BMC Neurology BioMed Central

Study protocol Open Access

Getting the Balance Right: A randomised controlled trial of
physiotherapy and Exercise Interventions for ambulatory people
with multiple sclerosis
Susan Coote*1, Maria Garrett1, Neasa Hogan1, Aidan Larkin2 and
Jean Saunders3

Address: 1Department of Physiotherapy, University of Limerick, Limerick, Ireland, 2Project Coordinator, Multiple Sclerosis Society of Ireland,
Galway, Ireland and 3Statistical Consulting Unit, University of Limerick, Limerick, Ireland
Email: Susan Coote* - susan.coote@ul.ie; Maria Garrett - maria.garrett@ul.ie; Neasa Hogan - neasa.hogan@ul.ie; Aidan Larkin - aidanl@ms-
society.ie; Jean Saunders - jean.saunders@ul.ie
* Corresponding author

Published: 16 July 2009 Received: 29 April 2009

Accepted: 16 July 2009
BMC Neurology 2009, 9:34 doi:10.1186/1471-2377-9-34
This article is available from: http://www.biomedcentral.com/1471-2377/9/34
© 2009 Coote et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background : People with Multiple Sclerosis have a life long need for physiotherapy and exercise interventions
due to the progressive nature of the disease and their greater risk of the complications of inactivity. The Multiple
Sclerosis Society of Ireland run physiotherapy, yoga and exercise classes for their members, however there is little
evidence to suggest which form of physical activity optimises outcome for people with the many and varied
impairments associated with MS.
Methods and design : This is a multi-centre, single blind, block randomised, controlled trial. Participants will be
recruited via the ten regional offices of MS Ireland. Telephone screening will establish eligibility and stratification
according to the mobility section of the Guys Neurological Disability Scale. Once a block of people of the same
strand in the same geographical region have given consent, participants will be randomised. Strand A will concern
individuals with MS who walk independently or use one stick to walk outside. Participants will be randomised to
yoga, physiotherapy led exercise class, fitness instructor led exercise class or to a control group who don't change
their exercise habits.
Strand B will concern individuals with MS who walk with bilateral support or a rollator, they may use a wheelchair
for longer distance outdoors. Participants will be randomised to 1:1 Physiotherapist led intervention, group
intervention led by Physiotherapist, group yoga intervention or a control group who don't change their exercise
habits. Participants will be assessed by physiotherapist who is blind to the group allocation at week 1, week 12
(following 10 weeks intervention or control), and at 12 week follow up. The primary outcome measure for both
strands is the Multiple Sclerosis Impact Scale. Secondary outcomes are Modified Fatigue Impact Scale, 6 Minute
Walk test, and muscle strength measured with hand held dynamometry. Strand B will also use Berg Balance Test
and the Modified Ashworth Scale. Confounding variables such as sensation, coordination, proprioception, range
of motion and other impairments will be recorded at initial assessment.
Discussion : Data analysis will analyse change in each group, and the differences between groups. Sub group
analysis may be performed if sufficient numbers are recruited.
Trial registration: ISRCTN77610415

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Background reviewed for those with an EDSS of 0–6 and for those with
Multiple sclerosis (MS) is a demyelinating, degenerative an EDSS of >6.
disease of the central nervous system. It can cause a mul-
titude of motor, sensory, visual, psychological, sexual, and The literature published since the Cochrane review[6] on
bladder and bowel symptoms. Europe has the highest the specific benefits of physiotherapy and exercise inter-
estimated prevalence of MS in the world at 80 per ventions for PwMS with an EDSS of 0–6 suggests that aer-
100,000[1] and in Ireland people with MS (PwMS) make obic exercise positively influences fitness, walking speed,
up the largest diagnostic group (9.2%) of those registered gait parameters, disability, fatigue and quality of life [11-
on the National Physical and Sensory Disability Data- 16]. Additionally, Progressive Resistance Exercise (PRE)
base[2]. MS is a progressive disease that can lead to disa- improved strength, walking over short distances,
bility, functional limitations and a poor quality of life improved stepping time, improved fatigue and reduced
(QoL). In a recent profiling study[3], 59% of the people the physical impact of MS[16]. However, there was only
with MS had EDSS scores between 0 and 4.0, 18% had one intervention followed up at three months [17-20] and
scores of 6.0 ± 6.5, and 6% had a score of 8.0. It is sug- this found that benefits were maintained for the Func-
gested that within 15 – 25 years of diagnosis nearly 50% tional Assessment of MS and the MSIS-29 only.
of PwMS will reach an EDSS score of at least 6 meaning
they will require the use of a walking aid[4,5]. PwMS have Several studies have combined aerobic exercise and PRE,
a normal life expectancy, therefore, they may have to live [21] and have reported no deleterious effects. However,
for many years with severe mobility problems and have a the intervention has been delivered as a home exercise
need for regular therapeutic intervention. Therefore the programme, bringing into question the issue of compli-
importance of appropriate and timely intervention in ance.
patients with relapsing disease to slow or prevent the accu-
mulation of physical disability associated with progres- To date, a lot of studies considering exercise interventions
sive types of disease is apparent. for people with an EDSS of < 6 have a moderate to high
risk of bias – mostly due to lack of blinding or not having
There is a significant body of evidence to suggest that exer- a control group, questioning the validity of the results.
cise programmes have a beneficial effect on both disease More rigorous methodologies are needed to eliminate this
symptoms and general fitness of people with MS who are bias and allow firm conclusions to be drawn.
ambulatory [6]. The authors recommend that future stud-
ies should adhere to methodological principles of alloca- Yoga is frequently provided to its members by MS Society
tion concealment, blind recording and description of of Ireland (MSI) and has been show to be feasible in this
dropouts. population[22] however, only one small scale study has
evaluated it.
A meta-analysis of physical activity levels of people with
MS concluded that they engage in significantly less physi- It is possible that the exercise needs of this group of PwMS
cal activity than non-diseased populations[7]. In a study can be met by fitness instructors in gyms providing a non
investigating coronary heart disease risk in women with medical environment for exercise participation. This study
MS, those who had higher levels of leisure time physical therefore aimed to assess the effect of intervention deliv-
activity had a lower risk of secondary disease[8] and ered by fitness instructors, following assessment by a
ambulatory women with MS who took part in a resistance physiotherapist to ensure that no impairments existed
training programme also had a decreased risk of coronary that would prevent this.
artery disease[9]. A meta analysis of the relationship
between exercise and quality of life for people with MS A review of the literature for those with an EDSS score > 6
suggested that quality of life can be optimally improved suggests that a multitude of interventions can be benefi-
through exercise programmes less than three months cial in this population. These include physiotherapy, aer-
duration, involve greater than 90 minutes a week, and be obic exercise and strength exercise. It is unclear, however,
evaluated using MS specific measures[10]. Given the pos- to what extent the results can be applied to PwMS with an
itive relationship between physical activity and improving EDSS score of >6 as PwMS with EDSS scores of between 1
disease symptoms and quality of life, and reducing sec- and 6.5 were given the same interventions even though
ondary disease, it is essential that the optimal physical their treatment needs vary greatly. The positive outcomes
activity programmes are identified. were specific to the intervention used, for example, bal-
ance rehabilitation showed improvements in balance
In physiotherapy practice it is acknowledged that people scores [12] and aerobic exercise showed improvements in
with differing levels of mobility will have varying treat- fitness levels[23]. The optimal type of intervention and its
ment needs therefore the literature has been separately frequency and duration for this population is, however,

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still unknown and further research is needed to develop Participants

treatment recommendations for clinicians treating PwMS Anyone with a diagnosis of MS confirmed by their con-
with more severe mobility problems. In completing a sultant physician or neurologist, resident in the republic
large multi centre trial it may be possible to examine the of Ireland is eligible to take part. It is not necessary for par-
subgroups of individuals with specific needs to establish ticipants to be members of MSI.
what intervention is best for which sub groups of people
with differing impairments in order to allow clinicians to People with MS will be excluded from the study if they are
deliver the optimal intervention to match the differing currently experiencing an exacerbation of symptoms due
impairments. to relapse, have had steroid treatment within 3 months of
the baseline measurement, are pregnant at the time of
The Getting the Balance Right (GTBR) projects is a collab- referral, or are under 18 years of age
oration between the Physiotherapy Department of the
University of Limerick, and MSI that aims to both deliver Recruitment and Randomisation
and evaluate physiotherapy and exercise interventions for Participants can be referred to the project by themselves,
people with MS. There are many unknown variables to be their carer, MSI, Chartered Physiotherapists, Neurologists,
examined in this population, therefore in order to deter- GPs or Clinical nurse specialists.
mine the research questions with the highest priority a
group of physiotherapists specialising in MS, the regional Referral will be made to the ten regional offices of MSI. A
offices of MSI and the latest findings from the literature form completed over the telephone will be used to screen
were consulted. The conclusions of this consultancy for exclusion criteria and to stratify according to mobility
period was that the overarching question was what exer- level. Participants will then be sent the information leaflet
cise interventions should MSI provide for their members for the relevant strand and a consent form. The consent
in order to optimise function, reduce fatigue and increase form will be returned to the regional office and consent-
quality of life. ing subjects will be coded by region, number and then
strand (e.g. MW1A, MW2A, MW3B...). The participants
Methods and design General Practitioner will be sent a letter informing them
Design of their participation and enclosing the relevant informa-
This will be a multi-centre, prospective, single blinded, tion leaflet. Once consent for 8 people of a strand is
block randomised controlled trial. Participants will be obtained, the regional office will contact the National
stratified according to mobility level using the mobility Coordinator who will allocate that block of subjects to the
section of the Guys Neurological Disability Scale[24]. control or an intervention condition. Block randomisa-
Those who score 0, 1 or 2 are stratified to stand A, those tion was done using a sealed enveloped with pieces of
scoring 3 and 4 to strand B. For each strand blocks of sub- paper with the four groups written on them. The paper
jects will be randomised to one of the interventions or to chosen will be emitted each time until four groups are
the control group. chosen to ensure even numbers of groups. When the fifth
group is ready to go, all the pieces of paper will be
Strand A will concern individuals with MS who walk inde- returned to the envelope, and so on. The order of alloca-
pendently or use one stick to walk outside. The objective tion to control or intervention will be concealed from the
is to compare the immediate and long term effect of yoga, regional offices until they have scheduled that block of 8
physiotherapy led exercise class, fitness instructor led exer- people for assessment.
cise class to a control group who don't change their exer-
cise habits. Assessment
Each participant will be assessed by a blinded assessor
Strand B will concern individuals with MS who walk with who is unaware of group allocation. Assessors will attend
bilateral support or a rollator, they may use a wheelchair training days in order to standardise the measurements.
for longer distance outdoors. The objective is to compare
the immediate and long term effect of 1:1 Physiotherapist Assessments will be carried out at baseline (week 1), post-
led intervention, group intervention led by Physiothera- intervention (week 12) and at follow-up (week 24). The
pist, or group yoga intervention to a control group who following outcome measures will be used for all three
don't change their exercise habits. assessments: Multiple Sclerosis Impact Scale 29 version 2
(MSIS), Modified Fatigue Impact Scale (MFIS), six minute
The study protocol was approved by 10 regional ethics walk test (6MWT), physiological cost index (PCI), and
committees in the Republic of Ireland hand held dynamometry (HHD). In addition the Berg
Balance Scale (BBS) and the Modified Ashworth Scale
(MAS) will be used for strand B. As equipment for PCI and

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HHD are not available to all assessors some participants sis[31]. It was found to have good concurrent validity and
will not have these measures recorded. The more physi- a cut off score of 44 (out of 56) was established as a crite-
cally demanding outcome measures were separated to rion to identify PwMS who have a high risk of falls. The
avoid fatigue and so the order of testing for strand A was reliability of the BBS has also been examined in
6MWT including PCI, MSIS, HHD, MFIS. For strand B it PwMS[32,33]. It was found to have high test retest and
was 6MWT including PCI, MSIS, BBS, MFIS, MAS, HHD interrater reliability, both having intraclass correlation
coefficients (ICCs) of 0.96. The BBS is widely used by
A standardised assessment at baseline considered the par- physiotherapists and takes approximately 15 minutes to
ticipants suitability for exercise and measured confound- complete. It is also used in other studies evaluating inter-
ing variables such as level of sensory loss, coordination ventions in PwMS[34], therefore, making it possible to
deficits etc. compare results to other studies.

The 6 Minute Walk Test including Physiological Cost Index The Modified Fatigue Impact Scale (MFIS)
In the 6MWT, the participants will be asked to walk for a The MFIS is a structured self report questionnaire. The
period of six minutes and the distance walked is recorded. subscales are how fatigue relates to physical, cognitive and
Paltamaa et al[25] found that the 6MWT is highly reliable psychosocial aspects functioning. This version has a Cron-
in people with mild to moderate MS (EDSS 2–6.5) and bachs alpha of .81 indicating good reliability[35]. A recent
Marrie and Goldman[26] validated the 6MWT as an out- review of the literature[36] suggested that the MFIS may
come measure for PwMS. Subjects will be instructed to have greater sensitivity to change than the Fatigue Severity
walk as quickly and safely as possible as recommended by Score. Administration time is approximately 5 to 10 min-
Fry and Pfalzer[27]. utes.

During the 6MWT the heart rate of each participant will be The Modified Ashworth Scale
recorded in order to calculate the PCI. The PCI is a meas- The Modified Ashworth Scale (MAS) is a 6 point ordinal
ure of energy is measured by calculating the heart rate dur- scale that is used to measure spasticity. It is designed to
ing locomotion minus the resting hear rate divided by the grade the level of resistance encountered during passive
speed of walking[28]. movement and scores range from 0 (no increase in muscle
tone) to 5 (rigidity of the affected limb). It is widely used
The exercising heart rate will be measured by a polar mon- in clinical practice and has been shown to have good to
itor (a strap around the chest and a watch). The resting excellent interrater and intrarater reliability in people with
heart rate will be measured by the patient first thing in the spasticity post stroke[37]. Its validity has been determined
morning using the carotid pulse in the neck. with the use of electromyographic recordings of muscle
activity in patients with spinal cord injury [38-40]. It has
The Multiple Sclerosis Impact Scale 29 (MSIS-29) also been used in other studies evaluating interventions
The MSIS – 29 is a measure of the physical and psycholog- for PwMS[41], making comparisons between results pos-
ical impact of MS from the patient's perspective. The MSIS sible.
– 29 was found to have good psychometric properties in
an Irish Community dwelling population of PwMS[29]. Handheld Dynamometry
The MSIS – 29 is an easy instrument to administer, taking Handheld dynamometry has been found to be more reli-
approximately 5 minutes to complete. All estimates of able than manual muscle testing (REF). The standardised
reliability using Cronbach's alpha were in excess of the positions described by Bohannon[42,43] will be used to
recommended 0.80. The convergent and divergent valid- measure strength in both the upper limbs and the lower
ity is established and it has moderate sensitivity to change. limbs.
It has been shown to have better responsiveness com-
pared to SF – 36 and the FAMs which also consider quality Sample size calculations
of life[30]. High scores on the MSIS-29 indicate greater Strand A
impact of MS. Based on a pilot study and the MSIS physical component
scores then a sample size of 60 in each group will be suf-
The Berg Balance Scale (BBS) ficient to show a similar probability (0.329) that an obser-
The BBS is a clinical scale that evaluates balance in sitting vation after intervention will be less than before
and standing and rates performance from 0 (cannot per- intervention as in the pilot study (mean before interven-
form) to 4 (normal performance). The scale has fifteen tion 62.4, after intervention 53.6). This is based on using
items that explore the ability to sit, stand, lean, turn and the Wilcoxon Signed Rank Test, significance level 0.05
maintain the upright position on one leg. The BBS has and a power of 90%.
been validated for use in people with multiple Sclero-

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Strand B achieve gains in strength. Participants will be educated

Based on a pilot study and the MSIS physical and psycho- about the overload principle and that delayed onset of
logical component scores then a sample size of 22 in each muscle soreness is a normal phenomenon. After five
group will be sufficient to show a similar probability weeks of attending the class, participants will be advised
(0.217) that an observation after intervention will be less to complete a second hour of strengthening themselves at
than before intervention as in the pilot study (mean home.
before intervention 23.0, after intervention 18.8). This is
based on using the Wilcoxon Signed Rank Test, signifi- A second component of the class will be advice regarding
cance level 0.05 and a power of 90%. aerobic exercise. In the first class, 10 minutes will be
devoted to formally explaining aerobic exercise, Uhtoff's
As parametric tests require less subjects for the same phenomenon (whereby increasing heat in people with MS
power these numbers should be sufficient even if these can temporarily exacerbate symptoms) and the evidence
tests are used instead of the non-parametric tests given supporting aerobic activity.
above.
Each participant will be given a target heart rate. This will
Interventions be calculated using the Karvonen formula which is: Target
The physiotherapy interventions for strands A and B are Heart Rate = Resting Heart Rate + 65% (Maximum Heart
standardised and based on the latest evidence for practice Rate).
in order to allow reproduction of the programmes. The
Yoga and Fitness Instructor interventions are not speci- The participants will be advised in the initial assessment
fied, in order to represent normal practice, but are well how to get their resting heart rate, by feeling their carotid
documented to allow comparison later. pulse for 30 seconds first thing on waking. The first beat
they feel will be zero. As a maximal exercise test will not
To ensure standardisation of physiotherapy interventions, be conducted, each participant's age predicted maximum
training for those physiotherapists delivering the pro- heart rate will be used as the target HR (i.e. 220 – age). If
grammes will be held on three occasions, supporting doc- they are unable to detect a pulse they will aim to exercise
umentation will be provided and follow up advice and at a Rate of Perceived Exertion level of 11 – 14.
information for deliverers was supplied as necessary by e-
mail and telephone. The content of the interventions for Participants will be initially asked to complete two ses-
both strands is described below. The attendance and par- sions of independent aerobic activity per week for twenty
ticipation of each study participant will be documented – thirty minutes. From week 5, they will be asked com-
on a weekly basis. plete this three times a week. Participants can choose the
type activity that they did (i.e. swimming/walking/run-
The control groups in both strands will not receive any ning/cycling). They will take their pulse every ten minutes
intervention for the 12 weeks and were told to continue to ensure they are achieving the correct intensity.
with their normal routine. Once the control period is over
participants will receive the treatment of their choice but Intervention 2 – Fitness Instructor led group exercise
the response to this will not be assessed as part of this trial. The fitness instructors be registered by the National Coun-
cil for Exercise and Fitness. They will be given a standard-
Strand A ised pack in order to document the interventions.
Intervention 1 – Physiotherapy led strength and aerobic training
Participants will attend an hour long circuit class once a Intervention 3 – Yoga classes
week for ten weeks. This will be a circuit style class consist- Yoga instructors will be accredited by the Yoga Federation
ing of Sit to stand/squat, bridging, resisted shoulder flex- of Ireland. They will be given a standardised pack in order
ion, walking/bike, resisted elbow flexion, lunges or to document the interventions.
resisted knee extension, hip extension, calf raises. All exer-
cises will be completed at 50 – 80% of the participants' Strand B
one-repetition-maximum and the load will be increased Intervention 1 – Group Physiotherapy
by 2 – 5% when twelve repetitions are easily achieved. The Participants attended a weekly hour long class for 10
aim is for the participant to be failing on the last repeti- weeks. The circuit style class will consist of exercises that
tion. If the next available load is higher than 2 – 5% (such combine strength and balance. Participants will complete
as going from 1 kg to 2 kg in resisted shoulder flexion) the 6 different exercises at each class. The exercises were
participant can increase the repetitions so that they are adapted from the falls prevention literature where similar
still failing to achieve full range on motion on the last one. programmes have been seen to improve, balance and
The primary aim is to achieve "overload" of the muscle to reduce the number of falls in an elderly population.

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The six exercises and possible progressions are described 4. Step ups, progressed by altering;
below. These are to be performed in sets of 12. When a
participant is able to perform 12 repetitions of an exercise Support – Participants may begin with bilateral support,
safely this can be progressed up to 3 sets of 12 repetitions. and then decrease to unilateral support, then to no sup-
When a participant can perform 3 sets safely the exercise port.
will be progressed so as to continuously challenge the par-
ticipant. Not all participants will progress through all the Stepping – Initially participants may step onto step and
exercises. The progression is dependent on the ability of back to starting position, then step onto step and over,
the participant and their safety while performing the exer- and then onto step, over and backwards to starting posi-
cises tion.

1. Sit to Stand, progressed by altering; Step Height – When participants are comfortable with all
directions of stepping step height may be increased.
Hand Positioning – Participants may initially need to use
hands for support to rise from chair, then progressing to 5. Side Stepping – progressed by altering;
hands by side and then to hands across chest.
Support – Participants may begin with bilateral support,
Seat Height – Participants may initially require a higher and then decrease to unilateral support, then to no sup-
seat height which can be lowered to increase the intensity port.
of the exercise.
Number of steps – Initially participants may only take one
Repetitions – To be performed in sets of 12 and number step in each direction. This can be increased as partici-
of sets to be increased to 3 as participant progresses. pants' ability increases.

Weights – Handheld weights may be given to participants If a participant is unable to take a step to the side, weight
who need further progression. shifting from side to side in standing may be performed
and progressed to stepping when the participant is able.
2. Squat, progressed by altering;
6. Tandem Stepping/Walking – progressed by altering;
Support – Participants may initially need bilateral sup-
port, this can be decreased to unilateral and then to no Support – Participants may begin bilateral support, and
support as participants' ability increases. then decrease to unilateral support, then to no support.

Repetitions – To be performed in sets of 12 and number Stepping – Participants may initially just place one foot in
of sets to be increased to 3 as participant progresses. front of the other and hold this position. The number of
steps can then be increased as the participant progresses.
Weights – May be given to participants who are able to
perform 3 sets of 12 squats safely with no support. Crossover – Participants may become competent at tan-
dem walking. This can then be progressed to one foot
3. Calf Raises, progressed by altering; crossing over in front of the other.

Support – Participants may initially need bilateral sup- Intervention 2 – One on one Physiotherapy
port, this can be decreased to unilateral support and then These participants will receive individual treatment
to independent calf raises as participant progresses. depending on the problem list and goals established by
the Chartered Physiotherapist who was treating them. The
Repetitions – To be performed in sets of 12, to be content of the intervention will be recorded for each indi-
increased as participant progresses. vidual treatment session. The duration of the individual
sessions will be the same as the group led physiotherapy.
Other options – If participants are able they may perform
single leg calf raises or if they can perform 3 sets of 12 Intervention 3 – Yoga
independent calf raises weights can be added as further Participants will attend a weekly yoga class of approxi-
progression. mately one hour's duration. All yoga instructors will be
members of The Yoga Federation of Ireland and will keep
The following three exercises are to be completed within a log of the content of each yoga class.
parallel bars.

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Statistical Analyses 4. Confavreux CV, Vukusic S, Adeleine P: Early clinical predictors

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D, Chetta A: Effect of Aerobic Training on Walking Capacity
Authors' contributions and Maximal Exercise Tolerance in Patients With Multiple
SC is PI for the trial and wrote this paper with contribu- Sclerosis: A Randomized Crossover, Controlled Study. Phys-
ical Therapy 2007, 87(5):545.
tions from all authors. MG and NH are PhD students 16. McCullagh R, Fitzgerald AP, Murphy RP, Mater GC: Long-term ben-
working on strand A and B respectively. They conducted efits of exercising on quality of life and fatigue in multiple
the literature reviews and developed the study protocol sclerosis patients with mild disability: a pilot study. Clinical
Rehabilitation 2008, 22(3):206-214.
under the supervision of SC. AL is project coordinator for 17. Surakka J, Romberg A, Ruutiainen J, Aunola S, Virtanen A, Karppi S,
MS Ireland and contributed to the practical aspects of Mäentaka K: Effects of aerobic and strength exercise on motor
fatigue in men and women with multiple sclerosis: a rand-
study design and implementation and proof read this omized controlled trial. Clinical Rehabilitation 2004,
paper. JS is Executive Director of the Statistical Consulting 18(7):737-746.
Unit and performed power calculations and gave advice 18. Romberg A, Virtanen A, Ruutiainen J, Aunola S, Karppi SL, Vaara M,
Surakka J, Pohjolainen T, Seppänen A: Effects of a 6-month exer-
on statistical analysis of the data. cise program on patients with multiple sclerosis: a rand-
omized study. 63(11):2034-8.
19. Romberg A, Virtanen A, Aunola S, Karppi SL, Karanko H, Ruutiainen
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42. Means KM, Rodell DE, O'Sullivan PS: Balance, Mobility, and Falls scientist can read your work free of charge
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at-risk older people: a randomised controlled trial. Age and
Ageing 2003, 32(4):407-414. available free of charge to the entire biomedical community
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