Self administration of oxycodone alters synaptic plasticity gene expression in the hippocampus differentially in male adolescent and adult mice.

Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available "synaptic plasticity" PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age × Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self-administration differentially alters synaptic plasticity gene expression in the hippocampus of adolescent and adult mice.

Regional mRNA expression of GABAergic receptor subunits in brains of C57BL/6J and 129P3/J mice: strain and heroin effects.

C57BL/6J and 129 substrains of mice are known to differ in their basal levels of anxiety and behavioral response to drugs of abuse. We have previously shown strain differences in heroin-induced conditioned place preference (CPP) between C57BL/6J (C57) and 129P3/J (129) mice, and in the regional expression of several receptor and peptide mRNAs. In this study, we examined the contribution of the GABAergic system in the cortex, nucleus accumbens (NAc), caudate putamen (CPu) and the region containing the substantia nigra and ventral tegmental area (SN/VTA) to heroin reward by measuring mRNA levels of 7 of the most commonly expressed GABA-A receptor subunits, and both GABA-B receptor subunits, in these same mice following saline (control) or heroin administration in a CPP design. Using real-time PCR, we studied the effects of strain and heroin administration on GABA-A α1, α2, α3, ß2, and γ2 subunits, which typically constitute synaptic GABA-A receptors, GABA-A α4 and δ subunits, which typically constitute extrasynaptic GABA-A receptors, and GABA-B R1 and R2 subunits. In saline-treated animals, we found an experiment-wise significant strain difference in GABA-Aα2 mRNA expression in the SN/VTA. Point-wise significant strain differences were also observed in GABA-Aα2, GABA-Aα3, and GABA-Aα4 mRNA expression in the NAc, as well as GABA-BR2 mRNA expression in the NAc and CPu, and GABA-BR1 mRNA expression in the cortex. For all differences, 129 mice had higher mRNA expression compared to C57 animals, with the exception of GABA-BR1 mRNA in the cortex where we observed lower levels in 129 mice. Therefore, it may be possible that known behavioral differences between these two strains are, in part, due to differences in their GABAergic systems. While we did not find heroin dose-related changes in mRNA expression levels in C57 mice, we did observe dose-related differences in 129 mice. These results may relate to our earlier behavioral finding that 129 mice are hyporesponsive to the rewarding effects of heroin.

A compelling rationale for using preoperative visits to complete adult immunizations.

Immunization is a safe and cost-effective method to protect adult patients against many diseases, including hepatitis B, pneumococcal infections, and influenza. Despite this fact, only 10% to 40% of adults in the United States who would benefit have been immunized. Approximately 62% to 92% of patients who develop a disease preventable by vaccination have visited an outpatient clinic at least once in the 3 years preceding their illness. Efforts to educate providers about immunization guidelines have not increased immunization rates. In this report, we propose using the preanesthesia clinic as an alternative site to screen, identify, and immunize adults at risk. We also discuss three vaccines that could be offered to patients and analyze the efficacy of the vaccines.

Functional co-expression of the beta 1 and type IIA alpha subunits of sodium channels in a mammalian cell line.

Brain sodium channels are a complex of alpha (260 kDa), beta 1 (36 kDa), and beta 2 (33 kDa) subunits, alpha subunits are functional as voltage-gated sodium channels by themselves. When expressed in Xenopus oocytes, beta 1 subunits accelerate the time course of sodium channel activation and inactivation by shifting them to a fast gating mode, but alpha subunits expressed alone in mammalian cells activate and inactivate rapidly without co-expression of beta 1 subunits. In these experiments, we show that the Chinese hamster cell lines CHO and 1610 do not express endogenous beta 1 subunits as determined by Northern blotting, immunoblotting, and assay for beta 1 subunit function by expression of cellular mRNA in Xenopus oocytes. alpha subunits expressed alone in stable lines of these cells activate and inactivate rapidly. Co-expression of beta 1 subunits increases the level of sodium channels 2- to 4-fold as determined from saxitoxin binding, but does not affect the Kd for saxitoxin. Co-expression of beta 1 subunits also shifts the voltage dependence of sodium channel inactivation to more negative membrane potentials by 10 to 12 mV and shifts the voltage dependence of channel activation to more negative membrane potentials by 2 to 11 mV. These effects of beta 1 subunits on sodium channel function in mammalian cells may be physiologically important determinants of sodium channel function in vivo.

Human immunodeficiency virus infection due to clotting factor concentrates: results of the Seroconversion Surveillance Project.

From 1987 to the present, the Seroconversion Surveillance Project has provided the means by which to monitor the risk of transmission of human immunodeficiency virus (HIV) by clotting factor concentrates. One hundred thirty-one hemophilia treatment centers in the United States are contacted regularly, and data on HIV testing of patients are collected. To date, 4366 (46.0%) of 9496 patients have been reported to be seropositive, and 37 new seroconversions have been identified. Nine of these have met the Centers for Disease Control criteria for seroconversion while the patient was taking factor concentrate. None of the nine seroconversions were due to concentrates that had been treated to inactivate viruses and made from plasma that had been tested for HIV antibody. These results indicate that there is a high prevalence of seropositivity in affected patient groups, but that the risk of HIV infection from currently available clotting factor concentrates is extremely low.

A comparison of neurobehavioral performance of healthy term and low-risk preterm infants at term.

The neurobehavioral performance of a group of low-risk preterm and healthy term infants was assessed at term using the standardized Einstein Neonatal Neurobehavioral Assessment Scale. There was greater similarity than dissimilarity between the two groups; however, preterm infants demonstrated less consistent following to face and voice, and less sustained rooting and grasp reflexes. Preterm infants were more likely to have a more sustained asymmetric tonic neck reflex, a greater popliteal angle and evidence of tremor. These results support the view that processing capability appears to mature on an intrinsically programmed time- and environment-independent pathway, with environmental exposure challenging this adaptive capacity and modifying performance--predominantly with respect to reflexive elements.

Who should set CEO pay? The press? Congress? Shareholders?

Populist fervor in an election year has transformed executive compensation from a business issue into a political one. Critics, led by Graef Crystal, author of In Search of Excess: The Overcompensation of American Executives, charge that CEOs are ripping off shareholders with their outrageous salaries while running U.S. corporations into the ground. Politicians claim overpaid CEOs are the root cause of the U.S. competitiveness problem. Add a recessionary business climate to the fact that some CEOs earn 130 times more than their lowest paid employees, and you have the makings of a populist rebellion. In a bid to appease voters, Congress is considering several bills that would limit the deductibility of "excessive executive salaries," the SEC has opened the issue to shareholder comment, and the Financial Accounting Standards Board is looking at new accounting standards for granting stock options to executives as part of company compensation schemes. Andrew R. Brownstein and Morris J. Panner say it's time to put the debate back where it belongs--in a business context. The real question is not are executives paid too much, but are shareholders getting their money's worth. Most U.S. corporations use stock compensation to link company long-term performance to executive salaries. And because of the staggering market performance of U.S. corporations in the 1980s, an overwhelming majority of CEOs are actually paid in line with their performance. Rather than cut executive pay, Brownstein and Panner suggest that corporations extend incentive-based compensation plans to all employees, thus narrowing the salary gap and establishing pay for performance at every level of the organization.

Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia. NHF-ACTG 036 Study Group.

One hundred ninety-three asymptomatic patients with hereditary coagulation disorders and human immunodeficiency virus (HIV) infection were studied in a controlled trial of zidovudine (ZDV) versus a placebo (with an average of 9.7 months on study). Pretreatment characteristics were well balanced between the placebo and drug-treated groups, including CD4 distributions, types of clotting disorders, transaminase abnormalities, and use of various hemostatic agents. At the time of analysis, 161 patients either were still receiving treatment or had previously reached an endpoint of disease progression while receiving treatment. Twenty-five patients withdrew voluntarily. The toxic effects noted included granulocytopenia and anemia, especially in older patients, and subjective symptoms of asthenia, malaise, and nausea, consistent with the known consequences of treatment with 300 mg ZDV five times daily. There was a trend toward more diagnoses of acquired immunodeficiency syndrome (AIDS), advanced or early AIDS-related complex (ARC), single ARC symptoms, or death in placebo recipients as compared with those receiving ZDV (22 v 13). Because older patients with hemophilia have more rapid disease progression, the same efficacy analysis was performed in the 89 patients aged more than 30 years who were receiving treatment. In this subgroup, there was a similar trend (11 v 6). With regard to the most advanced problems of the infection among the older patients, there were five patients who were newly diagnosed with AIDS or died in the placebo group versus none in the ZDV group (P = .02) among the older patients. The pretreatment distribution of CD4 counts for the placebo and ZDV groups were similar, but patients aged more than 30 years had significantly (P less than .049) fewer CD4 cells than patients aged less than 30 years. A beneficial ZDV effect is also supported by a trend toward higher CD4 counts (a 48-cell increase in the ZDV group at 24 weeks as compared with a four-cell increase in the placebo group) and a significant (P = .03) difference in weight gain in the ZDV patients aged more than 30 years (8 pounds) as compared with the older placebo patients (aged more than 30 years) (2 pounds) at week 24. The findings in the asymptomatic hemophilic patients aged more than 30 years support a useful effect of ZDV, which is similar to observations in the larger study of its use in asymptomatic, nonhemophilic patients.

Reinforcement, stereotypy, and rule discovery.

The effects of reinforced pretraining on subsequent rule discovery were examined with college students as subjects. Levels of behavioral stereotypy observed during reinforced and non-contingent pretraining were compared. During pretraining subjects received reinforcement if they pressed two keys in a particular sequence. During the problem session pressing each key four times was a necessary condition for reinforcement, but each problem had additional different requirements for reinforcement. Subjects were asked to solve the problems by discovering the rule that determined whether or not they received reinforcement. Levels of stereotyped responding during pretraining were equivalent for contingently and non-contingently trained subjects. During the problem session contingently pretrained, non-contingently pretrained, and naive subjects required equal numbers of trials to solve problems and solved the same number of problems. The results suggest that behavioral stereotypy observed in this experimental preparation may be due to repeated exposure to the task. Differences between the results observed in this study and that of Schwartz (1982) and implications for the use of reinforcement procedures in applied settings are discussed.

Treatment of essential hypertension with yoga relaxation therapy in a USAF aviator: a case report.

A 46-year-old Caucasian male USAF aviator with a 6-year history of mild essential hypertension (medical waiver for flight duty) under unsuccessful treatment with hydrochlorothiazide, dietary modification, and exercise, was subsequently trained in yoga relaxation. After 6 weeks, medication had been discontinued, and his diastolic blood pressure remained within normal levels. The patient was subsequently returned to full flight status without recurrence of diastolic hypertension at followup 6 months later. Relaxation training, of which yoga is one type, has been reported in the medical literature to have wide clinical application. It should be considered as a nonpharmacological therapy adjunct or alternative for medical disorders among personnel in occupations (e.g., aviation) where the side effects from medications are of great concern and could be disqualifying from those duties.

The use of purified clotting factor concentrates in hemophilia. Influence of viral safety, cost, and supply on therapy.

Treatment of hemophilia, although greatly improved in recent years, continues to be problematic owing to infectious complications of blood product replacement therapy. This report examines the therapeutic options presently available for the treatment of hemophilia, focusing on the potential for repeated viral exposure to influence the progression of infectious disease, decreased risks of viral transmission with blood products produced using newer viral inactivation procedures, higher economic costs of newer blood products, and the current inadequate supply of blood products in the United States.

Hemophiliac patient's knowledge and educational needs concerning acquired immunodeficiency syndrome.

The Patient Knowledge Assessment Study (PKAS) was conducted among 107 male hemophilic patients, aged 15 to 67 years, at 19 hemophilia treatment centers (HTC). Participants were given a 30-item questionnaire concerning the cause of acquired immunodeficiency syndrome (AIDS), the groups at risk, and modes of transmission. The questionnaire included questions on the participant's status in regard to antibody to human T-lymphotropic retrovirus, type III/lymphadenopathy-associated virus (HTLV-III/LAV), and the meaning of this test result. HTC health-care providers were asked to complete a separate questionnaire containing 17 questions about information given patients concerning their HTLV-III/LAV antibody status and its meaning. Overall, patients had a good base of knowledge about AIDS; however, there were gaps in this knowledge. Twenty-nine percent of patients did not know that spouses of AIDS patients were at risk for AIDS; 47% did not know that sexual partners of persons with hemophilia were at risk; and 32% did not know that hemophilic children were at risk. Further, only 69% understood that antibody-positive individuals had had contact with the AIDS virus. Identifying these and other areas of misunderstanding will provide the information needed to design educational strategies and psychosocial support programs appropriate for the hemophilic population, and which may serve as a model for other populations.

Instructions, multiple schedules, and extinction: Distinguishing rule-governed from schedule-controlled behavior.

Schedule sensitivity has usually been examined either through a multiple schedule or through changes in schedules after steady-state responding has been established. This study compared the effects of these two procedures when various instructions were given. Fifty-five college students responded in two 32-min sessions under a multiple fixed-ratio 18/differential-reinforcement-of-low-rate 6-s schedule, followed by one session of extinction. Some subjects received no instructions regarding the appropriate rates of responding, whereas others received instructions to respond slowly, rapidly, or both. Relative to the schedule in operation, the instructions were minimal, partially inaccurate, or accurate. When there was little schedule sensitivity in the multiple schedule, there was little in extinction. When apparently schedule-sensitive responding occurred in the multiple schedule, however, sensitivity in extinction occurred only if differential responding in the multiple schedule could not be due to rules supplied by the experimenter. This evidence shows that rule-governed behavior that occurs in the form of schedule-sensitive behavior may not in fact become schedule-sensitive even though it makes contact with the scheduled reinforcers.

Rule-governed behavior and sensitivity to changing consequences of responding.

Humans were presented with a task that required moving a light through a matrix. Button presses could produce light movements according to a multiple fixed-ratio 18/differential-reinforcement-of-low-rate 6-s schedule, with components alternating every 2 min. Moving the light through the maze earned points worth chances on money prizes. In Experiment 1 four conditions were assessed through between-subject comparisons: minimal instructions, instructions to press rapidly, instructions to press slowly, and instructions that sometimes rapid responding would work while at other times a slow rate would work best. Subjects responded in three successive sessions of 32 min each. The results suggested that instructions affected the nature of the contact made with the programmed consequences and thus subsequent performance. In some cases, responding seemed to result from added contingencies introduced by stating rules. In Experiment 2 the relative contribution of these two effects was assessed by presenting and then withdrawing two lights that had been paired with two specific instructions: "Go Fast" or "Go Slow." There were three conditions. In one condition, only the Go Fast light was on; in a second, only the Go Slow light was on; and in a third, the lights alternated each minute. In each condition, half the subjects had all instruction lights turned off after the first session. The results once again showed an effect of instructions on contact with the programmed consequences. However, responding sometimes continued in a manner consistent with added contingencies for rule-following even when the programmed consequences had been contacted and would have controlled a different type of responding in the absence of instructions. The relevance of added contingencies for rule-following in determining the effects of explicitly programmed consequences is emphasized.

Mentalism, behavior-behavior relations, and a behavior-analytic view of the purposes of science.

In a behavioral view, the purposes of science are primarily prediction and control. To the extent that a scientist embraces both of these as a unified and generally applicable criterion for science, certain philosophical and theoretical practices are counterproductive, including mentalism in both its metaphysical and metatheoretical forms. It is possible and often worthwhile to recast some mentalistic talk into an issue of behavior-behavior relations. When behavior-behavior relations are approached non-mechanistically, however, analysis cannot stop at the level of the relations themselves. Several analytic concepts common in the behavioral community share some of the dangers of mentalism if not employed properly, including such concepts as self-reinforcement, response-produced stimulation, and self-rules.

Acquired immunodeficiency syndrome among patients attending hemophilia treatment centers and mortality experience of hemophiliacs in the United States.

The acquired immunodeficiency syndrome (AIDS) was first recognized among hemophiliacs in 1982. The authors have conducted investigations to determine the onset and incidence of AIDS among hemophiliacs and to determine trends in hemophilia mortality since the introduction of clotting-factor concentrates in the late 1960s. A survey of United States hemophilia treatment centers, supported by the Centers for Disease Control and the National Hemophilia Foundation, defined a population of hemophiliacs which was monitored for AIDS cases through June 1984. Death reports from the United States Vital Statistics System and from the hemophilia treatment center survey provided mortality trends for 1968-1979 and for 1978-1982, respectively. The results of these investigations demonstrate the following points. 1) The AIDS epidemic is a new and important cause of illness and mortality among hemophiliacs, although a very low incidence of AIDS among hemophiliacs prior to 1982 cannot be ruled out. 2) The AIDS cases who attended the surveyed hemophilia treatment centers were distributed throughout the United States and were older than hemophilia treatment center patients without AIDS. AIDS cases also used more lyophilized clotting-factor concentrate, but only a small number of cases were reported with this information. 3) Improved care for hemophilia, including the use of clotting-factor concentrates, dramatically reduced hemophilia mortality rates during the 1970s. 4) In 1982, hemorrhage was the major cause of death among hemophiliacs. Deaths from non-alcoholic liver disease were also increased. AIDS incidence among hemophilia treatment center attendees was stable at 0.6 cases per 1,000 hemophilia treatment center attendees per year during 1982 and 1983 but increased sharply to 5.4 cases per 1,000 during the first quarter of 1984.