Obesity & Antioxidants (Phytotherapy Research)

To develop a therapeutic agent for obesity-related metabolic disorders, a mixture of dietary components was prepared, including grape extract, green tea extract and l-carnitine (RGTC), and its effects on obesity, hyperlipidemia and non-alcoholic fatty liver disease examined. The RGTC dramatically inhibited the high-fat diet (HFD)-induced increase in body weight and fat in C57BL/6 mice, whereas food consumption was not affected by RGTC treatment. The RGTC also concentration-dependently suppressed the HFD-induced increase in plasma lipids, such as low-density lipoprotein cholesterol and triglycerides. In addition, increases in liver weight and liver steatosis were returned to normal by RGTC treatment in HFD-fed C57BL/6 mice. The plasma levels of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase were also significantly down-regulated by RGTC treatment. These results suggest that RGTC suppressed HFD-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease, suggesting that RGTC supplementation might be a promising adjuvant therapy for the treatment of these metabolic disorders.

Kang, J. S., Lee, W. K., Yoon, W. K., Kim, N., Park, S.-K., Park, H. K., Ly, S. Y., Han, S.-B., Yun, J., Lee, C. W., Lee, K., Lee, K. H., Park, S.-K. and Kim, H. M. (2011), A Combination of Grape Extract, Green Tea Extract and l-Carnitine Improves High-fat Diet-induced Obesity, Hyperlipidemia and Non-alcoholic Fatty Liver Disease in Mice. Phytotherapy Research, 25: n/a. doi: 10.1002/ptr.3476

OBJECTIVE: The objective of this study was to determine the efficacy and safety of Curcuma domestica extracts in pain reduction and functional improvement in patients with knee osteoarthritis.

C. domestica extracts seem to be similarly efficacious and safe as ibuprofen for the treatment of knee OA. 
  • It’s a natural liver detoxifier.
  • It is a potent natural anti-inflammatory and helpful in treating arthritis and rheumatoid arthritis.
  • Turmeric may aid in fat metabolism and help in weight management.
  • Studies indicate that turmeric may help in preventing prostate and breast cancer, and may prove helpful in reducing the risk of childhood leukemia. Other studies show that turmeric may be helpful in preventing metastases from occurring in different types of cancer and may stop the growth of new blood vessels in tumors.
  • It may prevent and slow the progression of Alzheimer’s disease by removing amyloid plaque buildup in the brain.
  • It’s a natural antiseptic and antibacterial agent – useful in disinfecting cuts and burns.
  • Turmeric has shown promise in slowing the progression of multiple sclerosis in mice.
  • It may help in the treatment of psoriasis and other skin conditions.
  • It speeds up wound healing and assists in repair of damaged skin.
  • Turmeric may lower cholesterol.

Turmeric is an excellent source of both iron and manganese. It is also a good source of vitamin B6, dietary fiber and potassium. Plus, turmeric is a beneficial or neutral for every blood group, secretor or non-secretor, and a super-beneficial for cancer protection! In this issue of the newsletter, you’ll find several recipes that include turmeric, making getting this delicious, sunny spice, super easy to include in your diet.

Strawberries Help Neural Growth, Decrease Inflammation, Prevent Kidney Damage, and More (Dr. Amen)

Previously, the lab showed that fisetin promoted neural growth, and enhanced memory in healthy mice. Fisetin can target multiple organs which means that a single drug using this ingredient could  help with a variety of medical complications. This was the first drug to prevent both kidney and brain complications in a mouse with type 1 diabetes.

Pam Maher, Ph.D., a senior staff scientist in the CNL, is the study’s corresponding author. Maher initially identified fisetin as a flavonoid that protects neurons ten years ago. “In plants, flavonoids act as sunscreens and protect leaves and fruit from insects,” she explains. “As foods they are implicated in the protective effect of the ‘Mediterranean Diet.’”

Mice fed a fisetin-enriched diet remained diabetic, but acute kidney enlargement that was seen in other mice was reversed, and high urine protein levels, a sure sign of kidney disease, fell. Interestingly the fisetin seemed to have an anti-anxiety effect on the diabetic mice as well, calming them in situations where mice tend to show anxiety.Fisetin enriched diets also help lower inflammation thought to promote some cancers in the body. 


Children Getting Too Many Scans (Medscape)

A study in the April issue of the journal Radiology[1] revealed that the number of CT scans performed on pediatric patients in the emergency department (ED) has increased fivefold over a 13-year period ending in 2008. This pattern essentially duplicates what has happened with CT scans for adult patients in the ED.

The findings raised questions about CT use and radiation exposure in radiosensitive children, issues that were debated extensively in the media. Scratch the surface, though, and you will find that multiple efforts are underway to ensure not only appropriate use of CT in pediatric patients but also that those scans are conducted at the lowest dose rates possible.

That CT scan rates have risen for pediatric populations should not be surprising. The modality has seen tremendous technological advancements over the past dozen years and offers decided advantages in scanning children.

“The main driver is, frankly, that CT is an amazing technology,” said Marilyn Goske, MD, a pediatric radiologist at Cincinnati Children’s Hospital Medical Center. “Thirty years ago, we couldn’t see inside the brain. Now, we can do a child’s body in half a second. We have technology that gives us exquisite imaging and we don’t need to sedate the child. We can have a definitive answer.”

That level of accuracy has improved the quality of pediatric care, making procedures such as exploratory surgery for tumors and staging laparotomies for lymphoma are no longer necessary, Dr. Goske added.

Donald Frush, MD, a pediatric radiologist at Duke University Health System, echoes this point. Twenty years ago, he noted, the accepted false-negative rate for laparotomies for appendicitis was 30%; with the availability of CT, the false-negative rate has dropped to the 5%-7% range.

Heightened concerns about pediatric radiation exposure from medical scans have led to increased awareness among patients and physicians. One of the most visible manifestations of this has been the Image Gently™ campaign,[2] a multiorganizational drive to change practice by increasing opportunities to lower radiation dose in the imaging of children. The Image Gently campaign, now 3 years old, counts among its supporters dozens of organizations throughout the world. According to Dr. Frush, preliminary data from an ongoing survey of non-pediatric-focused practices in the United States found that approximately 50%-70% of respondents said information from the Image Gently campaign prompted them to lower their dose rates for CT in children.

David Larson, MD, MBA, Assistant Professor of Radiology at Cincinnati Children’s Hospital, and the lead investigator in the pediatric utilization growth study, said the Image Gently campaign is prompting more questions from patients and physicians. “Patients are checking to make sure we are adjusting dose, and other radiology practices are making inquiries about how to adjust dose,” he said. (CT Use and Radiation Exposure in Children. Medscape Radiology. John C. Hayes. Posted: 06/17/2011).

‘Global Trigger Tool’ Shows that Adverse Events in Hospitals May Be Ten Times Greater Than Previously Measured.  [Link]
 (Health Aff (Millwood). 2011 Apr;30(4):581-9).
Identification and measurement of adverse medical events is central to patient safety, forming a foundation for accountability, prioritizing problems to work on, generating ideas for safer care, and testing which interventions work. We compared three methods to detect adverse events in hospitalized patients, using the same patient sample set from three leading hospitals. We found that the adverse event detection methods commonly used to track patient safety in the United States today-voluntary reporting and the Agency for Healthcare Research and Quality’s Patient Safety Indicators-fared very poorly compared to other methods and missed 90 percent of the adverse events. The Institute for Healthcare Improvement’s Global Trigger Tool found at least ten times more confirmed, serious events than these other methods. Overall, adverse events occurred in one-third of hospital admissions. Reliance on voluntary reporting and the Patient Safety Indicators could produce misleading conclusions about the current safety of care in the US health care system and misdirect efforts to improve patient safety.

The women who had the highest intake of calcium (above 1100 mg a day) actually had a hint of increased risk for hip fracture. The bottom line of this study was that more moderate levels of calcium intake were best for bone health and that more was not better. We should be recommending more moderate intakes of calcium for our patients and not above the RDA of 1000-1200 mg a day total. Assuming that many women will get about 700 mg a day from dietary sources alone, many women may require no more than an additional 500-600 mg a day from calcium supplements. In contrast, many women are taking a very high dose of calcium, often 1200-1500 mg a day just from the supplements alone, and this could lead to very high total intake.

The Problem with the New Plate (Dr. Mercola)

Mercola argues, where’s the healthy fat, discussion of trans-fats, organic, non-pasteurized dairy, and quality carb discussion?

Check Your “Greens”-Household Products That Is! (Dr. Mercola)

According to this Material Data Safety Sheet for Simple Green, as reported by GreenMedInfo, the “green” cleaner Simple Green also contains the petrochemical solvent 2-Butoxyethanol. Simple Green claims to be non-toxic, non-hazardous, and biodegradable … yet it contains a chemical that, in animal studies, has been shown to destroy red blood cells and cause reproductive problems and minor birth defects. As for further health effects, absolutely no studies on carcinogenicity have been conducted in people or animals, so it’s not known whether the chemical causes cancer.

Another Stike on Aspartame (Am. J. Ind. Med. 53:1197-1206, 2010.)

BACKGROUND: Aspartame (APM) is a well-known intense artificial sweetener used in more than 6,000 products. Among the major users of aspartame are children and women of childbearing age. In previous lifespan experiments conducted on Sprague-Dawley rats we have shown that APM is a carcinogenic agent in multiple sites and that its effects are increased when exposure starts from prenatal life.

OBJECTIVE:The aim of this study is to evaluate the potential of APM to induce carcinogenic effects in mice.

METHODS: Six groups of 62-122 male and female Swiss mice were treated with APM in feed at doses of 32,000, 16,000, 8,000, 2,000, or 0 ?ppm from prenatal life (12 days of gestation) until death. At death each animal underwent complete necropsy and all tissues and organs of all animals in the experiment were microscopically examined.

RESULTS: APM in our experimental conditions induces in males a significant dose-related increased incidence of hepatocellular carcinomas (P?<?0.01), and a significant increase at the dose levels of 32,000 ?ppm (P?<?0.01) and 16,000? ppm (P?<?0.05). Moreover, the results show a significant dose-related increased incidence of alveolar/bronchiolar carcinomas in males (P?<?0.05), and a significant increase at 32,000 ?ppm (P?<?0.05).

CONCLUSIONS: The results of the present study confirm that APM is a carcinogenic agent in multiple sites in rodents, and that this effect is induced in two species, rats (males and females) and mice (males). No carcinogenic effects were observed in female mice. © 2010 Wiley-Liss, Inc.PMID: 20886530

Mercury Free Denistry in Process (Dr. Mercola)

Most recently, the U.S. State Department has called for a “phase down” of mercury fillings, followed by an “eventual” phase out. The State Department’s submission to the Mercury International Negotiation Committee also called for:

  • Educating patients and parents (about amalgam) in order to protect children and fetuses
  • Training of dental professionals on the environmental impacts of mercury in dental amalgams
  • This is an incredible turn of events that brings us one step closer to mercury-free dentistry for all, although even though the FDA signed on to this statement internationally, they have yet to change the rule at home, so U.S. support is still needed. Similarly, on the Canadian front, your help is urgently needed.

Is HDL the Answer to Protecting High Cholesterol? (Dr. Dean Ornish)

Many people, including most physicians, believe that HDL is “good cholesterol” and LDL is “bad cholesterol.” Therefore, anything that raises HDL cholesterol is good.

It’s not so simple. Not everything that raises HDL is good, and not everything that lowers it is bad.
Think of HDL like the garbage trucks of your body. Your body makes HDL to remove excessive cholesterol from your blood and tissues, a process known as “reverse cholesterol transport.” HDL transports cholesterol back to your liver where it is metabolized and removed from your body.

Most Americans eat a diet that’s relatively high in saturated fat, animal protein, and cholesterol–i.e., a lot of “garbage.” Those people who have a lot of garbage trucks–in other words, who have high HDL levels–are more efficient at getting rid of extra fat and cholesterol in their diet.

Your body’s ability to make more garbage trucks (raise your HDL) is, in part, genetically determined. Some people can make more garbage trucks than others. As a result, they have a lower risk of a heart attack or stroke than those who eat a high-fat, high-cholesterol diet who have lower HDL levels.

However, the relationship of HDL to risk of heart disease and stroke assumes that people are not changing their diet or drugs. This relationship was first noticed in Framingham, a town outside of Boston in which most people ate a high-fat, high-cholesterol diet. Those people who had higher HDL levels had lower rates of heart disease than those with lower HDL levels. More garbage trucks, less garbage left behind.

To Screen or Not Screen? Mammography (Cochrane Database Syst Rev. 2011;1:CD001877. )

Screening is likely to reduce breast cancer mortality. As the effect was lowest in the adequately randomised trials, a reasonable estimate is a 15% reduction corresponding to an absolute risk reduction of 0.05%. Screening led to 30% overdiagnosis and overtreatment, or an absolute risk increase of 0.5%. This means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress for many months because of false positive findings. It is thus not clear whether screening does more good than harm. To help ensure that the women are fully informed of both benefits and harms before they decide whether or not to attend screening, we have written an evidence-based leaflet for lay people that is available in several languages on  

 Traces of GM Pesticides Found in Pregnant Women (Vitalchoice)

The Canadian doctors took blood samples from 30 pregnant women and from 39 non-pregnant women.Blood tests found traces of the two synthetic herbicides used with GM crops – glyphosate and gluphosinate – or a breakdown product of gluphosinate (3-MPPA) in the pregnant and non-pregnant women alike. Fortunately, the levels of gluphosinate found in this study (53.6ng/ml) were much lower than the doses that produced harm in mouse tests (10ug/ml).

Traces of Bt CRY protein were detected in pregnant and non-pregnant women and in umbilical cords. Specifically, traces of Bt CRY protein were found in the blood of 27 out of 39 non-pregnant women (69 percent). In the pregnant group, Bt CRY protein was found in the blood of 28 out of 30 women (93 percent). And Bt CRY protein was found in 24 out of 30 umbilical cords (80 percent). Thus, Bt CRY protein crossed the umbilical barrier. It’s presumed that the synthetic herbicides and the Bt CRY protein both came from eating GM crops and from meat, milk, and eggs from livestock fed GM crops. As the Canadian team wrote, “This is the first study to highlight the presence of pesticides associated with genetically modified foods in maternal, fetal and non-pregnant women’s blood.” (Aris A, Leblanc S 2011)

Moisturizing Creams Increase Tumor Growth (J Invest Dermatol. 2009 February; 129(2): 468–475)

Irradiation of SKH-1 mice with UVB (30 mJ cm?2) twice a week for 20 weeks resulted in mice with a high risk of developing skin tumors over the next several months in the absence of further irradiation with UVB (high-risk mice). Topical applications of 100 mg of Dermabase, Dermovan, Eucerin Original Moisturizing Cream (Eucerin), or Vanicream once a day, 5 days a week for 17 weeks to these high-risk mice increased significantly the rate of formation of tumors and the rate of increase in tumor size per mouse. Additional studies indicated that treatment of high-risk mice with Dermabase, Dermovan, Eucerin, or Vanicream for 17 weeks increased the total number of histologically characterized tumors by 69% (average of two experiments; P < 0.0001 in each experiment), 95% (P < 0.0001), 24% (P < 0.01), and 58% (P < 0.0001), respectively. Topical applications of a specially designed Custom Blend cream to high-risk mice was not tumorigenic.

Dead jellyfish release especially high levels of carbon, which the bacteria cannot absorb well, and instead breathe out as carbon dioxide, putting more CO2 into the seas and atmosphere.

Dr Carol Turley, a scientist at the UK’s Plymouth University, said the research highlighted the growing problem of ocean acidification … the so-called “evil twin” of global warming.

 “Oceans have been taking up 25% of the carbon dioxide that man has produced over the last 200 years, so it’s been acting as a buffer for climate change. When you add more carbon dioxide to sea water it becomes more acidic. And already that is happening at a rate that hasn’t occurred in 600 million years.”

As Turley says, “The acidification of the oceans is already predicted to have such a corrosive effect that unprotected shellfish will dissolve by the middle of the century.”

The shellfish affected by increasing ocean acidity include krill and other “zooplankton” in the crustacean family, which are critical to the ocean food web … especially salmon and whales.

Drug Updates:

FDA Posts Warning on Multaq (atrial fibrillation drug) (Webmd)

July 22, 2011 — If you’re taking the atrial fibrillation drug Multaq, the FDA wants you to call your doctor right away. Don’t stop taking the drug — that could be dangerous. But the FDA wants patients to be aware that a clinical trial of Multaq, called PALLAS, was halted when the drug doubled the risk of death, stroke, and heart failure hospitalization in heart patients with permanent atrial fibrillation.

Multaq is approved to treat paroxysmal atrial fibrillation (intermittent), persistent atrial fibrillation, or atrial flutter. The big question — now the subject of an FDA investigation — is exactly how the PALLAS findings apply to current patients.

Use of Mist Inhaler for COPD Carries Higher Mortality Rate ( Medscape. Jim Kling)

June 15, 2011 — Patients using tiotropium via a mist inhaler for chronic obstructive pulmonary disease (COPD) have a 52% higher risk for all-cause mortality compared with placebo, according to a meta-analysis published online June 14 in the British Medical Journal.

Diabetic Drug Linked to Bladder Cancer, France Pulls, Still in US (Medscape. June 10, 2011. TZD or not to TZD? That is the question. Mintz, M. MD.

Today, as reported by several media outlets, Germany followed France by suspending the marketing of Actos (pioglitazone) due to concerns of bladder cancer.  Like Avandia (rosiglitazone), Actos is in the class of medications known as the thiazolidinediones commonly referred to as TZD’s.  TZD’s have been found to be useful in the treatment of type 2 diabetes, but have come under scrutiny recently.  Most of the attention has surrounded Avandia due to concerns of increased myocardial infarction.  Back in July, the FDA severely restricted the use of Avandia.  Though the data on cardiovascular risk is limited and therefore controversial the consensus from the FDA’s advisory panel was that Actos did not show similar cardiovascular signals seen with Avandia.

More recent concerns about the bladder cancer link stem from a recent report analyzing the FDA’s Adverse Event Reporting System (AERS), which found that 93 cases of cancer were recorded between 2004 and 2009 in patients treated with antidiabetic drugs of which 31 patients were treated with pioglitazone, representing a statistically significant increased risk of bladder cancer (ROR 4.30, 95% CI 2.82-6.52; p<0.001). 

TZD’s have many advantages. As in my previous post, Metformin is first, but what diabetes medicine should be your second choice?, though the safety of the older, generic medications such as metformin and sulfonylurea is well established, most patients on either therapy lose glycemic control as soon as 3 year.  Five year data from the ADOPT study show that TZD’s like Avandia actually sustain glycemic control better than metformin or SU.  In addition, TZD’s have positive beneficial effects on lipids, which may confer cardiovascular benefit as seen in the PROACTIVE study with Actos.  Pioglitazone will also soon go generic, making cost much less of an issue.

On the other hand, TZD’s have risks.  In addition to the CV concerns with Avandia and the new concerns of bladder cancer with Actos, TZD’s via fluid retention can lead to congestive heart failure.  More recently, a clear link has been established between TZD’s and non-vertebral osteoporotic fractures, though the increased risk is small.?

Statin Therapy Decreases Myocardial Function as Evaluated Via Strain Imaging. (Rubinstein J, Aloka F, Abela GS. Clin Cardiol. 2009 Dec;32(12):684-9.)


OBJECTIVES: The purpose of this study was to evaluate the effects of statin therapy on myocardial function as measured with echocardiography with tissue Doppler imaging (TDI) and strain imaging (SI) independent of its lipid-lowering effect.

BACKGROUND: Statin use is known to improve outcomes in the primary and secondary prevention of ischemic heart disease, but their use is also associated with myopathy, muscle weakness and in rare cases, rhabdomyolysis. We sought to evaluate whether TDI and SI is able to identify changes in myocardial function associated with statin use.

CONCLUSION: Statin therapy is associated with decreased myocardial function as evaluated with SI.

Statins Cause Diabetes (Dr. Hyman)

The latest cholesterol guidelines (ATP III) increased the number of Americans who should take statin therapy from 13 to 40 million.  Those additional 27 million are ones without heart disease, but who have high cholesterol.  This type of treatment is called primary prevention.  I have extensively reviewed the research on using statins to prevent heart attacks in people who never had them.  The data is weak and shows no benefit, except the Jupiter trial, which ONLY showed benefit if patients also had inflammation (high C-reactive protein), not just high cholesterol or LDL.   If you just had an elevated cholesterol, statins didn’t help.

I have previously written about research that showed that statins increase the risk of diabetes. This latest study examined five major clinical trials on statins including 32,752 non-diabetics over 4.9 years.  During the study period 2,749 patients (or 8.4 percent) developed diabetes.  Those on the highest doses of statins (which are increasingly prescribed by physicians) were at the highest risk of developing diabetes. (The Lancet, Volume 376, Issue 9753, Pages 1658 – 1669, 13 November 2010 doi:10.1016/S0140-6736(10)60310-8).

Statins and Diabetes (Dr. Mercola)

The meta-analysis, published in JAMA in June, concluded that those taking higher doses of statins were at increased risk of diabetes compared to those taking moderate doses. What this means is that the higher your dose, the higher your risk of developing diabetes.

The “number needed to harm” for intensive-dose statin therapy was 498 for new-onset diabetes—that’s the number of people who need to take the drug in order for one person to develop diabetes. In even simpler terms, one out of every 498 people who are on a high-dose statin regimen will develop diabetes. (The lower the “number needed to harm,” the greater the risk factor is.)

(As a side note, the “number needed to treat” per year for intensive-dose statins was 155 for cardiovascular events. This means that 155 people have to take the drug in order to prevent one person from having a cardiovascular event.)

The following scientific reviews also reached the conclusion that statin use is associated with increased incidence of new-onset diabetes:

  • A 2010 meta-analysis of 13 statin trials, consisting of 91,140 participants, found that statin therapy was associated with a 9 percent increased risk for incident diabetes. Here, the number needed to harm was 255 over four years, meaning for every 255 people on the drug, one developed diabetes as a result of the drug in that period of time.
  • In this 2009 study, statin use was associated with a rise of fasting plasma glucose in patients with and without diabetes, independently of other factors such as age, and use of aspirin, ?-blockers, or angiotensin-converting enzyme inhibitors. The study included data from more than 345,400 patients over a period of two years.On average, statins increased fasting plasma glucose in non-diabetic statin users by 7 mg/dL, and in diabetics, statins increased glucose levels by 39 mg/dL.

Lowering of LDL cholesterol reduces major vascular events, but whether more intensive therapy safely produces extra benefits is uncertain. We aimed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk.MethodsWe undertook a double-blind randomised trial in 12 064 men and women aged 18—80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not. Randomisation to either 80 mg or 20 mg simvastatin daily was done centrally using a minimisation algorithm. Participants were assessed at 2, 4, 8, and 12 months after randomisation and then every 6 months until final follow-up. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN74348595.Findings6031 participants were allocated 80 mg simvastatin daily, and 6033 allocated 20 mg simvastatin daily. During a mean follow-up of 6·7 (SD 1·5) years, allocation to 80 mg simvastatin produced an average 0·35 (SE 0·01) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg. Major vascular events occurred in 1477 (24·5%) participants allocated 80 mg simvastatin versus 1553 (25·7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0·94, 95% CI 0·88—1·01; p=0·10). There were no apparent differences in numbers of haemorrhagic strokes (24 [0·4%] vs 25 [0·4%]) or deaths attributed to vascular (565 [9·4%] vs 572 [9·5%]) or non-vascular (399 [6·6%] vs 398 [6·6%]) causes. Compared with two (0·03%) cases of myopathy in patients taking 20 mg simvastatin daily, there were 53 (0·9%) cases in the 80 mg group.InterpretationThe 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens.FundingMerck; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation.