p53 peptide prevents LITAF-induced TNF-alpha-mediated mouse lung lesions and endotoxic shock.

Abnormal and prolonged inflammatory reaction is seen in a wide variety of disorders, and high level of Tumor Necrosis Factor alpha (TNF-α) has been linked to these disorders. Therefore, modulation of TNF-α expression is important in the regulation of inflammatory disorders. In our previous study, we have shown that a transcription factor LPS-induced TNF factor (LITAF) significantly induces TNF-α production. Furthermore, we found that p53 and its synthetic peptide 162-motif specifically downregulate LITAF/TNF-α gene expression in human cells in vitro. Thus, in the present study, the role of p53 in regulating TNF-α-mediated inflammation was investigated. Our data showed that a synthetic peptide, named 162-motif, corresponding to this region functions independently from p53 to cause a significant suppression of TNF-α gene expression in mouse primary macrophages. The 162-motif, when delivered into cells and organs, reduces serum TNF-α level in mice and prevents TNF-α-induced lung lesions and endotoxic shock. Our findings highlight the regulation of LITAF/TNF-α by p53 and its short peptide 162-motif. These in vitro and in vivo observations serve to pave the way for pharmacotherapeutic approaches in the treatment of inflammatory diseases.

Pc2 and SUMOylation.

Polycomb proteins are key regulators of transcription in metazoan organisms. Recent work has shed light on the nature of the polycomb protein complexes in flies and mammalian cells. Multiple enzymatic activities have been shown to associate with polycomb complexes, including histone methyltransferase, histone deacetylase and ubiquitination activities, which are primarily directed towards the modification of chromatin structure. In addition to these chromatin-based functions, other potential roles for polycomb proteins exist. Here, we present a comparison of vertebrate Pc2 (polycomb 2 protein) homologues, and review the known functions of the mammalian Pc2 focusing on its role as a SUMO (small ubiquitin-related modifier) E3 ligase. Pc2 is an E3 for several SUMO substrates, but still appears to have a more limited repertoire than other SUMO E3s, perhaps due to its association with polycomb complexes. One possibility is that Pc2 represents a relatively specialized polycomb protein, which has additional functions to those associated with other mammalian Pc (polycomb protein) paralogues.

Women on welfare: a study of the Florida WAGES population.

Using the ASI, a multi-dimensional survey instrument, data were collected on women in Florida's welfare program (WAGES). The women manifested serious problems in terms of physical and mental health, employment skills and childcare needs. Length of time on welfare was strongly associated with the severity of recipients' problems. Women with 2 + years on welfare were significantly more likely to have problems. However, substance use was lower than anticipated which may be because substance abusers are dropping out of welfare. This possibility raises concerns that, rather than going into the workfore, women may be returning to the streets. If so, instead of reducing the welfare costs, we are shifting those costs to local health, social service and criminal justice systems.

Treatment services received by supplemental security income drug and alcoholic clients.

This study examined self reported problems and treatment services received by 237 recipients of Supplemental Security Income (SSI) benefits for "drug abusers and alcoholics" who had been assigned and entered into substance abuse treatment. All were administered the Treatment Services Review (TSR), a brief interview in which patients describe treatment services they have received during the past month and substance-related problems they are currently experiencing. In addition to describing serious alcohol and drug problems, SSI recipients reported a need for treatment for medical and psychiatric problems. The TSR data revealed that these clients primarily received drug and alcohol services and more limited medical, psychiatric, and employment services during treatment. There was relatively little indication of the provision of legal or family/social treatment services. The data are consistent with other findings that indicate that treatment for substance dependence provides only limited services other than those for alcohol and drug abuse.

Cigarettes, alcohol, marijuana, other risk behaviors, and American youth.

Increases in adolescent marijuana and other drug use have created widespread concern. One theory argues that increased use of cigarettes and alcohol among younger adolescents leads to greater use of marijuana which, in turn, leads to subsequent use of other drugs (e.g. cocaine, heroin, hallucinogens). Detractors of this theory claim that use of these substances is a symptom of a larger set of destructive behaviors (e.g. violence, suicide, promiscuous sex), and marijuana has no independent effect on the use of other more serious drugs. The authors examined whether, for high school seniors, early use of cigarettes, alcohol and marijuana has an independent effect on more serious drug use even when other behaviors are considered. Using the 1995 Youth Risk Behavior Survey (n = 2871) and logistic analysis, after accounting for selected other behaviors, seniors using cigarettes before age 13 were 3.3 (95% C.I. 2.3,4.6) times likelier to have used marijuana than ones who never smoked; for alcohol, the odds ratio was 4.5 (2.6,7.7). Seniors using marijuana before the age of 14 were 7.4 times (4.0,13.6) likelier to have used other drugs. Though no causal effect is demonstrated, cigarette and alcohol use was associated with the likelihood of marijuana use; marijuana use was associated with the likelihood of other drug use, even after selected other risk and protective behaviors were considered.

Polybrominated biphenyl induction of cytochrome P450 mixed function oxidase activity in primary rat and human hepatocytes.

Polybrominated biphenyl (PBB) is an industrial chemical and environmental contaminant with known incidence of significant human exposure. PBB has been studied in laboratory animals and found to have significant toxicological effects as well as being a potent inducer of hepatic cytochrome P450 mixed function oxidase (MFO) activity. As part of our program to compare the response of laboratory animals and humans to industrial and environmental toxicants, we studied the effect of a major component of commercial PBB mixtures, 2,2',4,4',5,5'-hexabromobiphenyl (HBB), on MFO induction in primary cultures of human and rat hepatocytes. MFO induction was evaluated by measuring the deethylation of 7-ethoxycoumarin by intact hepatocytes. Rat hepatocytes were found to be highly susceptible to HBB induction of 7-ethoxycoumarin O-deethylase (ECOD) activity, with significant induction observed at the lowest concentration tested of 10(-8) M. Human hepatocytes were found to have a higher threshold for HBB induction of ECOD activity than rat hepatocytes. The lowest concentration of HBB required for ECOD induction observed for human hepatocytes was 10- to 1000-fold higher (10(-7), 10(-6), 10(-5) M for the four human samples) than that found in rat hepatocytes. Future mechanistic investigation of this observed difference in sensitivity towards PBB between rat and human hepatocytes may aid the extrapolation of human health risk from toxicological data obtained from laboratory animals.

Estimating the costs of substance abuse to the Medicaid hospital care program.

OBJECTIVES: The purpose of this study was to develop a model, using the epidemiologic tool of attributable risk, for estimating the cost of substance abuse to Medicaid. METHODS: Based on prior substance-use and morbidity research, population attributable risks for substance abuse-related diseases were calculated. (These risks measure the proportion of total disease cases attributable to smoking, drinking, and drug use.) The risks for each disease were applied to Medicaid hospital discharges and days on the 1991 National Hospital Discharge Survey that had these diseases as primary diagnoses. The cost of these substance abuse-related days were added to Medicaid hospital costs for direct treatment of substance abuse. RESULTS: More than 60 medical conditions involving 1100 diagnoses were identified, at least in part, as attributable to substance abuse. Factoring these substance abuse-related conditions into hospital costs, 1 out of 5 Medicaid hospital days, or 4 million days, were spent on substance abuse-related care in 1991. In 1994, this would account for almost $8 billion in Medicaid expenditures. CONCLUSIONS: The use of tobacco, alcohol, and drugs contributes significantly to hospital costs. To address rising costs, substance abuse treatment and prevention should be an integral part of any health care reform effort.

State initiatives for the medically uninsured.

Recently, Medicaid has changed in terms of both perception and reality. After a period of decline in entitlement, that trend has been reversed through both Federal mandates and an increasing role for Medicaid in dealing with the uninsured. As States and the Federal Government seek structural solutions, further eligibility expansions may be necessary, such as public subsidies of private insurance of using Medicaid as a reinsurance mechanism. Currently, there is considerable State activity in identifying such solutions. These activities have given us some ideas about what is necessary to expand coverage to more of the population. Continued demonstrations and better definitions of the respective roles of the private and public sectors are needed.

Role of glutathione in the toxicity of the sesquiterpene lactones hymenoxon and helenalin.

Hymenoxon and helenalin are toxic sesquiterpene lactones present in the toxic range plants Hymenoxys odorata and Helenium microcephalum. Helenalin (25 mg/kg) or hymenoxon (30 mg/kg) administered to immature male ICR mice caused a rapid decrease in hepatic glutathione levels and were lethally toxic to greater than 60% of the animals within 6 d. L-2-Oxothiazolidine 4-carboxylate (OTC), a compound that elevates cellular glutathione levels, administered to mice 6 or 12 h before either helenalin or hymenoxon protected against hepatic glutathione depletion and the lethal toxicity of these toxins. OTC administered at the same time as the sesquiterpene lactones was not protective, suggesting that the critical events against which glutathione is protective occur within the first 6 h. In primary rat hepatocyte cultures, hymenoxon and helenalin (4-16 microM) caused a rapid lethal injury as determined by the release of lactate dehydrogenase. Cotreatment of cultures with N-acetylcysteine at high concentrations (4 mM) afforded significant protection against lethal injury by both toxins. In contrast, BCNU, which inhibits glutathione reductase, or diethylmaleate, which depletes hepatocellular glutathione, potentiated the hepatotoxicity of helenalin and hymenoxon in monolayer rat hepatocytes. These studies suggest that the in vivo and in vitro toxicity of hymenoxon and helenalin is strongly dependent on hepatic glutathione levels, which hymenoxon and helenalin rapidly deplete at very low concentrations.