Award winning research at the Dutch Atherosclerosis Symposium, 2009

The years to come are going to be very busy for persons working in the field of atherosclerosis and cardiovascular disease. Basic-science researchers are hot on the trail of targeted drugs that will be much more focused than available drugs, and some remarkable progress is being made. The 12th Dutch Atherosclerosis Symposium took place on March 12 and 13, 2009 and showcased some of this progress taking place in the Netherlands. I would like to briefly present 4 of the interesting research topics that received jury awards.

Exercise
Meissner et al.1 investigated the effect of exercise on cholesterol metabolism in mice either exposed to voluntary running wheel for 2 weeks or which remained sedentary. Exercise appears to increase cholesterol and bile acids turnover via specific changes in the intestine that decrease intestinal bile acid and cholesterol absorption and promote their fecal excretion. If the same holds true in humans, exercised-induced modulation of bile acids and cholesterol turnover leading to reduced plasma cholesterol levels might contribute to the beneficial effects of exercise on cardiovascular disease.

Cathepsin inhibition
The research aim of Waard et al.2 is to develop pharmaceutical therapies for abdominal aortic aneurysm to prevent surgical intervention in elderly patients. They have previously shown that cathepsins are functionally involved in collagen degradation in human aneurysm tissue. In the present study they showed that E64 (a cathepsin inhibitor) treatment resulted in a decreased number and severity of aneurysms and in a less inflammatory profile in serum in a mouse model. The inhibition of cathepsins may be therefore an attractive therapeutic approach to prevent aortic aneurysms expansion.

Microarray antigen chip
The immune system is thought to play an important role in initiation and progression of atherosclerosis. Den Dekker et al.3 aimed to explore the potential of auto-antibody profiles as a biomarker for a cardiovascular event. A generic version of the antigen microarray was used bearing over 740 proteins related to a variety of conditions including immune regulation, inflammation, angiogenesis, apoptosis and more. The antigen microarray was able to identify patients with previous myocardial infarction with a high sensitivity and specificity. In conclusion, a microarray antigen chip may be used as a novel biomarker for cardiovascular disease.

Nuclear receptor Nurr1
Bonta et al.4 have investigated the role of nuclear receptor Nurr1 in stent restenosis. They found that Nurr1 is expressed in human in-stent restenosis lesions. Nurr1 inhibits inflammatory gene expression in both macrophages and smooth muscle cells and it inhibits proliferation of smooth muscle cells. In vivo Nurr1 reduces neointima formation in mice. Small-molecule drugs have been identified that enhance the transcriptional activity of this nuclear receptor. It seems therefore that Nurr1 may be an attractive novel target for local intervention against in-stent neointima formation.

Comment
Genetics and biochemistry have now become the unchallenged leaders of cardiovascular research. New drugs to be soon perfected together with the immense progress in the invasive field will completely change the cardiology that we all knew.

By: Sandrin C. Bergheanu, MD, Dept. of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (s.c.bergheanu@lumc.nl)

References

1. Maxi Meissner et al., Department of Pediatrics, University Medical Center Groningen, The Netherlands. E-mail: M.Meissner@med.umcg.nl

2. Vivian de Waard et al. Division of Biopharmaceutics of the Leiden/Amsterdam Center for Drug Research, Leiden and Department of Medical Biochemistry, AMC, Amsterdam, The Netherlands. E-mail: v.dewaard@amc.uva.nl

3. Wijnand den Dekker et al. Molecular Cardiology Laboratory, Erasmus Medical Center Rotterdam, The Netherlands.

4. Peter Bonta et al. Department of Medical Biochemistry, Academic Medical Center Amsterdam, The Nertherlands. E-mail: P.I.Bonta@amc.uva.nl

Open repositories VS the Publisher

On March 18th the MIT introduced a policy requiring all scholarly articles written by its faculty members to be made freely available in an open access repository. While researchers understandably applaud the free and open dissemination of data, there are questions that should be considered with regards to the impact of a growing number of open repositories on the value added by Publishers, and how this value would be retained if in the long term the open access journal turns out to be unsustainable.

How important is the value added by the Publisher (and this is not an open access versus non-open access journal debate)? While the peer review process is certainly not without its failings, to any Publisher or Editor worth their salt, the integrity of the peer review process is paramount. To quote a previous blog post on this site, an author of a CMRO article on receiving his peer review comments said "I have never received 58 referee comments on a manuscript less than 3000 words long, but the referees' comments and the revision definitely improved the paper." An author of a recent paper submitted to Expert Opinion on Medical Diagnostics fed back "a comment about the reviewers: it was clear that they read the manuscript carefully. Regardless of whether they agreed with some of our arguments, their comments reflected readers that thought about what they read. This is how peer review is supposed to work. Excellent reviewer selection on your part, and a thorough job on theirs." Aside from assisting the author in critically reviewing their work and ultimately leading to a better paper, without the peer review process how do we ensure no dangerously inaccurate information is published that is indistinguishable from high calibre scientific research?

And it’s not just in the peer review that value is added by the Publisher. Who checks references are cited correctly and terms are not misspelled - will the institutions running their own open access repositories employ copyeditors? Who will ensure the figures are legible and of good quality – will the institutions employ production editors who lay the work out in such a way that it is easy on the eye and doesn’t give readers a headache? Will there be any independent quality check before the research is published? With a limitless amount of potentially unqualified freely available literature, how will the busy physician who only has 5 minutes in his/her day to digest the most important findings even know where to start? These are just a few of the questions that would need to be answered.

Ok, I’m playing devil’s advocate a little here. I do not envisage a world where the peer-reviewed journal ceases to exist, but the open access model of publishing is widely debated, both in terms of quality and sustainability. So what is the future of publishing? Even if the open access, pay to publish model is viable in the long term, does the scientific community agree to paying to publish all of their work in the future, rather than pay to read the work of others? The fact is, publishing a journal is a costly business and the money has to come from somewhere. Publishers are accused of placing scientific research behind ‘commercial barriers’, but surely the same argument could be applied to the pay to publish model. Is it fair that only authors with funding can afford to have it published? Will this lead to a bias in the literature towards sponsored research, not even so much through the choices of the Editor, but through the fact that only authors who can pay can publish? Or is there an alternative, free to publish, free to read, sustainable model for open access publishing that still maintains high standards of peer review and editorial quality?

While Publishers undoubtedly need to take steps to ensure the advancement of science through the widest possible dissemination of research, with respect to the whole principal of open access, how do we do this for free? Surely someone, somewhere has to pay something?

In summary:

• How important is value added by the Publisher?
• How will high calibre research be distinguished?
• How will the reader filter the wealth of freely available literature?
• Does the scientific community want to pay to publish all of their work in the future?
• Could this lead to bias in the literature?
• What if the pay to publish model doesn't work?
• Is there an alternative, free to publish, free to read, sustainable model for open access publishing that still maintains high standards of peer review and editorial quality?

By Anna Heinink, Publisher, Expert Opinion

Informa Pharmaceutical Science’s policy on NIH-funded research can be found here http://www.informapharmascience.com/page/resources/authors#nihfundedresearch

Reuben’s Research: A Pain In The Analgesia

Research on multimodal analgesia took a hit when one of its leading proponents, Scott S. Reuben, MD – aka the Medical Madoff - was caught fudging his data. Baystate Medical Center’s internal review board launched a full-fledged investigation into Reuben’s work last May when he appeared to be conducting studies on humans without approval. The investigation, completed in January, uncovered some 21 published articles—dating as far back as 1996—in which Reuben made up some or all of the data. Baystate's chief academic officer is quoted as saying that in many cases, "there was no clinical trial because there were no patients." Whew!

At least it looks like nobody got hurt. But the incident raises questions in our industry that beg for answers:

Where Were The Peer Reviewers? In my opinion, that’s an unfair question some people are asking. Peer reviewers, and editors for that matter, can only work with the data they’re given. We can’t be expected to show up on every study site to make sure a prospective author’s data is pure before we decide to accept it for publication.

Why did it take 13 years to catch him? We can only speculate on why it took so long to uncover Reuben’s fraud, but it may have been because, like the Piltdown Man, nobody was taking his research all that seriously—nobody else could replicate his findings. Replication, albeit slow, is the surest way to keep fraud in check.

What was Industry’s role? Outside of partially funding some of Reuben’s research—and there’s nothing inherently wrong with that--Pfizer is not suspected of any wrongdoing. However, Reuben’s relationship with Pfizer, at least in the papers I was able to fully access, was not properly disclosed in most cases.

Would full disclosure have mattered? I think so. Knowing the financial ties an author has to a study’s sponsor alerts readers to the potential for biased results.

What Can Be Done About It? Reuben’s case is every Editor’s worst nightmare. Patient care is ultimately affected by erroneous data. While CMRO has never published a Reuben paper, something like this could happen to us. But rest assured that we are doing everything within our power to prevent such a thing from happening.

All CMRO articles undergo such a stringent peer review process that caused one author recently to say, “I have never received 58 referee comments on a manuscript <3000 words long, but the referees' comments and the revision definitely improved the paper.” We will also be introducing new measures soon to stay at the forefront of ethical publishing - keep your eyes open for more news soon.

By Terri Metules, US Deputy Managing Editor, Current Medical Research and Opinion

Further Reading

Good publication practice guidelines for medical communications agencies: a MedComm perspective Bareket-Samish et al. CMRO 2009;25(2):453-61

Working with compliance - the role of healthcare communications agencies Cairns & Yarker CMRO 2008; 24(5): 1371-78

International Society for Medical Publication Professionals (ISMPP) Position Statement Norris et al. CMRO2007 23(8): 1837-40

‘JUPITER’ and the risk of heart disease

Statins are blockbuster drugs taken by millions around the world. Results from the ‘JUPITER’ clinical trial[1] indicate that these cholesterol-lowering agents could decrease the risk of heart disease even for persons with low cholesterol levels; meaning that millions more could benefit from popping a statin pill…

But could they really? What indicators and risk factors dictate the prescription of statins? How should vascular risk be measured? And what are the factors that count towards this risk? An Editorial in the January 2009 issue of CMRO discusses the JUPITER study and explores these interesting themes.

The trial suggests that hsCRP, a protein associated with inflammation, can be used to identify subjects without vascular disease who should receive statins despite a low or intermediate calculated risk. The CMRO editorial highlights the fact that risk assessment needs to be re-examined, and discusses the role of hsCRP-testing in what the authors call risk stratification. The authors also feel that guidelines (and clinical practice) may need changing if indeed statins do have a much wider role in preventing vascular disease than was previously thought.

Of course, if relatively healthy persons (‘low or intermediate risk’) are to be prescribed statins, then there are terrific cost implications too. The authors of the editorial remark that this is all the more so if the benefits observed from taking Crestor (used in the JUPITER trial) can not be reproduced by cheaper, generic statins.

At the heart of the ongoing scientific debate, the fundamental question remains: do statins have a convincing role in primary prevention of heart disease? Read the editorial (an open access article) here find out what the authors think.

[1] JUPITER: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

Profile: Dimitri Mikhailidis

It seems appropriate that our first profile for the Informa Pharmaceutical Science blog should feature Dr. Dimitri P. Mikhailidis. Dimitri is currently Editor-In-Chief of four journals published by Informa Pharmaceutical Science: Expert Opinion on Investigational Drugs, Expert Opinion on Therapeutic Targets, Expert Opinion on Pharmacotherapy, and Current Medical Research and Opinion. Beyond Dimitri's editorial role, he has been an author on numerous original research articles, reviews, and editorials, with over 60 published articles in Expert Opinion and CMRO since 2000. Lest we give the impression that Dimitri favours our journals over others click here to see his 600+ Pubmed listings.

Dimitri is currently the Academic Head & Honorary Consultant to the Department of Clinical Biochemistry at the Royal Free University College Medical School, University College London, and he holds Visiting Professor positions at Robert Gordon University (Scotland) and University of Ioannina Medical School (Greece). Dimitri has travelled widely to present his research, having lectured in 40 countries around the world. Beyond the editorial posts he holds with the Informa Pharmaceutical Science journals, Dimitri is also Editor-in-Chief of four other medical journals, and holds other editorial positions with several more. And sometimes, apparently, he eats and sleeps, although we have no empirical evidence to support this claim.

Research by Dimitri and his network of collaborators primarily focuses on treatment and prevention of cardiovascular disease, and Dimitri was awarded the British Medical Association (BMA) award for vascular research in 1995. His articles cover a broad spectrum of topics: many are written with an eye towards utility for current clinicians, some cast needed attention on new promising therapies in the drug development pipeline, while still others focus on future directions for research in cardiovascular disease. A notable recent paper published in EOP, authored by Dimitri and his colleague Martin Press from the Royal Free Hospital, reviewed the importance of targeting multiple risk factors, including both traditional and novel cardiometabolic factors, in the prevention of cardiovascular events in patients with type 2 diabetes (available for free download). In another recent publication, an editorial commentary in the March 2008 issue of CMRO, Dimitri and his colleagues present an interesting discussion on how age affects how cholesterol levels can and should be used to predict vascular risk and the implications for elderly patients (available for free download).

Dimitri's most recent article, an editorial in CMRO, is likely to create some waves in the cardiovascular community. The editorial focuses on the growing controversy over the potential danger of abruptly stopping statin use in high-risk patients. Instead of giving away the punchline, read the paper for free here.