Jean-Louis Lamboray of the World Bank uses this story to illustrate
what can happen when aid to a poor nation is not coordinated. The country
can find itself with an abundance of help in some areas – perhaps more than
it knows what to do with – while basic needs are left unmet.

Lamboray, who is acting health adviser at the Population, Health and
Nutrition Department of the World Bank, says haphazard aid giving has damaged
health services in some countries. They will continue to suffer, he says,
unless donor agencies start to work together. This message is being taken
to heart at the WHO in Geneva, where John Martin has his own version of
Lamboray’s tale. Go behind almost any hospital in the Third World, he says,
and you will see the fruits of inappropriate donations – mounds of equipment
that is wasted because there is no money to run it. Martin is second in
command of a division set up by the WHO earlier this year specifically to
bring some coordination to foreign aid for health care.

One of the commonest problems in Third World countries is the development
of ‘aid enclaves’, says Lamboray. A country might have family planning services
run by the Dutch, say, a childhood immunisation programme organised by UNICEF,
and services to control diarrhoeal disease paid for by the Germans. Or some
regions might have good services of a particular kind, while people elsewhere
go without. ‘All these org-anisations are likely to have different approaches,’
Lamboray says. ‘As a result, the country risks losing the capacity to steer
the whole health sector in the way it wants.’

The policies of donor nations make their biggest impact in some of the
least developed countries, where foreign aid can provide a huge slice of
the health budget. According to the World Bank, an average of 20 per cent
of health spending in Africa, excluding South Africa, comes from foreign
aid. In Burkina Faso, Chad, Guinea-Bissau, Mozambique and Tanzania, more
than half of all expenditure on health comes from foreign aid. In Mozambique,
aid accounted for 90 per cent of capital expenditure for health in 1991.

The World Bank has called for the national and international agencies
and nongovernmental organisations that offer health aid to coordinate their
efforts more, and concentrate on giving basic clinical services rather than
high-profile projects such as big hospitals. For this to happen, donors
will have to make big adjustments to their programmes. The World Bank points
out that between 1988 and 1990 Japan spent more than 33 per cent of its
bilateral aid for health on building hospitals, while France spent 25 per
cent and Germany and Italy nearly 15 per cent.

One country with first-hand experience of what this approach means is
Zambia. Katele Kalumba, the deputy minister of health, says plenty of hospitals
in Zambia are white elephants. ‘We had some very good structures but there
was nothing inside, the buildings were just empty shells,’ he says. ‘There
were no medical records systems, no financial management systems, no quality
assurance systems.’ What he calls the ‘software aspects’ of health care
had been completely neglected.

If the right backup is not provided, the results can be disastrous.
In the Maldives, for example, a ‘free’ hospital consumed half the country’s
health budget (This Week, 16 April). In other cases, initial gains are quickly
lost. Zambia managed to immunise between 80 and 90 per cent of children
under the WHO/UNICEF Expanded Programme on Immunization during the mid-1980s.
But by 1990, when the money from abroad began to dry up, coverage was down
to 40 per cent. ‘That worried us,’ Kalumba says. ‘When Frederick Chiluba’s
government came into power in 1991, we decided to move towards national
health care reform with the emphasis on sustainability.’

This plan happened to coincide with an initiative by a small team within
the WHO to promote sustainable health services. To achieve this, the team
aimed to coordinate donations from abroad to meet the recipient’s needs
in a way that would ensure health services did not collapse after foreign
aid was withdrawn. Working with the WHO team, Zambia designed a coordinated
programme which donors were confident about investing in. As a result,
the country received ‘massive support’ from foreign donors, Kalumba says.

The WHO team, led by Michel Jancloes with Martin as his deputy, has
since been given the status of a full division, the Division of Intensified
Cooperation with Countries in Greatest Need. ‘We started out by considering
what WHO was not doing well, or not doing well enough, for the poorest countries,’
Jancloes says.

Local solutions

In the past, the WHO has focused on regional or global programmes for
controlling diseases. Now Jancloes and his team are trying to tailor health
care policies to individual countries, taking into account such factors
as the political system, level of poverty, environment and resources. ‘You
can’t just come out with a global menu in Geneva and expect it to be relevant
everywhere, because it won’t be,’ says Martin.

The team starts by meeting government officials to identify problems,
estimate needs and draw up a plan to improve the health care system. ‘At
these meetings, we try to make links between the local and the central levels,
between economic and social sectors and between various donors,’ says Jancloes.
Rather than focusing solely on health ministers, the team targets ministers
of finance, planning and transport.

Jancloes and his colleagues stress the links between health and economic
development. They describe, for example, how the WHO’s programme to eradicate
the fly-borne disease onchocerciasis, or river blindness, has made 24 million
hectares of land in West Africa habitable and available for development.
Conversely, improving health services may depend more on factors such as
building roads and the availability of fuel and power than on providing
medical staff, drugs or new technology.

To stress this point, Dominique Egger, another member of the WHO team,
uses the example of Guinea-Bissau, where only a minority of people are within
easy reach of basic health services. With the team’s help, the authorities
in Guinea-Bissau decided to strengthen the management of health services
in outlying areas. ‘In one region, medical staff knew that there were about
90 basic health posts,’ says Egger. ‘But no one had a clue how many were
still functioning because they had not been supervised for years. No one
had visited them because there was no transport.’

A series of workshops to help local staff agree on priorities led to
an inventory of the cars, bicycles and motorbikes available to workers,
and what spare parts might be needed. Managers were then able to present
donors with a list of supplies they needed, including new vehicles.

But every country has different problems. In Vietnam, for example, many
health centres operated effectively but were suffering because the government
cut the heavy subsidies it used to give them. The team’s focus there has
been to meet the shortfall by helping the country develop health insurance
schemes, starting with training a team of health economists.

Jancloes and his team still face huge obstacles. The division has $3.1
million a year to spend, about 2 per cent of the WHO’s annual budget. But
this is a tiny fraction of the $4.8 billion that developing countries receive
in aid for health care.

Jancloes admits that there is ‘very strong resistance’ to change, even
within the WHO. ‘We are a medical organisation with many people who have
highly specialised qualifications who therefore see problems in a very fragmented
way,’ he says. ‘WHO’s budget has always been structured by diseases and
by programmes, and people like to protect their territory. It’s not going
to be easy to change these attitudes.’ But everyone agrees in principle
that the division’s approach is needed, he says. Part of its brief is to
improve coordination between other WHO divisions, Martin says, so its influence
should be felt more widely than its limited budget would suggest.

Reluctant

Aid-giving nations, too, may be reluctant to change their policies.
Martin says donors often pay for the construction of a hospital and sometimes
some equipment. ‘But they do not usually give the recurrent costs, which
are required to keep the hospital running,’ he says. ‘The government has
to switch the money from elsewhere, and the danger is that it will come
from the community level, where money spent on health care buys much more.’

And developing countries often dislike rejecting what is offered, even
if it is inappropriate. Martin cites the case of Chad, where the team discovered
that two donors had offered to pay for two new hospitals in the capital
city, Ndjamena. Eventually, the government of Chad rejected these offers
after the WHO, the UN Development Programme and the World Bank told it that
accepting them would seriously handicap the health policy they were helping
to develop.

So why do donors choose to fund inappropriate projects? Kalumba says
it is because they like to see a hospital with a plaque proclaiming that
they helped to build it. By contrast, a management system to keep health
services running is less visible, he says. Martin says countries like to
give high-profile aid, perhaps because it gives them kudos. ‘Sometimes it
is done cynically for trade reasons, to boost their own exports, which does
more for the donor than for the recipient.’

Lamboray sees the launch of the new division as a step in the right
direction for the WHO. ‘This is not to say that WHO has not been getting
it right up to now,’ he stresses. ‘But this reflects an effort to strike
a more appropriate balance.’ The WHO’s great success was the eradication
of smallpox. But compared with many diseases that still exist, such as TB
or measles, it was easy to deal with: deliver an effective vaccine to everyone
in the world, and with just one injection it was gone. Other health problems
are more complex, and the new policy acknowledges this fact.

‘What we are working for is for WHO in its entirety to recognise that
health is a part of economic development,’ Jancloes says. ‘We have to put
health on the economic agenda of the poorest countries. That is the challenge
for the future.’

Sharon Kingman is a freelance journalist who specialises in health and
medicine.

The substance was discovered by Synergen, a biotechnology company based in
Boulder, Colorado. Frank Collins, the company’s vice-president of
neuroscience, says: ‘If this molecule works in the way that it seems to in
animals, we would hope to be able to restore significant function to
patients.’ Collins emphasises that more research into the safety and
efficacy of the growth factor has to be carried out before tests on people.

Parkinson’s disease affects 1 in 100 people over the age of 70, causing
symptoms such as tremor, rigidity and an inability to control movements. It
is caused by the death of cells in the substantia nigra of the brain. These
cells usually release the neurotransmitter dopamine.

Drug therapy with L-dopa can be used to boost the brain’s production of
dopamine, but the drug loses its effect eventually. So researchers have been
looking for a way of replacing the faulty cells with dopamine producing
cells from the brains of aborted fetuses. A growth factor that could promote
the survival of the transplanted cells might assist this process.

Researchers at Synergen set out to find a substance that would stimulate
dopamine-producing nerve cells but would not encourage other brain cells to
grow. They screened many types of cells from rat brains, concentrating on
glial cells, which provide support for nerve cells in the brain.

They identified a substance which they named glial cell line-derived
neurotrophic factor or GDNF. The researchers purified it and determined the
DNA sequence so they could identify the corresponding human gene. The human
gene was inserted into bacterial cells to produce a lot of the protein.
Tests on the purified GDNF showed that it helps to keep dopamine-producing
nerve cells alive (Science, 21 May). Usually, when nerve cells are cultured
about 70 per cent die within three weeks. But adding GDNF stops this. Other
nerve cells die at the usual rate.

The dopamine-producing cells grew in size and sprouted long fibres. The
growth factor also stimulated the cells to make more dopamine and to recycle
the dopamine they produce. Other cells that produce neurotransmitters did
not respond in this way. Nor did GDNF cause astrocytes (a type of glial
cell) to divide, as do many other nerve growth factors that act on
dopamine-producing nerve cells.

Collins says: ‘This molecule has the right effect on the dopamine-producing
neurons without having the wrong effects on other cells in the same region
of the brain.’

One crucial question was whether GDNF worked in the brains of live animals.
According to Collins, when it was injected into animals, it caused sprouting
of the dopamine-producing cells, increased production of an enzyme used to
make dopa-mine, and increased turnover of dopamine.

One problem will be getting such a large protein into the human brain.
Possible routes include inserting a fine tube directly into the brain or
carrier molecules that ferry the protein from the blood into the brain.
Alternatively, a smaller molecule could be found that would have the same
effect but could be taken orally or injected.

Stephen Dunnett, of the Medical Research Council Cambridge Centre for Brain
Repair, says the work opens up the possibility of inserting the gene for
GDNF into cells that could be transplanted into the brain alongside the
fetal cells – and so help these to survive. Fetal cells could also be
engineered to secrete growth factor.

Researchers hope that pictures of the molecule, taken with a powerful
electron microscope, will make it possible to identify the defects in nervous
transmission thought to play a part in conditions such as Parkinson’s disease.
More immediately, the work could lead to new drugs for treating myasthenia
gravis, a potentially fatal disease affecting one in 30 000 people, and
caused by the failure of the nervous system to transmit impulses to the
muscles.

Under normal circumstances, a nerve impulse arriving at a junction with
another nerve or a muscle triggers the release of molecules of a neurotransmitter.
One that has been widely studied is acetylcholine. After its release, the
neurotransmitter passes rapidly across the junction and latches onto receptor
molecules sitting on the membrane of the cell on the other side.

The receptor molecule changes shape when it binds to acetylcholine,
with the result that a tiny pore opens in the membrane. The formation of
the channel, which stays open for about a millisecond, allows about 10 000
ions of sodium and potassium to flood in and out of the cell, triggering
a second nerve impulse or causing the muscle fibre to contract.

The new images, obtained by Nigel Unwin of the Laboratory of Molecular
Biology in Cambridge, show the receptor molecule in great detail (Journal
of Molecular Biology, vol 230 (2)). Unwin says the site at which the neurotransmitter
binds is surrounded by proteins folded into three alpha helices set slightly
apart from a tunnel lined with protein subunits, which form the channel
that regulates the flow of ions.

Unwin works on the electric organ of the torpedo ray, which has many
acetylcholine receptors for producing electric shocks. The receptors, isolated
from their cells, form tubular crystals, which can be analysed with an electron
microscope. So far, the views show the molecule with the channel closed.
But Unwin hopes to take pictures which show the channel open.

Unwin says: ‘Once we can see what structural changes take place when
the channel opens, we can think about describing compounds that affect
its behaviour. It might be possible to design substances that make it open
for longer, make the channel smaller or that make the neurotransmitter bind
less or more easily to the receptor’.

In the case of the disease myasthenia gravis, he says, the body makes
an antibody that binds to the receptor, causing it to be sucked into the
cell. As a result, the nerve impulse cannot be transmitted to the muscles,
which weaken and waste away. ‘If we know the structure of the receptor,
particularly in the region where the antibody binds,’ says Unwin, ‘it might
be possible to design a small compound that binds to that site and protects
it.

In England and Wales, respiratory failure kills some 200 babies a year.
The condition is caused by, among other things, a failure of the circulation
to adapt to life outside the womb. The lungs cease to function properly,
depriving the body of oxygen. Until now, most babies have been put on a
mechanical ventilator which forces air in and out of the lungs. But some
of these babies die, and little is known about the quality of life of those
who survive.

The new study will compare this procedure with extra-corporeal membrane
oxygenation, or ECMO. In this technique, tubes are inserted into major
blood vessels close to a baby’s heart to divert the blood to a machine which
removes the carbon dioxide and adds oxygen. The blood is then warmed and
pumped back to the body. In theory, this will allow the lungs to rest and
repair themselves.

Adrian Grant, director of the Perinatal Trials Service at the National
Perinatal Epidemiology Unit in Oxford, one of the two coordinating centres
for the trial, says such a study will help to prevent medical and surgical
methods from being introduced without thorough testing. Before drugs are
licensed they must undergo stringent tests to determine their benefits and
risks, says Grant. But there is no national approval system for new techniques.

Concern over this has grown in recent months. At least two of the Royal
medical colleges are examining ways to control the introduction of new techniques
(‘Trial and error in the operating theatre’, ¿ìè¶ÌÊÓƵ, 7 November 1992).

ECMO has been used in the US for about 15 years. But according to Diana
Elbourne, deputy director of the trials service, research carried out so
far does not make it possible to judge whether ECMO is better than conventional
care. ‘In some countries such as the US, it is now virtually impossible
to do this research because the technique has become so widely accepted,
even to the extent that doctors fear being sued for not giving it,’ she
says.

Data from North America show that 80 per cent of 6000 babies given ECMO
survived. While this is encouraging, no one knows how these infants would
have fared if they had received conventional treatment, says David Field,
chairman of the trial’s steering committee and senior lecturer in paediatrics
at the University of Leicester.

Nor are there any conclusive studies comparing the long-term quality
of life of children who survived after being given ECMO with that of those
who were not. Elbourne says: ‘It is possible that ECMO saves lives but leaves
more severely disabled children. We just do not know.’ The British trial
will include health checks on children at one year and possibly against
at four or five.

The study, which is receiving funding of more than £1 million
from the Department of Health and the Scottish Office’s Home and Health
Department, will focus on children born at term rather than prematurely.
ECMO cannot be offered to very immature babies. Only infants who are very
sick will be eligible for the trial, which will allocate them at random
to either conventional care or the new technique.

David Ray and his colleagues at the Medical Research Council’s Toxicology
Unit in Carshalton, Surrey, made the discovery in the course of studying
the effects of neurotoxic chemicals (Neurotoxicology, vol 13(2), p 379).

Neurotoxins can either affect the function of the nervous system or
cause damage to the structure of the brain. One chemical being studied by
the researchers is 1,3 dinitrobenzene (DNB), which is used in the manufacture
of dyes and explosives. It causes characteristic damage to part of the
brainstem.

John Cavanagh, a colleague of Ray’s, noticed that the damage caused
by DNB was very similar to that caused by a variety of other substances.
The mystery was how they caused similar effects, despite being very different
chemically.

The team realised that all of these compounds interfered in different
ways with the energy metabolism of the brain. Also, the parts of the brain
that were particularly susceptible to these chemicals turned out to be those
with high metabolic activity.

The next step was to find out whether reducing the metabolic activity
of these parts of the brain could affect the chemicals’ ability to cause
damage. In the case of DNB, one part of the brain that was affected was
the inferior colliculus, which processes information about sound from the
ear before passing it to the higher centres of the brain where sound is
perceived.

One way to study metabolic activity in a tissue is by measuring its
uptake of glucose. The researchers perforated a rat’s ear drum on one side,
reducing the animal’s ability to hear on that side by 40 to 60 decibels.
They found that the corresponding inferior colliculus used 75 per cent less
glucose than the opposite side.

Next, Ray and his colleagues exposed animals which had a perforated
ear drum on one side to DNB. Normally, the damage caused by DNB is symmetrical.
But in these animals, glucose metabolism was lower than normal in the inferior
colliculus receiving reduced sound input. As a result, it was almost completely
protected from the effects of DNB.

To check that the effects really were due to the lower glucose metabolism
resulting from the animals’ impaired hearing, the researchers exposed them
to noise. This was loud enough to bring the metabolism of the inferior colliculus
back up to normal. When these animals were then exposed to DNB, the team
found that their brains had again become susceptible to the chemical.

‘The loud noise was making the damage from DNB worse, while quiet protected
the brain,’ says Ray. ‘This is true synergy because noise itself is incapable
of causing brain damage. For DNB and, we think, for the other metabolically
acting toxins, the hazard of the chemical seems to vary with the job the
brain is doing. If the brain is being forced into a state of high metabolic
activity, then the compound is more dangerous than it would otherwise be.’

If the same happens in people, the work could have implications for
industrial safety standards, says Ray. A certain level of noise may be safe
on its own, as may a certain level of exposure to a chemical. But the two
may not be safe in combination.

A study from Brazil has already suggested that this may be the case.
Tais Morata, working in Brazil, has found that factory workers exposed to
carbon disulphide in a rayon factory, and those exposed to toluene in a
print works, had hearing loss greater than would be expected from either
the noise levels or the chemical levels alone.

Ray and his colleagues now intend to do a further study in animals
to investigate the effects of the chemicals to which the Brazilian workers
were exposed.

A team working at the Institute of Cancer Research and the Royal Marsden
Hospital in London, in collaboration with scientists at the National Cancer
Institute in Bethesda, Maryland, has found that tamoxifen also works by
encouraging the cells surrounding a tumour to produce a ‘growth factor’.
They report their work, which was funded by the Cancer Research Campaign,
in this month’s issue of the American journal Cancer Research.

Anthony Colletta, leader of the team, says studies had shown that women
benefited from taking tamoxifen even if their breast cancer cells had no
oestrogen receptors. So the team began to look for alternative modes of
action for the drug.

One possibility was that the drug affected stromal fibroblasts, cells
that surround and support the tumour. Earlier laboratory studies had shown
that fetal fibroblasts, closely related cells from the fetus, respond to
tamoxifen by producing a natural peptide called transforming growth factor
beta-1 (TGF beta-1).

A later study to evaluate different treatments for women with breast
cancer gave the researchers the opportunity they needed to find out whether
a similar change took place in the breast. This study compared women who
had surgery immediately after breast cancer was diagnosed with those whose
surgery followed three months’ treatment with tamoxifen. The outcome was
the same; but Colletta’s group could compare samples of tumours from women
who had been taking tamoxifen with those who had never taken the drug.

The team found a ‘massive quantity’ of TGF beta-1 in all 10 samples
from the women who had been taking tamoxifen, says Colletta. The TGF beta-1
was produced by the stromal fibroblasts which surrounded the tumour cells.

‘Although the study was small, the difference in TGF beta-1 levels between
those who had and those who had not had tamoxifen was enormous and statistically
significant,’ says Colletta. ‘This means that tamoxifen, which is probably
the best therapy for breast cancer available, is not working solely through
blocking the oestrogen receptors, which everyone thought it did. Hopefully
we will be able to identify the mechanism by which this is happening and
then identify new compounds that will work even better against breast cancer.’

TGF beta-1 is found everywhere in the body, being concentrated mainly
in the platelets and the bone. Its normal functions include the repair of
wounds, healing, embryogenesis and organ manufacture. Laboratory work has
also shown that it strongly inhibits most types of epithelial tumour, including
those of the breast.

The gene for this growth factor has been cloned and several companies
manufacture its recombinant form. But Colletta says injections of TGF beta-1
are unlikely to prove an appropriate treatment for human cancers because
of possible side effects. However, because it has a very short half-life
in the body, of about five minutes, ‘most people believe that the way to
utilise the TGF beta-1 response therapeutically is to find ways of inducing
it locally using other pharmacological agents’, he says.

The WHO sent a mission to Romania in early February and its investigations
have confirmed the scale of the outbreak (This Week, 3 February). David
Heymann, an epidemiologist with the WHO’s Global Programme on AIDS and a
member of the mission, said the WHO identified 24 adults with AIDS and 123
who are infected with HIV. Eight adults have died from AIDS. Some 50 children
have AIDS and 550 are infected with HIV. So far, 68 children have died from
AIDS. Heymann said that the Romanian health ministry is fairly sure that
the outbreak is partly due to the practice of giving children so-called
‘microtransfusions’ of blood in order to nourish them.

There are about 50 000 children under the age of six in orphanages in
Romania, Heymann said. Many of these children were abandoned and malnourished.
Paediatricians in hospitals were also under pressure to account for increases
in the number of infant deaths, as any rise would counteract the government’s
policy of expanding the population.

For these reasons, doctors persisted with their practice of giving microtransfusions,
Heymann said. This involved giving the child 10 millilitres of blood per
kilogram of body weight. Whole blood was used to replace iron, and pooled
plasma was administered to give the child extra protein.

Heymann said that this practice is not used in developed countries.
Now that doctors in Romania understand the risks that it poses to health,
they have stopped it.

Not all the children found to be infected with HIV appear to have had
microtransfusions. This raises the possibility, Heymann said, that the infection
also spread as a result of using unsterilised needles and syringes. One
reason for the lack of sterilisation was that hospitals had no gas or electricity
supplies during the day. Many children also have hepatitis B, which is also
spread via unsterilised needles.

Doctors who tested children for HIV in July 1989 with kits supplied
by the WHO found 12 who were positive. The government then stopped the investigation.
Ceausescu banned testing for HIV because he believed that AIDS was a disease
of the West and due to Western decadence. Ion Patrascu, a veterinarian at
the Bucharest Institute of Virology, was threatened with imprisonment if
he continued investigations.

Dan Enachescu, the Romanian minister of health, and Jo Eirik Asvall,
the WHO’s regional director for Europe, have devised a seven-point plan
to tackle the epidemic:

physicians, nurses and social workers should attend courses on medical
care and AIDS;

patients and their families should be counselled;

an integrated national network for epidemiological surveillance should
be introduced;

a national health education policy stressing sexuality and family planning
should be developed;

staff should be trained as managers at regional and national levels;

teams of district health officers should be set up;

screening for the disease should take place.

One problem with screening, however, is a national shortage of test
kits. Romania will need 1.5 million kits a year. So far, only two months’
supply is guaranteed.

The WHO’s Global Programme on AIDS, funded by 16 nations, is expected
to help with the relief effort. The WHO is also expected to announce a plan
for tackling AIDS throughout Eastern Europe.

Another team from the WHO arrived in Romania last week and will stay
for as long as it is needed. It includes laboratory experts, blood screening
experts and clinicians. One goal is to coordinate the work of non-governmental
organisations to avoid duplication of effort.