Use of plain radiography and computed tomography to identify fish bone foreign bodies.

INTRODUCTION: Fish bones are the most common aerodigestive foreign bodies in adults. Radiographic studies, often ordered for diagnosis, have questionable utility. METHODS: With a laryngoscope, bones from 10 fish species were placed in a variety of positions in a human head and neck cadaver specimen. Plain films and CT scans were obtained and evaluated by blinded readers. RESULTS: Plain radiography exhibited a sensitivity and specificity of 39% and 72%. Cooking did not grossly change radio-opacity. The species of fish affected visibility in soft tissue, without correlation to the characteristic optical density of each species. Bones placed orthogonal to the film in the vallecula were most readily identified. CT scanning correctly identified 9 of 10 bones. CONCLUSIONS: Plain radiography poorly visualizes fish bone foreign bodies in soft tissue; visibility varied with fish species, location, and orientation. CT is the test of choice to radiographically diagnose fish bone impactions.

L-histidinol selectively modulates daunomycin toxicity in normal and tumorigenic kidney epithelial cells.

L-Histidinol protects normal cells from anticancer drugs while enhancing the ability of these agents to eradicate tumor cells. We now report that this attribute, previously documented in normal and tumor cells of fibroblastic or myeloid origin, extends to epithelial lines. Clonogenic cell survival assays showed that L-histidinol protected the normal Madin-Darby canine kidney (MDCK) epithelial cell line from daunomycin (DAU) toxicity, but enhanced DAU toxicity in MDCK-T1, a tumorigenic derivative of MDCK. The protection of MDCK cells from DAU by L-histidinol was improved by increasing L-histidine in the media, a condition known to diminish L-histidinol's capacity to inhibit protein synthesis. In contrast, similar conditions markedly diminished the capacity of L-histidinol to enhance DAU killing of MDCK-T1 cells. These data suggest that the differential effects of L-histidinol on DAU toxicity cannot be attributed totally to its ability to inhibit protein synthesis.

Mimetics of L-histidinol which selectively modulate daunomycin toxicity in normal and tumorigenic epithelial cells.

In the accompanying publication, it was shown that L-histidinol protected the normal Madin-Darby canine kidney (MDCK) epithelial cell line from daunomycin (DAU) toxicity, but enhanced DAU toxicity in MDCK-T1, a tumorigenic derivative of MDCK. The protection of MDCK cells from DAU by L-histidinol was also shown to be independent of its ability to inhibit protein synthesis. Here, clonogenic cell survival assays show that imidazole was as effective as L-histidinol in protecting MDCK cells from DAU, but had less impact on MDCK-T1 line. Certain antieicosanoids and antihistamines mimicked, to varying extents, the DAU-modulating action of L-histidinol. These data suggest that the selective modulation of DAU toxicity by L-histidinol involves both inhibition of protein synthesis and unknown action(s) attributable to its imidazole moiety and that other pharmacological agents are modulators of anticancer drug toxicity.

L-histidinol reverses resistance to cisplatinum and other antineoplastics in a tumorigenic epithelial cell line.

L-Histidinol protects normal cells from various anticancer drugs, while enhancing the toxicity of the same agents in drug-sensitive and multidrug-resistant tumor cells. Here, we report that L-histidinol circumvents a novel form of multiple-drug resistance in the MDCK-T1 line, a tumorigenic derivative of the phenotypically-normal Madin-Darby canine kidney (MDCK) epithelial cell line. Clonogenic cells survival assays showed that, compared to the parental MDCK line, the MDCK-T1 line was resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea (approximately 15 fold), to cisplatinum (approximately 10 fold), to 5-fluorouracil (approximately 10-fold) and to cytosine arabinoside (approximately 15-fold). L-Histidinol reversed the resistance of MDCK-T1 cells to these anticancer drugs while protecting the parental MDCK line from these agents. These studies indicate that L-histidinol reverses a unique form of drug-resistance in MDCK-T1 cells by a mechanism dependent upon protein synthesis inhibition.

Farrowing induction with a combination of prostaglandin F(2alpha) and a peripherally acting alpha(2)--adrenergic agonist AGN 190851 and a combination of prostaglandin F(2alpha) and oxytocin.

We studied the effect of prostaglandin (PG) F(2alpha)-AGN 190851 on farrowing induction and compared it with that of PGF(2alpha)-oxytocin. Eighty crossbred, multiparous sows were randomly assigned to the following 4 treatment groups of 20 sows each: 1) control, saline-saline; 2) PGF(2alpha) (10 mg/sow)-oxytocin (30 IU/sow); 3) PGF(2alpha) (10 mg/sow)-AGN 190851 (0.06 mg/kg); and 4) PGF(2alpha) (10 mg/sow)-AGN 190851 (0.1 mg/kg). Either PGF(2alpha) or saline was administered intramuscularly on Day 111 of gestation at 11:30 h; AGN 190851, oxytocin or saline was administered intramuscularly 20 h after the first injection. The PGF(2alpha)-AGN 190851 (0.1 mg/kg) treated sows had the shortest mean farrowing interval (2.1 +/- 1.6 h, mean +/- SD) compared with the remaining treatment groups (control: 67.1 +/- 26.2 h; PGF(2alpha)-oxytocin: 5.6 +/- 6.7 h; PGF(2alpha)-AGN 190851 [0.06 mg/kg]: 3.0 +/- 2.8 h). Duration of farrowing, litter size, litter weight and interval from weaning to first estrus in sows were not significantly changed by these treatments. The PGF(2alpha)-oxytocin group had a significantly higher stillbirth rate than the control group, whereas the PGF(2alpha)-AGN 190851 (0.1 mg/kg) group had the lowest number of pigs born dead and stillbirth rate among the 4 treatment groups. These results suggested that the PGF(2alpha)-AGN 190851 combination can be used as an alternative method to PGF(2alpha)-oxytocin for synchronizing farrowing.

Susceptibility of human colon carcinoma cells to anticancer drugs is enhanced by L-histidinol.

The effects of L-histidinol on cell cycle transit and anticancer drug susceptibility of four cultured human colon carcinoma cell lines have been examined. The lines studied included two lines, SW480 and SW 620, which were derived from the same patient as a grade III adenocarcinoma of the colon and a lymphatic metastatic form of colon carcinoma, respectively, as well as the human colon adenocarcinoma lines HT-29 and WiDr. L-Histidinol accentuates the vulnerability of all of these human carcinoma lines to several different classes of anticancer drugs, including 5-fluorouracil, the most effective and most commonly used single agent for metastatic colon carcinoma. The ability of L-histidinol to accentuate the sensitivity of these colocarcinoma lines to anticancer drugs, including those which are cell cycle-dependent, is in apparent contradiction to the finding that L-histidinol markedly slows cycle transit in all lines tested.

L-histidinol increases the vulnerability of cultured human leukemia and lymphoma cells to anticancer drugs.

L-Histidinol, a structural analogue of the essential amino acid L-histidine, enhances the toxicity of a variety of anticancer drugs for many tumor cells of animal origin. In this study, the effects of L-histidinol on the proliferation and anticancer drug susceptibility of two human tumor cell lines of lymphoid origin, Daudi and MOLT 4, have been examined. L-Histidinol increased the inherent capacity of six different antineoplastic agents to kill these human tumor cells, in a dose- and time-dependent manner, in spite of the observation that it slowed cell cycle progression in both lines.

Improved treatment of disseminated B16f10 melanoma in mice with anticancer drugs in combination with L-histidinol.

An artificial hematogenous-metastasis model, in which B16f10 melanoma cells injected into the tail veins of C57/BL mice arrest in the lungs and proliferate as discrete pulmonary foci, was employed to examine effects of L-histidinol on the capacity of a number of conventional antineoplastic agents to manage disseminated disease. Treatment responses were evaluated by determining both the number of lung foci and/or by evaluating animal survival. L-Histidinol, on its own, was found to have a significant and dose-dependent capacity to reduce the number of lung foci and to extend survival of animals bearing disseminated B16f10 melanoma. L-Histidinol enhanced the ability of bis-chloroethylnitrosourea, 5-fluorouracil, and 1-beta-D-arabinofuranosulcytosine to reduce the number of lung foci. The latter combinations also gave marked improvements in survival, whether administered 1 or 7 days after the intravenous injection of tumor cells.

Different effects of L-histidinol and homoharringtonine on 5-fluorouracil and bis-chloroethylnitrosourea activity in a murine model.

A comparison of the effects of L-histidinol and homoharringtonine (HHT) on the activity of 5-fluorouracil (FUra) and bis-chloroehtylnitrosourea (BCNU) in C57/BL mice, without or with disseminated B16f10 melanoma, was carried out. Although L-histidinol and HHT are both protein synthesis inhibitors with apparently identical modes of action, these two compounds had very different effects in the test systems. HHT failed to prevent the body weight lose and subsequent death of C57/BL mice treated with supralethal doses of FUra; it was also unable to prevent the toxicity of FUra for bone marrow cells. In contrast, L-histidinol prevented the weight loss, death and bone marrow damage otherwise resulting from identical doses of FUra. Furthermore, L-histidinol was far more effective than HHT in its ability to improve the management of disseminated B16f10 melanoma in C57/BL mice by BCNU, both in terms of reducing pulmonary foci and extending survival.

3,5-Bis-benzylidene-4-piperidones and related compounds with high activity towards P388 leukemia cells.

3,5-Bis(benzylidene)-4-piperidones and related compounds were prepared and found to have between 100 and 9700 times the activity of N,N'-bis(2-chloroethyl)-N-nitrosourea towards P388 leukemia cells. The shapes of six of these molecules--determined by X-ray crystallography--were compared, but no correlation between the stereochemistry of the molecules or their electronic properties and cytotoxicity was apparent. Molecular modification of the compounds by forming two mono-benzylidene compounds, a related acyclic derivative and an N-acyl compound resulted in diminished but retained high cytotoxicity. Two representative compounds lowered glutathione levels of liver following their intraperitoneal injection into mice. Two quaternary ammonium compounds were shown to bind in the minor groove of DNA, while four related non-quaternary ammonium derivatives did not demonstrate this property. We conclude that the modes of action of these highly cytotoxic compounds include alkylation of cellular thiols and DNA binding, but interference with other biochemical processes is also probably involved.

L-histidinol improves the selectivity and efficacy of alkylating agents and daunomycin in mice with P388 leukaemia.

DBA/2J mice bearing a clonal isolate of the transplantable murine lymphocytic leukaemia line P388 were used to examine the effects of L-histidinol on the antitumour activity of three alkalyating agents (bis-chloroethylnitrosourea (BCNU), cis-diamminedichloroplatinum (II) (cisDDP) and cyclophosphamide) and the antitumour antibiotic daunomycin. Single, combined treatments with L-histidinol and either BCNU or cisDDP, at doses of the alkylating agents which were ineffective when used alone, were completely curative. Dose-response studies showed that L-histidinol conferred dose-dependent, synergistic improvements on the capacities of both BCNU and cisDDP to increase the life-span of DBA/2J mice bearing P388 leukemia. For combinations of L-histidinol and cyclophosphamide or daunomycin, two successive treatments with L-histidinol and drug were required to obtain a significant portion of long-term survivors. Thus, in this model system, the L-histidinol/anticancer drug combination approach for improving experimental cancer chemotherapy can be employed successfully with three alkylating agents and the antitumour antibiotic daunomycin.

Reversal of the multidrug-resistant phenotype of Chinese hamster ovary cells by L-histidinol.

The amino acid analogue L-histidinol reverses the multidrug-resistance (MDR) attribute of the colchicine-resistant (CHR) variant CHRC5, a Chinese hamster ovary cell line that overexpresses a plasma membrane-associated glycoprotein and is resistant to colchicine (CH), daunorubicin, and vinblastine sulfate (VS). The level of cell kill achieved in CHRC5 cells by combinations of L-histidinol and either daunorubicin or CH approached that achieved in AUXB1 parent cells by these two drugs, whereas L-histidinol-VS combinations killed even more CHRC5 cells than VS in the parental line. The capacity of L-histidinol to reverse the MDR phenotype of the CHRC5 line was time and dose dependent and was eliminated by the addition of a twofold molar excess of L-histidine. The reversal of the MDR trait by L-histidinol appears to be independent of the drug uptake mechanism.

Evaluation of Mannich bases of styryl ketones and related hydrazones for activity against P388 leukemia.

A Mannich base namely 4-dimethylaminomethyl-1-phenyl-1-penten-3-one hydrochloride was shown to have far greater activity than 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) towards P388 leukemia cells in vitro. However, the compound was inactive in an in vivo P388 murine screen, and the object of this study was to discern molecular features which conferred in vivo activity. Mannich bases containing electron-attracting substituents in the aryl ring had in vivo potency in contrast to the analogs which had electron-donating groups in the ring. A number of hydrazones of the Mannich bases were prepared as potential prodrugs and did not enhance bioactivity. This observation was probably due to a lack of facile hydrolysis of the hydrazones to the corresponding Mannich bases in vivo since high resolution 1H NMR spectroscopy revealed that representative hydrazones either did not regenerate the ketones or produced them only in minute quantities at pH values normally encountered in living tissues.

Effects of L-histidinol on the susceptibility of P815 mastocytoma cells to selected anticancer drugs in vitro and in DBA/2J mice.

The effects of L-histidinol on the susceptibility of the transplantable murine mast-cell neoplasm P815 mastocytoma to selected anticancer drugs have been evaluated on cells growing in culture and in syngeneic DBA/2J mice. Combinations of L-histidinol and anticancer drugs of either phase specificity [cytarabine (ara-C) and vinblastine sulfate] or cycle specificity [5-fluorouracil (FUra) and methotrexate] had diverse effects on cultured mastocytoma cells as scored by clonogenic cell survival assays. Flow cytometric analysis of randomly proliferating P815 mastocytoma cells revealed that although exposure to L-histidinol did not preclude cells from traversing the cell cycle, the analogue nonetheless conferred a dose-dependent and apparently nonspecific delay of cell cycle transit. DBA/2J mice bearing intraperitoneal P815 mastocytoma cells were used to evaluate the in vivo efficacy of L-histidinol-ara-C and of L-histidinol-FUra combinations. Quantitative cell survival assays of murine bone marrow cells and of clonogenic tumor cells obtained from treated animals demonstrated that L-histidinol eliminated the bone marrow toxicity otherwise attending the use of the drugs ara-C and FUra. Simultaneously, the inclusion of L-histidinol provided a statistically significant increase in the capacity of these two anticancer drugs to eradicate intraperitoneal mastocytoma cells.

Histidinol-mediated enhancement of the specificity of two anticancer drugs in mice bearing leukemic bone marrow disease.

The possibility was investigated that L-histidinol-anticancer drug combinations may provide increased tumor cell eradication and eliminate in vivo bone marrow toxicity of proliferation-dependent anticancer agents in animals bearing an established, intrafemoral bone marrow disease. It was previously demonstrated that L-histidinol, a structural analogue of the essential amino acid L-histidine, improves the specificity of cytarabine (ara-C) and 5-fluorouracil (FUra) in DBA/2J mice bearing intraperitoneal L 1210 leukemia. Accordingly, DBA/2J mice were given iv injections of 1 X 10(6) L1210 leukemia cells 3 days before histidinol-anticancer drug treatments. During the postinjection, pretreatment interval, injected tumor cells populated the femoral marrows, shown by clonogenic assays and flow cytometric analyses. Following various drug treatments, quantitative and selective survival assays were performed of normal femoral cells and of clonogenic L1210 leukemia cells isolated from the femurs of treated mice. These experiments demonstrated that L-histidinol not only protected the marrow cell population from both ara-C and FUra, but also increased significantly the toxicities of these agents for the intrafemoral tumor cells. Thus L-histidinol mediates a substantial increase in the specificities of ara-C and FUra in mice bearing an established bone marrow leukemic condition.

Histidinol-mediated improvement in the specificity of 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil in L 1210 leukemia-bearing mice.

We have demonstrated previously that L-histidinol, a structural analogue of the essential amino acid L-histidine, protects a variety of phenotypically normal cell lines from certain proliferation-dependent anticancer drugs without decreasing the toxicity of these agents for corresponding tumorigenic derivatives of the normal cells. Histidinol modulates the toxicity of selected anticancer drugs in tissue culture systems by its ability to arrest, specifically and reversibly, cells of normal phenotype in a G0-like, noncycling state while allowing continued cell cycle transit in most of their tumorigenic counterparts. Thus, in the presence of comparable levels of histidinol, the toxicities of the proliferation-dependent anticancer drugs 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil are eliminated for a variety of normal cell lines but significantly increased for a number of tumorigenic lines. We report here that histidinol confers substantial protection upon the bone marrow cells of DBA/2J mice from the drugs 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil. The protective responses were evaluated by quantitative cell survival assays and by animal survival studies. We report also that the histidinol-mediated protection to bone marrow cells persists in L1210 leukemia-bearing DBA/2J mice treated with combinations of histidinol and 1-beta-D-arabinofuranosylcytosine or 5-fluorouracil without diminishing the toxicities of these agents for in situ leukemia cells.

L-histidinol protection against cytotoxic action of cytosine arabinoside and 5-fluorouracil in cultured mouse spleen cells.

The effects of L-histidinol, a structural analog of the essential amino acid L-histidine, on the proliferative responses and anticancer drug vulnerability of cultured spleen cells from male C57BL/6J mice exposed to optimal mitogenic doses of concanavalin A (Con A) or E. coli lipopolysaccharide (LPS) were investigated. By means of tritiated thymidine ([3H]dThd) incorporation into acid-insoluble material as the criterion for proliferation. L-histidinol was shown to provide a dose-dependent inhibition of mitogenic responses elicited by Con A and LPS. Total (apparent) inhibition was provided by 1-mM concentrations of the analog and, at this concentration, [3H]dThd incorporation was totally reversible even after 72 hours of sustained exposure. Simultaneous addition of L-histidinol and either of the mitogens provide a Go-like arrest for 24 hours. Thereafter, the cells appeared to begin slow cell cycle transit but did not traverse the G1/S boundary within 96 hours of incubation. These responses of cultured murine lymphocytes to L-histidinol provided dramatic and extended protection from the cell cycle phase-specific drug cytosine arabinoside and dramatic but transient protection from the cell cycle-specific drug 5-fluorouracil. In principle, these findings extend the L-histidinol anticancer drug approach for improving the therapeutic index of antineoplastic agents, not only to both cycle- and phase-specific drugs, but also to primary cells of myeloid origin.