Paranasal sinus mucocele in cystic fibrosis

The relationship between cystic fibrosis, nasal polyposis and chronic sinusitis is clearly defined. Mucoceles of the paranasal sinuses, however, are a well-described complication of chronic sinusitis in adults; but they rarely occur in the pediatric age group. We report a three-year-old who presented with epiphora and fullness at the right medial canthus. Computed tomography confirmed a right ethmoid mucocele which was surgically drained, with resolution of symptoms. Approximately 12 other cases of mucoceles have been reported in the pediatric age group. Although many of these patients had recognized cystic fibrosis, some were previously undiagnosed. Only after presentation with a mucocele, did sweat testing reveal their underlying pathology. No pediatric patients in the literature were found with mucoceles and normal sweat tests. Paranasal sinus mucoceles may be diagnostic of cystic fibrosis and may be the presenting sign in some patients.     

Resistance of Salmonella typhimurium TA 1535 to O6-guanine methylation and mutagenesis induced by low doses of N-methyl-N'-nitro-N-nitrosoguanidine: an apparent constitutive repair activity

Salmonella tester strains which are reverted by base-pair substitutionmutagens are relatively insensitive to the mutagenic effectsof N-methyl-N-nitroso compounds. One reason for this insensitivityis the ability of these strains to withstand low doses of thesecompounds before they become sensitive to their mutagenic effects.In this report it is shown that mutagenesis induced by treatmentof Salmonella typhimurium TA 1535 with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) in buffer is biphasic with a low sensitivity range atlow doses where little mutagenesis occurs, followed by a highsensitivity range whose onset begins after an apparent thresholddose has been exceeded. Levels of O⁶-methylguanine (O⁶-MeG)in the DNA extracted from the bacteria follow a similar dose-responsecurve suggesting a dependency of mutagenesis on O⁶-MeG. In contrast,levels of 7-methylguanine (7-MeG) in the DNA increase linearlywith dose. O⁶-MeG was undetectable at the lowest dose of MNNGwhereas 7-MeG was readily detectable. Although such resistanceto O⁶-alkylation has been demonstrated in MNNG-pretreated (adapted)E. coli, it has not been reported in unpretreated cells. Whenisolated DNA was treated with MNNG a linear dose-response inthe generation of O⁶-MeG was observed. The lack of O⁶-MeG inDNA isolated from MNNG treated cells after low doses is attributedto a saturable, constitutive repair activity in the bacteria.An attempt to observe the removal of O⁶-MeG from the bacteriaafter exposure to a short challenge dose of N-nitroso-N-methylurea(NMU) followed by a subsequent incubation in buffer was unsuccessful,probably because all the repair occurred within the time necessaryto treat and lyse the cells.     

Usefulness of radiofrequency ablation of supraventricular tachycardia to decrease inappropriate shocks from implantable cardioverter-defibrillators

Inappropriate implantable cardioverter-defibrillator (ICD) therapies can lead to significant adverse events and increased mortality. These therapies are often the result of supraventricular tachycardias (SVTs). The objective of this study was to evaluate the incidence of SVT leading to inappropriate shocks in a large cohort of patients with ICDs and assess the efficacy of radiofrequency ablation (RFA) in decreasing these therapies. Patients with ICDs and recurrent SVTs were identified. A cohort of patients with ICD therapies subsequently underwent electrophysiologic study and RFA. Eighty-four patients (13%) were found to have SVT leading to 122 inappropriate ICD shocks and 130 episodes of antitachycardia pacing therapies. Median time to SVT onset after ICD implantation was 269 days. Electrophysiologic studies were performed in 30 patients. Successful RFA was performed for atrial tachycardia, atrial flutter, or atrioventricular nodal reentrant tachycardia in 22 patients. Ninety-five percent of patients who underwent successful SVT ablation had no further inappropriate ICD therapies compared to 63% of patients in whom ablation was not performed during a mean follow-up of 20.7 ± 11.9 months. In conclusion, SVT is responsible for a significant number of inappropriate ICD therapies. RFA is an effective strategy to substantially decrease subsequent inappropriate ICD therapies.     

Mutagenesis and O6-ethylguanine levels in DNA from N-nitroso-N-ethylurea-treated Salmonella typhimurium: evidence for a high mutational efficiency of O6-ethylguanine

The dose-responses for N-nitroso-N-ethylurea (NEU)-induced mutagenesisin the hisG46 mutant, Salmonella typhimurium TA1535, and forthe formation of O⁶-ethylguanine (O⁶-EtGua) and 7-ethylguaninein the DNA isolated from these cells were measured. Mutagenesisand O⁶-EtGua formation exhibited threshold-like behavior, whereasthe formation of 7-ethylguanine was linear with dose. Theseresults are consistent with a dependence of mutagenesis on O⁶-EtGua.There was no threshold in the production of O⁶-EtGua in isolatedDNA treated with NEU. The failure of O⁶-EtGua to appreciablyaccumulate in the cellular DNA at low doses of NEU was attributedto a saturable, constitutive repair activity in the bacteria.Based on (i) the ratio of O⁶-EtGua in DNA to revertant fraction,(ii) published values for the size of the Salmonella genomeand (iii) the target size and target bases (guanine-cytosinebase pairs) for reversion of the hisG46 (missense) mutation,it was calculated that about 1/3 of the O⁶-EtGua's in the DNAled to mutations. Using the same calculations and data fromprevious experiments, a mutational efficiency for O⁶-methylguanineof 2/3 was obtained. Threshold-type responses in NEU-inducedmutagenesis were observed in the other hisG46 mutants, TA100and TA1975, but not in the frameshift mutant, TA98 where thedose response was linear. As TA98 contains the same DNA repairsystems as TA100, frameshift mutations induced by NEU may resultfrom DNA adducts produced linearly with dose.     

Mechanisms of inhibition by ascorbate of microbial mutagenesis induced by N-nitroso compounds.

Mutagenesis induced by N-methyl-N-nitrosoguanidine (MNNG) and dimethylnitrosamine (DMN) in Salmonella TA 1530 was inhibited by ascorbate. Inhibition of MNNG-induced mutagenesis resulted from a reaction between ascorbate and MNNG that led to consumption of MNNG. The rate of this reaction was considerably enhanced by catalytic amounts of Cu(II) and Fe(III). No direct reaction between DMN and ascorbate was detectable, but relatively high concentrations of Cu(II) enchanced inhibition of DMN-induced mutagenesis by ascorbate. Added protein reduced the effectiveness of Cu(II) as a catalyst of the reaction between ascorbate and MNNG, which suggested that the microsomal protein necessary to activate DMN, may reduce the concentration of free Cu(II) and thereby lower its catalytic efficiency. Mutagenesis by N-methyl-N-nitrosourea was not inhibited by ascorbate.     

Unexpected genetic toxicity to rodents of the N′, N′-dimethyl analogues of MNU andENU

Lijinsky and his colleagues have reported that the N′, N′-dimethyl analogues of ENU and MNU [N′, N′-dimethyl-N-ethyl-N-nitrosourea (DMENU) and trimethylnitrosourea (TMNU), respectively] are carcinogenic to rats despite their extreme hydrolytic stability which would reduce or preclude generation of alkylating species analogous to those formed upon hydrolysis of ENU and MNU. Lijinsky and his colleagues were unable to rationalize those activities of DMENU and TMNU despite extensive experimentation. We therefore decided to study this problem further. Whichever mode is accepted for the generation of electrophilic/mutagenic/carcinogenic reactive species from ENU and MNU, blocking of the free-NH₂ group with methyl groups (−NMe₂) should ablate or abolish activity. Consistent with this, DMENU and TMNU gave negative results in the NBP alkylation test while the parent compounds gave an instantaneous deep blue coloration. Studies of the rate of hydrolysis of these four compounds revealed ENU and MNU to have half-lives of 8 min, while the alkylated analogues (DMENU and TMNU) had half-lives of 25 and 41 days, respectively. Hydrolysis of ENU and MNU, to yield the alkylating species, proceeds either via proton abstraction from the −NH₂ group or by attack by water on the carbon of the carbonyl group. Methylation will inhibit both of these pathways, the first absolutely (no −NH₂ protons) and the second partially, via steric inhibition. The slow hydrolysis observed for DMENU and TMNU suggests that the latter route of hydrolysis is applicable. Studies with strain TA1535 of Salmonella typhimurium (without S9 mix) confirmed the potent mutagenic activity for ENU and MNU (∼300-fold increase in revertants at 2,000 μg/plate and ∼180-fold increase in revertants at 150 μg/plate respectively). In contrast, the methylated analogues showed only weak mutagenic activity (∼3-fold) at ∼100-fold higher dose-levels. Addition of S9 mix did not affect the mutagenicity of DMENU or TMNU. To this point, hypothesis and data coincide. ENU and MNU are potent micronucleus-inducing agents to the mouse bone marrow, and given the above data, it was expected that DMENU and TMNU would show weak or no activity in that assay. In fact, the methylated analogues were as effective as ENU and MNU as clastogens to the mouse bone marrow. Four possible reasons for this conflict of theory and data are explored. The speculative explanation we favour for these effects is that the net alkylation of bone marrow DNA is the same for all four chemicals. With ENU and MNU, most of the alkylating activity is dissipated by rapid hydrolysis. Thus, only a small fraction of the administered dose survives to alkylate the bone marrow. Due to the enhanced stability of the methyl analogues most of the delivered dose will reach the bone marrow. However, because of their lower intrinsic reactivity, only a small fraction of the target dose will alkylate the bone marrow DNA during the time window of the experiment. If these opposing influences happen to balance out, the essentially identical bone marrow genetic toxicity for the four chemicals could be explained. © 1996 Wiley-Liss, Inc.     

Mutagenesis and carcinogenesis induced by dibenzo[a,l]pyrene in the mouse oral cavity: a potential new model for oral cancer

Cancer of the oral cavity is a serious disease, affecting about 30,000 individuals in US annually. There are several animal models of oral cancer, but each has certain disadvantages. As a new model, we investigated whether topical application of the tobacco smoke carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) is mutagenic and carcinogenic in the oral cavity of the B6C3F1 lacI and B6C3F1 mouse, respectively. B6C3F1 lacI mice received DB[a,l]P (0, 3, 6, 12 nmol) 3× per week. B6C3F1 mice received the same doses and also 24 nmol. At 38 weeks mutagenesis was measured in oral tissues in lacI mice. For the high dose group, the mutant fraction (MF) in upper mucosa and tongue increased about twofold relative to that in vehicle-alone. The increases were statistically significant. The mutational profile in the DB[a,l]P-induced mutants was compared with that induced by benzo[a]pyrene (BaP) in oral tissue. BaP is mutagenic in many tissues when administered by gavage. The mutational profile for DB[a,l]P was more similar to that reported for p53 mutations in head and neck cancers than was that of BaP. At 47 weeks, oral squamous cell carcinomas (OSCC) were found in 31% of the high-dose B6C3F1 group. Elevations of p53 and COX-2 protein were observed in tumor and dysplastic tissue. As DB[a,l]P induces mutations and tumors in the oral cavity, and has a mutational profile in oral tissue similar to that found in p53 in human OSCC, the treatment protocol described here may represent a new and relevant model for cancer of the oral cavity.     

Immediate oral amiodarone re-challenge following the development of parenteral-induced acute liver toxicity

Dear editor, Amiodarone is a class Ⅲ antiarrhythmic medication commonly used in the emergency department (ED) and other critical care settings to treat several ...     

DNA binding by [2, 5-14C]N7-nitrosopyrrolidine in excision-repair proficient and deficient strains of Salmonella. Evidence for a major premutagenic adduct

Little is known about the nature and possible genotoxic effectsof the DNA adducts formed by N-nitrosopyrrolidine (NPYR) inwhole animals. DNA binding in DNA isolated from [2, 5-¹⁴C]NPYR-treatedSalmonella was studied and attempts were made to monitor DNAadducts and correlated DNA binding with mutagenesis. NPYR wasmetabolized by hamster liver S-9 fraction in the presence ofS.typhimurium TA1535 (uvrB^–) or TA1975(uvrB⁺ DNA isolatedfrom TA1535 contained about three times as much radioactivityas that isolated from TA1975, and NPYR-induced mutagenesis wasseveral-fold higher in TA1535. The fraction of radioactivityincorporated into TA1535 was {small tilde}10^-5. Thermal hydrolysisof the ¹⁴C-containing DNA at neutral pH, followed by precipitation,released {small tilde}2/3 of the radioactivity into the supernatant.HPLC analysis of the supernatant revealed one major peak. Thispeak was absent in DNA from TA1975. Acid hydrolysis of the DNAprecipitate after neutral hydrolysis released most of the residualradioactivity. Several small peaks were observed after HPLCanalysis of the TA1535 acid hydrolysate or the TA1975 acid hydrolysate.These results demonstrate that NPYR is capable of binding toSalmonella DNA yielding one major product after hydrolysis andthis DNA binding product appears to be repaired by the excisionrepair system. The fact that the major peak of radioactivityreleased from Salmonella is only found in the strain which isefficiently reverted by NPYR suggests that mutagenesis is dependenton the DNA modification leading to this peak.