Use of PC12 Cells as a Neurotoxicological Screen: Characterization of Anticyanide Compounds

A series of six biochemical markers of cyanide toxicity (dopaminerelease, hydroperoxide generation, cytosolic-free calcium levels,catalase activity, cytochrome oxidase activity, and superoxidedismutase activity) in cultured rat pheochromocytoma (PC12)cells were used to establish a screen for evaluation of potentialanticyanide compounds. Thirty-nine substances, including anticonvulsants,adrenergic blockers, antioxidants, and antipsychotics were testedand ranked according to the results. Based on the compositescoring in all six assays, carbamazepine, mannitol, allopurinol,and phenytoin were ranked as the most effective anticyanidecompounds. Additionally, known cyanide antidotes (e.g., pyruvate,mercaptopyruvate, -ketoglutarate, naloxone, and flunarizine)obtained relatively high ranking in the PC12 cell screen. Furthermore,a significant correlation was found between protective effects(based on LD50s) of cyanide antidotes in mice and ranking inthe in vitro screen. This study illustrates that by assayinga series of biochemical markers in a neuronal-type cell line,a rapid, cost-effective in vitro toxicological screen is possible.Several compounds have been identified which inhibit the biochemicaleffects of cyanide and may be used to enhance effectivenessof the standard cyanide antidotes.     

Pulmonary Immunotoxicity of Inhaled Ammonium Metavanadate in Fisher 344 Rats

Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m³ (asammonium metavanadate NH⁴VO³, 0.32 µm MMD) atmospheresfor 8 hr/day for 4 days in a nose-only exposure system. In exposedrats, lung V burdens increased in a time-dependent fashion.Analysis of lung cells and lavage fluid 24 hr after the finalexposure suggested that tissue damage and a strong inflammatoryresponse was elicited; numbers of neutrophil and small macrophages(M), as well as levels of lavageable protein and lactate dehydrogenase,were significantly elevated as compared with levels observedwith air-exposed rats. Vanadium also affected pulmonary alveolarM (PAM) capacities to produce and respond to immunoregulatingcytokines. Inducible PAM production of tumor necrosis factor-awas significantly inhibited, as was the ability to increasecell surface Class II/I-A molecule expression in response tointerferon- (rFN-). PAM from V-exposed hosts were also inhibitedin their ability to be primed by EFN- to produce superorideanion and hydrogen peroxide in response to stimulation withopsonized zy-mosan. These studies indicate that short-term repeatedexposure of rats to atmospheric V, at levels encountered inan occupational setting, can alter host pulmonary immunomocompetence,with one major effect occurring at the level of cytokine-relatedfunctions. These alterations may be underlying mechanisms forthe well-documented increases in bronchopulmonary infectionsand cancers in workers chronically exposed to V-containing atmospheres.     

The development of resistance in different inbred strains of mice to infection with Nematospiroides dubius

Infection by the intestinal nematode parasite Nematospiroides dubius was studied in seven different inbred mouse strains. Although there was some minor variation in the susceptibility of the different strains to a primary infection there were marked differences in their ability to develop resistance to infection following repeated exposure to infective larvae. The strains of mice which developed the best resistance also expelled adult worms arising from the previous infections. The adult worms resulting from a primary infection were slowly eliminated in two inbred strains studied whereas no loss occurred from outbred LACA mice. Although males and females of two strains, C3H/HeJ and CBA/H were equally susceptible to a primary infection, the females developed better resistance than the male mice following two oral administrations of third stage larvae. Infected mice of every strain and both sexes contained high levels of IgG1 in the serum.     

Microbial colonization of the Groningen speaking valve and its relationship to valve failure

Speaking valve failure may be related to biofilm development. An inter-observer validated method of assessing microbial overgrowth in defective prostheses was developed. Two independent observers recorded colonisation of the valves on a 100 mm linear analogue scale in several defined areas. Inter-observer agreement was high in all areas. In vitro opening pressure and derived forward resistances were measured. The relationship between colonization of the valves and the in vitro measurements was investigated. Significant correlations for a two-tailed Spearman's test were recorded between the resistance and microbial colonization of the hinge and oesophageal areas (r_s 0.22: P < 0.05, r_s 0.25: P < 0.05, n= 80). There was no significant association for resistance and colonization of the tracheal surface, and no significant association between the opening pressure and the colonization. This work suggests that microbial colonization of the prosthesis in the oesophageal and hinge areas is associated with valve failure.     

Efficacy and tolerability of lower-dose topotecan in recurrent ovarian cancer: a retrospective case review

Topotecan (1.5 mg/m(2)/day for 5 consecutive days of a 21-day cycle) is an established recurrent ovarian cancer treatment, but myelosuppression can be dose limiting. This study evaluates the activity and tolerability of low-dose topotecan in our clinical experience. Case records were reviewed for patients with recurrent ovarian cancer in first through third relapse. Eligible patients had received > or =2 cycles of < or =1.25 mg/m(2) topotecan. Adverse events were evaluated using laboratory and clinical evaluation data. Twenty-seven eligible patients, most with advanced disease, received a total of 209 cycles (median, six cycles). Grade 3 or 4 hematologic toxicities during 184 cycles in 24 assessed patients were neutropenia, leukopenia, thrombocytopenia, and anemia in 35%, 28%, 36%, and 11% of cycles, and 21, 19, 16, and 10 patients, respectively. Only four grade 4 toxicities occurred: anemia (one) and thrombocytopenia (three). Myelosuppression was reversible, noncumulative, and manageable. Moreover, nonhematologic toxicity was generally mild to moderate, and the only two grade 3 events were constipation and deep vein thrombosis. Low-dose topotecan was active in this setting. Lower-dose topotecan is generally well tolerated and active in patients with pretreated ovarian cancer. Prospective clinical trials of low-dose topotecan in recurrent ovarian cancer are warranted.     

Aphysiologic performance on dynamic posturography

The remarkable ability of the body to maintain balance is the result of central nervous system integration of sophisticated inputs from the vestibular, visual, and somatosensory systems. Strategies by patients with balance dysfunction are aphysiologic when their performance is relatively better on more difficult conditions of sensory conflict than on easier ones. Twenty-two aphysiologic patterns on computerized dynamic posturography were compared with age-matched normal and vestibular patterns. The aphysiologic group performed significantly better than the patients in the vestibular dysfunction group on the most difficult subtests of computerized dynamic posturography, conditions 5 and 6, yet significantly poorer on the easier subtests, conditions 1 through 4. In addition, patients in the aphysiologic group tended to show greater intertrial variability compared with patients in both normal and vestibular system dysfunction groups. A stepwise linear discriminant analysis was used to determine a set of conditions that had significant value in discriminating between the three patient groups. Case studies are presented to further illustrate the clinical usefulness of computerized dynamic posturography testing in the evaluation of patients suspected of having a functional component to their on-feet balance problems. (OTOLARYNGOL HEAD NECK SURG 1995;112:676-88.)