Publications

AIMS

Sphingosine-1-phosphate (S1P) plays a vital role in cytoskeletal rearrangement, development, and apoptosis. Sphingosine kinase-1 (SphK1), the key enzyme catalyzing the formation of S1P, mediates ischaemic preconditioning. Ischaemic postconditioning (POST) has been shown to protect hearts against ischaemia/reperfusion injury (IR). To date, no studies have examined the role of SphK1 in POST.

METHODS AND RESULTS

Wild-type (WT) and SphK1 null (KO) mouse hearts were subjected to IR (45 min of global ischaemia and 45 min of reperfusion) in a Langendorff apparatus. Left ventricular developed pressure (LVDP), maximum velocity of increase or decrease of LV pressure (+/-dP/dtmax), and LV end-diastolic pressure (LVEDP) were recorded. Infarction size was measured by 1% triphenyltetrazolium chloride staining. POST, consisting of 5 s of ischaemia and 5 s of reperfusion for three cycles after the index ischaemia, protected hearts against IR: recovery of LVDP and +/-dP/dtmax were elevated; LVEDP was decreased; infarction size (% of risk area) was reduced from 40 +/- 2% in the control group to 29 +/- 2% of the risk area in the POST group (P < 0.05, n = 4 per group). Phosphorylation of Akt and extracellular signal-regulated kinases detected by Western blotting was increased at 10 min of reperfusion. The protection induced by POST was abolished in KO hearts. Infarction size in KO hearts (57 +/- 5%) was not different from the KO control group (53 +/- 5% of risk area, n = 4, P = NS).

CONCLUSIONS

A short period of ischaemic POST protected WT mouse hearts against IR. The cardiac protection induced by POST was abrogated in SphK1-KO mouse hearts. Thus, SphK1 is critical for successful ischaemic POST.

OBJECTIVE

To explore viral marketing strategies for Eclipse cigarettes used by the RJ Reynolds Company (Winston-Salem, North Carolina, USA).

METHODS

Analysis of previously secret tobacco industry documents and multimedia materials.

RESULTS

The failure of RJ Reynolds' (RJR) 1988 "smokeless" cigarette, Premier, was in part due to widespread bad word of mouth about the product's flavour, quality and difficulty of use. In 1994 RJR introduced an updated version of Premier, the ostensibly "reduced risk" Eclipse cigarette. RJR developed viral marketing channels to promote Eclipse using (1) exploratory interviews to motivate consumers to spread the word about Eclipse prior to market release, (2) promotional videos featuring positive feedback from test group participants to portray majority consensus among triers, (3) "Tupperware"-like parties for Eclipse where participants received samples to pass around in their social circles and (4) the Eclipse website's bulletin board as a forum for potential users to discuss the brand in their own words. These strategies targeted the brand's likeliest adopters, recruited informal and credible representatives of the product unaffiliated with RJR, and controlled the information spread about the product.

CONCLUSIONS

Viral marketing techniques may be particularly useful to promote new tobacco products such as Eclipse that have limited appeal and need a highly motivated audience of early adopters and acceptors. Such techniques help evade the mass rejection that could follow mass promotion, circumvent marketing restrictions, and allow tobacco companies to benefit from health claims made by consumers. Cigarette manufacturers must be held accountable for perceived health benefits encouraged by all promotional activities including viral marketing.

BACKGROUND

Wealthy women have higher rates of screening mammography than poor women do. Screening mammography is beneficial for women with substantial life expectancies, but women with limited life expectancies are unlikely to benefit. It is unknown whether higher screening rates in wealthy women are due to increased screening in women with substantial life expectancies, limited life expectancies, or both. This study examines the relationship between wealth and screening mammography use in older women according to life expectancy.

METHODS

A cohort study was performed of 4222 women 65 years or older with Medicare participating in the 2002 and 2004 Health and Retirement Survey. Women were categorized according to wealth and life expectancy (based on 5-year prognosis from a validated prognostic index). The outcome was self-reported receipt of screening mammography within 2 years.

RESULTS

Overall, within 2 years, 68% of women (2871 of 4222) received a screening mammogram. Screening was associated with wealth (net worth, > $100 000) and good prognosis (< or = 10% probability of dying in 5 years). Screening mammography was more common among wealthy women than among poor women (net worth, < $10 000) both for women with good prognosis (82% vs 68%; P < .001) and for women with limited prognoses (> or = 50% probability of dying in 5 years) (48% vs 32%; P = .02). These associations remained after multivariate analysis accounting for age, race, education, proxy report, and rural residence.

CONCLUSIONS

Poorer older women with favorable prognoses are at risk of not receiving screening mammography when they are likely to benefit. Wealthier older women with limited prognoses are often screened when they are unlikely to benefit.

BACKGROUNDS & AIMS

ATP8B1 is a phosphatidylserine flippase in the canalicular membrane; patients with mutations in ATP8B1 develop severe chronic (PFIC1) or periodic (BRIC1) cholestatic liver disease. We have observed that Atp8b1 deficiency leads to enhanced biliary cholesterol excretion. It has been established that biliary cholesterol excretion depends on transport by the heterodimer Abcg5/Abcg8. We hypothesized that the increased cholesterol output was due to enhanced extraction from the altered canalicular membrane rather than to higher Abcg5/Abcg8 activity. We therefore studied the relation between Abcg5/Abcg8 expression and biliary cholesterol excretion in mice lacking Atp8b1, Abcg8, or both (GF mice).

METHODS

Bile formation was studied in LXR agonist-fed wild-type mice as well as mice lacking Atp8b1 or Abcg8, or in GF mice upon infusion of taurocholate. Bile samples were analyzed for cholesterol, bile salt, phospholipids, and ectoenzyme content.

RESULTS

LXR agonist increased Abcg5/8 expression, and this was accompanied by increased biliary cholesterol output in both wild-type and Atp8b1(G308V/G308V) mice. However, Atp8b1(G308V/G308V) mice maintained higher cholesterol output. Although in Abcg8(-/-) mice biliary cholesterol output was severely reduced, GF mice displayed high biliary cholesterol output, which was comparable with wild-type mice. Bile of both Atp8b1(G308V/G308V) and GF mice displayed elevated levels of phosphatidylserine and sphingomyelin, indicating membrane stress.

CONCLUSIONS

Our data demonstrate that the increased biliary cholesterol excretion in Atp8b1-deficient mice is independent of Abcg5/8 activity. This implicates that Atp8b1 deficiency leads to a decrease in the detergent resistance and subsequent nonspecific extraction of cholesterol from the canalicular membrane by bile salts.