Central opioid receptors differentially regulate the nalmefene-induced suppression of ethanol- and saccharin-reinforced behaviors in alcohol-preferring (P) rats.

The exact opioid-sensitive receptors participating in EtOH-seeking behaviors remains unclear. Previous studies have reported higher densities of micro-opioid receptor binding in the nucleus accumbens (NACC) of P relative to NP rats; however, no differences were seen in delta-receptor binding. In contrast to the NACC, substantially lower levels of micro-receptor binding have been observed in the ventral tegmental area (VTA) of both P and NP rats, albeit no line differences have been observed. In the present study, opioid receptors in the NACC, VTA, and hippocampus were evaluated for their capacity to regulate both EtOH- and saccharin-motivated behaviors in the genetically selected alcohol-preferring (P) rat. To accomplish this, nalmefene, an opiate antagonist with preferential binding affinity for the micro-opioid receptor was unilaterally or bilaterally infused during concurrent availability of 1 h daily EtOH (10% v/v) and saccharin (0.025 or 0.050% w/v) solutions. Rats performed under a two-lever fixed ratio (FR) schedule in which four responses on one lever produced the EtOH solution, and four on a second lever produced the saccharin solution. The results demonstrated that when responding maintained by both EtOH and saccharin are matched at basal levels, unilateral (1-60 microg) or bilateral (0.5-10 microg) microinjections of nalmefene into the NACC produced selective dose-dependent reductions on responding maintained by EtOH. Unilateral (40, 60 microg) and bilateral (10 microg) VTA infusions were also observed to selectively reduced EtOH responding; however, greater nalmefene doses were required and the magnitude of suppression on EtOH responding was markedly less compared with the NACC. The greater sensitivity of nalmefene to suppress EtOH responding in the NACC is likely due to the greater number of opioid receptors in the NACC relative to the VTA. Only bilateral infusion of the 40 microg dose in the NACC and VTA suppressed responding maintained by both EtOH and saccharin. In contrast, intrahippocampal infusions dose dependently suppressed EtOH- and saccharin-maintained responding over a range of doses (1-20 microg). The present study provides evidence that nalmefene suppresses EtOH-motivated behaviors via blockade of opioid receptors within the NACC and VTA, and under various dose conditions both reinforcer and neuroanatomical specificity can be observed.     

The cigarette controversy.

This study examines the history of the cigarette controversy using the tobacco documents as a roadmap to explore the following four questions: (a) What did tobacco companies know about the health risks of smoking and when did they know it? (b) What evidence is there that tobacco companies conspired to deliberately mislead the public about the health risks of smoking? (c) How were scientists involved in the cigarette controversy? (d) Have tobacco companies changed the way they do business since signing the 1998 Master Settlement Agreement? The tobacco companies knew and for most part accepted the evidence that cigarette smoking was a cause of cancer by the late 1950s. The documents also reveal that the tobacco companies helped manufacture the smoking controversy by funding scientific research that was intended to obfuscate and prolong the debate about smoking and health. Today, the tobacco companies acknowledge that smoking is a cause of disease, but they have not materially altered the way they do business. In our opinion, it is not sufficient for the tobacco industry to merely concede the obvious point that smoking is a cause of disease when it is evident that decades of misinformation has resulted in a public that is massively ignorant about the risks of smoking low-tar cigarettes, nicotine addiction, and secondhand smoke exposure. Public education efforts are still needed to correct these misperceptions along with government oversight to ensure that the industry is not permitted to mislead the public further. If the past 50 years have taught us anything, it is that the tobacco industry cannot be trusted to put the public's interest above their profits no matter what they say.     

Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug.

GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.     

Patient expectations and satisfaction with medical care for upper respiratory infections

To describe the determinants of patient satisfaction with medical care, self-administered questionnaires were given to a consecutive sample of 237 patients coming to an ambulatory care practice for the treatment of upper respiratory infections (URIs). Patients' most important goal was to obtain a diagnosis (57%). They usually got more reassurance, medication, and personal interest than they had expected (p = 0.0001). In a multivariate model, patients' satisfaction was related to the degrees of personal interest and reassurance they had received and to whether they felt they had received the right medication (r2 = 0.45, p = 0.0001). The authors concluded that patients with URIs generally want a diagnosis but are primarily satisfied by the personal interest, the reassurance, and the medication they receive.     

Fluorescence in situ hybridization analysis of chromosome 12p in paraffin-embedded tissue is useful for establishing germ cell origin of metastatic tumors.

The over-representation of chromosome 12p sequences is crucial for the development of invasive testicular germ cell tumors. Testicular cancer patients may have metastatic tumors of diverse histologic types, including adenocarcinoma, undifferentiated carcinoma, sarcoma, or other malignancies that lack features of germ cell tumors. We sought to investigate the possible germ cell origin of such tumors using interphase fluorescence in situ hybridization. In all, 10 metastatic malignant somatic-type tumors from patients with histories of testicular cancer, as well as one malignant somatic-type tumor from a patient with primary mediastinal germ cell tumor were studied and included: adenocarcinoma (five cases), poorly differentiated carcinoma (one), sarcoma (four), and neuroendocrine carcinoma (one). The tumors were analyzed using fluorescence in situ hybridization using 12p spectrum green and 12 centromeric spectrum orange probes in paraffin sections. The patients ranged in age from 27 to 55 years (mean, 43). Colon and lung cancers from patients without germ cell tumors were used as controls. Adequate signals were observed in all tumors. Gain of chromosome 12p was seen in six tumors. None of the control tumors showed 12p amplification. Fluorescence in situ hybridization for 12p amplification in routinely processed surgical specimens is a useful adjuvant diagnostic tool in confirming the germ cell origin of metastatic tumors having the histologic appearance of somatic-type neoplasms.     

苯丙胺诱发小鼠激怒反应及其机制

苯丙胺15mg/kg ip能诱发小鼠激怒反应,使小鼠出现攻击和殴斗行为。强安定药、弱安定药和利血平有明显拮抗效果。镇静剂如巴比妥类、抗胆碱药及抗肾上腺素药均无拮抗作用。金刚胺、左旋多巴和阿扑吗啡均能增强苯丙胺的激怒效应。因苯丙胺激怒小鼠的方法简便易行,可作为筛选抗精神病药的动物模型。苯丙胺产生激怒作用的机制与增强多巴胺能神经的功能有关,推测可能是促进边缘系统多巴胺释放的结果。     

The illegal sale of cigarettes to US minors: estimates by state.

Data available from recent national surveys on the cigarette consumption and purchasing practices of teenage smokers were used to generate state-specific estimates of the number of teenage smokers and cigarette sales to minors. In 1991, approximately 2.7 million teenage cigarette smokers consumed an average of 28.3 million cigarettes per day (516 million packs per year). An estimated 255 million packs of cigarettes were sold illegally to minors in 1991. To make cigarettes and other tobacco products less accessible to minors, policymakers should consider implementing various legislative and economic measures such as banning cigarette vending machines and raising tobacco excise taxes.     

A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin.

OBJECTIVES: Very low birth weight (VLBW) infants are vulnerable to nosocomial infections and subsequent morbidity; including infections caused by Staphylococcus aureus: 85% of nosocomial S. aureus infections are caused by capsular polysaccharide (CPS) types 5 and 8. Altastaph is a polyclonal investigational human immunoglobulin G (IgG) with high levels of opsonizing S. aureus CPS types 5 and 8 IgG. METHODS: A Phase 2 clinical trial to assess the safety and kinetics of Altastaph in VLBW infants. Neonates in this multicenter study were randomized to receive two identical 20 ml/kg i.v. infusions of either 0.45% NaCl placebo or 1000 mg Altastaph/kg. Each infant was followed for 28 days after the second infusion or until discharge. Serum S. aureus CPS types 5 and 8 IgG levels were measured preinfusion and at various times after each infusion. RESULTS: Of 206 neonates, 158 received both infusions. Adverse events were similar in the two treatment groups. Six subjects (3% in each group) discontinued owing to an adverse event. Geometric mean anti-type 5 IgG levels were 402 and 642 mcg/ml 1 day following infusion of the first (day 0) and Second (day 14) doses, respectively, in neonates < or =1000 g and slightly higher in neonates 1001 to 1500 g. Trough levels before second infusion were 188 mcg/ml. Type 8 IgG levels were similar. Geometric mean IgG levels among placebo recipients were consistently <2 and <5 mcg/ml for types 5 and 8 in both weight groups. Three episodes of S. aureus bacteremia occurred in each arm. CONCLUSIONS: Infusion of Altastaph in VLBW neonates resulted in high levels of specific S. aureus types 5 and 8 CPS IgG. The administration of this anti-staphylococcal hyperimmune globulin was well tolerated in this population.