Bitter pills banished by taste-blocking compounds
19:00 26 February 03 Exclusive from New Scientist Print Edition

A spoonful of sugar may no longer be needed to help the medicine go down - it could be replaced by natural compounds that block the taste of bitter substances.
Bitter blockers
Bitter blockers

The compounds could not only help drug companies make bitter-tasting medicines more palatable, they could also help food manufacturers reduce the vast amounts of sugar, salt and fat they add to most processed foods. Part of the reason these additives make food taste better is that they mask bitter tastes.

Biotech firm Linguagen of New York received patent protection for the family of blockers it has discovered in January, and it says there is already interest from food and drug companies. "A major food ingredient company is testing them, and a major pharmaceutical company," says chief operating officer Shawn Marcell.

"This has been a real breakthrough," says Linda Bartoshuk of Yale University, who studies taste perception. "For most of the stuff you hear out there, they almost never have data and they almost never publish anywhere reliable. But this is good solid science."


Cascade of reactions

Linguagen was founded by Robert Margolskee of the Mount Sinai School of Medicine in New York, who discovered the particular cascade of reactions that leads to bitterness perception. When taste receptor cells in the mouth detect bitter compounds such as naringin, found in grapefruit, caffeine and the painkiller ibuprofen, they release a protein called gustducin (see graphic). This triggers a series of reactions that finally results in a nerve impulse being sent to the brain saying "bitter".

Researchers at Linguagen tested a huge range of compounds from chemical libraries to see if any could block gustducin release. In test tubes they mixed the compounds one by one with a dye and the relevant components found in the mouth.

When the dye turned blue, it signalled that gustducin had been produced. If it did not turn blue, the researchers assumed that the compound was blocking gustducin production. The team confirmed that the potential blockers really did prevent bitterness being perceived when lab mice could not distinguish a bitter solution doped with the blocker from plain water.

Then the researchers tried the best ones themselves, sipping coffee and grapefruit juice containing the compounds. Stephen Gravina, who carried out the experiments, said the coffee's flavour was "milder and more mellow".


Naturally occurring

Usefully, all the compounds that blocked bitterness are nucleotides, the family of molecules that includes the building blocks for DNA and RNA. All of them are naturally occurring and already found in various foods. That means the compounds will not require FDA approval when small amounts are added to food and drugs.

"We don't know exactly how it works," admits Gravina. But the researchers think that by bonding to the mouth's bitter taste receptors in place of the bitter compounds, they inhibit the release of gustducin.

Trying to block bitter flavours is far more practical than, say, trying to remove any of the vast range of compounds that can make food taste unpleasant. And only tiny amounts of bitter blockers are required to stop the bitter signal reaching the brain. The reason is evolutionary: some bitter substances are highly poisonous, so we need to detect compounds like them at very low concentrations.

Broccoli and soya

If Linguagen's blockers are proven safe and effective, they could go a long way to making food healthier. At the moment, vast amounts of sugar, fat and salt, which are known to contribute to obesity, high blood pressure and the risk of strokes, are added to processed foods. One tin of soup can contain half the recommended daily intake of salt.

Bitter blockers would avoid the need to mask unpleasant flavours and could also make bitter-tasting, healthy foods such as broccoli and soya more palatable.

Adding bitter blockers will not stop us detecting food that is rotten, adds Linguagen scientist Richard McGregor. Bad smells and sour tastes, conveyed to the brain through a different set of receptors and chemical messenger, warn us when food has gone off.

As well as working to develop more potent blockers to work in extremely bitter medicines, such as HIV drugs, Linguagen also hopes to tackle entirely different messengers and reaction pathways to produce artificial sweeteners and salt substitutes.


Celeste Biever

Global population forecast falls
11:18 27 February 03 NewScientist.com news service

Fast-falling birth rates and rising AIDS deaths are stifling the population explosion - and could lead to a decline in global population in the second half of the 21st century.

In new forecasts released on Wednesday evening, UN demographers cut 400 million from their best estimate of the world's population in 2050. Joseph Chamie, the head of the UN population division in New York, said he now expected 8.9 billion people on Earth in 2050, rather than the 9.3 billion that he forecast in 2002. The current figure is 6.3 billion.

The 400-million reduction equates to the current populations of the US, Canada and Mexico combined. Chamie said half arose from birth rates falling faster than expected and the other half was due to rising forecasts of the death toll from AIDS. "HIV/AIDS is a disease of mass destruction," he said.

The new population projections stretch to the year 2050, but not beyond. However, he warned that "fertility rates will be below replacement levels in three-quarters of the world by 2050". The great majority of women worldwide will be having fewer than two children.


Radical re-think

In fact, the new projections assume that most countries will eventually approach a fertility rate of 1.85 children per woman. This represents a clear break with past thinking - demographers had always assumed countries would settle down to replacement fertility levels.

Chamie agrees that it has "momentous" implications for humanity. After a time-lag during which past "baby boom" generations pass through child-bearing age, it will cause most countries to go into a demographic decline.

The detailed projections for individual countries show 33 countries with smaller populations in 2050 than today. Japan is expected to be 14 per cent smaller; Italy 22 per cent; and a slew of eastern European countries, including Russia and Ukraine, will see their populations crash by between 30 and 50 per cent.

Inward migration

The population of South Africa and three neighbours is also expected to reduce, but as a result of the AIDS. Chamie predicts the disease will have claimed 278 million lives by mid-century.

The US is expected to be one of a handful of developed nations whose population will continue to grow strongly, largely through an inward migration of more than a million people a year.

The US population is predicted to rise from 285 million now to 409 million in 2050. The UK is also expected to have more people then, rising from 59 million to 66 million.

The next five decades are also set to see a massive ageing of the world population. The number of people over 80 will rise fivefold. The median citizen - the one with half the world older than him or her and half younger, will be aged 37 in 2050, compared to 26 today.


Fred Pearce

Journal Watch Emergency Medicine
January 29, 2003
Steroids for Croup: Put Away Those Needles!

from Journal Watch
Physician-authored summaries and commentary
from the publishers of the New England Journal
of Medicine

Posted 02/18/2003


Summary

Intramuscular dexamethasone ameliorates croup, which is usually a several-day illness characterized by long nights of incessant, barking cough. The authors of this study compared IM and oral administration of dexamethasone in children with moderate-to-severe croup.

In a prospective, randomized, double-blind trial, 95 children aged 3 to 84 months with a Westley croup score of 2 or greater received either 0.6-mg/kg IM dexamethasone plus oral placebo or 0.6-mg/kg oral dexamethasone plus a sham injection. All patients were treated with cool mist therapy for 10 to 15 minutes. Parents were questioned by telephone approximately 24 hours and 10 days after the initial visit. At those intervals, there were no statistically significant differences between groups in the proportion of patients with barking cough, stridor, expiratory sounds, sleep pattern, degree of improvement, or complete resolution of symptoms.
Comment

For any parent who has spent several sleepless nights with a child who has croup, steroids are heaven-sent. IM dexamethasone, however, involves giving children what they fear most -- a shot. This study shows that oral dexamethasone is as effective as IM dexamethasone, so the oral route is a win-win for everyone.

— Diane M. Birnbaumer, MD, FACEP
Source

Donaldson D et al. Intramuscular versus oral dexamethasone for the treatment of moderate-to-severe croup: A randomized, double-blind trial. Acad Emerg Med 2003 Jan; 10:16-21.

Journal Watch Cardiology
January 3, 2003
Exercise in Men: Intensity vs. Amount

from Journal Watch
Physician-authored summaries and commentary
from the publishers of the New England Journal
of Medicine

Posted 02/19/2003


Summary

Many studies have linked exercise with reduced rates of coronary heart disease, but few have assessed the effect of exercise intensity on CHD risk. Investigators did just that by analyzing self-report data from 44,452 men (age range at baseline, 40-75) enrolled in the Health Professionals Follow-Up Study (1986-1998).

In analyses adjusted for typical CHD risk factors, exercise intensity was associated inversely with incident CHD: There was a 4% risk reduction for each 1-MET increase, independent of the total amount of exercise. Activity type also mattered: In analyses adjusted for traditional CHD risk factors and for other types of physical activity, high-intensity activities were associated with lower risk. For example, running at >/=6 mph for >/=1 hour/week was associated with 42% lower risk than no running. Also, weight training, a resistance exercise, for >/=30 minutes/week was linked with 23% lower risk than no weight training. Risk reduction was not evident for low-intensity activities (e.g., jogging at <6 mph for >/=1 hour/week). Fast walking pace was related to reduced CHD risk beyond -- and independent of -- a relation that was found for total walking amount.
Comment

These data suggest that high-intensity exercise and resistance exercise (including weight training) are associated with reduced risk for CHD events in men. Randomized trials must corroborate these findings. Current ACC/AHA guidelines recommend at least 30 minutes/day of aerobic exercise, but these new findings suggest that exercise intensity may need to be incorporated into the recommendations. Note that in a recent observational study of postmenopausal women, walking and vigorous exercise were found to have equal value for preventing adverse cardiovascular events; however, fast walking was associated with lower risk than slow walking (Journal Watch Cardiology Oct 11 2002).

— JoAnne M. Foody, MD
Source

Tanasescu M et al. Exercise type and intensity in relation to coronary heart disease in men. JAMA 2002 Oct 23/30; 288:1994-2000.

New gauze promotes natural healing

www.nature.com

Biodegradable bandage made from wound-healing proteins.
24 February 2003

PHILIP BALL

"The new dressing never need be removed."

A new bandage mimics the natural tissue that forms as a wound heals. The gauze, made from the blood protein fibrinogen, could be applied as a dressing that need never be removed. The body would treat it simply as part of normal healing, gradually dissolving it as new skin grows over the wound.

During natural blood clotting at a wound, an enzyme converts fibrinogen into a web of insoluble fibres of the related protein fibrin. This mesh protects the injury from infection and stops bleeding.

Gary Bowlin and colleagues from Virginia Commonwealth University in Richmond, USA, have devised a way to spin extremely fine fibrinogen fibres1.

They extract the protein from human or cow blood and dissolve it in an organic solvent. They then squirt a jet of this solution from an electrically charged hypodermic needle — the electric field stops the stream breaking up into droplets.

As the jet flies through the air, the solvent evaporates and the fibrinogen molecules stick together into fibres a thousand times narrower than a human hair, at just 80 millionths of a millimetre wide. This is about the same thickness as fibrinogen fibres in normal blood clots.

These fibres hit a rotating steel drum, and gather into a tangled mat. The researchers remove the mat when it gets to about a tenth of a millimetre thick, by which time it is strong enough to act as a wound dressing.

A sheet of this fibrinogen gauze should both stop bleeding quickly and speed up the healing process, claims Bowlin's team. It should act as a scaffold into which tissue-forming cells can grow and move. A snippet, for example, would help staunch shaving nicks.

The next step is to make shaped biodegradable scaffolds to guide the regrowth of damaged tissues. Bowlin and colleagues hope to combine different kinds of material in one mesh, including the skin protein collagen and growth factors, to stimulate the formation of specific tissue types.

References

Wnek, G. E., Carr, M. E., Simpson, D. G. & Bowlin, G. L. Electrospinning of nanofiber fibrinogen structures. Nano Letters, 3, 213 - 216, (2003). |Article|

Tiny gene changes means big differences in pain

18:16 21 February 03
NewScientist.com news service

When it comes to pain, a tiny variation in a single gene divides the men from the boys, reveals a new study.

US researchers have pinpointed differences in the way people withstand pain - both physical and emotional stress - to a gene which makes a protein important for brain chemistry.

The gene makes catechol-O-methyl transferase (COMT), an enzyme vital for mopping up the dopamine brain chemical linked with sensing pain.

Tough guys and wimps carry different forms of the gene, showed Jon-Kar Zubieta and his team at the University of Michigan and The National Institute of Alcohol and Alcoholism, Rocksville, Maryland.

People with a particularly active form of COMT were hardier, whereas people with a lazier form felt pain more acutely. Those with both forms of the gene, one from each parent, experienced intermediate pain, the researchers found.

Zubieta, told New Scientist: "This is the first time that a gene has been linked to particular changes both to the chemical systems of the brain and behaviour."


Lazier genes

The COMT gene exists in two forms which make copies differing by a single amino acid only - either valine or methionine.

This small variation has a big effect on the activity of COMT, say the researchers. People with the laziest form of the gene - who have two copies of the methionine version - make enzymes three- to four-fold less effective than the other variants contained just valine or one of each.

The team used brain imaging or positron emission tomography to examine the brain activity of 29 people who were subjected to a "tolerable" pain over 20 minutes.

The volunteers were given a salt water injection into their jaw muscles to simulate a condition called temporomandibular joint pain disorder. They rated their own level of pain every 15 seconds during the brain imaging.

Zubieta predicted correctly that those people who were able to metabolise dopamine best because both copies of their gene were of the valine form would feel least pain.

"Depending on the genotype you got - which had lowest, intermediate and highest activity - people had a gradation in response," said Zubieta.

In people with two copies of the methionine form of COMT, the dopamine is not cleared fast enough. If this becomes chronic the uncleared dopamine also acts on a second brain pathway regulating pain and stress.

Zubieta said a quarter of the population would be pain sensitive types, a quarter would be more stoic types, and half would be in between.

Journal reference: Science (vol 299, p 1240)