Topical gentamicin and ethacrynic acid: effects on cochlear function

OBJECTIVE: To determine whether concurrent intravenous administration of the loop diuretic ethacrynic acid potentiates the toxicity of the aminoglycoside antibiotic gentamicin applied topically on the round window. STUDY DESIGN: The authors studied the effects on cochlear sensitivity of co-administered intracardiac ethacrynic acid (40 mg/kg) and high-dose topical gentamicin solution (100%) applied to the round window. Comparisons were made with animals receiving ethacrynic acid plus systemic gentamicin (100 mg/kg); topical gentamicin alone; systemic gentamicin alone; and intravenous ethacrynic acid alone. METHODS: Experiments were carried out on pigmented guinea pigs weighing 400 to 500 g. Changes in cochlear function were characterized by monitoring shifts in compound action potential (CAP) thresholds by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. RESULTS: After 20 days animals receiving ethacrynic acid in combination with topical gentamicin to the round window failed to demonstrate a significant deterioration in cochlear sensitivity, whereas all animals receiving systemic gentamicin plus ethacrynic acid experienced profound increases in CAP thresholds. CONCLUSIONS: This study supports the contention that ethacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph. In addition, this study answers important clinical concerns regarding the safety of the use of topical aminoglycoside agents in combination with loop diuretics.     

Pulmonary carcinogenicity of relatively low doses of beta-particle radiation from inhaled 144CeO2 in rats

This study was conducted to examine the carcinogenic effects of inhaled beta-particle-emitting radionuclides, particularly in lower dose regions in which there were substantial uncertainties associated with available information. A total of 2751 F344/N rats (1358 males and 1393 females) approximately 12 weeks of age at exposure were used. Of these, 1059 rats were exposed to aerosols of 144CeO2 to achieve mean desired initial lung burdens (ILBs) of 18 kBq (low level), 247 rats to achieve mean ILBs of 60 kBq (medium level) and 381 rats to achieve mean ILBs of 180 kBq (high level). Control rats (total of 1064) were exposed to aerosols of stable CeO2. Based on the 95% confidence intervals of the median survival times and the cumulative survival curves, there were no significant differences in the survival of groups of female and male exposed rats relative to controls. The mean lifetime beta-particle doses to the lungs of the rats in the four groups were: low level, 3.6 +/- 1.3 (+/-SD) Gy; medium level, 12 +/- 4.5 Gy; and high level, 37 +/- 5.9 Gy. The crude incidence of lung neoplasms increased linearly with increasing doses to the lungs (controls, 0.57%; low level, 2.0%; medium level, 6.1%; and high level, 19%). The estimated linear risk coefficients for lung neoplasms per unit of dose to the lung were not significantly different for the three dose levels studied. The risk coefficient at the lower level was 39 +/- 14 (+/-SE) excess lung neoplasms per 10(4) rat Gy; at the medium level the risk was 47 +/- 12; and at the higher level the risk was 50 +/- 9.0. The relationship of beta-particle dose to the lung and the crude incidence of lung neoplasms was described adequately by a linear function. We concluded that the risk of lung neoplasms in rats per unit of radiation dose did not increase with decreasing mean beta-particle dose to the lung over the range of 3.6 to 37 Gy. The weighted average of these three values was 47 +/- 6.4 (+/-SE) excess lung neoplasms per 10(4) rat Gy. To extend the risk coefficients for lung neoplasms to lower doses by experimentation will require much larger numbers of rats than used in this study.     

Predicting length of stay in an acute psychiatric hospital

OBJECTIVE: Multivariate statistical methods were used to identify patient-related variables that predicted length of stay in a single psychiatric facility. The study investigated whether these variables remained stable over time and could be used to provide individual physicians with data on length of stay adjusted for differences in clinical caseloads and to detect trends in the physicians' practice patterns. METHODS: Data on all patients discharged over two six-month periods were collected at an acute psychiatric inpatient facility. Stepwise multiple regression analyses were conducted on the two datasets. RESULTS: The results from both analyses revealed that five variables significantly predicted length of stay and were stable over time. They were a primary diagnosis of schizophrenia, the number of previous admissions, a primary diagnosis of a mood disorder, age, and a secondary diagnosis of an alcohol- or other drug-related disorder. For some physicians, the mean length of stay of their patients differed significantly from the length predicted by the regression model--generally, it was shorter. CONCLUSIONS: The results demonstrate that patient-related predictors of length of stay in a single psychiatric hospital can be identified using relatively simple statistical procedures and can be consistent across a large dataset and over time.     

IL-1 beta and TNF alpha modulate delta 9-tetrahydrocannabinol-induced catalepsy in mice

The role of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) in THC-induced catalepsy in mice was examined. Recombinant IL-1 beta (400 ng/mouse, IV) and TNF alpha (500 ng/mouse, IV) were effective in potentiating the cataleptic effect of low-dose THC (10 micrograms/mouse, IV). Recombinant IL-1 alpha and IL-6 did not potentiate catalepsy at any dose tested. Anti-IL-1 beta and anti-TNF alpha antibodies were effective in attenuating high-dose (75 micrograms/mouse) THC-induced catalepsy. Antibodies to IL-1 alpha and IL-6 had no effect on catalepsy. Early onset catalepsy (10 min postinjection) was potentiated by exogenous recombinant IL-1 beta and TNF alpha but only later catalepsy (2 h postinjection) was attenuated by antibodies to endogenous IL-1 beta or TNF alpha. This divergence of the cytokine effect suggests that these substances regulate, by different mechanisms, the early and late THC-induced cataleptic response.     

Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1)

BACKGROUND: Phosphorylation critically regulates the catalytic function of most members of the protein kinase superfamily. One such member, protein kinase C (PKC), contains two phosphorylation switches: a site on the activation loop that is phosphorylated by another kinase, and two autophosphorylation sites in the carboxyl terminus. For conventional PKC isozymes, the mature enzyme, which is present in the detergent-soluble fraction of cells, is quantitatively phosphorylated at the carboxy-terminal sites but only partially phosphorylated on the activation loop. RESULTS: This study identifies the recently discovered phosphoinositide-dependent kinase 1, PDK-1, as a regulator of the activation loop of conventional PKC isozymes. First, studies in vivo revealed that PDK-1 controls the amount of mature (carboxy-terminally phosphorylated) conventional PKC. More specifically, co-expression of the conventional PKC isoform PKC betaII with a catalytically inactive form of PDK-1 in COS-7 cells resulted in both the accumulation of non-phosphorylated PKC and a corresponding decrease in PKC activity. Second, studies in vitro using purified proteins established that PDK-1 specifically phosphorylates the activation loop of PKC alpha and betaII. The phosphorylation of the mature PKC enzyme did not modulate its basal activity or its maximal cofactor-dependent activity. Rather, the phosphorylation of non-phosphorylated enzyme by PDK-1 triggered carboxy-terminal phosphorylation of PKC, thus providing the first step in the generation of catalytically competent (mature) enzyme. CONCLUSIONS: We have shown that PDK-1 controls the phosphorylation of conventional PKC isozymes in vivo. Studies performed in vitro establish that PDK-1 directly phosphorylates PKC on the activation loop, thereby allowing carboxy-terminal phosphorylation of PKC. These data suggest that phosphorylation of the activation loop by PDK-1 provides the first step in the processing of conventional PKC isozymes by phosphorylation.     

Improving indoor air quality through the use of continual multipoint monitoring of carbon dioxide and dew point

This article summarizes an approach for improving the indoor air quality (IAQ) in a building by providing feedback on the performance of the ventilation system. The delivery of adequate quantities of ventilation to all building occupants is necessary for the achievement of good IAQ. Feedback on the performance includes information on the adequacy of ventilation provided, the effectiveness of the distribution of this air, the adequacy of the duration of operation of the ventilation system, and the identification of leakage into the return plenum, either of outdoor or supply air. Keeping track of ventilation system performance is important not only in terms of maintaining good IAQ, but also making sure that this system continues to perform as intended after changes in building use. Information on the performance of the ventilation system is achieved by means of an automated sampling system that draws air from multiple locations and delivers it to both a carbon dioxide monitor and dew point sensor. The use of single shared sensors facilitates calibration checks as well as helps to guarantee data integrity. This approach to monitoring a building's ventilation system offers the possibility of achieving sustainable performance of this important aspect of good IAQ.