Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.

BACKGROUND AND PURPOSE: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. EXPERIMENTAL APPROACH: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. KEY RESULTS: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. CONCLUSIONS AND IMPLICATIONS: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.

Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis.

OBJECTIVE: Animal models of hindlimb ischemia are critical to our understanding of peripheral vascular disease and allow us to evaluate therapeutic strategies aimed to improve peripheral collateral circulation. To further elucidate the processes involved in revascularization following ischemia, we evaluated the temporal association between tissue ischemia, vascular endothelial cell growth factor (VEGF) release, angiogenesis (capillary sprouting), arteriogenesis (growth of the larger muscular arteries), and reserve blood flow (functional collateral flow). METHODS: New Zealand White rabbits (male 3-4 kg) were evaluated at specific days (0, 5, 10, 20 or 40) following femoral artery removal for measurement of hindlimb blood flow, skeletal muscle lactate production and VEGF content, capillary density (a marker of angiogenesis), and angiographic score (a marker of arteriogenesis). RESULTS: Maximal capillary sprouting occurred within 5 days of femoral artery removal and was temporally associated with reduced resting hindlimb blood flow, increased lactate release and detectable levels of skeletal muscle VEGF. The growth of larger angiographically visible collateral vessels occurred after 10 days and was not temporally associated with ischemia or skeletal muscle VEGF content, but did coincide with a large functional improvement in the reserve blood flow capacity of the limb. CONCLUSIONS: Following femoral artery removal in the rabbit, the time course of angiogenesis and arteriogenesis were clearly distinct. Tissue ischemia and/or VEGF may stimulate capillary sprouting, but this response does not translate to a significant improvement in collateral flow. The growth and development of the larger collateral vessels was correlated with a large functional improvement in collateral flow, and occurred at a time when VEGF levels were undetectable.

Determinants of priority for risk reduction: the role of worry.

One hundred twenty-two members (experts) of the Society for Risk Analysis completed a mailed questionnaire and 150 nonexperts completed a similar questionnaire on the World Wide Web. Questions asked included those about priorities on personal and government action for risk reduction, badness of the risk, number of people affected, worry, and probabilities for self and others. Individual differences in mean desire for action were largely explained in terms of worry. Worry, in turn, was largely affected by probability judgments, which were lower for experts than for nonexperts. Differences across risks in the desire for action, within each subject, were also determined largely by worry and probability. Belief in expert knowledge about the risk increased worry and the priority for risk reduction. A second study involving 91 nonexperts (42 interviewed and 49 on the Web) replicated the main findings for nonexperts from the first study. Interviews also probed the determinants of worry, attitudes toward government versus personal control, and protective behaviors.

Further explorations of medical decisions for individuals and for groups.

BACKGROUND: Important discrepancies between clinical practice and health policy may be related to the ways in which physicians and others make decisions about individuals and groups. Previous research has found that physicians and laypersons asked to consider an individual patient generally make different decisions than those asked to consider a group of comparable patients, but this discrepancy has not been observed in more recent studies. This study was designed to explore possible reasons for these findings. METHODS: Prospective jurors (N = 1,013) each made a recommendation regarding a risky treatment for an incurable blood condition. Perspective (individual vs group) was crossed with uncertainty frame (probability vs frequency) and response wording (original vs revised) in a 2 x 2 x 2 between-participants design. RESULTS: When the strength of participants' recommendations was considered, the effects of perspective, uncertainty frame, and response wording were not statistically significant. When recommendations were dichotomized, participants in the revised-response-wording conditions were more likely to recommend treatment to the group than to the individual. CONCLUSIONS: These results conflict with previous findings for this scenario and suggest that reported differences between decisions for individuals and decisions for groups are not robust.

Phosphorylation of the rRNA transcription factor upstream binding factor promotes its association with TATA binding protein.

rRNA synthesis by RNA polymerase I requires both the promoter selectivity factor 1, which is composed of TATA binding protein (TBP) and three TBP-associated factors, and the activator upstream binding factor (UBF). Whereas there is strong evidence implicating a role for phosphorylation of UBF in the control of growth-induced increases in rRNA transcription, the mechanism of this effect is not known. Results of immunoprecipitation studies with TBP antibodies showed increased recovery of phosphorylated UBF from growth-stimulated smooth muscle cells. Moreover, using an immobilized protein-binding assay, we found that phosphorylation of UBF in vivo in response to stimulation with different growth factors or in vitro with smooth muscle cell nuclear extract increased its binding to TBP. Finally, we demonstrated that UBF-TBP binding depended on the C-terminal 'acidic tail' of UBF that was hyperphosphorylated at multiple serine sites after growth factor stimulation. Results of these studies suggest that phosphorylation of UBF and subsequent binding to TBP represent a key regulatory step in control of growth-induced increases in rRNA synthesis.

Public preferences for prevention versus cure: what if an ounce of prevention is worth only an ounce of cure?

BACKGROUND: The belief that small preventive efforts bring large benefits may explain why many people say they value prevention above all other types of health care. However, it often takes a great deal of preventive medicine to prevent a bad outcome. This study explores whether people value prevention or cure more when each brings the same magnitude of benefit and examines whether preferences for prevention or cure vary according to the severity of the disability of the patients who can receive the preventive or curative intervention. METHODS: 289 prospective jurors were presented with a policy dilemma involving how best to allocate funds to benefit people with varying levels of disability. Each project was said to influence the functional ability of 100 nursing home residents, either by improving their level of function or by preventing their level of function from declining. RESULTS: When given a choice between preventive and curative interventions, more subjects preferred the preventive intervention (37% vs 21%, p=0.002). However, when the strength of people's preferences was taken into account, the preference for preventive interventions was not statistically significant (p=0.135). With both preventive and curative interventions, the subjects preferred helping patients with more severe disabilities (p < 0.005 for both comparisons). This preference for helping more severely disabled patients did not differ for prevention and cure (p=0.663). CONCLUSION: When the magnitude of benefit was held constant, the subjects slightly preferred prevention over cure. In addition, they preferred directing limited resources toward those with greater disabilities, regardless of whether those resources were targeted toward prevention or cure. These findings suggest that previously stated preferences for prevention over cure may result from a belief that small efforts at prevention will be repaid by large reductions in the later need for cure.

Carrier screening for cystic fibrosis: costs and clinical outcomes.

OBJECTIVES: To evaluate the costs and clinical effects of 16 alternative strategies for cystic fibrosis (CF) carrier screening in the reproductive setting; and to test the sensitivity of the results to assumptions about cost and detection rate, stakeholder perspective, DNA test specificity, chance of nonpaternity, and couples' reproductive plans. METHOD: Cost-effectiveness analysis. RESULTS: A sequential screening strategy had the lowest cost per CF birth avoided. In this strategy, the first partner was screened with a standard test that identifies 85% of carriers. The second partner was screened with an expanded test if the first partner's screen was positive. This strategy identified 75% of anticipated CF births at a cost of $367,000 each. This figure does not include the lifetime medical costs of caring for a patient with CF, and it assumes that couples who identify a pregnancy at risk will choose to have prenatal diagnosis and termination of affected pregnancies. The cost per CF birth identified is approximately half this figure when couples plan two children. CONCLUSIONS: The cost-effectiveness of CF carrier screening depends greatly on couples' reproductive plans. CF carrier screening is most cost-effective when it is performed sequentially, when the information is used for more than one pregnancy, and when the intention of the couple is to identify and terminate affected pregnancies. These conclusions are important for policy considerations regarding population-based screening for CF, and may also have important implications for screening for less common diseases.

Expression of the smooth muscle myosin heavy chain gene is regulated by a negative-acting GC-rich element located between two positive-acting serum response factor-binding elements.

To identify cis- and trans-acting factors that regulate smooth muscle-specific gene expression, we studied the smooth muscle myosin heavy chain gene, a rigorous marker of differentiated smooth muscle. A comparison of smooth muscle myosin heavy chain promoter sequences from multiple species revealed the presence of a highly conserved 227-base pair domain (nucleotides -1321 to -1095 in rat). Results of a deletion analysis of a 4.3-kilobase pair segment of the rat promoter (nucleotides -4220 to +88) demonstrated that this domain was necessary for maximal transcriptional activity in smooth muscle cells. Gel-shift analysis and site-directed mutagenesis demonstrated that one true CArG and another CArG-like element contained within this domain were both recognized by the serum response factor and were both required for the positive activity attributable to this domain. Additional studies demonstrated that mutation of a GC-rich sequence within the 227-base pair conserved domain resulted in a nearly 100% increase in transcriptional activity. Gel-shift analysis showed that this GC-rich repressor element was recognized by both Sp1 and Sp3. These data demonstrate that transcriptional control of the smooth muscle myosin heavy chain gene is highly complex, involving both negative and positive regulatory elements, including CArG sequences found in the promoters of multiple smooth muscle differentiation marker genes.

Undercontribution bias in health care spending account decisions.

Results from this work describe 239 responses to a mailed survey regarding employee benefits decisions at a large eastern university. The primary objective of this work is to test for an undercontribution bias in health care financing decisions. The results establish the existence of an undercontribution bias in both actual employee decisions and hypothetical flexible spending account contribution decisions. We describe this bias within the context of related biases including loss aversion, mental accounting, status quo and omission biases. Surprisingly, we find a significant order effect in this study and posit that preference construction in this context is an active, reference-dependent process. In addition, results from this work demonstrate the endogenous nature of health care flexible spending account expenditures. The results have important implications both for the descriptive framework of and the normative solution to the flexible spending account contribution decision.

Measuring hospital outcomes from a buyer's perspective.

This study reports lessons learned from a project to develop a flexible, generalizable, and valid method for corporate buyers of hospital care that would permit them to use available secondary data to rate the outcomes quality of all hospitals in a local market area. As hospitalization insurance has moved from coverage that applied equally to all licensed hospitals to arrangements which selected a certain preferred hospital or hospitals and rejected others, the need to determine the quality of different hospitals (as well as what they would cost the insurer or buyer) has become apparent. The product of this project was the development and demonstration of a set of rating methods that build on the strengths available in large hospital discharge data bases, such as (but by no means limited to) that of the Pennsylvania Health Care Cost Containment Council (PHC4). These measures, or others developed using these methods, deal with uncertainty in the data--its diagnosis and treatment--in a conceptually valid and practically useful way, illustrate a process that might be used in the general development of quality measures, and provide a useful critique of some other measures.

Cognitive processes and the decisions of some parents to forego pertussis vaccination for their children.

Public health analyses suggest that, in spite of the possibility that pertussis vaccine may cause rare cases of neurological injury, catastrophic risks to individual children are lower if they are vaccinated. A number of parents, however, choose not to vaccinate their children. The purpose of this study was to investigate the decision processes of some parents who choose to vaccinate and some parents who choose not to do so. Surveys were mailed to 500 randomly selected subscribers of Mothering magazine. Two hundred and ninety-four completed questionnaires were returned (59%). In addition to well-recognized factors in vaccination decisions, perceived dangers of the vaccine, and of the disease and susceptibility to the disease, several cognitive processes not previously considered in vaccination decision studies were found to be important predictors in this population of parents: perceived ability to control children's susceptibility to the disease and the outcome of the disease; ambiguity or doubts about the reliability of vaccine information; a preference for errors of omission over errors of commission; and recognition that if many other children are vaccinated, the risk to unvaccinated children may be lowered. Although perhaps most cases of undervaccination for pertussis reflect more general problems of health care access, some parents choose to forego vaccination for their children for other reasons. Traditional risk-benefit arguments alone will be unlikely to persuade these parents to reassess their decisions. Efforts to increase childhood vaccination must incorporate an understanding of the cognitive processes that help drive these decisions.

Individual choice in spending accounts. Can we rely on employees to choose well?

Flexible spending accounts (FSA) represent a current health care financing tool that may become an important component of incremental health care reform. Because FSAs require employees to make financial contributions based on anticipated health care needs, contribution decisions are likely to be subject to many of the errors made in other insurance decisions. The authors analyzed the benefits selections, benefits forms completion, and FSA contribution levels of approximately 9,500 employees of the University of Pennsylvania from 1987 to 1992. Default and repeat choice trends characterize the completion of benefits forms and the reselection of health insurance options by employees. Despite the economic benefits of contributing to an FSA, only 14% of employees contributed in any one year and 73% never made a contribution. Multivariate models of these contributions fail to demonstrate the importance of what ought to be relevant influences in contribution decisions (for example, age, income, family status, or underlying health insurance). Whereas most FSA decisions are characterized by default contributions of $0, employees who contribute in one year are most likely to contribute exactly the same amount the next year, even when other circumstances change. The pervasiveness of these patterns raises concerns that health care reform plans that rely on financial incentives at the consumer level--for example, proposed medical saving accounts--will be inefficient.

Genetic screening for reproductive planning: methodological and conceptual issues in policy analysis.

OBJECTIVES: This paper explores several critical assumptions and methodological issues arising in cost-effectiveness analyses of genetic screening strategies in the reproductive setting. METHODS: Seven issues that arose in the development of a decision analysis of alternative strategies for cystic fibrosis carrier screening are discussed. Each of these issues required a choice in technique. RESULTS: The presentations of these analyses frequently mask underlying assumptions and methodological choices. Often there is no best choice. In the case of genetic screening in the reproductive setting, these underlying issues often touch on deeply felt human values. CONCLUSIONS: Space limitations for published papers often preclude explaining such choices in detail; yet these decisions determine the way the results should be interpreted. Those who develop these analyses need to make sure that the implications of important assumptions are understood by the clinicians who will use them. At the same time, clinicians need to enhance their understanding of what these models truly mean and how they address underlying clinical, ethical, and economic issues.

Angiotensin II-induced hypertrophy of rat vascular smooth muscle is associated with increased 18 S rRNA synthesis and phosphorylation of the rRNA transcription factor, upstream binding factor.

Hypertrophy of vascular smooth muscle cells (VSMC) is an important adaptive response of hypertension. Drug intervention studies have implicated a role for angiotensin II (A-II) in the mediation of VSMC hypertrophy in vivo, and A-II is a potent hypertrophic agent for VSMC in culture. Our laboratory has previously shown that A-II-induced hypertrophy of cultured VSMC is due in part to generalized increases in protein synthesis and increased content of rRNA. The aim of the present study was to determine if A-II stimulates rRNA gene synthesis and whether the rRNA transcription factor, upstream binding factor (UBF), is involved. Nuclear run-on analysis demonstrated that A-II induced a greater than 5-fold increase in rRNA gene synthesis within 6 h of stimulation. A-II also stimulated a rapid increase in UBF phosphorylation as well as nucleolar localization, but no changes in the content of UBF. Phosphoamino acid analysis showed that phosphorylation occurred only on serine residue(s). Results demonstrate that increased transcription of ribosomal DNA contributes to the A-II-induced increase in protein synthesis and VSMC hypertrophy, and suggest that an important regulatory event in this pathway may be the phosphorylation and/or nucleolar localization of UBF.

Why some health policies don't make sense at the bedside.

Cost-effectiveness analysis and other forms of decision analysis are becoming more common in the medical literature and are increasingly influential in the development of health policy. Nevertheless, many clinicians find it difficult to apply policies developed from these analyses to individual encounters with patients. We examine the assumptions behind these analyses and argue that the perspective they embody can make clinical strategies appear to be less risky in theory than they are at the bedside. We believe that this problem underlies the intuitive concern many physicians have about policy analyses and calls into question the value of these analyses in shaping clinical practice. These analyses aggregate the benefits and burdens of alternative interventions across different individual persons. Thus, overall population risk appears blunted, as it would in a diversified portfolio of stocks that react differently to financial forces or in a herd of cattle that react differently to veterinary interventions. The assumptions behind these analyses make sense if aggregate outcome is what matters, but not if one cares about each individual investment or animal. Because such aggregation tends to understate individual risk, when applied to human health policy, it may misrepresent the interests of patients and cannot be assumed to provide useful guidelines for decision making at the bedside.