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Steroid receptors bind to site-specific response elements in chromatin and modulate gene expression in a hormone-dependent fashion. With the use of a tandem array of mouse mammary tumor virus reporter elements and a form of glucocorticoid receptor labeled with green fluorescent protein, targeting of the receptor to response elements in live mouse cells was observed. Photobleaching experiments provide direct evidence that the hormone-occupied receptor undergoes rapid exchange between chromatin and the nucleoplasmic compartment. Thus, the interaction of regulatory proteins with target sites in chromatin is a more dynamic process than previously believed.

Methemoglobinemia is a rare cause of cyanosis in pediatric patients. A 16-month-old male presented to the Emergency Department cyanotic and short of breath after ingestion of a hair-care-equipment cleaning solution. After calling the salon and consulting Poisindex, the substance was found to be Mar-V-cide, containing 20% Hyamine 3500, 50% cationic detergents, 20% isopropyl alcohol, and 1% sodium nitrite, which caused the methemoglobinemia in this case. Initial pulse oximetry on room air was 72% and improved minimally with supplemented oxygen. The patient's methemoglobin level was 63%. Methylene blue was administered (2 mg/kg intravenously), and the patient rapidly improved. Nitrates occur in high concentrations in some food and water. Infants are particularly susceptible to chronic nitrate-induced methemoglobinemia because of their low stomach acid production, large numbers of nitrite-reducing bacteria, and the relatively easy oxidation of fetal hemoglobin. Acute nitrite toxicity results from industrial exposure, accidental ingestion (e.g., abuse of organic nitrites as an aphrodisiac, especially in the male homosexual population), and suicidal ingestion. Methemoglobinemia may occur in a number of drug or chemical ingestions, but a comprehensive review of the literature failed to identify a similar reported case.

This paper presents a theory on which to base intervention research in the construction industry, along with a hypothetical case study involving construction painters. The hypothetical case is based on data from research in a three-state study of construction painters currently under way. Difficulties facing researchers who conduct research in construction are described. Advantages of the intervention research design for construction are discussed.

New strategies for representing acoustic information with multichannel cochlear implants have produced substantial improvements in speech recognition for implant users. This report reviews within-subject comparison of a new continuous interleaved sampling (CIS) strategy with a compressed analog (CA) strategy used in a standard clinical device. In general, the comparison show higher levels of open-set speech recognition with CIS for each of the 11 subjects studied. Data on the importance of the patients variable in determining outcomes with cochlear implants are presented. A brief description of another new strategy, the spectral maxima sound processor (SMSP) strategy is given as well as information on the availability of CIS in various implant systems.

Removal of an acoustic neuroma using the translabyrinthine approach has previously been considered "incompatible" with hearing preservation. By modifying the approach and preventing the loss of endolymph, we have successfully removed two intracanalicular acoustic neuromas that originated from the inferior vestibular nerves, and preserved serviceable hearing in the ears operated on. This report represents the preliminary findings using this particular technique in the management of intracanalicular acoustic neuromas.

Within-subjects comparisons of processing strategies for cochlear implants are reviewed. Compressed analog strategies were compared to interleaved pulses strategies in tests with one group of 8 subjects, and to continuous interleaved sampling strategies in tests with another group of 11 subjects. The tests included open-set recognition of words and sentences. The results show that, while different strategies may produce quite different outcomes across subjects, individual performances with one processing strategy are significantly correlated with those of alternative strategies. These findings emphasize the importance of patient variables in determining outcomes across a variety of prosthesis designs.

Two approaches for representing speech information with multichannel cochlear prostheses are being compared in tests with implant patients. Included in these studies are the compressed analog (CA) approach of a standard clinical device and research processors utilizing continuous interleaved sampling (CIS). Initial studies have been completed with nine subjects, seven of whom were selected on the basis of excellent performance with the Ineraid clinical processor, and the remaining two for their relatively poor performance with the same device. The tests include open-set recognition of words and sentences. Every subject has obtained a higher score--or repeated a score of 100% correct--on every test when using a CIS processor. These results are discussed in terms of their implications for processor design.

The mouse mammary tumor virus (MMTV) promoter attains a phased array of six nucleosomes when introduced into rodent cells. This architecture excludes nuclear factor 1/CCAAT transcription factor (NF1/CTF) from the promoter before glucocorticoid treatment and hormone-dependent access of nucleolytic agents to promoter DNA. In contrast, when the promoter was transiently introduced into cells, NF1/CTF was bound constitutively and nucleolytic attack was hormone-independent. Thus, induction at this promoter was a bimodal process involving receptor-dependent remodeling of chromatin that allows NF1/CTF loading and direct receptor-mediated recruitment of additional transcription factors.

The POMC gene is expressed predominantly in the anterior pituitary. The high level of POMC transcription in this tissue is modulated by peptide hormones and repressed by glucocorticoids. In this present study we have investigated promoter elements required for the high basal transcription and glucocorticoid repression using transient transfection and in vitro transcription assays. We first determined that the region between -77 to -51 of the promoter, which has previously been shown to harbor a glucocorticoid receptor-binding site, is required for high basal expression both in vivo and in vitro. This promoter domain is also required for glucocorticoid repression of transcription in vivo. Two site-directed mutants within this area both decreased basal transcription, but were fully repressed by glucocorticoids, implying that the -77 to -51 region is a complex regulatory region harboring separable basal and glucocorticoid-repressible elements. Electrophoretic mobility shift and exonuclease III footprinting analysis revealed the existence of two factors that bind in this region. We also examined the effect of broad promoter deletions on basal expression and glucocorticoid repression. These experiments revealed that the region between -480 and -320 is also required for glucocorticoid repression. Taken together, the data suggest a model in which high basal transcription is generated by direct interaction of factors binding between -480 to -320 and -77 to -51. Glucocorticoid repression could occur by direct receptor disruption of these interactions.

HIGH levels of speech recognition have been achieved with a new sound processing strategy for multielectrode cochlear implants. A cochlear implant system consists of one or more implanted electrodes for direct electrical activation of the auditory nerve, an external speech processor that transforms a microphone input into stimuli for each electrode, and a transcutaneous (rf-link) or percutaneous (direct) connection between the processor and the electrodes. We report here the comparison of the new strategy and a standard clinical processor. The standard compressed analogue (CA) processor presented analogue waveforms simultaneously to all electrodes, whereas the new continuous interleaved sampling (CIS) strategy presented brief pulses to each electrode in a nonoverlapping sequence. Seven experienced implant users, selected for their excellent performance with the CA processor, participated as subjects. The new strategy produced large improvements in the scores of speech reception tests for all subjects. These results have important implications for the treatment of deafness and for minimal representations of speech at the auditory periphery.

Comparisons of analog and pulsatile coding strategies for multichannel cochlear prostheses are reviewed. The results are related to design considerations for pediatric implants, including efficacy, safety, ease of fitting, and access to future improvements.

This study evaluated risk factors for injurious and noninjurious slips, trips, and falls among painters and investigated the hypothesis that exposure to solvents influenced the risk of such accidents. The data were collected longitudinally over an 11 month period. Weekly self-administered questionnaires detailed paint solvent exposure; work-related slips, trips, and falls (STFs); and potentially hazardous job tasks and environmental conditions. An initial questionnaire ascertained personal data, such as age, solvent exposure history, and alcohol consumption. During the study, 2,088 person-weeks of data were collected. Some participants provided many weeks of data, while others responded sporadically. Exposure to potentially hazardous environmental conditions was significantly related to the occurrence of STFs during a week. Several measures of solvent exposure were evaluated for their effect on STFs. Low solvent exposure during a week significantly increased the occurrence of slips, trips, and falls compared to no exposure. Moderate and high weekly exposure were not associated with increased risk, however. Week-to-week variability in the amount of solvent exposure was a strong positive predictor of STFs. Further analysis showed that both increases and decreases in solvent exposure between the preceding 2 weeks and the week of the STF were positively related to the risk of such events. The strongest effect was observed for exposure increases over the preceding 2 weeks. Overall, the results suggest that solvent exposure variability may increase accident risk, and possible explanations are explored.

Removing an acoustic schwannoma using the translabyrinthine approach has previously been considered incompatible with hearing preservation. By modifying the approach and preventing the loss of endolymph, we have successfully removed an intracanalicular acoustic schwannoma, which originated from the inferior vestibular nerve, and preserved hearing in the operated ear. This report represents the preliminary findings using this particular technique in the management of an intracanalicular acoustic tumour.

A 14,000-dalton polypeptide (p14) from RIII murine mammary tumor virus (MMTV) has been isolated by column chromatography in 6 M GuHCl. Antiserum prepared in rabbits specifically precipitated 125I-labeled p14; in double antibody competition, radioimmunoassays performed with limiting amounts of antibody, both purified p14 and disrupted MMTV, competed specifically with labeled antigen. The expression of this MMTV type B virus antigen could be measured by competition radioimmunoassays in milks, mammary glands, tumors, and tissue culture cells. MMTV expression measured by p14 immunoassay correlated well with the spontaneous incidence of mammary adenocarcinomas in different murine strains but not with type C MuLV p30 antigen expression. Levels of MMTV gp52, the major type-B viral glycoprotein, corresponded to p14 levels, suggesting that their control is comparably regulated. Evidence that this low m.w. polypeptide is present in feral and inbred strains of widely differing geographic origin and in MMTV with apparently different biologic properties suggests surprising conservation of MMTV protein homology.

We present a case of a 79-year-old woman with periods of syncope, complete heart block (CHB), and ventricular standstill during periods of increased vagal tone following sublingual nifedipine for hypertension. The syncopal episodes were associated with periods of elevated vagal tone (micturition and vomiting) with one monitored episode showing a clear time course of emesis; CHB then ensued, progressing to ventricular standstill with loss of consciousness that resolved over several minutes. Although nifedipine is not thought to affect conduction at current clinical dosages, it seems likely that the additive effects of nifedipine and elevated vagal tone produced the observed conduction abnormalities. This is the first case report of nifedipine administration followed by syncope and conduction disturbances.

5'-Methylthioadenosine (MTA), a naturally occurring nucleoside, inhibited in vitro colony formation by murine erythroid (CFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells in a dose-dependent fashion with maximal inhibition at concentrations of 2 X 10(-3) M and 1 X 10(-4) M, respectively. The inhibitory effect was reversible after up to 8 h of exposure to MTA but was irreversible after 24 h. MTA also inhibited hematopoietic progenitors in vivo. In mice given daily intraperitoneal injections of MTA for 28 days, CFU-GM were maximally reduced on day 14 to 51% of control. CFU-GM returned toward control levels by day 28 despite the continued administration of MTA. Hematocrit and leukocyte count were not reduced until day 28 and then only to 90% and 70% of control, respectively. MTA reached peak plasma levels of 2.8 X 10(-5) M 5 min after a single intraperitoneal injection of 75 mg/kg and was almost completely cleared by 60 min. These findings indicate that MTA produces reversible inhibition of murine hematopoietic progenitors both in vitro and in vivo. Despite the inhibitory effect on progenitors there is little effect on peripheral blood counts, which suggests that MTA inhibits hematopoietic proliferation without affecting hematopoietic differentiation.

Addition of the transcriptional enhancers present in the U3 region of the Harvey murine sarcoma virus (HaMuSV) long terminal repeat (LTR) to recombinant chimeras in which the HaMuSV transforming gene (Ha-v-ras) is expressed from the mouse mammary tumor virus (MMTV) promoter increases the ability of the MMTV v-ras chimeras to transform mouse fibroblasts in culture 50- to 100-fold. Significant stimulation of transfection efficiency occurs only when glucocorticoids are present in the culture medium. Glucocorticoids also elevate the steady-state concentration of MMTV-initiated v-ras mRNA in cell lines isolated from these transfections, and MMTV-v-ras fusion transcripts are initiated at the normal MMTV cap site; potential cryptic initiation events associated with the enhancer could not be detected. The ability of the enhancer to increase the transcriptional activity of the MMTV promoter was also studied in acute transfection assays where expression of the chloramphenical acetyl transferase (CAT) gene is driven by the MMTV promoter. In this system the strong positive effect on MMTV transcription is again obtained only when the cells are hormone treated. These experiments indicate that the hormone-regulatory region is capable of modulating the function of an exogenously introduced enhancer element.

The effect of 5'-deoxy-5'-methylthioadenosine (MTA) on the growth of culture murine lymphoid cells was examined. MTA inhibited the growth of murine lymphoid cell lines of both B- and T-cell origin in a reversible, nontoxic, and dose-dependent fashion. When measured 2 days after the addition of MTA to the cells, the concentration that inhibited proliferation by 50% for MTA was about 250 muM. Cells incubated in the presence of 0.5 mM MTA for 1, 2, or 3 days were able to recover from the inhibitory effect of the nucleoside and resumed growth. Six structural analogs of MTA were also found to inhibit cell growth. Five of these analogs served as alternative substrates for MTA phosphorylase, while one, the 7-deaza analog (5'-deoxy-5'-methylthiotubercidin), was not a substrate for the phosphorylase but was a potent inhibitor of enzyme activity. Inhibition of growth by 5'-deoxy-5'-methylthiotubercidin was dose dependent (the concentration that inhibited proliferation by 50% approximately or equal to 10 muM) and at 50 muM was reversible and nontoxic.

Adenovirus type 12 (Huie) inoculated into cultures of primary whole rat embryo produced foci of morphologically altered cells. The number and identification of these transformed areas was dependent upon the calcium concentration of the medium; more foci appeared in 0.1 mm than in 1.8 mm calcium. Cell lines derived from these inoculated cultures did not yield infectious virus, and also were similar to cell lines derived from adenovirus type 12-induced tumors with respect to morphology, presence of virus-specific tumor antigen, and oncogenicity. Dose-response curves revealed that transformation of rat embryo cells by adenovirus type 12 followed one-hit kinetics, and that approximately 7 x 10(5) infectious virus particles were required for one transformation event. Our results indicate that the transformation system described for adenovirus type 12 is reproducible, and that previous difficulties experienced in developing such a system may well be explained by the higher calcium concentration of the tissue culture media used.

Low-passage rat-embryo cells were not transformed by 3-methylcholanthrene or by 5-bromo-2' deoxyuridine. However, prior treatment with bromodeoxyuridine, followed by treatment with methylcholanthrene, resulted in cell transformation about three subpassages after removal of the carcinogen. RNA-directed DNA polymerase activity could not be detected in either normal or transformed cells. However, gs-1 antigen specific for rat C-type RNA virus was detected in cultures derived from bromodeoxyuridine-treated cells. No gs-1 antigen for the C-type RNA virus was detected in cultures that had not been treated with bromodeoxyuridine during the 25 subpassages of these experiments.High-passage rat-embryo cells, derived from a different cell pool, were transformed by either methylcholanthrene or dimethylbenzanthracene without prior infection with an exogenous virus, and without prior treatment with bromodeoxyuridine, gs-1 antigen for C-type RNA virus was also detected in 4 of 4 randomly selected transformed cell lines; the gs-1 antigen was not detected in any of 4 nontransformed control cultures. Considering these and previously published findings, we conclude that the lowpassage cells cannot be transformed by methylcholanthrene because of powerful cellular controls over the endogenous virus. Bromodeoxyuridine triggers some expressions of the endogenous virus; thus, the bromodeoxyuridine-treated cells are more susceptible to the transforming effects of methylcholanthrene. High-passage rat cells do not maintain perfect control over expression of their endogenous virus; the cell cultures are susceptible to the transforming effects of chemical carcinogens.

Five nonionic detergents (Tweens 20, 40, 60, and 80, and Triton WR-1339) were tested for their ability to inactivate four Mycoplasma species which are common contaminants of animal cell cultures. Tween 20 was found to be the most effective, in that a concentration of 2.5 mg/ml completely inactivated cultures of M. hominis, M. hyorhinis, and Acholeplasma laidlawii within 1 hr and a culture of M. orale within 3 hr. The other detergents exhibited various degree of activity against the different mycoplasmas, with Triton WR-1339 being the least effective. The virucidal activity of the detergents was determined for six viruses. All four Tween compounds were highly virucidal for herpes simplex virus. Tween 20 also exhibited virucidal effects against vesicular stomatitis virus, California encephalitis virus, and Newcastle disease virus, and Tween 80 was found to be active against California encephalitis and Newcastle disease viruses. Detergent treatment procedures were effective in two instances in eliminating mycoplasma contaminants from virus preparations while the preparations retained most of the viral infectivity. The limitations of this technique for routine use are discussed.