Tag Archives: American Journal of Epidemiology

All Wound Up

Our body wants to eat, sleep and work at specific times. Scientists now know what makes the biological clock tick, writes T.V. Jayan

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All living organisms — humans are no exception — are controlled by a master clock. This biological timepiece, located in the brain, aligns an organism’s biological, behavioural and physiological activities with the day and night cycle. Its tick tock wakes us up in the morning, reminds us to eat at regular intervals and tells us when to go to bed.

But what sets this internal timekeeping, known as the circadian rhythm, has remained a mystery for long. This, despite scientists having had clues about its existence for more than a century.

The puzzle is slowly unfolding, thanks to advances in modern biology that offer a better insight into genes and their workings. Scientists now know the exact location of the master pacemaker and how is it regulated.

Research has also shown the circadian rhythm shares a reciprocal relationship with metabolism. In other words, while the circadian rhythm can influence metabolic activity, food intake can also modulate the functioning of the biological clock.

The mechanism by which feeding modulates the components of the clock machinery was discovered last month by a team of researchers led by Gad Asher of the University of Geneva. The paper, which appeared in the latest issue of Cell, shows that a protein called PARP-1 is at play here. The scientists found that mice that lack the gene that secretes PARP-1 fail to give the correct food intake cues to the circadian clock, thereby disrupting the synchronisation.

“This is an important finding,” says Raga Krishnakumar, a University of California San Francisco University researcher who, together with her former mentor W. Lee Kraus, showed early this year that PARP-1 is a multi-faceted protein that also regulates the expression of another protein which plays a vital role in aging, apart from helping contain DNA damage.

Scientists believe disruptions in the synchronisation between the circadian rhythm and metabolism play a key role in triggering many disorders that plague the modern world such as obesity, diabetes and cardiovascular diseases.

The master clock occupies a tiny area in the hypothalamus region of the brain. Called the suprachiasmatic nucleus (SCN), this brain region — the size of a grain of rice — contains a cluster of nearly 20,000 neurons. These neurons, in response to light signals received from the retina, send signals to other parts of the brain as well as the rest of the body to control a host of bodily functions such as sleep, metabolism, body temperature and hormone production.

As per the cues received through these neurons from the master clock, the cellular clocks in the tissues in different body organs are reset on a daily basis. The operation of these cellular clocks is controlled by the co-ordinated action of a limited number of core clock genes.

The year 1994 was a watershed year in research on the circadian rhythm. American Japanese scientist Joseph Takahashi, working at Northwestern University in the US, discovered the genetic basis for the mammalian circadian clock. The gene his team discovered was named CLOCK in 1997. Subsequently, scientists discovered several other genes associated with the timekeeping function such as BMAL1, PER and CRY, which are also involved in the working of the main SCN clock machinery as well as subsidiary clocks in other parts of the body.

The cues received from the master clock are important. Based on them, various genes in the cells change their expression rhythmically over a 24-hour period. It times the production of various body chemicals such as enzymes and hormones so that the body can function in an optimal fashion.

In the normal course, the body follows the master clock in setting its physiological and psychological conditions for optimal performance. While the 24-hour solar cycle is the main cue for resetting the master clock — just like a wall-mounted clock resets after a 24-hour cycle — there are other time cues as well: food intake, social activity, temperature and so on. “Unlike geophysical time, the biological clock does not follow an exact 24-hour cycle on its own. Various external and internal time cues that it receives play a vital role in bringing the periodicity close to 24 hours,” says Vijay Kumar Sharma of the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, who has been studying the circadian rhythm for years.

However , modern society often imposes deviations from the regular work-rest cycle. “Basically, mammals including humans are diurnal (active during the day rather than at night). Whatever be the external compulsions (night shifts or partying late), the inner mechanisms of the body follow a diurnal pattern,” says Sharma. “It is bound to be out of sync if we deviate from the routine.”

“A major consequence of modern lifestyle is the disruption of the circadian rhythm. This leads to a number of pathological conditions, including sleep disturbances, depression, metabolic disorders and cancer. Studies reveal the risk of breast cancer is significantly higher in industrialised societies, and that the risk increases as developing countries become more and more westernised. Moreover, a moderate increase in the incidence of breast cancer is reported in women working nightshifts,” says Sourabh Sahar, a researcher working on the circadian rhythm at the University of California, Irvine.

Need more proof that the body has a mind of its own?

Source: The Telegraph (Kolkata, India)

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Green Tea May Help Reduce Risk of Certain Cancers

Researchers in Japan have said drinking green tea may be an important health resource to reduce the risk of developing certain types of cancer.

The study appearing in the American Journal of Epidemiology suggests drinking five or more cups of the antioxidant-rich beverage can reduce the risk of developing blood cancer by 42 percent. The same amount of green tea was also associated with a 48 percent lower risk of lymph system cancer, according to Reuters.

Researchers followed 19,749 men and 22,012 women with no previous history of cancer over a period of nine years for the study.

WebMD notes that previous research has linked the tea to fighting heart disease, lowering cholesterol and preventing diabetes and dementia.

“Taken altogether, the evidence certainly suggests that incorporating at least a few cups of green tea every day will positively affect your health. It’s not going to cure anything and it shouldn’t be consumed as a drug, but it can complement the rest of the diet,” Tufts University scientist Dr. Diane McKay tells WebMD.

Researchers involved with this study say further work is needed to confirm the health benefits of drinking green tea, and to determine whether daily consumption might prevent certain cancers.

Source:Better Health Research. Oct.20 ’09

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Fish-Eating Moms’ Diet Affects Kids, Study Shows

Since the current guidelines on fish consumption were issued, Dr. Emily Oken, a physician and assistant professor at Harvard Medical School, has led studies to examine the sum effect of eating fish.

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One of those was published in May in the American Journal of Epidemiology. Researchers asked 341 pregnant women in Massachusetts about their diet and tested their blood mercury levels during the second trimester. Then, when their children were 3, they were tested in a range of thinking and movement tasks.

Children of mothers who ate more than two servings of fish per week had higher scores than kids of non-fish-eating moms, even when other influences of early childhood development, such as birth weight and breast-feeding duration, were factored out. No measurable benefit was seen in kids born to women who ate fewer than two servings of fish per week, which corresponds to the current FDA/EPA advice.

The improvements in kids were even more striking in kids of moms with lower mercury levels, suggesting that choosing low-mercury fish is key. Researchers did ask about broad categories of fish, but, Oken says, it’s a big uncertainty in this kind of research. “We don’t really know a lot of detail about the kind of fish that women are eating.”

On the flip side, children of mothers with the highest mercury levels in their blood scored poorly, and if their moms ate less fish, the detriments were greater.

In short, Oken was able to demonstrate both the benefits of fish eating and the risks of mercury intake. When both fish and mercury are taken together, Oken’s study suggests that the good may outweigh the bad, at least in the fish-eating habits of her subjects.

Sources: The Times Of India

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New Anti-Cancer Compound Found

A marine compound discovered off the coast of Key Largo in Florida inhibits cancer cell growth in lab tests and is likely to prompt the development of effective new drugs.

The University of Florida (UF)-patented compound, largazole, is derived from cyanobacteria that grow on coral reefs. It is being described as one of the most promising finds since the college’s marine lab was established three years ago.

The molecule’s natural chemical structure and its ability to inhibit cancer cell growth were first described in the Journal of American Chemical Society in February, and the lab synthesis and description of the molecular basis for its anti-cancer activity appeared on July 2.

“It’s exciting because we’ve found a compound in nature that may one day surpass a currently marketed drug or could become the structural template for rationally designed drugs with improved selectivity,” said Hendrik Luesch, assistant professor in UF’s Department of Medicinal Chemistry and the study’s principal investigator.

Largazole, discovered and named by Luesch for its Florida location and structural features, seeks out a family of enzymes called histone deacetylase, or HDAC. Overactivity of certain HDACs has been associated with several cancers such as prostate and colon tumours, and inhibition of HDACs can activate tumour-suppressor genes that have been silenced in these cancers.

Although scientists have been probing the depths of the ocean for marine products since the early 1960s, many pharmaceutical companies lost interest before researchers could deliver useful compounds because natural products were considered too costly and time-consuming to research and develop.

Many common medications, from pain relievers to cholesterol-reducing statins, stem from natural products that grow on the earth, but there is literally an ocean of compounds yet to be discovered in our seas.

Only 14 natural marine products developed are in clinical trials today, Luesch said, and one drug recently approved in Europe is the first-ever marine-derived anti-cancer agent.

“Marine study is in its infancy”, said William Fenical, professor of oceanography and pharmaceutical sciences at the University of California, San Diego. “The ocean is a genetically distinct environment and the single, most diverse source of new molecules to be discovered”.

HDACs are already targeted by a drug approved for cutaneous T-cell lymphoma manufactured by the global pharmaceutical company Merck & Co. Inc. However, UF’s compound does not inhibit all HDACs equally, meaning a largazole-based drug might result in improved therapies and fewer side effects, Luesch said.

Luesch said that, within the next few months, he plans to study whether largazole reduces or prevents tumour growth in mice. Luesch has several other anti-tumour natural products from Atlantic and Pacific cyanobacteria in the pipeline.

These results were presented on Thursday at an international natural products scientific meeting in Athens.

Sources: The Times Of Imdia

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Fruit And Veg May Slash Gullet Cancer Risk

An increased intake of fruit and vegetables may cut the risk of Barrett’s oesophagus, a precursor to oesophageal cancer, suggests a new study form California.
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Healthy dietary habits, rich in fruit and vegetables, was associated with a 65 per cent reduction in the occurrence of Barrett’s oesophagus, according to the new study involving 913 people and published in the American Journal of Epidemiology.

The study, by researchers from Kaiser Permanente Northern California and the University of California, also heaps more pressure on the Western diet pattern, high in fast food and meat, with the data indicating an adverse effect on the risk of Barrett’s oesophagus

Barrett’s oesophagus is cause by acid reflux, and although it can occur early in life, most sufferers are in their 40s and 50s. Although it has been reported to be a precursor to oesophageal cancer, 90 per cent of patients are said to never develop into cancer, and although some speculation as to dietary and drug history, the reason why this is so is not really known.

The new study, which recruited 296 people with Barrett’s oesophagus, 308 people with gastroesophageal reflux disease but no Barrett’s oesophagus, and 309 healthy controls, used a 110-item food frequency questionnaire to evaluate dietary patterns.

Lead author Ai Kubo and co-workers report that two major dietary patterns were observed amongst the participants, with subjects classified as eating either the Western or “health-conscious” diet. The latter was characterised by being high in fruits, vegetables, and non-fried fish.

The researchers report that strong adherence to the health-conscious diet was associated with a 65 per cent reduction in the risk of developing Barrett’s oesophagus.

Moreover, while an increased risk was suggested by stronger adherence to the Western diet pattern, no dose-effect relation was reported by Kubo and co-workers.

“Results suggest strong associations between a diet rich in fruits and vegetables and the risk of Barrett’s oesophagus,” concluded Kubo.

The study does have limitations, most notable is the use of the FFQ to establish dietary patterns. Such questionnaires are susceptible to recall errors by the participants, and may no reflect dietary changes. Significant further research is needed. A mechanistic study to elucidate the bioactive constituents of the fruit and vegetables which may be responsible for the benefits is also necessary.

The “five-a-day” message is well known, but applying this does not seem to be filtering down into everyday life. Recent studies have shown that consumers in both Europe and the US are failing to meet recommendations from the WHO to eat 400 grams of fruit and vegetables a day.

A report from the European Union showed that global fruit and vegetable production was over 1,230 million tonnes in 2001-2002, worth over $50 bn (€41 bn). Asia produced 61 per cent, while Europe and North/Central America both producing nine per cent.

Source: American Journal of Epidemiology
Published online ahead of print, doi:10.1093/aje/kwm381
“Dietary Patterns and the Risk of Barrett’s Esophagus”
Authors: A. Kubo, T. R. Levin, G. Block, G.J. Rumore, C.P. Quesenberry Jr, P. Buffler, D.A. Corley