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.     

The treatment of lateral clavicle fractures

This study assesses the results of surgical treatment of 15 displaced Neer type II fractures of the lateral clavicle in 15 patients, which occurred between November 1988 and March 1995 and which were followed up for a mean period of 4.6 years (range 2-9 years). The patients fell into two groups, one 'acute group' and one 'non-union' group.Patients treated initially by a non-operative approach had suffered prolonged morbidity and time off work prior to and after surgery. The ultimate result was good. The fixation used was a Dacron arterial graft as a sling around the clavicle and coracoid process. Delayed (non-union) cases were augmented with bone graft and inter-fragmentary screw fixation. All fractures eventually united.We question the place of prolonged non-operative management in the treatment of displaced Neer type II fractures of the lateral clavicle.     

The functional characterization of interleukin-10 receptor expression on human natural killer cells

Human natural killer (NK) cells are large granular lymphocytes that constitutively express functional forms of the interleukin-2 receptor (IL-2R) and lyse tumor and virally infected cells without prior sensitization. NK cells with high density expression of CD56 (CD56bright) express the high affinity IL-2R and proliferate in response to low (picomolar) concentrations of IL-2. CD56dim NK cells express the intermediate affinity IL-2R and demonstrate enhanced cytotoxic activity without proliferation in response to high (nanomolar) concentrations of IL-2. In the present study, we characterized IL-10R expression on human NK cells and the functional consequences of IL-10 binding directly to highly purified subsets of CD56bright and CD56dim NK cells. Binding studies using 125I-IL-10 indicated that resting human NK cells constitutively express the IL-10 receptor protein at a surface density of approximately 90 receptor sites per cell, with a kd of approximately 1 nmol/L. Alone, IL-10 did not induce proliferation of CD56bright or CD56dim NK cell subsets. However, at low concentrations (0.5 to 5 ng/mL), IL-10 significantly augmented IL-2-induced proliferation of the CD56bright NK cell subset mediated via the high-affinity IL-2R. In the absence of IL-2, IL-10 was able to induce significant NK cytotoxic activity against NK-resistant tumor cell targets in both subsets of NK cells in a dose-dependent fashion. Furthermore, the combination of IL-10 and IL-2 had an additive effect on NK cytotoxic activity, whereas that of IL-10 and IL-12 did not. Production of interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor by IL-2-activated NK cells was also significantly enhanced by IL-10. Neither resting nor activated human NK cells appear to produce human IL-10 protein. In summary, NK cells constitutively express the IL-10R protein in low density, and the functional consequences of IL-10 binding directly to human NK cell subsets appear to be stimulatory and dose-dependent. In contrast to its direct effects on human T cells and monocytes/macrophages, IL-10 potentiates cytokine production by human NK cells.