Nanoparticles to pinpoint viruses in body scans

19:00 20 August 03
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An injection of magnetic nanoparticles into your bloodstream could reveal precisely where harmful viruses are lurking.

The particles are coated with antibodies to a particular virus, so they will form clumps that should be visible on conventional body scans if that virus is present. The team working on the technology, from the Harvard Medical School's Center for Molecular Imaging Research in Charlestown, Massachusetts, have already managed to detect viruses in body fluids and tissue samples.

They hope to be able to detect viruses in patients' bodies within a couple of years. Much of the technology has already been tested in humans, so the scientists are confident that it will be safe.

Spotting a virus

Scans revealing where virus populations are - HIV, for example, tends to concentrate in the lymph nodes - could help doctors improve treatments. And a scan could reveal whether viruses used in gene therapy to ferry new DNA into patients have actually reached the parts of the body they are intended for - and in sufficient numbers to do any good (Journal of the American Chemical Society, DOI: 10.1021/ ja036409g).


Sugar-coated

Usually, viruses can only be detected indirectly, by capturing and amplifying viral DNA through the PCR technique, which takes about two hours. "It's cumbersome, takes time, gives you false positives and negatives, and only detects fragments of the virus," says Manuel Perez, head of the team developing the new technique - which gives an answer in half the time.

It relies on particles 50 nanometres wide. They have a core of iron oxide and a coating of dextran, a sugar to which antibodies stick easily. A top coat of antibodies to the virus under investigation is added, and the particles are ready for use.

In lab tests, the nanoparticles have been added to samples of body fluids; in patients, they would simply be injected. If live viruses are present, they stick to the antibodies on the nanoparticles, forming a large cluster of particles which can then be detected through magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) scans.

"The antibodies recognise specific proteins on the surface of the virus, and it makes the nanoparticles clump with the virus," explains Perez.


Relaxation time

But the scanners do not detect the nanoparticles directly. First, the particles' iron oxide cores are turned into magnets by a scanner's strong magnetic field, which also forces the nuclei of surrounding water molecules into different energy states.

A radio-frequency signal can then be used to make the water nuclei return to their original state. The time it takes to return to that state, the "relaxation time", is a measure of the density of molecules at that point. The magnetised particles lengthen the relaxation time of water molecules next to them, which makes the viral clusters visible in the MRI or NMR scans.

The Harvard team says its system has successfully detected the herpes simplex virus, which causes cold sores, and an adenovirus, which causes colds, in blood samples.

Perez says the magnetic nanoparticle technique could rapidly become a reality, as all the components it uses are already available commercially. Similar particles have already been shown to be safe in the body in earlier experiments on the detection of secondary prostate cancer.


Andy Coghlan

Docking blocking drug hope for HIV

14:03 19 August 03

NewScientist.com news service


An experimental molecule which stops the HIV from entering cells could pave the way to a new class of HIV inhibitor drugs, suggests a study by US researchers.

A new weapon against the virus would be especially valuable given that resistance to established drug therapies is growing. These mainly target the HIV's replication.

The drug, called BMS-378806, successfully halted the HIV-1 virus from penetrating cells in the lab - this strain infects over 42 million people. It also showed no harmful effects when tested in dogs, rats and monkeys.

It is one of a new class of HIV drugs with the potential to become a "valued addition to our current armamentarium of antiretroviral drugs," write the team that conducted the study, at Bristol-Myers Squibb in Connecticut. Pin Fang Lin, who led the team, told New Scientist she is "cautiously optimistic" about the drug's potential in humans.

The molecule could be a "potent antiretroviral drug" and is a "most promising start" say Áine McKnight and Robin Weiss at University College London in the UK, in an editorial accompanying the Proceedings of the National Academy of Sciences paper.


Invading cells

Most current HIV drugs inhibit vital enzymes, called reverse transcriptase and protease, that the virus needs to copy itself. But resistance to these drugs is growing, says the team, with almost 20 per cent of newly diagnosed HIV patients being infected with resistant viruses.

BMS-378806 works by preventing HIV from "docking" with a cell, and then squeezing inside. The molecule attaches itself to a protein on the surface on HIV's outer coat that would otherwise dock with a molecule called CD4 on the surface of cells.

Tests in the lab showed "potent inhibitory" effects against HIV-1, but not HIV-2 or SIV. A two-week study in rats showed the drug could be safely given every day in an oral form. It was also safe in dogs and monkeys.

Importantly, preliminary data showed the drug was effective against HIV strains that were resistant to more conventional drug therapies.

The concept of stopping HIV by interfering with the first stage in its infection process is not new. However, this is the first time this particular docking system has been targeted.

McKnight and Weiss note that the HIV coat protein, called gp120, is one of the better preserved features of the highly changeable virus. HIV's ability to rapidly evolve has been the major challenge in the search for a cure.

Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.1832214100)


Shaoni Bhattacharya

Chinese herb reveals vital malaria weakness

18:00 20 August 03

NewScientist.com news service


A hitherto unknown but vital weakness in the malaria parasite has been exposed by studying extracts from ancient Chinese anti-fever remedies. The discovery opens a new front in the fight against the parasite, which has become resistant in most parts of the world to the most common anti-malarial drug, chloroquine.

Derived from the Chinese herb qinghao, or sweet wormwood (Artemisia annua), the extracts have already saved millions of patients in south-east Asia who would otherwise have suffered or died when conventional drugs failed.

Now researchers have discovered how the drugs, called artemisinins, actually work, revealing a chink in the Plasmodium falciparum parasite's armour. The chink is one of the two enzymes that enable the parasite to pump the correct amount of calcium into its cell membranes.

"Artemisinin hits one of those pumps directly," says Sanjeev Krishna of St George's Hospital Medical School in London, UK, the head of the research team. Once the calcium pump is disabled, the parasite dies within hours, although Krishna does not yet know the precise mechanism.


Killing power

The discovery of the enzyme, called Plasmodium falciparum ATP6, or PfATP6, provides a juicy new target for drug makers and for researchers like Krishna who want to improve the killing power of artemisinins.

What is more, the gene that encodes the pump can now be monitored in parasites worldwide to see if it mutates to make the parasite resistant to artemisinins. "We could look for and anticipate resistance, instead of responding when it happens," says Krishna.

The discovery that artimisinins hit the enzyme came as a surprise, because the assumption till now has been that the extracts damage chambers where the parasite digests blood meals.

To prove the enzyme was the key, Krishna's team isolated it by injecting the messenger RNA that codes for PfATP6 into eggs of the frog Xenopus laevis. By comparing the effects of artemisinins with a chemical known to block the enzyme's action, as well as with as drugs such as chloroquine, they were able to show that artemisinins block PfATPt both in the eggs and in intact malarial parasites.

Vulnerable enzyme

Manufactured in China and Vietnam, artemisinins are already having a huge impact in areas of south-east Asia where resistance to other drugs is rife.

Krishna says that the drugs are now beginning to prove their worth in Africa too, and combinations of artemisinins with other drugs are proving most effective. Together with Peter Kremsner of the University of Tubingen in Germany, Krishna's team is testing a combination with amodiaquine on children in Gabon.

Robert Ridley, coordinator of product development for tropical diseases at the World Health Organization in Geneva, says that the discovery should allow new artemisinins to be developed that work in three to four days, rather than the week that current formulations take. This would make it easier to patients to stick to a drug regime, he says.

And the discovery of the vulnerable enzyme should encourage the search for new drugs, which are desperately needed as resistance to older drugs escalates (see graphic).

Journal reference: Nature (vol 424, p 957)


Andy Coghlan

Copper link to Alzheimer's disease

13:58 12 August 03

NewScientist.com news service


Copper may increase the growth of the protein clumps in the brain that are a trademark of Alzheimer's disease, according to a new US study on rabbits.

Researchers first noticed that the rabbits they use to model Alzheimer's disease developed fewer plaques in their brains when they drank distilled water rather than tap water. These insoluble plaques, generated in the rabbits via a high-cholesterol diet, are a trademark of the degenerative illness.

The tap water contained significant amounts of copper, so Larry Sparks, at the Sun Health Institute in Sun City, Arizona, and Bernard Schreurs, at West Virginia University, then gave the rabbits distilled water spiked with copper supplements.

These rabbits developed significantly more plaques than those drinking only distilled water. They also suffered dramatically poorer memories in complex tests.


Two-step process

"We believe that this is a two-step process," Sparks told New Scientist. "Cholesterol causes overproduction of Alzheimer's proteins and then copper inhibits the clearance of beta-amyloid [a plaque-inducing protein] from the brain to the blood."

"The most striking thing was probably the fact we got full blown plaques in the brains of [these rabbits] which were regionally distributed similarly to Alzheimer's," he says.

Harriet Millward, deputy chief executive of the UK's Alzheimer's Research Trust, says a link between copper and Alzheimer's has been suggested before but that research so far has been contradictory.

"These are certainly interesting results - but we still need more research," she told New Scientist. She also notes that using cholesterol-fed rabbits as a model for Alzheimer's disease is a "very novel".


Memory deficit

In the latest experiments, the cholesterol-fed rabbits were given water laced with 0.12 parts per million copper, one tenth of US safety limit for humans. Three-quarters of the rabbits showed senile plaque-like deposits in their brains after 10 weeks. These rabbits also showed an 80 per cent deficit in memory in complex conditioning tests.

The plaques were not found in the brains of animals given pure distilled water and were rare among those drinking tap water.


"Although we can only speculate about how the effects of copper consumption in cholesterol-fed rabbits relate to those in humans, it is of note that the levels of copper ... that induced beta-amyloid and senile plaque-like structures are well below those considered safe for humans," Sparks and Schreurs write in Proceedings of the National Academy of Sciences:

Sparks says the pair are now working on understanding the mechanism by which copper might cause beta-amyloid to accumulate in the brain.

Ashley Bush and colleagues at Harvard Medical School have previously proposed a different mechanism by which metals like copper and zinc could cause Alzheimer's (New Scientist print edition, 3 August 2002). They have suggested that the metals may cause beta-amyloid to turn into a rogue enzyme, catalysing the production of hydrogen peroxide, which then damages brain cells.

Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.1832769100)


Shaoni Bhattacharya

Deadly alliance killing thousands in India

00:01 15 August 03

NewScientist.com news service


A deadly alliance of two of the world's biggest health threats is killing many thousands of men in India, researchers have revealed. According to the study, smoking causes half of the deaths from tuberculosis in Indian men.

The discovery not only highlights the known dangers of smoking, but shows that tobacco use could be helping to sustain the TB epidemics that are plaguing many parts of the world.

The researchers, led by Vendhan Gajalakshmi of the Epidemiological Research Center in Chennai, India, and Richard Peto, at the University of Oxford, UK, compared the smoking habits of 43,000 Indian men who had died of various diseases with those of 35,000 men who were still alive and from the same area.

The risk of TB among smokers was four times that of non-smokers, says Gajalakshmi. "Almost 200,000 people a year in India die from TB because they smoked," she says.


Billion carriers

More than a billion people worldwide carry the tuberculosis microbe, Mycobacterium tuberculosis, but only eight million people a year become seriously ill from it.

"Most of the billion people who have TB will just carry it and not die from it - their bodies are keeping that infection under control," Peto told New Scientist. "But smoking makes the breakdown of that control more likely."

The exact mechanism by which smoking increases TB risk is uncertain, but Gajalakshmi adds: "Smoking damages the lung's defence mechanism against chronic TB infection and the infection becomes uncontrollable."


The link between smoking and TB suggests that tobacco use may play a role in increasing TB infections in the general population. Another member of the research team, Prabhat Jha at the University of Toronto, Canada, says: "Not only in Asia and Africa, but also throughout America and Europe, smoking will increase the number of people who develop clinical TB themselves and can then infect others, unless they are properly treated and cured."

The researchers' next step is to follow up TB sufferers who are currently alive to determine whether smoking is playing a role. "And we need to determine the proportion of TB caused by smoking in lots of different countries - Africa, Asia, America, Russia," says Peto.

The researchers also want to emphasise the dangers of smoking to people in India. "We have to bring out smoking cessation clinics in India and promote awareness in the community about the harm of smoking," Gajalakshmi concludes.

Journal reference: The Lancet (vol 362, p 507)


Daphne Chung

Statins Benefit Diabetics, Regardless of Cholesterol Levels

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

Posted 08/13/2003


Summary

In the randomized, placebo-controlled, U.K. Heart Protection Study, simvastatin therapy (40 mg daily) reduced morbidity and mortality among 20,000 patients with total cholesterol levels of at least 135 mg/dL (3.5 mmol/L) and with coronary disease, other arterial disease, hypertension, or diabetes (Journal Watch Jul 30 2002). Now, the researchers report results from the trial's subgroup of nearly 6000 diabetic patients, most of whom had type 2 diabetes. At baseline, mean total cholesterol level was 220 mg/dL (5.7 mmol/L), and mean LDL cholesterol level was 124 mg/dL (3.2 mmol/L).

The rate of major vascular events was 25% in the placebo group and 20% in the simvastatin group -- a significant 22% difference. Even among participants who had pretreatment LDL cholesterol levels lower than 116 mg/dL (3.0 mmol/L) and without diagnosed arterial disease at study entry, the vascular event rate was significantly lower in the simvastatin group (8% vs. 11%). Among participants who experienced first major vascular events after randomization, subsequent events were significantly less common in the simvastatin group.
Comment

These results show that simvastatin therapy leads to significant risk reductions for vascular events in type 2 diabetic patients, even if they don't have diagnosed coronary disease or high cholesterol levels. The authors estimate that 5 years of treatment would prevent about 45 major vascular events per 1000 patients and suggest that statins should be offered to high-risk diabetic patients regardless of their cholesterol levels. An editorialist suggests that this conclusion might even apply to all type 2 diabetic patients.

-- Sir Brian Jarman, PhD, FRCP, FRCGP, FFPHM, FMedSci
Source

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: A randomised placebo-controlled trial. Lancet 2003 Jun 14; 361:2005-16.

Lindholm LH. Major benefits from cholesterol-lowering in patients with diabetes. Lancet 2003 Jun 14; 361:2000-1.

Chlamydia Pneumoniae Infection Interacts With Other Cardiovascular Risk Factors

By Will Boggs, MD

NEW YORK (Reuters Health) Aug 12 - The presence of Chlamydia pneumoniae-specific immunoglobulin A adds to classic coronary risk factors to increase the risk of acute myocardial infarction, according to a report in the August American Heart Journal.

"We need to extend our concern from classical risk factors to the newly established risk factor, inflammation," Dr. Hiroshi Sato told Reuters Health.

Dr. Sato from Osaka University Graduate School of Medicine in Osaka, Japan and colleagues assessed C. pneumoniae IgG and IgA titers and classic cardiovascular risk factors in 618 patients with acute myocardial infarction (AMI) and in 967 controls from the general population.

C. pneumoniae IgG antibody titers did not differ between patients and controls, the authors report, but more patients than controls had C. pneumoniae IgA antibody titers above each of the various cutoff values used.

Most of the excess risk of AMI was confined to those patients whose IgA titers were in the 75th or higher percentiles, the report indicates, and patients with the highest IgA titers (95th percentile) faced a 75% higher risk of AMI after adjustment for other risk factors, age, and sex.

The presence of higher IgA titers increased the AMI risk associated with obesity, hypercholesterolemia, and smoking, the researchers report.

In a multivariate analysis, only age was independently associated with C. pneumoniae seropositivity in patients with AMI or controls, the results indicate, and classic risk factors did not differ between C. pneumoniae-seropositive and -seronegative subjects.

"I recommend measuring C. pneumoniae IgA in patients with AMI," Dr. Sato said. "The anti-inflammatory effects of aspirin and HMG-CoA reductase inhibitors should be considered [for these patients],"

He added, "We are now checking single nucleotide polymorphisms (SNPs) which may relate to continuation of inflammation."

Am Heart J 2003;146:324-330.