Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung

Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic hydrocarbon, is the most potent carcinogen ever tested in mouse skin and rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction, tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in strain A/J mouse lung. Groups of mice received a single i.p. injection of 0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment, DNA adducts were measured at times between 1 and 28 days, while tumors were counted at 250 days and analyzed for the occurrence of point mutations in codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung induced six major and four minor DNA adducts. Maximal levels of adduction occurred between 5 and 10 days after injection followed by a gradual decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti- and syn-11,12- dihydroxy-13,14-epoxy- 11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed by cochromatography. The major adduct was identified as a product of the reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced significant numbers of lung adenomas in a dose- dependent manner, with the highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based on the administered dose, DB[a,l]P was more active than other environmental carcinogens including benzo[a]pyrene. As a function of time-integrated DNA adduct levels, DB[a,l]P induced lung adenomas with about the same potency as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar in carcinogenic potency to other PAHs in the strain A/J mouse lung model. Analysis of the Ki- ras mutation spectrum in DB[a,l]P-induced lung tumors revealed the predominant mutations to be G-->T transversions in the first base of codon 12, A-->G transitions in the second base of codon 12, and A-->T transversions in the second or third base of codon 61, concordant with the DNA adduct profile.      

Otoacoustic emissions as a screening test for hearing impairment in children recovering from acute bacterial meningitis

OBJECTIVES: To study the efficacy of otoacoustic emissions (OAEs) as a screening test for hearing impairment in children with acute bacterial meningitis. Hearing tests were performed before discharge from the hospital in an attempt to improve coverage and avoid delays in the diagnosis of postmeningitic hearing loss. METHODS: Children with bacterial meningitis were recruited from 21 centers. In the 48 hours before discharge from the hospital, all patients underwent a thorough audiologic assessment consisting of transient evoked OAEs, auditory brainstem responses (ABRs), otoscopy, and tympanometry. Hearing loss was defined as ABR threshold >/=30 dB. The results of OAE screening were compared with the gold standard of ABR threshold. RESULTS: Of 124 children recruited, we were able to perform both OAEs and ABRs on 110 children. Seven (6.3%) of the 110 children had ABR threshold >/=30 dB; 2 had sensorineural hearing loss and 5 had conductive hearing loss. At follow-up, hearing loss persisted in both cases of sensorineural hearing loss and no new cases were identified. All 7 children with hearing loss failed the OAE screening test. Ninety-four children with normal hearing thresholds passed the test, and 9 failed. Thus, the screening test had a sensitivity of 1.00 (95% confidence interval, 0.59 to 1.00), a specificity of 0.91 (0.85 to 0.97), a positive predictive value of 0. 44 (0.20 to 0.70), and a negative predictive value of 1.00 (0.96 to 1.00). CONCLUSIONS: OAE screening in children recovering from meningitis was found to be feasible and effective. The test was highly sensitive and reasonably specific. Inpatient OAE screening should allow early diagnosis of postmeningitic hearing loss and prompt auditory rehabilitation.     

Cutaneous metastases from adenocarcinoma of unknown primary

Cutaneous manifestations of malignancy are not uncommon, especially in advanced disease. They may also occur early in malignant disease or they may even signify recurrence particularly if they are paraneoplastic in nature. Clinical diagnosis can be difficult because of the wide spectrum of appearance of these lesions, and, in many cases, because of the lack of an identifiable underlying primary. Presented here is the case of a 65-year-old woman with multiple inflammatory cutaneous metastases, which were sclerodermoid in nature. These appeared 14 months after initial diagnosis of adenocarcinoma of unknown primary (ACUP) and signified the beginning of a rapid deterioration in her condition. The coexistence of limited systemic sclerosis (scleroderma) and ACUP initially raised several interesting diagnostic possibilities. Adenocarcinoma of unknown primary and the sclerodermoid reaction in malignancy are discussed.     

Improved freedom from PSA failure with whole pelvic irradiation for high-risk prostate cancer

Purpose: To determine the impact of whole pelvic irradiation on the risk of PSA failure in prostate cancer patients, at high predicted risk for lymph node involvement, receiving definitive radiotherapy.

Materials and Methods: Between October 1987 and December 1995, 506 patients with clinically localized prostate cancer were treated with definitive radiotherapy at UCSF and affiliated institutions. Treatment consisted of 4-field whole pelvic irradiation followed by a prostate-only boost, or prostate-only treatment (median follow-up was 35 months and 30 months, respectively). PSA failure was defined as: 1. a PSA value ≥ 1 ng/ml; or 2. a PSA value that rose ≥ 0.5 ng/ml in ≤ 1 year posttreatment on two consecutive measurements, with the first rise defined as the time of failure. The calculated risk of lymph node positivity (%rLN+) was defined as (iPSA) + 10(GS-6), and high risk was defined as %rLN+ ≥ 15%. Univariate and multivariate analyses were performed.

Results: A total of 201 high-risk patients were identified. High-risk patients who received whole pelvic irradiation had significantly improved freedom from PSA failure compared to those who received prostate-only treatment (median PFS = 34.3 months vs. 21.0 months; p = 0.0001). Potential confounding variables, including initial PSA, Gleason score, T stage, radiation dose, year of treatment, use of three-dimensional (3D) conformal techniques, and use of hormone therapy, did not account for the observed difference in time to PSA failure. Multivariate analysis revealed type of radiation treatment to be the most significant independent predictor of outcome.

Conclusion: Whole pelvic radiotherapy significantly improves the PSA failure-free survival in patients with a high calculated risk of lymph node positivity.     

Lost working days, productivity, and restraint use among occupants of motor vehicles that crashed in the United States

BACKGROUND: In 2001, 6.3 million passengers were involved in motor vehicle crashes. This study aimed to determine the number of work days lost as a result of motor vehicle crashes and factors that influenced people's return to work. METHODS: This was a retrospective, population based cohort study of occupants in motor vehicles involved in crashes from the 1993-2001 Crashworthiness Data System produced by the National Highway Traffic Safety Administration. The sample population of people aged 18-65 years included two groups: occupants who survived and were working before the crash and occupants who were injured fatally and were estimated to have been working before the crash. Multivariate linear regression was used to analyze the impact of restraint use and injury type on return to work. RESULTS: Overall, 30.1% of occupants of vehicles that crashed missed one or more days of work. A crash resulted in a mean 28.0 (95% confidence interval 15.8 to 40.1) days lost from work, including losses associated with fatalities. The 2.1 million working occupants of vehicles that crashed in 2001 lost a total of 60 million days of work, resulting in annual productivity losses of over $7.5 billion (2964 to 12 075). Unrestrained vehicle occupants accounted for $5.6 billion in lost productivity. CONCLUSIONS: Motor vehicle crashes result in large and potentially preventable productive losses that are mostly attributable to fatal injuries.     

Ovarian hormones can organize the rat corpus callosum in adulthood

The rat corpus callosum (CC) is larger in males than females, and is responsive to hormone manipulations during development. Previous data suggest that CC sensitivity to testosterone ends by postnatal day 8 (P8). In contrast, responsivity to ovarian hormones extends as late as P25. The current series of experiments investigates whether ovarian hormone effects on the callosum are permanent and whether CC sensitivity to ovarian hormones extends beyond P25. We found that P70 ovariectomy (Ovx) did not affect callosal size, suggesting that ovarian hormone exposure sometime prior to P70 is sufficient to feminize the CC, and that once the callosum is feminized, the effects can not be reversed. We also found that P25 ovariectomy enlarged, or defeminized, adult female CC, whereas ovary transfer starting on P55 or P70 counteracted this enlarging effect, resulting in feminized adult CC. Thus, although a previously feminized callosum is not affected by P70 ovarian hormone removal, a not-yet feminized callosum can still be feminized after P70. These findings indicate that there is flexibility in the developmental window within which the female brain is responsive to the active feminization process initiated by ovarian hormones.