Ethanol-enhanced cytotoxicity of alkylating agents

BACKGROUND: Although ethanol itself is not genotoxic, chronic alcohol consumption increases the risk of neoplastic disease. The mechanism by which ethanol exerts a cocarcinogenic effect is not well established, and the aim of this study was to determine whether exposure to ethanol increased the cytotoxicity of known carcinogens. METHODS: To assess cell survival, the ability of Chinese hamster A10 cells, which express alcohol dehydrogenase, to form colonies was determined after exposure to ethanol and other substances, including both genotoxicants and non-DNA-reactive cytotoxic agents. RESULTS: 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) is an alkylating agent that forms covalent bonds with DNA. The cytotoxicity of MNNG at concentrations of 0.17 to 0.68 microM was markedly enhanced when cells were also treated with 50 mM ethanol. When combined with 0.34 microM MNNG, concentrations of ethanol as low as 2 mM exacerbated the toxicity of this alkylating agent. When these experiments were repeated in the presence of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, pretreatment with ethanol did not affect the toxicity of MNNG. When ethanol treatment was combined with exposure to other carcinogens, as well as agents that do not directly damage DNA, the cytotoxicity of the DNA-reactive agents 4-nitroquinoline-N-oxide, mitomycin C, and 6-chloro-9-(3-[2-chloroethyl]aminopropylamino)-2-methoxyacridine was modestly enhanced, and that of a second alkylating agent, ethyl methanesulfonate, was markedly increased. CONCLUSIONS: The results are consistent with impairment of DNA repair processes, particularly base excision repair, by acetaldehyde, as a mechanism by which ethanol increases the genotoxicity of certain genotoxic agents.     

Interactions of NMDA antagonists and an alpha 2 agonist with mu,delta and kappa opioids in an acute nociception assay

Animal and clinical studies have reported potentiation of opioid antinociception by co-administration of alpha-2 adrenoceptor agonists such as clonidine and NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available compounds in combination with classical morphine, fentanyl-like opioids, the delta opioid agonist SNC80 and the kappa opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of clonidine, ketamine or dextromethorphan. Clonidine was also evaluated in combination with ketamine and dextromethorphan. ED50 values were calculated from the proportion of animals reaching a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED50 values for morphine, fentanyl and sufentanil but exerted no effect on SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive efficacy of morphine and sufentanil but not SNC80 or U50,488H. By contrast, clonidine potentiated all opioids tested. In addition, the potency of clonidine was found to increase with co-administration of ketamine but not dextromethorphan. The strongest opioid sparing interactions occurred between clonidine and the lipophilic mu opioids fentanyl and sufentanil and the delta opioid SNC80. In summary, these results suggest an important role for lipophilic opioids in combination therapies particularly with clonidine as well as possible advantages of specific delta or kappa opioid combinations with alpha-2 agonists.     

Unilateral lesions of the cholinergic basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere produce severe learning impairments in rhesus monkeys

It has been proposed that isolation of the inferior temporal cortex and medial temporal lobe from their cholinergic afferents results in a severe anterograde amnesia. To test this hypothesis directly, seven rhesus monkeys received a unilateral immunotoxic lesion of the cholinergic cells of the basal forebrain with an ipsilesional section of the fornix. In a second surgery, inferior temporal cortex was ablated in the opposite hemisphere. All animals were severely impaired at learning visual scenes and object-reward associations. The impairment in learning scenes was correlated with cholinergic cell loss in the basal forebrain, but not with generalized tissue damage. Two monkeys served as surgical controls with saline injection in place of the immunotoxin, but all other procedures the same, and were not as severely impaired as those with immunotoxic lesions. Previous work has shown that monkeys with bilateral section of the anterior temporal stem (white matter of the temporal lobe), amygdala and fornix show a severe new learning impairment, and provide a model of human medial temporal lobe amnesia. One effect of this combined ablation is to isolate inferior temporal cortex and medial temporal lobe from their cholinergic afferents, possibly in addition to a direct disruption of the hippocampal system. The results of the present study, then, provide a novel link between the mechanisms of medial temporal lobe amnesia and Alzheimer's disease in which the cholinergic basal forebrain shows pathology. We propose that in both cases the mnemonic impairments result from isolating inferior temporal cortex and medial temporal lobe from their cholinergic afferents, possibly in addition to a direct disruption of the hippocampal system.     

Improving quality of care for acute myocardial infarction: The Guidelines Applied in Practice (GAP) Initiative

Context  Quality of care of patients with acute myocardial infarction (AMI) has received intense attention. However, it is unknown if a structured initiative for improving care of patients with AMI can be effectively implemented at a wide variety of hospitals. Objective  To measure the effects of a quality improvement project on adherence to evidence-based therapies for patients with AMI. Design and Setting  The Guidelines Applied in Practice (GAP) quality improvement project, which consisted of baseline measurement, implementation of improvement strategies, and remeasurement, in 10 acute-care hospitals in southeast Michigan. Patients  A random sample of Medicare and non-Medicare patients at baseline (July 1998–June 1999; n = 735) and following intervention (September 1–December 15, 2000; n = 914) admitted at the 10 study centers for treatment of confirmed AMI. A random sample of Medicare patients at baseline (January–December 1998; n = 513) and at remeasurement (March–August 2001; n = 388) admitted to 11 hospitals that volunteered, but were not selected, served as a control group. Intervention  The GAP project consisted of a kickoff presentation; creation of customized, guideline-oriented tools designed to facilitate adherence to key quality indicators; identification and assignment of local physician and nurse opinion leaders; grand rounds site visits; and premeasurement and postmeasurement of quality indicators. Main Outcome Measures  Differences in adherence to quality indicators (use of aspirin, -blockers, and angiotensin-converting enzyme [ACE] inhibitors at discharge; time to reperfusion; smoking cessation and diet counseling; and cholesterol assessment and treatment) in ideal patients, compared between baseline and postintervention samples and among Medicare patients in GAP hospitals and the control group. Results  Increases in adherence to key treatments were seen in the administration of aspirin (81% vs 87%; P = .02) and -blockers (65% vs 74%; P = .04) on admission and use of aspirin (84% vs 92%; P = .002) and smoking cessation counseling (53% vs 65%; P = .02) at discharge. For most of the other indicators, nonsignificant but favorable trends toward improvement in adherence to treatment goals were observed. Compared with the control group, Medicare patients in GAP hospitals showed a significant increase in the use of aspirin at discharge (5% vs 10%; P<.001). Use of aspirin on admission, ACE inhibitors at discharge, and documentation of smoking cessation also showed a trend for greater improvement among GAP hospitals compared with control hospitals, although none of these were statistically significant. Evidence of tool use noted during chart review was associated with a very high level of adherence to most quality indicators. Conclusions  Implementation of guideline-based tools for AMI may facilitate quality improvement among a variety of institutions, patients, and caregivers. This initial project provides a foundation for future initiatives aimed at quality improvement.      

Change Trajectories in Women's STD/HIV Risk Behaviors Following Intervention

Three 16-month sexual risk-taking trajectories were identified in 287 women in an STD/HIV intervention study. The Risk Eliminator group reported no sex risk following intervention while the Risk Reducer group reported continuous drops over time. The High Risk group reported higher initial risk than the other two and no subsequent changes. The trajectory groups showed no between- or within-group effects of intervention exposure. Trajectory groups were compared on baseline characteristics. No differences were seen in demographics or STD/HIV knowledge. Compared to one or both of the other groups, the High Risk women reported more lifetime partners, recent paying partners, adult rape, and recent substance use. Their steady partners were more likely to be abusive, intoxicated during sex (as were the women themselves), and believed to be non-monogamous. The Risk Eliminator group differed from the other two by being less likely to report a history of childhood sexual abuse.     

The crucible of public health practice: major trends shaping the design of the Management Academy for Public Health.

Public health leaders and managers need new leadership and management skills as well as greater entrepreneurial acumen to respond effectively to broad demographic, socioeconomic, and political trends reshaping public health. This article asserts that the need for such training and skills was the impetus for the conceptualization, design, and launch of the Management Academy for Public Health--an innovative executive education program jointly offered by the schools of business and public health at the University of North Carolina at Chapel Hill.