulation and thrombocytopenia and were reversible. CONCLUSION: Pentosan polysulfate was well tolerated in this patient population. However, no objective tumor response or evidence of anti-HIV activity was noted; therefore, no claim of activity can be made in this trial. IMPLICATION: Continued investigation into the use of angiogenesis inhibitors with improved activity and toxicity profiles or different mechanisms of action is warranted.
Adult↗
Allopurinol administered prior to hepatic ischaemia in the rat prevents chemiluminescence following restoration of circulation.
Oxygen-derived free radicals produced during reperfusion may be responsible for the disturbed pathology which follows prolonged ischaemia. Measurement of hepatic chemiluminescence (low level light emission resulting from the energy released during chemical reactions of free radicals) allowed determination of whether allopurinol could prevent formation of oxygen-derived free radicals during reperfusion of the ischaemic liver. While control animals demonstrated a burst of light emission shortly after reperfusion, the rats pretreated with allupurinol showed no evidence of chemiluminescence during either ischaemia or reperfusion. It is concluded that allopurinol may modify reperfusion-induced free radical formation and possibly ameliorate the organ damage which can follow ischaemia.
Administration, Oral↗
Cultured human Langerhans cells process and present intact protein antigens.
Epidermal Langerhans cells (LC) undergo profound phenotypic and functional alterations when cultured for 2 to 3 d. To determine whether the in vitro culture of human LC modulates their capacity to process and present intact protein antigens, we compared the ability of freshly isolated LC (fLC) and cultured LC (cLC) to stimulate in vitro T-cell proliferative responses to recall antigens. We found that human fLC and cLC were able to process and present recall antigens to primed T cells, inducing significant proliferative responses. For tetanus toxoid and Candida albicans extract, T-cell proliferative responses at 6 d to antigen-pulsed fLC were slightly greater than responses to antigen-pulsed cLC. For live influenza A virus, the T-cell responses induced by antigen-pulsed cLC were comparable or slightly greater compared with fLC. Allogeneic T-cell proliferation for both LC preparations were also comparable. The exogenous pathway of antigen processing was demonstrated by chloroquine inhibition.
Antigens↗
Phorbol myristate acetate-induced lung injury: involvement of reactive oxygen species.
Using lucigenin-enhanced chemiluminescence, isolated rat lungs perfused with physiological salt-Ficoll solution were studied to test whether phorbol myristate acetate (PMA)-induced lung injury was mediated by reactive oxygen species (ROS). PMA (0.03 micrograms ml-1) caused small but significant increases in lung ROS levels and pulmonary arterial perfusion pressure (Ppa) but did not induce lung oedema. PMA (0.15 micrograms ml-1) induced lung oedema with large increases in ROS production and Ppa. Superoxide dismutase (SOD) inhibited the increases in ROS, Ppa, and lung oedema. Catalase and dimethylthiourea inhibited lung oedema but did not attenuate the increases in ROS and Ppa entirely. Indomethacin attenuated lung oedema partially but did not inhibit the increases in ROS and Ppa. These data indicate that PMA-induced lung injury is dependent on PMA concentration and ROS are responsible for such lung injury. Thromboxane plays a minor role for PMA-induced lung injury. The different effects of oxygen radical scavengers suggest that different radical species contribute to the increased pulmonary vascular response and lung injury.
Acridines↗
Do-not-resuscitate orders in the operating room.
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Advance Directives↗
Administration of allopurinol prior to occlusion of hepatic blood flow in the rat prevents the appearance of chemiluminescence following reperfusion.
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Allopurinol↗
Continuous in vivo measurement of hepatic lipoperoxidation using chemiluminescence: halothane and chloroform compared.
Hepatic necrosis, rarely occurring after administration of modern halogenated general anesthetics, has been ascribed to free radical-induced lipoperoxidation. As evaluation of hepatic chemiluminescence has been shown to provide a noninvasive assay for oxidative radical reactions, we have made continuous in vivo measurements of hepatic light output in the phenobarbital-induced halothane anesthetized rat and compared them with observations made during chloroform anesthesia. Chloroform produced a far more rapid and more profound increase in chemiluminescence, a phenomenon probably related to depletion of hepatic glutathione. These findings are consistent with significant differences in hepatic pathology associated with the two agents.
Animals↗
Dysplastic nevi and malignant melanoma.
The incidence of melanoma has been steadily increasing, with a trend for this tumor to develop at younger ages. The only satisfactory treatment for melanoma is early intervention; therefore, routine screening for melanoma and dysplastic nevi during the general physical examination is important. The prevalence of dysplastic nevi is estimated to be 2 to 5 percent. Patients with dysplastic nevi appear to have at least a 6 percent lifetime risk of melanoma. In the most severely affected patients (those with a family history of dysplastic nevi and more than one melanoma), the lifetime risk may exceed 50 percent. Patients with dysplastic nevi merit periodic follow-up. Since these nevi tend to be familial, close relatives of affected patients may also benefit from a screening examination. Individuals at increased risk for melanoma may display one or more of the following risk factors: dysplastic nevi, freckling, tendency to sunburn and numerous common nevi. Such individuals may benefit most from education in sunburn avoidance, sunscreen use and self-examination for changing nevi. A better informed public and heightened physician awareness are the most effective means of reducing mortality from this virulent malignancy.
Diagnosis, Differential↗
Hyperbaric pressure does not affect the analgesia produced by nitrous oxide in the mouse.
Hydrostatic pressure antagonizes some, but not all, of the phenomena associated with general anaesthesia. For example, while unconsciousness produced by general anaesthesia in a wide variety of species is reversed by compression, anaesthetic-induced inhibition of synaptic transmission is potentiated by application of pressure. To date, the effect of pressure on analgesia has not been evaluated. In this study, hyperbaric pressure of 75 ata did not antagonize analgesia which had been produced by exposure of mice to 1.2 ata of nitrous oxide. However, the same hyperbaric pressure restored righting in animals which had been anesthetized with 1.5 ata of nitrous oxide. These data add to the suggestion that the multiple effects of general anaesthetics may be mediated at different loci.
Analgesia↗
The Muir-Torre syndrome: a disease of sebaceous and colonic neoplasms.
The Muir-Torre syndrome of sebaceous neoplasms of the skin, with or without keratoacanthomas, and multiple low-grade visceral malignancies with prolonged survival is a rare disorder. Colonic polyps are frequently present, and the syndrome appears to be familial. We report 2 unrelated patients with the Muir-Torre syndrome. Each case exhibited sebaceous adenomas. Gastrointestinal findings included colonic adenocarcinomas and a tubulovillous adenoma. Although an unusual disease, the Muir-Torre syndrome requires recognition because these patients are at risk for multiple primary malignancies and may have family members also at risk.
Adenocarcinoma↗
Excision of the large congenital melanocytic nevus facilitated by the use of the tissue expander.
Large congenital melanocytic nevi both present a cosmetic problem and may predispose to the development of a melanoma. We present a series of three patients in whom the tissue expander was employed to facilitate a large excision with primary closure and excellent cosmesis.
Adolescent↗
Meningeal carcinomatosis in the VX2 rabbit tumor model: detection with Gd-DTPA-enhanced MR imaging.
Meningeal carcinomatosis developed in 14 of 14 New Zealand White rabbits after infusion of a VX2 tumor cell suspension into the cisterna magna. All died or were killed 7-15 days after inoculation. Within days of the tumor infusion, magnetic resonance (MR) imaging with gadolinium-diethylenetriaminepentaacetic acid (DTPA) at 0.5 or 1.5 T demonstrated enhancement of the cerebrospinal fluid (CSF) secondary to disruption of the blood-CSF barrier by plaquelike lesions along the meninges. Eventually, meningeal enhancement was observed along the base of the brain and cervical spine. Quantitative assessment of the contrast enhancement on T1-weighted images revealed an increase in mean signal intensity of 213% +/- 130%. Contrast enhancement was not observed in four control animals who received an infusion of cell culture medium. These results demonstrate in an animal model that contrast material-enhanced MR imaging can be used to detect meningeal carcinomatosis by revealing breakdown of the blood-CSF barrier.
Animals↗
Immunopathological changes after multiple spider bites.
Utilizing a panel of immune complex assays, antigen-antibody complex formation in a 29-year-old man shortly after a spider bite was documented. The clinical picture and laboratory parameters were consistent with a serum sickness reaction. Immune hyperactivity was evidenced by a detectable autoimmune serological response. This constellation of findings may be a common attendant to arthropod envenomation.
Adult↗
Ocular and cerebral metastases in the VX2 rabbit tumor model: contrast-enhanced MR imaging.
Ocular and cerebral metastases developed after the inoculation of a VX2 tumor cell suspension into the internal carotid artery of 15 rabbits. The hematogenous spread of tumor cells resulted in ocular metastases in 13 of 15 animals (86.7%) and cerebral system metastases in 14 of 15 animals (93%). Magnetic resonance (MR) imaging with Gd-DTPA demonstrated early disruption of the blood-ocular barrier and blood-brain barrier 5-7 days after infusion of tumor cells. Quantitative assessment of contrast enhancement revealed a mean increase in signal intensity of 145% +/- 51% in the anterior chambers, 102% +/- 70% for choroidal metastases, and 51% +/- 29% for central nervous system (CNS) metastases. These results indicate that contrast-enhanced MR imaging can be used to demonstrate a loss of blood-ocular barrier integrity that is similar to the breakdown of the blood-brain barrier associated with metastatic tumors to the CNS and eye.
Animals↗