Scientists at the Medical Research Council (MRC), UK have identified the structure of the critical enzyme respiratory complex I, solving an important part of the puzzle of how our cells get their energy from food. This discovery will result in new avenues of research into future potential treatments for neuromuscular and neurodegenerative diseases, such as Parkinson’s. An image of this L-shaped enzyme features on the cover of today’s edition of the journal Nature.Respiratory complex I is the first in a set of molecular ‘machines’ in mitochondria that transform energy in food into a form that can be utilized by cells. Mitochondria are the ‘power stations’ inside our cells.

As the first stage for cellular energy production, this enzyme is critical for the continued existence of the majority of cells in our bodies. However, it also creates chemical by-products, such as H2O2 (hydrogen peroxide), a strongly oxidizing liquid which can damage the DNA within the mitochondria. This damage builds up during a human’s life and probably contributes to ageing and to neurodegenerative diseases, such as Parkinson’s.By better understanding exactly how this enzyme works within cells, scientists will be able to identify when and where significant damage is likely to happen, hopefully resulting in new treatment options.

Dr Sazanov and team at the MRC (Medical Research Council) Mitochondrial Biology Unit had previously established the detailed structure of half of this enzyme with its distinctive L-shape. However, it took this most recent study for them to understand fully that its action appears to mimic that of a piston-driven steam engine, using an up and down motion to drive protons or ‘fuel’ across the mitochondrial membrane barrier.

Lead author, Dr Leonid Sazanov said:

“Determining the structure of ‘respiratory complex I’ will help us to better understand how the enzyme works at a fundamental level. Until now this has been a real mystery to researchers in the field, including those working towards limiting the damage to mitochondrial DNA in our cells and curbing the vicious effects of neurodegenerative diseases. As a scientist, I admit that I also find it very satisfying that one of the most efficient and elegant processes in the body bears a striking resemblance to one of the great man-made inventions.

In a previous study, Professor Sir John Walked, Director of the MRC Mitochondrial Biology Unit, had determined that respiratory complex V, or ATP synthase, that carries out the final process in the biological energy production, is a rotary machine that resembles a turbine engine. Professor Walker was awarded the 1997 Nobel Prize in Chemistry for this work.

Copyright: Medical News Today

Mice that are missing a protein involved in the response to low oxygen stay lean and healthy, even on a high-fat diet, a new study has found.

“They process fat differently,” said Randall Johnson, professor of biology at the University of California, San Diego, who directed the research, which is published in the April 15 issue of the journal Cell Metabolism. While their normal littermates gain weight, develop fatty livers and become resistant to insulin on a high fat diet, just like overweight humans do, the mutant mice suffered none of these ill effects.

The protein, an enzyme called FIH, plays a key role in the physiological response to low levels of oxygen and could be a new target for drugs to help people who struggle with weight gain. “The enzyme is easily inhibited by drugs,” Johnson said.

Because the protein influences a wide range of genes involved in development, the scientists were surprised that its deletion improved health.

“We expected them to die as embryos,” said Na Zhang, a graduate student in Johnson’s lab and lead author of the study. “Then we saw they can survive for a long time.”

“From the beginning I noticed that these mice are smaller, but not sick. These mice seem to be healthy,” Zhang said. The lean mice have a high metabolism, and a common check for insulin resistance, a symptom of diabetes, revealed a super sensitivity to insulin.

“We fed the mice with a very high fat diet – 60 percent fat – just to see how they would respond,” Zhang said. “Mutants can eat a lot, but they didn’t gain a lot of weight. They are less fatty around their middles compared with their littermates.”

Obese people develop a “fatty liver,” and so did the wild type littermates. The fat mice also developed high blood cholesterol with elevated levels of the “bad” type, LDL. In lean mutants, LDL increased much less.

“All of these observations support that the modified mice have better metabolic profiles,” Zhang said.

The genetic manipulations disabled the FIH gene entirely. “In every tissue, in every cell, the protein is gone,” Zhang said. But the scientists wanted to know what part of the mouse physiology was responsible for the changes, so they created new mice in which the FIH protein was deleted only in specific tissues: the nervous system or the liver.Mice that were missing FIH only from their nervous system showed most of the same effects. “But if it was only deleted in the liver, then no.” Zhang said.Though smaller, the mutant mice eat and drink 30 to 40 percent more than wild-type mice.

“Where do those calories go? To heat generation and an increased heart rate.” Johnson said. They also breathe heavily compared with normal mice, taking in 20 to 40% more air. “This deep breathing is like exercise for them.”

The FIH protein is part of a wide system that responds to low levels of oxygen. The mice behave as if they are breathing thin air. When people travel to higher altitudes, they breathe heavily for a few days, then adjust by producing more oxygen-carrying blood cells. “These mice never adjust to the apparent low oxygen,” Johnson said. “They stay in this acute phase of hypoxic response their whole lives.”

Co-authors include Zhenxing Fu, DeeAnn Visk, Gabriel Haddad and Frank Powell of the UC San Diego School of Medicine; Sarah Linke and Daniel Peet of the University of Adelaide, Australia; Johana Chicher of the Queensland Institute of Medical Research, Australia; and Lorenz Poellinger, of the Karolinska Institute.

Source:
University of California – San Diego

A large study of over 400,000 people living in ten western European countries found only a modest link between high intake of fruit and vegetables and reduction in overall cancer risk: thus failing to confirm the widely held belief enshrined in the World Health Organization’s recommendation that people should eat five servings of fruit and vegetables a day to prevent cancer and other diseases.Dr Paolo Boffetta, of the Mount Sinai School of Medicine in New York, and colleagues, wrote about their findings in a study published in the 6 April online issue of the Journal of the National Cancer Institute.

In 1990 the World Health Organization recommended people eat five helpings of fruit and vegetables a day to reduce their risk of cancer, cardiovascular and other diseases. But since then, many studies have either produced inconsistent results or failed to find a significant link between fruit and vegetable intake and cancer risk, wrote the authors.For their prospective study, Boffetta and colleagues analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC), which recruited 142,605 men and 335,873 women in Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden and the United Kingdom, between 1992 and 2000.The data was mostly self-reported by the participants and detailed their dietary and lifestyle habits. The participants were followed for a median of 8.7 years, during which time deaths and incidents of cancer diagnoses were noted.

The researchers then analysed the data using Cox regression analysis to find links between diet, lifestyle and cancer risk. Their results showed:

* 9,604 men and 21,000 women received a cancer diagnosis (out of 142,605 men and 335,873 women initially included in the study).

* A “crude” (ie unadjusted) cancer incidence rate of 7.9 per 1000 person-years in men and 7.1 per 1000 person-years in women.

* A modest reduced risk of cancer risk linked to increased intake of total fruit and vegetables (3 per cent), increased vegetable intake (2 per cent, but this was restricted to women only), and increased fruit intake (1 per cent).

* Heavy drinkers who consumed higher amounts of fruits and vegetables showed stronger reductions, but this was confined to cancers related to smoking and alcohol.

The authors concluded that:

“A very small inverse association between intake of total fruits and vegetables and cancer risk was observed in this study. Given the small magnitude of the observed associations, caution should be applied in their interpretation.”

The researchers also noted that participants who ate more fruits and vegetables also tended to consume less alcohol, either never smoked or only for a short time, and were physically more active, and these lifestyle factors could have equally contributed to lower cancer risk.In an accompanying editorial, Dr Walter C. Willett, Chair, Department of Nutrition Fredrick John Stare Professor of Epidemiology and Nutrition at the the Harvard School of Public Health, noted that the study “strongly confirms” the findings of other prospective studies (these follow people over a period of time, but do not compare a treatment group to a control group like they do in clinical trials), that eating more fruit and vegetables has little or no effect on reducing people’s risk of cancer, although it does appear to reduce their risk of cardiovascular disease.

This could be because the study only looked at all fruits and vegetables and all cancers, and Willett suggests that future studies concentrate on the effect of specific types of fruit and vegetables, perhaps on specific cancers, and starting at earlier periods of people’s lives.Experts commenting on the study might argue that while 2 or 3 per cent reduced risk may not seem very significant to individuals, in public health terms it translates to thousands of people not getting cancer by eating more fruit and vegetables.Another, perhaps more indirect argument, is that since we already know that obesity increases cancer risk, then the more fruit and vegetables we eat, the less chance we have of becoming obese and getting cancer that way because they would displace higher calorie foods in our diet.

“Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition (EPIC).”
Paolo Boffetta, Elisabeth Couto, Janine Wichmann, Pietro Ferrari, Dimitrios Trichopoulos, H. Bas Bueno-de-Mesquita, Fränzel J. B. van Duijnhoven, Frederike L. Büchner, Tim Key, Heiner Boeing, et al
J Natl Cancer Inst, Advance Access published on April 6, 2010
DOI:10.1093/jnci/djq072

Source: Oxford Journals, National Cancer Institute.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today

According to Vivus Inc, their experimental drug Qnexa for treating obesity showed positive results in late stage trials, where patients who took the new diet pill, a combination of phentermine (a stimulant) and topiramate (an anticonvulsant), shed an average of nearly 15 per cent of their body weight over a year and also showed significant improvements in cardiovascular and other obesity-related risk factors.

Vivus Inc announced results of the EQUIP and CONQUER Phase 3 trials in a public statement on Wednesday, 9 September. The 56-week pivotal studies evaluated the safety and efficacy of Qnexa in more than 3,750 patients in 93 centres.

According to the drug company, the studies:

“Met all primary endpoints by demonstrating statistically significant weight loss with all three doses of Qnexa, as compared to placebo.”

“Patients taking Qnexa also achieved significant improvements in cardiovascular and metabolic risk factors including blood pressure, lipid levels, and type 2 diabetes,” said the statement.

The key results showed that:

* On average, in the EQUIP study, patients treated with Qnexa lost 14.7 per cent of their body weight (an average of 37 lbs or 16.8 kg) over the 56 weeks of the study.

* Patients treated with Qnexa showed significant improvements in cardiovascular, metabolic and inflammatory risk factors.

* The drug exceeded FDA efficacy benchmarks for weight loss agents at all three doses tested in the trials.

* Completion rates were significantly higher than placebo at all three doses (up to 69 per cent), indicating the drug was well tolerated.

* The drug showed a favourable safety profile (the balance between benefits and risk).

EQUIP Study

For the randomized, double-blind, placebo-controlled EQUIP study, the investigators recruited 1,267 obese patients from 93 centers across the US (1,050 women and 217 men) with a starting average BMI of 42.1 kg/m2 and weight of 256 lbs (116 kg). The trial lasted 56 weeks, comprising four weeks of dose titration and then 52 weeks of treatment.

The study had 3 arms: low dose Qnexa, full dose Qnexa, and placebo, and patients were asked to follow a low calorie diet that left them short of around 500 calories a day. They were also required to make some simple changes to their lifestyle.

The EQUIP study results showed that:

* The average weight loss for patients taking Qnexa who completed the study was 37 pounds (16.8 kg) for the full dose group and 18 pounds (8.2 kg) for the low dose group, compared to 6 pounds (2.7 kg) in the placebo group.

* 60 per cent of the patients on the full dose who completed the study lost at least 10 per cent of their starting body weight, while 43 per cent lost at least 15 per cent.

* Completion rates were 47, 57 and 59 per cent for the placebo, low dose and full dose groups.

* Full dose patients showed significant improvements in blood pressure, triglycerides and cholesterol.

CONQUER Study

The CONQUER study was a randomized, double-blind, placebo-controlled, prospective trial, that like the EQUIP study had 3 arms, except that the patients took either a once a day mid-dose of Qnexa (as oppoosed to a low dose), a full dose or placebo.

From across 93 centers in the US, the trial investigators recruited 2,487 overweight and obese patients (1,737 women and 750 men) who had high blood pressure, high cholesterol or type 2 diabetes and whose average starting BMI was 36.6 kg/m2 and weight was 227 lbs (103.0 kg).

As in EQUIP, the patients underwent 4 weeks of dose titration period followed by 52 weeks of treatment, were asked to follow a low calorie diet with a daily deficit of 500 calories a day and were required to make some simple changes to their lifestyle.

The CONQUER study results showed that:

* The average weight of those who completed the study was 30 pounds (13.6 kg) in the full dose group, 24 pounds (10.9 kg) in the mid-dose group, and 6 pounds (2.7 kg) in the placebo group.

* 64 per cent of the full dose patients who completed the study lost at least 10 per cent of their starting weight, while 39 per cent lost at least 15 per cent.

* Completion rates were 57, 69 and 64 per cent for the placebo, mid dose and full dose groups

The CONQUER study results also showed a number of risk factor reductions in patients taking Qnexa compared to those taking placebo. The following results were reported for reductions among patients showing the highest levels at baseline for each risk factor (top 25th percentile) and who completed the 56 weeks of the study:

* The patients with highest blood pressure experienced a significant systolic blood pressure reduction of 20 mmHg from 147 mmHg, compared to 14 mmHg in the placebo group.

* There was also a significant reduction in blood pressure medication among the Qnexa patients compared to the placebo group.

* The patients with the highest triglyceride levels experienced a significant reduction of 98 mg/dL from 268 mg/dL, compared to 42 mg/dL from 262 mg/dL in the placebo group.

* The patients with the highest hemoglobin A1c levels (a measure of blood sugar for diabetes patients) experienced a significant reduction of 0.6 from 7.3 per cent compared to only 0.1 from 7.4 per cent for the placebo group.

* There was also a significant reduction in diabetes medication among the Qnexa patients compared to the placebo group (all patients were treated to standard of care for type 2 diabetes).

Adverse Events

Across both studies the most commonly reported side effects were dry mouth, tingling, constipation, altered taste and insomnia. Using tests that followed FDA guidelines, the investigators found no signals for suicide risk. There were no suicide attempts or behaviours, and there was no sign that people were thinking of suicide across all treatment groups, said the company statement.

Overall scores for depression and quality of life, including self esteem and general health showed significant improvement among patients who took Qnexa.

Scores for depression or depressed mood adverse events were similar in Qnexa and placebo groups and under 2 per cent for moderate to severe events.

Leland Wilson, president and chief executive officer of VIVUS said:

“The outstanding results from the EQUIP and CONQUER studies, in addition to the results from EQUATE that were reported late last year, confirm the positive effect of Qnexa and underscore the important role this therapy may play in the lives of patients battling obesity and related co-morbidities, if approved by the FDA.”

He said the company plans to file for federal approval by the end of this year and also submit the study reports for peer-reviewed journal publication.

“We believe these results may provide a compelling opportunity for global pharmaceutical companies, and we intend to initiate partnering discussions now that we have the full data set in hand,” said Wilson.

However while these results are impressive, according to various reactions in the media this week, there remains the question of what might happen in the longer term, both for patients who continue to use the drug and those who come off it.

In the 1990s the “fen-phen” combination of fenfluramine and phentermine also achieved impressive results with weight loss, but it was eventually withdrawn after reported links with pulmonary hypertension and serious heart valve problems, followed by lawsuits that are still being pursued against the drug maker.

For Qnexa Vivus have combined phentermine with topiramate which is better known as an anti-epilepsy drug although several studies have recently reported it has shown positive results in controlling weight loss and binge eating, according to a comment by Dr Mitchell Roslin, of Lenox Hill Hospital in New York City, reported by MedPage Today.

Source: Vivus Inc, MedPage Today.

A comment published in this week’s edition of The Lancet reports that nutrition experts have expressed their astonishment over the involvement of Sweden in a debate concerning support of low carbohydrate high fat (LCHF) diets in the country. The comment is the work of Dr Jim Mann and Dr Edwin R Nye, University of Otago, Dunedin, New Zealand.

Many ‘fad’ diets have been promoted in recent years, such as the ultra-low carbohydrate Atkins diet. Other similar LCHF diets have also been credited with considerable weight loss without apparent adverse effects. The authors explain: “Most authorities have argued against prescription of LCHF diets and such messages have not been incorporated into dietary guidelines for populations and people with diabetes. However, recent experiences in Sweden show the potential of committed adherents, supported by a potentially misguided mass media, to influence officialdom to an extent that might adversely influence national public health and the health of individuals.”

In 2007, the controversy began when two dieticians pointed out to Sweden’s National Board of Health and Welfare that LCHF dietary advice recommended to diabetic patients by general practitioner Dr Annika Dahlqvist was not compatible with either scientific evidence or conventional practice. However, following a report by diabetologist Dr Christian Berne, Dahlqvist was cleared. The report said there was some scientific basis for offering LCHF diets but with a number of warnings, such as the absence of long-term studies and the need for patient monitoring (including measurement of lipids). Dahlqvist’s justification resulted in headlines suggesting a shift by the Board. Dahlqvist herself indicated that her diet was suitable not only for diabetics but also for the general population for better health and weight control.

Soon, another aspect of the story surfaced. A group of experts which is a branch of the Board was scheduled to publish a report on nutritional recommendations for people with diabetes. However two of the experts on the panel were withdrawn by the newly appointed Director-General. He considered that their links to the food industry via the Swedish Nutrition Foundation might represent a conflict of interest. The Foundation receives food industry funding. It also provides independent advice to the industry through expert scientists. The two scientists involved (Bengt Vessby and Nils-Georg Asp) are internationally respected. Their dismissal caused outrage in the rest of the Board and the scientific community. The expert group began work in September 2008. But in the meantime the authors say that ‘misguided enthusiasm and reporting appear to have triumphed over expert opinion’. Aftonbladet, the country’s largest newspaper, has published details of high fat/low carbohydrate principle. An anonymous letter, quoting Dahlqvist’s blogs, has been sent to all schools, preschools, and day-care centres in the country, advocating this dietary approach to ’save our children’s brains’. The authors explain: “Despite the National Food Administration of Sweden having published a list of 72 articles which suggest that high fat diets are detrimental compared with eight articles suggesting that they are not, enthusiasm for high-fat diets persists. One of Dahlqvist’s popular books on the subject of high-fat diets has been number one on the non-fiction bestseller list in Sweden.”

The authors assume the Swedish public will deduce that the sequence of events is another example of experts failing to agree. Furthermore, they will conclude there is no point in making dietary changes associated with clinical and public health benefit, such as to lower-fat diets. They explain: “It is also ironic that this debate should have occurred in a country which helped to pioneer cardiac rehabilitation and preventive cardiology, and one of the few to report a decline in the rates of childhood obesity.”

They write in closing: “There are some lessons here for international agencies, professional organisations, and governmental and regulatory bodies. Perhaps one of the most important is the need for internationally accepted criteria for evidence-based nutrition guidelines as there are for evidence-based medicine.”