Publications

Carrageenan-induced inflammatory pain lasting hours to days produces a protein kinase C epsilon (PKC epsilon )-dependent 'primed' state lasting several weeks, during which time injection of prostaglandin E2 induces hyperalgesia which is markedly enhanced and prolonged compared to PGE2-induced hyperalgesia in normal 'unprimed' rats. In the present study, we demonstrate that while inhibition of prostaglandin synthesis and antagonism of beta2-adrenergic receptors markedly attenuated the hyperalgesia induced by carrageenan, these interventions did not affect hyperalgesic priming. Tumor necrosis factor-alpha (rat recombinant; rrTNFalpha), another mediator of carrageenan-induced inflammation, alone produced hyperalgesia and priming, which were attenuated and prevented, respectively, by intrathecal administration of antisense to PKC epsilon. Inhibition of TNFalpha with thalidomide or a rat polyclonal anti-TNFalpha antibody attenuated carrageenan-induced hyperalgesia and prevented priming. Intrathecal administration of antisense to tumour necrosis factor receptor type-1 (TNFR1) reduced the level of TNFR1 transported toward the peripheral terminals of sensory neurons, and attenuated both carrageenan- and rrTNFalpha-induced priming. Acute hyperalgesia induced by carrageenan or rrTNFalpha remained intact in animals treated with TNFR1 antisense. Our results demonstrate that the generation of the primed state does not require production of hyperalgesia and that TNFalpha, which is generated during acute inflammation, can act on sensory neurons to induce hyperalgesic priming by activating neuronal PKC epsilon.

Subdiaphragmatic vagotomy produces a decrease in mechanical nociceptive threshold that is greater in male rats and an enhancement of bradykinin hyperalgesia that is greater in female rats. To examine the role of gonadal hormones in these sex differences, we evaluated the effect of gonadectomy, with or without gonadal hormone replacement, on vagal modulation of nociceptive threshold and bradykinin hyperalgesia by using the Randall-Selitto paw withdrawal test. Gonadectomy (before sexual maturation) plus vagotomy decreased nociceptive threshold in male rats more than either lesion alone, whereas neither lesion nor in combination had an effect on nociceptive threshold in female rats. Testosterone or dihydrotestosterone replacement in gonadectomized plus vagotomized males and 17 beta-estradiol in females did not significantly alter nociceptive threshold compared to vagotomy plus gonadectomy, respectively. Combined vagotomy and gonadectomy unexpectedly almost completely abolished bradykinin hyperalgesia, whereas gonadectomy alone had no effect on bradykinin hyperalgesia in both sexes. Testosterone replacement in vagotomized males and 17 beta-estradiol in vagotomized females reversed the effect of gonadectomy. Dihydrotestosterone replacement in vagotomized males also reversed the effect of gonadectomy on bradykinin hyperalgesia, although to a lesser degree than testosterone. We conclude that although gonadal hormones and other gonadal-dependent mechanisms influence nociception, they do not account for sexual dimorphism in vagal modulation of mechanical nociceptive threshold or bradykinin hyperalgesia.

Hepatic cytochromes P450 (P450s) are monotopic endoplasmic reticulum (ER)-anchored hemoproteins that exhibit heterogenous physiological protein turnover. The molecular/cellular basis for such heterogeneity is not well understood. Although both autophagic-lysosomal and nonlysosomal pathways are available for their cellular degradation, native P450s such as CYP2B1 are preferentially degraded by the former route, whereas others such as CYPs 3A are degraded largely by the proteasomal pathway, and yet others such as CYP2E1 may be degraded by both. The molecular/structural determinants that dictate this differential proteolytic targeting of the native P450 proteins remain to be unraveled. In contrast, the bulk of the evidence indicates that inactivated and/or otherwise posttranslationally modified P450 proteins undergo adenosine triphosphate-dependent proteolytic degradation in the cytosol. Whether this process specifically involves the ubiquitin (Ub)-/26S proteasome-dependent, the Ub-independent 20S proteasome-dependent, or even a recently characterized Ub- and proteasome-independent pathway may depend on the particular P450 species targeted for degradation. Nevertheless, the collective evidence on P450 degradation attests to a remarkably versatile cellular sanitation brigade available for their disposal. Given that the P450s are integral ER proteins, this mechanistic diversity in their cellular disposal should further expand the repertoire of proteolytic processes available for ER proteins, thereby extending the currently held general notion of ER-associated degradation.

OBJECTIVE

Although home collection HIV tests are available in the United States, home HIV tests providing instant results are not available. The objective of this study was to examine willingness to use instant home HIV tests and what test characteristics are most important to individuals.

METHODS

Six questions were added to the 1999 California Behavioral Risk Factor Surveillance Survey (BRFSS) (n =2964). This state-representative survey is part of the ongoing, 50-state BRFSS sponsored by the Centers for Disease Control and Prevention. Chi-square tests and logistic regression were used to examine willingness to use instant home HIV tests and preferences for HIV test characteristics.

RESULTS

Over one third (37%) of respondents would consider using an instant home HIV test. Respondents willing to use instant home tests were more likely to be Hispanic (odds ratio [OR]=1.55; confidence interval [CI]=1.03-2.34); to have not previously been tested for HIV (OR=1.72; CI=1.20-2.45); to be more likely to plan to be tested in the next 12 months (OR=1.17; CI=1.00-1.37); and to prefer urine sample collection (OR=1.56; CI=1.03-2.37).

CONCLUSION

Over one third of respondents in a large, state-representative sample would consider using an instant home HIV test. Hispanics, individuals who planned to be tested in the next 12 months, and individuals who had never been tested were more willing to use instant home tests.

BACKGROUND

Consumer concerns about the restrictions of managed care may lead to distrust.

OBJECTIVES

To examine whether a community's level of gatekeeping activity is associated with an individual's trust in medical care.

RESEARCH DESIGN

Cross-sectional cohort (N = 49,929).

SUBJECTS

Participants in a nationally representative sample derived from the Community Tracking Survey who had health insurance, had a usual source of care, made at least 1 physician visit, and resided in one of the sampled metropolitan areas with corresponding community-level data, including the prevalence of gatekeeping activity.

MEASURES

Four questions measuring trust in physician.

RESULTS

Individuals from communities with a higher prevalence of gatekeeping activity report less trust than individuals from areas with a lower prevalence of gatekeeping activity, after adjusting for whether that individual had a health plan with a gatekeeper requirement. For example, in communities with the highest prevalence of gatekeeping activity relative to the lowest, the odds ratio for individuals to agree strongly that they trusted their doctor to put their medical needs above all other considerations was 0.77 (95% confidence interval, 0.71-0.84). Also, a higher prevalence of gatekeeping in the community was positively associated with the perception that a physician was strongly influenced by insurance company rules when making decisions about medical care. Conversely, a higher prevalence of gatekeeping in the community was negatively associated with the perception that a doctor might perform an unnecessary test or procedure and with concern about restricted referral for specialty care.

CONCLUSION

Individuals' trust in their physicians may be influenced by wider contextual variables, like the prevalence of gatekeeping in the community.

Methods of economic evaluation, especially cost-effectiveness analysis and cost-benefit analysis, are widely used to examine new healthcare technologies. However, few economic evaluations of pharmacogenomics have been conducted, and pharmacogenomic researchers may be unfamiliar with how to review or conduct these analyses. This review provides an overview of the methods of economic evaluation and examples of where they have been applied to pharmacogenomics. We discuss the steps in conducting a cost-effectiveness or cost-benefit analysis, demonstrating these steps using specific examples from the pharmacogenomics literature.

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.

Although federal initiatives have mandated broader inclusion of minorities in clinical research on diseases that have disparities in health by race and ethnicity, it is not clear whether these initiatives have affected reporting of trial results. The objective of this study was to examine the reporting of race/ethnicity in clinical trials reports in areas of known disparities in health (i.e., diabetes, cardiovascular disease, HIV/AIDS, and cancer) and to determine what factors were associated with reporting of race/ethnicity in results. We performed a Medline search covering the period January 1989 to Oct 2000 to identify clinical trials of diabetes, cardiovascular disease, HIV/AIDS, and cancer published in the Annals of Internal Medicine, JAMA, and New England Journal of Medicine. The main outcome measure was the reporting of participation and of results by race/ethnicity of trial participants. Of 253 eligible trials, 40% (n=102) were non race-focused yet did not report race, while 2% (n=4) were non gender-focused and did not report gender. Forty-six percent of trials that reported the race/ethnicity of the sample reported only one or two racial/ethnic categories, and in 43% of these trials the total number of individuals reported in each race/ethnicity category did not equal the total reported sample size. Analysis of results by race/ethnicity was reported in only two trials, and by gender in only three trials. In diseases with known racial and ethnic disparities, many clinical trials do not report the race/ethnicity of the study participants, and almost none report analyses by race/ethnicity. Although federal initiatives mandate inclusion of minority groups in research, that inclusion has not translated to reporting of results that might guide therapeutic decisions.