bluuebunny/crossref_metadata_2025 huggingface dataset:
The Tetanus Neurotoxin‐Sensitive and Insensitive Routes to and from the Plasma Membrane: Fast and Slow Pathways?
Authors: Proux‐Gillardeaux Véronique , Rudge Rachel , Galli Thierry
Published: April 2005

Intracellular membrane trafficking in eukaryotes involves the budding of vesicles from a donor compartment, their translocation, and subsequent fusion with a target membrane. This last step has been shown to involve SNARE proteins, classified into two categories, vesicular (v)‐SNAREs and target (t)‐SNAREs. It is the pairing of v‐ and t‐SNAREs that is responsible for bringing the lipid bilayers together for membrane fusion. Key to the discovery of SNAREs is the sensitivity of their neuronal synaptic prototypes, which mediate the release of neurotransmitters, to clostridial neurotoxins. In this review, we focus on tetanus neurotoxin‐sensitive and tetanus neurotoxin‐insensitive v‐SNAREs, in particular synaptobrevin and cellubrevin, both tetanus neurotoxin‐sensitive and Tetanus neurotoxin‐ Insensitive Vesicle‐Associated Membrane Protein (TI‐VAMP, also called VAMP7). The brevins are characterized by an RD sequence in the middle of their SNARE motif whereas TI‐VAMP has an RG sequence. These two categories of exocytic v‐SNAREs define two important routes to and from the plasma membrane: one sensitive, the other insensitive to tetanus neurotoxin. We also discuss the central role of the endosomal system that could be considered, as already suggested for Rab proteins, as a mosaic of v‐SNAREs, thus raising the question of whether or not these two routes can merge, and if so, how and where.
Transient Expression of CC Chemokine TECK in the Ovary during Ovulation: Its Potential Role in Ovulation
Authors: Zhou Cindy , Wu Jean , Borillo Jason , Torres Lisa , McMahon John , Bao Yongde , Lou Ya‐Huan
Published: April 2005

Problem:  Chemokine thymus‐expressed chemokine (TECK), which is expressed exclusively in the thymus and small intestine, plays a critical role in T‐cell development. Our previous study revealed its expression in the ovary also. This study investigated its ovarian expression during ovulatory process.

Method of study:  Super‐ovulation was induced in young female CD1 mice by equine chorionic gonadotropin (eCG) and human chorionic gonadotropic (hCG). Ovarian TECK expression during ovulation was determined by: (1) reverse transcriptase‐polymerase chain reaction (RT‐PCR) at mRNA level, (2) Western blot and immunohistology at the protein level, and (3) leukocyte infiltration assay at the bioactive level.

Results:  A transient, high‐level expression of TECK in murine ovaries at the mRNA level during hCG‐induced ovulation was detected. Sequencing of directly cloned PCR product confirmed the ovarian expression of TECK. The peak expression of TECK was observed at 10–12 hr post‐hCG injection; real‐time PCR revealed an 800‐fold increase during its expression peak over 0 hr. The expressed ovarian TECK protein was readily detectable by Western blot. Immunohistochemistry localized TECK expression to the ovarian interstitial tissue surrounding, or in the theca layer of the mature follicles undergoing ovulatory process. Expression of TECK receptor, the CC chemokine receptor (CCR9) was also detected in the ovulating ovaries. Using in vitro leukocyte infiltration assay, we first demonstrated that ovaries undergoing the ovulatory process were able to selectively chemoattract mononuclear cells. Importantly, neutralization of TECK by the antibody resulted in a 85% reduction in the chemotactic activities of the ovaries.

Conclusion:  This study suggested that ovarian expression of TECK is under a tight hormonal regulation, and expressed TECK may be responsible for recruitment of mononuclear cells into the ovary to participate in the ovulatory process.
Immunologic Uniqueness of the Genital Tract: Challenge for Vaccine Development
Authors: Mestecky Jiri , Moldoveanu Zina , Russell Michael W.
Published: April 2005

Although the genital tract is considered to be a component of the mucosal immune system, it displays several distinct features not shared by other typical mucosal tissues and external secretions. Both male and female genital tract tissues lack inductive mucosal sites analogous to intestinal Peyer's patches. Consequently, local humoral and cellular immune responses stimulated by infections [with e.g. Neisseria gonorrhoeae, Chlamydia trachomatis, papilloma virus, and human immunodeficiency virus (HIV‐1)] are weak or absent, and repeated local intravaginal immunizations result in minimal humoral responses. In contrast to typical external secretions such as intestinal fluid that contain secretory immunoglobulin A (S‐IgA) as the dominant isotype, semen and cervico‐vaginal fluid contain more IgG than IgA. Furthermore, irrespective of the route of infection, humoral immune responses to HIV‐1 are dominated by specific IgG and low or absent IgA antibodies in all external secretions. Because a significant proportion of IgG in genital tract secretions is derived from the circulation, systemic immunization may provide protective IgG antibody‐mediated immunity in the genital tract. Furthermore, combined systemic and mucosal (oral, rectal, and especially intranasal) immunization may induce protective humoral responses in both the systemic and mucosal compartments of the immune system.
Expression of Killer Immunoglobulin‐like Receptors on Peripheral Blood NK Cell Subsets of Women with Recurrent Spontaneous Abortions or Implantation Failures
Authors: Ntrivalas Evangelos I. , Bowser Chad R. , Kwak‐Kim Joanne , Beaman Kenneth D. , Gilman‐Sachs Alice
Published: April 2005

Problem:  Decidual natural killer (NK) cells express inhibitory receptors (killer immunoglobulin‐like receptors, KIRs), which bind to ligands on trophoblast cells (human leucocyte antigen, HLA‐C). This interaction appears to block NK cytotoxicity against trophoblast cells. In this study, we investigated the expression of inhibitory and activating receptors in peripheral blood NK cells of women with recurrent spontaneous abortion (RSA) or implantation failures.

Method of study:  CD56dim/CD16+, CD56bright/CD16− NK cells and CD56+/CD3+ NKT cells of women with RSA or in vitro fertilization (IVF) failures and normal controls were analyzed for the expression of CD158a, CD158b inhibitory KIRs or CD161‐activating receptors, by flow cytometric analysis.

Results:  CD158a and CD158b inhibitory receptor expression by CD56dim/CD16+ and CD56bright/CD16− NK cells were significantly decreased, and CD161‐activating receptor expression by CD56+/CD3+ NKT cells was significantly increased in women with implantation failures when compared with normal controls.

Conclusions:  An imbalance between inhibitory and activating receptor expression was found in NK cells of women with implantation failures. This imbalance may explain the adverse reproductive outcome.
Effect of Bacterial Virulence on IL‐18 Expression in the Amnion Infected withEscherichia coli
Authors: Šplíchalová Alla , Trebichavský Ilja , Muneta Yoshihiro , Mori Yasuyuki , Šplíchal Igor
Published: April 2005

Problem: The upregulation of inflammatory substances threatens pregnancy. Interleukin‐18 (IL‐18) is elevated in women who miscarried. The purpose of this study was to develop a pig model of chorioamnionitis to study the effect of bacterial virulence on IL‐18 response in experimentally infected amnion.

Method of study: A total of 20,000 colony‐forming units ofEscherichia coli(an enteropathogenic O55 strain, EPEC or O86 non‐pathogenic strain) were administered into the amniotic cavity of pig fetuses at 70% of gestation for 10 hr. Fetal amniotic fluid samples were analyzed for IL‐18 levels by enzyme‐linked immunosorbent assay. The expression of IL‐18 was studied also by immunohistochemistry on cryostat sections through amniotic membranes and pathological changes were observed by electron microscopy.

Results: BothE. colistrains propagated in amniotic fluids and reached similar counts. Only EPEC, however, caused a significant increase of IL‐18 amniotic fluid levels (P < 0.001) and cytokine expression in the amniotic epithelium.

Conclusions: The levels of IL‐18 in infected amniotic fluids correlated with bacterial virulence and pathological changes in the amnion.
THE EVA REVOLUTION
Authors: Ehrbar Al , Stewart G. Bennett
Published: April 2005

Stern Stewart's EVA framework for financial management and incentive compensation is the practical application of both modern financial theory and classical economics to the problems of running a business. It is a fundamental way of measuring and motivating corporate performance that encourages managers to make decisions that make economic sense, even when conventional accounting‐based measures of performance tell them to do otherwise. Moreover, EVA provides a consistent basis for a comprehensive system of corporate financial management—one that is capable of guiding all corporate decisions, from annual operating budgets to capital budgeting, strategic planning, and acquisitions and divestitures. It also provides companies with a “language” for communicating their goals and achievements to investors—a language that the market is increasingly coming to interpret as a sign of superior future performance.

The authors report that more than 300 companies have implemented Stern Stewart's EVA framework, including a growing number of converts in Europe, Asia, and Latin America. After describing significant behavioral changes at a number of EVA companies, the article focuses in detail on a single case history—that of auto parts manufacturer Federal‐Mogul. Besides bringing about a dramatic change in the company's strategy and significant operating efficiencies, the adoption of EVA also led to an interesting change in Federal—Mogul's organizational structure—a combination of two large business units into a single profit center designed to achieve greater cooperation and synergies between the units.
TO PURCHASE OR TO POOL: DOES IT MATTER?
Authors: Lindenberg Eric , Ross Michael P.
Published: April 2005

The recent decision by the Financial Accounting Standards Board to eliminate pooling accounting for acquisitions raises several important questions: Does the choice of “purchase” or “pooling” affect firm valuations? How do differences in goodwill and its amortization affect cash flow and price/earnings multiples? How has the market reacted to purchase and pooling acquisition announcements?

The authors' new research suggests that the market already judges mergers and acquisitions based on fundamental economics, not on GAAP earnings. In a study of 1,442 large acquisitions in the 1990s, the authors find that, in the first month after the announcement of pooled transactions, the acquirer's stock fell by an average of almost 4%. By contrast, the market reaction to purchase acquisitions was extremely favorable, with a 3% positive abnormal return in the first month.

But what about the ongoing effect of goodwill amortization on values? In the second part of their two‐part study, the authors report that the P/E multiples of acquirers reporting increases in goodwill amortization increase significantly following the acquisitions, and that the increases in P/E are large enough to offset the negative impact of goodwill amortization on earnings. Moreover, the authors also tested for and were unable to find any evidence of a market bias against balance sheet goodwill as an indicator of future amortization charges.

The authors thus conclude that changes in accounting for acquisitions should not be a concern for acquirers, and that the elimination of pooling should have no lasting impact on corporate strategic decisions or M&A activity. Nevertheless, they do suggest that companies with significant goodwill would benefit from making their amortization transparent in their financial statements by, for example, breaking out amortization from depreciation on their income statements.
SOME NEW EVIDENCE ON EVA COMPANIES
Authors: Kleiman Robert T.
Published: April 2005

The study of companies using EVA and EVA‐like systems discussed in the previous article provides evidence of changes in managerial behavior, such as reduced capital expenditures, increased share repurchases, and increased residual income, but stops short of concluding that such changes have increased shareholder value. This article presents evidence that directly addresses the issue: Do companies adopting EVA add more value for their shareholders than their industry competitors?

The author reports that U.S. companies adopting EVA during the period 1987–1996 outperformed the median firms with the same SIC codes by 28.8% during the four‐year period including and following the year of adoption. This paper also provides evidence of significant operating improvements that help explain such increases in shareholder value. But, in contrast to the finding of the Wallace study cited above, the capital expenditures of EVA companies increase (although at a slower rate than for S&P 500 companies) after going on to EVA.
A GUIDE TO VALUING EMPLOYEE STOCK OPTIONS WITH A RELOAD FEATURE
Authors: Hemmer Thomas , Matsunaga Steve , Shevlin Terry
Published: April 2005

At first glance, executive stock options with reload provisions appear to be more complicated than conventional options, and thus the valuation of such options would appear to be more difficult. But, as the authors demonstrate in this article, such reload options provide the employee with a dominant exercise strategy—namely, to exercise the option whenever it is “in‐the‐money.” And the fact that reload options will always be exercised simplifies their valuation by eliminating a major problem—that associated with employee's risk references and uncertain early exercise—in valuing conventional options.
WHY THE EFFICIENT MARKET OFFERS HOPE TO ACTIVE MANAGEMENT*
Authors: Bernstein Peter L.
Published: April 2005

This article provides an interesting resolution of the paradox at the heart of efficient markets theory: namely, in financial markets that appear to be becoming ever more efficient, with fewer and fewer fund managers able to beat the S&P 500, why do investors engage in active trading? Why not index? The key to the author's defense of active management lies in its critique of economists' concept of “equilibrium prices.”
EVIDENCE THAT GREATER DISCLOSURE LOWERS THE COST OF EQUITY CAPITAL
Authors: Botosan Christine A.
Published: April 2005

The effect of corporate disclosure on the cost of equity capital is a matter of considerable interest and importance to both corporations and the investment community. However, the relationship between disclosure level and cost of capital is not well established and has proved difficult for researchers to quantify.

As described in this article, the author's 1997 study (published in The Accounting Review) was the first to measure and detect a direct relationship between disclosure and cost of capital. After examining the annual reports of 122 manufacturing companies, the author concluded that companies providing more extensive disclosure had a lower (forward‐looking) cost of equity capital (measured using Value Line forecasts with an EBO valuation formula that derives from the dividend discount model).

For companies with extensive analyst coverage, differences in disclosure do not appear to affect cost of capital. But for companies with small analyst followings, differences in disclosure do appear to matter. Among this group of companies, the firms judged to have the highest level of disclosure had a cost of equity capital that was nine‐percentage points lower than otherwise similar firms with a minimal level of disclosure. Closer analysis of some of the specific disclosure practices also suggests that, for small firms with limited analyst coverage, there are benefits to providing more forward‐looking information, such as forecasts of sales, profits, and capital expenditures, and enhanced disclosure of key non‐financial statistics, such as order backlogs, market share, and growth in units sold.

In closing, the article also discusses an interesting new study (by Lang and Lundholm) that suggests there is an important distinction between effective corporate disclosure and “hyping the stock.” The findings of this study show that while higher levels of disclosures are associated with higher stock prices, sudden increases in the frequency of disclosure are viewed with skepticism.
BUYING AND SELLING COMPANIES IN THE NEW MILLENNIUM
Authors: BOSWELL STEWART
Published: April 2005

The growth in corporate mergers and acquisitions in the 1990s has been nothing short of spectacular. Among the most important contributors to the growth of M&A are globalization and technological change, which are working together to create excess capacity in virtually all global industries. When industries are experiencing overcapacity, some degree of consolidation becomes inevitable, and M&A is a primary means for accomplishing consolidation.

Although much of the dollar volume of M&A comes from the highly publicized mergers of large companies, by far the greatest number of transactions is taking place in the middle market—that is, companies with revenues less than $500 million or a market cap under $1 billion. Along with the sharp increase in middle‐market M&A, the author notes a relatively new financing practice in which private equity groups take large minority stakes in middle market companies. One factor contributing to this development, which the author calls “the small‐cap trap,” is that the stocks of small and mid‐sized public companies now appear to be trading “at large discounts to the values of their large‐cap peer group, even in cases where the operating performance of the smaller firms is better.” According to the author, the most plausible explanation for such discounts is the limited “float” of such companies; most receive little research coverage by Wall Street analysts and have limited institutional followings.

After reviewing broad trends in M&A, the author offers some tips on designing a broad M&A strategy and conducting a selling process. One of the keys to the selling process is to create a sense of “exclusivity” among interested buyers without removing the pressure of competition. Consistent with the message of other articles in this issue, the author argues that one of the most reliable ways to create a sense of exclusivity is by providing good information, relatively full disclosure. Indeed, the disclosure should be sufficiently revealing that the initial bids are based on all relevant information.
HARVESTING VALUE FROM ENTREPRENEURIAL SUCCESS
Authors: Kensinger John W. , Martin John D. , William Petty J.
Published: April 2005

This article discusses ways for entrepreneurs to gain liquidity from their businesses, either with or without a sale of the business. In today's financial arena there is a wide variety of methods and financing vehicles that can enable private companies to harvest liquidity to meet their own needs for growth, the consumption requirements of their founders, or the challenges of tax and estate planning. For companies with limited growth opportunities but fairly stable cash flows, the alternatives range from orderly liquidation to highly leveraged transfers of ownership such as those accomplished by leveraged buyouts, ESOPs, and mezzanine finance. For companies with abundant growth opportunities, value is typically maximized through sale to a strategic buyer or an initial public offering of equity (although a new hybrid called the “private IPO” has recently emerged that looks more like an LBO than an IPO).

In order to achieve its full potential, a company should be financed in such a way that enables it to continue through its natural business lifecycle, regardless of whether that matches the human lifecycle of its founder. So long as leadership succession can be arranged, the business lifecycle can determine the course of the company. Indeed, selling the business is the value‐maximizing solution only if there is a strategic buyer willing to pay a premium above the business's stand‐alone value, or if the founder wants to withdraw from the business and has no preferred successor.

Moreover, for the vast majority of companies, going public is not the recommended means for “cashing out.” An IPO is likely to be a value‐maximizing (and emotionally satisfying) experience only for (1) companies with valuable growth prospects that require funding for investment and (2) owner‐entrepreneurs who are willing to subject themselves to the scrutiny and fluctuations of the market.
TAX PROGRESSIVITY AND CORPORATE INCENTIVES TO HEDGE
Authors: Graham John R. , Smith Clifford W.
Published: April 2005

If a company faces some form of tax progressivity—that is, its marginal tax rate increases over the firm's expected range of reported taxable income—corporate hedging can reduce the firm's expected tax liability by reducing the volatility of pre‐tax income. In a study described in this article, the authors used simulation methods to investigate the extent to which tax progressivity arises from various provisions of the tax code, such as the AMT and tax carryforwards and carrybacks. Based on their analysis of over 80,000 COMPUSTAT firm‐year observations, the authors find that, in about 50% of the cases, corporations face effective tax functions that exhibit progressivity. The other 50% of cases are about evenly divided between firms that are tax neutral and those facing tax schedules that are “regressive” (again, over the relevant range of expected reported income).

For those companies facing progressive tax functions, the authors estimate that the projected average tax savings from a 5% reduction in the volatility of taxable income is about 5.4% of the expected tax liabilities. However, the distribution of expected reductions is highly skewed, in extreme cases exceeding 40% of the total tax liability. Most of these extreme cases are small to medium‐sized companies, since such firms are much more likely to meet the two conditions for achieving large tax benefits: (1) expected pretax income that is close to zero; and (2) sufficiently volatile income that the firm (in the absence of hedging) expects to report losses in some years. In sum, small to medium‐sized companies experience the greatest tax benefits from hedging.
Contemporary management of acute coronary syndrome
Authors: Large G A
Published: April 2005

This review focuses on the modern management of the non-ST elevation acute coronary syndromes (unstable angina and non-ST elevation myocardial infarction). Patients with these syndromes are at varying degrees of risk of (re)infarction and death. This risk can be reliably predicted by clinical, electrocardiographic, and biochemical markers. Aspirin, clopidogrel, heparin (unfractionated or low molecular weight), and anti-ischaemic drugs should be offered to all patients, irrespective of the predicted level of risk. Patients at high risk should also receive a glycoprotein IIb/IIIa receptor inhibitor and should undergo early coronary arteriography with a view to percutaneous or surgical revascularisation. Lower risk patients should undergo non-invasive testing. When inducible myocardial ischaemia is exhibited coronary arteriography should follow. When non-invasive testing is negative, a conservative management strategy is safe.
Substance misuse in the older population
Authors: McGrath A , Crome P , Crome I B
Published: April 2005

Substance misuse among the older population is largely overlooked and underreported. Many factors contribute to this, not least the fact that presentation may be atypical and hence easily missed by the medical practitioner. There may be many clues to its existence, provided the physician remains alert to these. Despite this it is quite comforting to know that once identified, the evidence to date suggests that older people may respond at least as well as younger people to treatment.
Acute liver failure: a message found under the skin
Authors: Meier M , Woywodt A , Hoeper M M , Schneider A , Manns M P , Strassburg C P
Published: April 2005

Acute liver failure is a rare syndrome with rapid progression and high mortality. It is characterised by the onset of coma and coagulopathy usually within six weeks but can occur up to six months after the onset of illness. Viral hepatitis, idiosyncratic drug induced liver injury, and acetaminophen ingestion are common causes. This report describes the case of a 35 year old man who presented with acute liver failure shortly after binge drinking. Repeated history taking disclosed a gluteal disulfiram implant that the patient had received to treat his alcohol dependence. The patient recovered with maximum supportive care after surgical removal but without liver transplantation. This case illustrates that only meticulous history taking will disclose the sometimes bewildering causes of acute liver failure.
Recurrent acute heart failure caused by sliding hiatus hernia
Authors: Siu C-W , Jim M-H , Ho H-H , Chu F , Chan H-W , Lau C-P , Tse H-F
Published: April 2005

The case is reported of a 75 year old woman who presented with recurrent nocturnal episodes of acute pulmonary oedema. The cause was uncertain as she had normal cardiothoracic ratio on chest radiography and normal left ventricular systolic and diastolic function by transthoracic echocardiogram. Another transthoracic echocardiogram was repeated when she was recumbent for an hour and had a full stomach. It showed a striking finding of severe left atrial compression by an external structure. Computed tomography of the thorax showed an intrathoracic mass behind the left atrium causing external compression of the left atrium suggestive of a sliding hiatus hernia. Cardiac catheterisation confirmed the diagnosis by showing a pronounced rise of pulmonary capillary wedge pressure in the recumbent position compared with the sitting up position.
Acute poisoning: understanding 90% of cases in a nutshell
Authors: Greene S L , Dargan P I , Jones A L
Published: April 2005

The acutely poisoned patient remains a common problem facing doctors working in acute medicine in the United Kingdom and worldwide. This review examines the initial management of the acutely poisoned patient. Aspects of general management are reviewed including immediate interventions, investigations, gastrointestinal decontamination techniques, use of antidotes, methods to increase poison elimination, and psychological assessment. More common and serious poisonings caused by paracetamol, salicylates, opioids, tricyclic antidepressants, selective serotonin reuptake inhibitors, benzodiazepines, non-steroidal anti-inflammatory drugs, and cocaine are discussed in detail. Specific aspects of common paediatric poisonings are reviewed.
Prospective study of acute gastrointestinal bleeding attributable to anti-inflammatory drug ingestion in the Yorkshire region of the United Kingdom
Authors: Lim C H , Heatley R V
Published: April 2005

Objective

To assess the general use of all non-steroidal anti-inflammatory drugs (NSAID) and their relation to upper gastrointestinal bleeding in view of National Institute for Clinical Excellence guidelines published in July 2001 in the UK.

Methods

Cross sectional study on all patients who were referred for endoscopy for suspected upper gastrointestinal bleeding in six hospitals in Yorkshire region of the UK.

Results

One hundred and sixty three patients presented for endoscopy for suspected upper gastrointestinal bleeding, 43 patients were taking at least one ulcerogenic drug, and 120 were not. The mean age difference between these two groups was eight years (p<0.01). The absolute difference between the proportion of patients with peptic ulcer disease/erosion (PUD) in NSAID with/without aspirin group and no ulcerogenic drug group was 31% (p = 0.02). The difference between the proportion of PUD in cyclo-oxygenase 2 with/without aspirin group and no ulcerogenic drug group was 30% (p = 0.1). The overall 30 days mortality rate was 14.1%.

Conclusions

Elderly patients are being inappropriately prescribed conventional NSAIDs. NSAIDs with or without aspirin use are still associated with a significant risk of upper gastrointestinal bleeding in the era of cyclo-oxygenase 2 selective agents. Substitution with cyclo-oxygenase 2 selective NSAIDs is not without risk of upper gastrointestinal bleeding.
Retinal vein thrombosis associated with a herbal phytoestrogen preparation in a susceptible patient
Authors: Cheong J L , Bucknall R
Published: April 2005

A 55 year old woman, known to have systemic lupus erythematosus and protein S deficiency, presented with sudden onset of visual loss in the left eye. Three days previously, she took a herbal phytoestrogen preparation for relief of her menopausal symptoms. Ophthalmological assessment showed a left inferior hemiretinal vein thrombosis. The temporal relation between the onset of visual symptoms and ingestion of this herbal preparation suggested that in this patient with a prior non-manifest prothrombotic tendency, there may be an association between the development of retinal vein thrombosis and herbal phytoestrogen use.
POLYUNSATURATED FATTY ACID REGULATION OF GENES OF LIPID METABOLISM
Authors: Sampath Harini , Ntambi James M.
Published: April 2005

▪ Abstract  Apart from being an important macronutrient, dietary fat has recently gained much prominence for its role in regulating gene expression. Polyunsaturated fatty acids (PUFAs) affect gene expression through various mechanisms including, but not limited to, changes in membrane composition, intracellular calcium levels, and eicosanoid production. Furthermore, PUFAs and their various metabolites can act at the level of the nucleus, in conjunction with nuclear receptors and transcription factors, to affect the transcription of a variety of genes. Several of these transcription mediators have been identified and include the nuclear receptors peroxisome proliferator-activated receptor (PPAR), hepatocyte nuclear factor (HNF)-4α, and liver X receptor (LXR) and the transcription factors sterol-regulatory element binding protein (SREBP) and nuclear factor-κB (NFκB). Their interaction with PUFAs has been shown to be critical to the regulation of several key genes of lipid metabolism. Working out the mechanisms by which these interactions and consequent effects occur is proving to be complicated but is invaluable to our understanding of the role that dietary fat can play in disease management and prevention.
Ximelagatran in Orthopaedic Surgery
Authors: Eriksson Bengt
Published: April 2005

Ximelagatran represents the first new oral anticoagulant since the introduction of warfarin almost 60 years ago, and has been evaluated for the treatment and prevention of a range of venous and arterial thromboembolic disorders. The MElagatran THRomboprophylaxis in Orthopaedic surgery (METHRO) and EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS) studies have investigated the efficacy and safety of subcutaneous (s.c.) melagatran followed by oral ximelagatran in preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement. In METHRO II, immediate pre-operative-initiated s.c. melagatran followed by post-operative ximelagatran dose-dependently reduced VTE, with the highest dose (melagatran 3 mg/ximelagatran 24 mg twice daily) associated with a significantly reduced incidence of VTE compared with the low-molecular-weight heparin (LMWH) dalteparin (15.1 vs. 28.2%; p < 0.0001). In METHRO III, the efficacy of s.c. melagatran 3 mg/ximelagatran 24 mg twice daily initiated post-operatively (4–12 h after surgery) was comparable to that of the LMWH enoxaparin initiated 12 h before surgery (total VTE incidence, 31.0 and 27.3%, respectively). Rates of severe bleeding were also comparable between treatments (melagatran/ximelaga tran = 1.4%; enoxaparin = 1.7%). Treatment with melagatran/ximelagatran was significantly more effective when initiated earlier (4–8 h) rather than later (8–12 h) after surgery (total VTE incidence, 27.5 vs. 35.4%; p = 0.0034). Based on the results of METHRO II and III, the EXPRESS study evaluated the efficacy and bleeding profile of s.c. melagatran 2 mg immediately before surgery, followed by s.c. melagatran 3 mg on the evening of the day of surgery and then ximelagatran 24 mg twice daily. This regimen was significantly more effective than enoxaparin (total VTE incidence, 20.3 vs. 26.6%; p < 0.0004). Excessive bleeding (as judged by the investigator) was more frequent with melagatran/ximelagatran, but rates of fatal bleeding, critical-site bleeding and bleeding requiring re-operation did not differ between the groups. Taken together, the METHRO and EXPRESS studies demonstrate that melagatran/ximelagatran has comparable or superior efficacy to LMWHs in the prevention of VTE in orthopaedic surgery patients, and that the timing and dose of melagatran is important in optimizing the balance of efficacy and bleeding risk.
Comparative Informativeness for Linkage of Multiple SNPs and Single Microsatellites
Authors: Lindholm Eva , Hodge Susan E. , Greenberg David A.
Published: April 2005

Single nucleotide polymorphisms (SNPs), or biallelic markers, are popular in genetic linkage studies due to their abundance in the genome, stability, and ease of scoring. We determined the ‘information ratio’ (IR) of closely spaced SNPs in simulated nuclear families and affected sib pairs (ASPs). (The IR is the ratio of actual average maximum lod score to the maximum lod score attainable if the marker were fully informative.) The nuclear families included parental information, whereas the ASPs did not. We analyzed these SNPs in two ways: (1) using multipoint analysis, and (2) treating the SNPs as ‘composite markers’ (i.e., haplotypes, as assigned by GENEHUNTER). (3) We also calculated the IR of a single microsatellite marker with multiple alleles and compared with the IR from the SNPs. For each set of input conditions, we simulated 1000 nuclear families, of 2, 3, 4, or 5 children each, as well as 1000 ASPs. We generated SNP marker data for strings of k = 1, 2, 3, 5, 7, and 10 SNP loci, with no recombination (Θ = 0) and no linkage disequilibrium among the SNPs. The MAF (minor allele frequency) was either 0.5 or 0.25, and allele frequencies were the same for all k loci in any analysis. We also generated marker data for one single-locus microsatellite marker, with m = 3, 4, 5, 6, 7, and 9 equally frequent alleles. In all simulations, the disease was fully penetrant dominant, and there was no recombination or linkage disequilibrium among markers or between marker and disease. When multipoint analysis was used, we found that 5–7 closely spaced SNPs were usually enough to yield an IR of ≈100%, for nuclear families of any size. However, for the ASPs, even 7–10 SNPs yielded an IR of only 70–80%. A microsatellite with 9 equally frequent alleles yielded about the same IR (86–88%) as a string of 4–5 SNPs, in nuclear families. SNPs analyzed as ‘composite markers’ analyses performed worse, due to the inherent ambiguity of SNP haplotyping.
Reduced Baroreceptor Sensitivity and Elasticity of the Carotid Artery in a Preeclamptic Patient
Authors: Rigó Jr. János , Visontai Zsuzsanna , Mersich Beatrix , Kollai Márk
Published: April 2005

Baroreflex sensitivity, distensibility coefficient, and intima-media thickness (IMT) of the common carotid artery were determined in a preeclamptic patient during 1st and 3rd trimesters as well as after childbirth. From the beginning of her pregnancy, baroreflex sensitivity and distensibility coefficient of the carotid artery exhibited a parallel decline, whereas the IMT increased as compared with normotensive pregnancies. The values of all parameters examined returned to their initial levels after 14 weeks of delivery. These results suggest that augmented IMT and carotid stiffness coupled to baroreceptor dysfunction may have contributed to the perturbation of blood pressure control in our preeclamptic patient.
American College of Cardiology and American Heart Association Methodology for the Selection and Creation of Performance Measures for Quantifying the Quality of Cardiovascular Care
Authors: Spertus John A. , Eagle Kim A. , Krumholz Harlan M. , Mitchell Kristi R. , Normand Sharon-Lise T.
Published: April 2005

The ability to quantify the quality of cardiovascular care critically depends on the translation of recommendations for high-quality care into the measurement of that care. As payers and regulatory agencies increasingly seek to quantify healthcare quality, the implications of the measurement process on practicing physicians are likely to grow. This statement describes the methodology by which the American College of Cardiology and the American Heart Association approach creating performance measures and devising techniques for quantifying those aspects of care that directly reflect the quality of cardiovascular care. Methods for defining target populations, identifying dimensions of care, synthesizing the literature, and operationalizing the process of selecting measures are proposed. It is hoped that new sets of measures will be created through the implementation of this approach, and consequently, through the use of such measurement sets in the context of quality improvement efforts, the quality of cardiovascular care will improve.
Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction
Authors: Lansky Alexandra J. , Pietras Cody , Costa Ricardo A. , Tsuchiya Yoshihiro , Brodie Bruce R. , Cox David A. , Aymong Eve D. , Stuckey Thomas D. , Garcia Eulogio , Tcheng James E. , Mehran Roxana , Negoita Manuela , Fahy Martin , Cristea Ecaterina , Turco Mark , Leon Martin B. , Grines Cindy L. , Stone Gregg W.
Published: April 2005

Background—

Women with acute myocardial infarction (AMI) undergoing primary angioplasty have higher rates of morbidity and mortality than do men. Whether contemporary interventional treatment strategies have improved outcomes for women compared with men is unknown.

Methods and Results—

In the CADILLAC trial, 2082 patients (27% women) with AMI within 12 hours of symptom onset were randomized to balloon angioplasty (PTCA; n=518), PTCA+abciximab (n=528), stenting (n=512), and stenting+abciximab (n=524). As compared with men, women had a lower body surface area; had a greater prevalence of diabetes, hypertension, and hyperlipidemia; experienced significant delays to treatment; and had better baseline and final TIMI grade 3 flows. Unadjusted 1-year event rates were higher for women, including death (7.6% versus 3.0%,
P
<0.001), ischemic target-vessel revascularization (TVR; 16.7% versus 12.1%,
P
=0.006), and major adverse cardiac events (MACE; 23.9% versus 15.3%,
P
<0.001). Female gender was an independent predictor of MACE and bleeding complications, although comorbid risk factors and body surface area but not gender predicted 1-year death. For women, primary stenting resulted in a reduction in 1-year MACE from 28.1% to 19.1% (
P
=0.01) and in ischemic TVR from 20.4% to 10.8% (
P
=0.002) compared with PTCA. The addition of abciximab to primary stenting significantly reduced the 30-day ischemic TVR without increasing bleeding or stroke rates.

Conclusions—

The higher mortality rate in women compared with men after interventional treatment for AMI may be explained by differences in body size and clinical risk factors, although female gender remains an important independent determinant of overall adverse outcomes. For women in the CADILLAC trial, the addition of abciximab reduced 30-day TVR without increasing bleeding risk, and primary stenting reduced 1-year TVR and MACE rates compared with PTCA.
Homozygosity for Factor V Leiden Leads to Enhanced Thrombosis and Atherosclerosis in Mice
Authors: Eitzman Daniel T. , Westrick Randal J. , Shen Yuechun , Bodary Peter F. , Gu Shufang , Manning Sara L. , Dobies Sarah L. , Ginsburg David
Published: April 2005

Background—

Activated protein C resistance due to factor V Leiden (FVL) is a common genetic risk factor for venous thrombosis in humans. Although the impact of FVL on the development of venous thrombosis is well established, its effect on arterial thrombosis and atherosclerosis is controversial.

Methods and Results—

To determine the effect of the FVL mutation on arterial thrombosis in the mouse, wild-type (
Fv
+/+
), heterozygous FVL (
Fv

Q
/+

), and homozygous FVL (
Fv

Q/Q

) mice underwent photochemical carotid arterial injury to induce occlusive thrombosis.
Fv

Q/Q

mice formed occlusive thromboses 27±3 minutes (n=7) after the onset of injury, which was significantly shorter than that observed for
Fv
+/+
mice (56±7 minutes, n=9,
P
<0.01), whereas
Fv

Q
/+

mice (41±7 minutes, n=5) were intermediate (
P
=0.5, compared with
Fv
+/+
). To determine the source of FVL relevant to the enhanced vascular thrombosis, bone marrow transplantation experiments were performed between
Fv
+/+
and
Fv

Q/Q

mice.
Fv

Q/Q

mice transplanted with
Fv
+/+
bone marrow formed occlusive thromboses at 35±5 minutes (n=7,
P
<0.05 compared with
Fv
+/+
mice), whereas
Fv
+/+
mice transplanted with
Fv

Q/Q

bone marrow occluded at 59±7 minutes (n=6,
P
<0.001 compared with
Fv

Q/Q

mice). To assess the effect of the FVL mutation on the development of atherosclerosis,
Fv

Q/Q

mice were crossed with the atherosclerosis-prone apolipoprotein E (ApoE)–deficient strain (
ApoE
−/−
) to generate
Fv

Q/Q

,ApoE
−/−
mice. By 52 weeks of age,
Fv

Q/Q

,ApoE
−/−
mice (n=8) had developed more aortic atherosclerosis (40±6% lesion area) compared with
Fv
+/+
,ApoE
−/−
mice (15±3% lesion area; n=12,
P
<0.02).

Conclusions—

In conclusion, homozygosity for the FVL mutation in mice leads to enhanced arterial thrombosis and atherosclerosis. The source of the FVL leading to accelerated thrombosis appears to be circulating, non–platelet-derived plasma FVL.
Exercise Single-Photon Emission Computed Tomography Provides Effective Risk Stratification of Elderly Men and Elderly Women
Authors: Valeti Uma S. , Miller Todd D. , Hodge David O. , Gibbons Raymond J.
Published: April 2005

Background—

In a recent study, we reported that the Duke treadmill score was unable to effectively stratify elderly patients according to risk. The purpose of this study was to evaluate the prognostic value of exercise single-photon emission computed tomography (SPECT) in this same population and to examine results by gender.

Methods and Results—

A cohort of 247 elderly (age ≥75 years) patients (108 women, 139 men, age 77±3 years) who underwent exercise thallium-201 SPECT were followed up for a median duration of 6.4 years. SPECT variables were significantly associated with cardiac death: summed stress score (SSS) χ
2
=19.5,
P
<0.001; summed difference score χ
2
=12.3,
P
<0.001; increased lung uptake χ
2
=9.6,
P
=0.002; and left ventricular enlargement χ
2
=8.3,
P
=0.004. The Duke score was not significantly associated with cardiac death (χ
2
<1,
P
=NS). The SSS classified most patients as low risk (49%) or high risk (35%); the Duke score classified the majority (68%) as intermediate risk. Annual cardiac mortality rates for patients categorized by SSS as low risk and high risk were 0.8% and 5.8%, respectively. Cardiac survival rates according to SSS risk categories were significantly different for both women (
P
=0.012) and men (
P
=0.003).

Conclusions—

SPECT classified most elderly patients into clinically useful low- and high-risk categories and accurately predicted outcomes in both genders. If these results can be validated in future studies, exercise SPECT rather than standard treadmill testing may emerge as the initial noninvasive testing strategy in elderly patients who are able to exercise.
Activation of the Unfolded Protein Response Occurs at All Stages of Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice
Authors: Zhou Ji , Lhoták Šárka , Hilditch Brooke A. , Austin Richard C.
Published: April 2005

Background—

Apoptotic cell death contributes to atherosclerotic lesion instability, rupture, and thrombogenicity. Recent findings suggest that free cholesterol (FC) accumulation in macrophages induces endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and apoptotic cell death; however, it is not known at what stage of lesion development the UPR is induced in macrophages or whether a correlation exists between UPR activation, FC accumulation, and apoptotic cell death.

Methods and Results—

Aortic root sections from apolipoprotein E–deficient (apoE
−/−
) mice at 9 weeks of age (early-lesion group) or 23 weeks of age (advanced-lesion group) fed a standard chow diet were examined for markers of UPR activation (GRP78, phospho-PERK, CHOP, and TDAG51), apoptotic cell death (TUNEL and cleaved caspase-3), and lipid accumulation (filipin and oil red O). UPR markers were dramatically increased in very early intimal macrophages and in macrophage foam cells from fatty streaks and advanced atherosclerotic lesions. Although accumulation of FC was observed in early-lesion–resident macrophage foam cells, no evidence of apoptotic cell death was observed; however, UPR activation, FC accumulation, and apoptotic cell death were observed in a small percentage of advanced-lesion–resident macrophage foam cells.

Conclusions—

UPR activation occurs at all stages of atherosclerotic lesion development. The additional finding that macrophage apoptosis did not correlate with UPR activation and FC accumulation in early-lesion–resident macrophages suggests that activation of other cellular mediators and/or pathways are required for apoptotic cell death.
Effect of Intensive Lipid Lowering, With or Without Antioxidant Vitamins, Compared With Moderate Lipid Lowering on Myocardial Ischemia in Patients With Stable Coronary Artery Disease
Authors: Stone Peter H. , Lloyd-Jones Donald M. , Kinlay Scott , Frei Balz , Carlson William , Rubenstein Joel , Andrews Thomas C. , Johnstone Michael , Sopko George , Cole Holly , Orav John , Selwyn Andrew P. , Creager Mark A.
Published: April 2005

Background—

Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia.

Methods and Results—

In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with ≥1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from ≈153 mg/dL at baseline in the 2 atorvastatin groups to ≈83 mg/dL at 12 months (each
P
<0.0001) and from 147 to 120 mg/dL in the control group (
P
<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each
P
<0.001;
P
=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each
P
<0.001;
P
=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes.

Conclusions—

Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.