Exercise

Effects of an exercise program on muscle performance in patients

undergoing allogeneic bone marrow transplantation
M Mello, C Tanaka and FL Dulley
Clinical Hospital of University of Sao Paulo, Sao Paulo Brazil
Summary:
Allogeneic bone marrow transplantation (BMT) has been
successfully used for the treatment of several hematolo-
gical malignancies; however, it is associated with trans-
plant-related toxicities such as functional impairment and
muscle weakness. In order to analyze how an exercise
program may inuence muscle strength in patients under-
going BMT, we carried out a prospective study assessing
patients from the pre-BMT phase to 16 weeks post-BMT.
In all, 18 patients underwent three trials: (1) pre-BMT, (2)
after marrow engraftment, and (3) 6 weeks after trial 2.
After trial 2, the patients were randomized in a control
group (CG) or treatment group (TG), which received a
6-week exercise program with active exercise, muscle
stretching and treadmill walking. The results obtained in
trial 1 showed similar values for CG and TG, as both
groups had muscle strength lower than normal patterns
based on data concerning age, sex and weight. In trial 2,
CG and TG showed similarly decreased values. In trial 3,
TG showed values higher than CG for all muscle groups
tested. These results suggest that the exercise program
was efcient in promoting an increase of muscle strength
after allogeneic BMT.
Bone Marrow Transplantation (2003) 32, 723728.
doi:10.1038/sj.bmt.1704227
Keywords: fatigue; exercise; physical therapy; rehabilit-
ation
Allogeneic bone marrow transplantation (BMT) has been
the treatment of choice for patients with a variety of
hematological diseases, providing them with good clinical
results and a longer life expectancy. However, BMT is
associated with transplant-related toxicities such as func-
tional impairment, which compromise full rehabilitation
and also contribute to the inherent morbidity associated
with the procedure itself.
1
It has been found that fatigue and weakness in
accomplishing daily living activities are the primary
symptoms of functional impairment.
2
It has been
reported that these symptoms are related to high-dose
chemotherapy for the treatment of breast
3,4
and prostate
cancer patients.
5
It has been hypothesized that the malignancy may
inuence this muscular fatigue as such fatigue has been
reported in other diseases. It is evident that in cancer
patients, physical, biochemical and psychological processes
are interwoven. Fatigue-inducing factors that have been
proposed include the primary impact of cancer tissue on
organic systems, higher cytokine production and changes in
the energy-transforming process.
6
The cancer therapy itself, such as chemotherapy or
radiotherapy, damage healthy cells throughout the body
leading to side effects including nausea, emesis, decreased
nutritional intake and anemia. Higher fatigue levels
associated with decreased levels of activity and lengthened
bed rest contribute to muscular catabolism and atrophy.
7
These side effects lead patients who have undergone
allogeneic BMT into a state of functional deprivation.
Graft-versus-host disease (GVHD) may be associated with
muscular ber necrosis.
8,9
Case reports have suggested that
muscle toxicity is related to the use of cyclosporin A
10,11
and glucocorticoids,
1216
which are often used in the
treatment of GVHD. Muscular atrophy and weakness
have also been reported in cardiac
17
and renal transplant
recipients,
18
who are receiving other immunosuppressive
drug treatments without chemotherapy. Despite the sever-
ity of this problem, research regarding muscle strength in
BMT recipients is difcult to nd in the literature.
Muscle strength assessment is a crucial component for
physical therapy diagnosis and treatment of patients with
fatigue and weakness. The degree to which a patients
muscle strength is impaired, however, can only be
established if the clinician is provided with appropriate,
objective normal values.
19
Manual muscle tests are standardized and very useful in
clinical settings, but fail to provide such precise values as
would a test using a device such as a dynamometer, which
provides quantitative data. Hand-held dynamometers are
mostly used to assess muscle performance even in patients
with neuromuscular diseases, who are severely com-
promised and may not tolerate aggressive or invasive
evaluations.
20
The maximal voluntary isometric contraction test is the
simplest method using a hand-held dynamometer because it
holds the velocity of joint motion and muscle length
constant.
21
Received 16 June 2002; accepted 8 April 2003
Correspondence: Dr M Mello, Av. Heitor Penteado, 1475 apto 503,
Sumare , Sa o Paulo 05437-001, Brazil.
E-mail: marciahm@usp.br
Bone Marrow Transplantation (2003) 32, 723728
& 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00
www.nature.com/bmt
There are few case reports in the literature regarding
respiratory muscle strength
2224
and the serial level of
muscle degradation enzymes.
25,26
In the literature there are reports that suggest that
exercise programs improve physical performance in pa-
tients undergoing BMT,
27
but these studies have evaluated
other parameters and did not directly address muscle
strength. The purpose of this study was to analyze how an
exercise program may affect the muscle strength of patients
undergoing BMT.
Materials and methods
Subjects
A total of 32 patients had initially been selected for this
study, 10 of them died, four were excluded because of
clinical complications and 18 concluded the study.
The criteria for inclusion were as follows: adult
recipients, controlled clinical status, absence of pain and
musculoskeletal or neurological disturbances, and no
evidence of cardiovascular, pulmonary or motor function
impairment. These clinical conditions were conrmed by a
normal electrocardiogram, echocardiogram and pulmonary
function tests, which were assessed in the pre-BMT period.
The Ethics Committee of the University of Sa o Paulo
approved the study and informed consent was obtained
from all participants.
All subjects underwent the muscle strength test in three
distinct trials: (trial 1) pre-BMT, (trial 2) after bone marrow
engraftment and (trial 3) 6 weeks after trial 2. After trial 2,
they were randomly assigned to a control group (CG) or a
treatment group (TG). The TG received an exercise
program with active exercises, muscle stretching and a
walking-based program on a treadmill lasting 6 weeks. The
characteristics of the groups are described in Table 1.
Instrumentation
The muscle strength test was performed with a Chatillon
Inc. strain-gauge dynamometer. The dynamometer incor-
porated a load cell and had a digital display. The
dynamometer was set to be read in Newtons (N), wherein
the limits ranged from 0 to 2.250 N.
Procedure
Maximal isometric voluntary strength tests (MIVS) from
four muscle groups of the upper limbs and ve muscle
groups of the lower limbs were collected to assess the
subjects muscle strength. A nonstretching strap was used
to connect the dynamometer to the lower or upper limbs to
be tested. The examiner always placed the dynamometer
perpendicular to the movement axis.
The muscle groups that were assessed as well as
the position of the joints and the dynamometer adopted in
the tests were standardized according to Bohannon.
21
The dominant side (DM) of the body was rst determined
by asking the subject which hand and foot were preferred to
throw and kick a ball. The contralateral side is known as
the nondominant side (NDM). Once the subject and the
dynamometer were placed in the proper position, the
subject was asked to pull the dynamometer strap, building
his or her maximal force so that he or she exerted the
maximum strength sustained for 3 s. This procedure was
repeated twice for each muscle group tested, and the rst
data collected were discharged as a patient learning
procedure. The whole process of data collection was
performed by the same examiner.
Exercise program
The exercise program was inspired by DIMEO
28
and was
carried out daily, on weekdays, over 6 weeks. This exercise
program was initiated during the inpatient period and was
concluded in the outpatient facility. The exercise program
comprised: (i) active range of motion exercises for shoulder,
elbow, hip, knee and ankle; (ii) stretching exercises for
hamstring, triceps surae and quadriceps muscles, and (iii) a
modied treadmill walking program; a schedule of intervals
for resting periods in the sitting position was needed
because of the inherent critical condition of patients after
BMT. This schedule progressed from ve sets of 3 min of
walking at a comfortable speed, with 3 min rest in between
each set in the rst week to two sets of 10 min of walking at
a comfortable speed intercalated with 20 min walking at an
accelerated speed in the 6th week (Figure 1).
Each therapy session lasted 40 min. The patient was
monitored during the exercise session by a Polar Sport
Tester monitor to guarantee that he or she would work
Table 1 Baseline characteristics of the groups
Characteristics Controlgroup Training group
N 9 9
Average age (years) 30.2 (1844) 27.9 (1839)
Gender Three males,
six females
Five males,
four females
Body mass index (kg/m
2
) 25.875.38 23.173.30
Disease
CML 6 4
AML 2 2
SAA 1 1
NHL, MDS 0 2
Conditioning protocol
Busulfan, melphalan 8 8
Busulfan, cyclophosphamide 1 1
Marrow engraftment (days) 19.7 (1523) 19 (1525)
Inpatient period (days) 35.4 (2357) 34.7 (2952)
GVHD (grade) 2 g0, 7 g II 3 g0, 4 g I, 2 g II
GVHD prophylaxis
Cyclosporine 3 mg/kg day,
begun day 1
Mehrotexate 15 mg/kg day,
on day 1
Mehrotexate 10 mg/kg day,
on days 3, 6, 11
GVHD treatment
Corticoesteroids 2 mg/kg day
CML=chronic myeloid leukemia; AML=acute myeloid leukemia;
SAA=severe aplastic anemia; NHL=non-Hodgkins lymphoma;
MDS=myelodysplastic syndrome.
Exercise program after allogeneic BMT
M Mello et al
724
Bone Marrow Transplantation
with a heart rate no higher than 70% of the maximal heart
rate calculated by Karvonens equation (220-age-HR
basal+60/70%). The exercise session was postponed to
the following day if the red blood cell count was above
10 mg/dl and/or platelets were above 20 000 cells/mg/dl.
Data analysis
Normalized ratio of strength was adopted to allow
comparative analysis to provide a stable reference. For
this normalization process, the collected data were divided
according to literature references, using specic regression
equations for each muscle tested.
21
It has been established
that normalized ratio of strength values 41 represent a
performance higher than normal, according to sex, age and
weight patterns, and normalized ratio of strength values
o1 represent a performance lower than normal. Average
(x) and standard deviations (s.d.s) were calculated for all
data. A Student t-test was used to determine if there had
been any differences between measurements obtained in the
trials for the correlated populations (same group, in the
three trials) and in the same trial for noncorrelated
populations (different groups in the same trial). An analysis
of variance (ANOVA) was used to determine comparisons
among groups in the three trials. Statistical signicance at a
level of 0.50 was used.
Results
(1) Same trial, different groups: The outcomes of muscle
strength, in trial 1, pre-BMT, were found to be similar
between the two groups of patients, for all muscle groups
tested, except the elbow exors DM (P0.042) and the hip
abductors DM (P0.035) where higher values were found
in the CG. However, both the CG and the TG obtained
values o1, indicating muscle strength lower than normal
patterns for all muscles tested. In trial 2, post-BMT, both
CG and TG showed similarly decreased values. In trial 3,
TG showed higher values than CG, for all muscle groups
tested, pointing to a signicant difference for hip exors
NDM (P0.011).
(2) Different trial, same group: In the comparison
between trials 1 and 2, both CG and TG showed lower
values for most of the analyzed muscle groups (Tables 2
and 3). On trials 2 and 3, the CG continued to reveal
decreased values for all muscle groups analyzed, with
statistical signicance in the lower limb groups. The TG
revealed signicantly increased values for three out of eight
upper limb muscle groups, and ve out of 10 lower limb
muscle groups.
Although both groups somehow achieved higher values
when comparing trials 2 and 3, when comparing trials 13,
we found that the TG was similar for all the muscle groups
in the upper limb, indicating full recovery, with signicantly
decreased values for only two groups out of 10 in the lower
limb muscle groups. In CG, it was found that seven out of
eight upper limb muscle groups had signicantly decreased
values, and four out of 10 lower limb muscle groups also
showed signicantly decreased values.
1st
2nd
3rd
4th
5th
6th
W
e
e
k
s
Time (minutes)
0 5 10 15 20 25 30
Normal speed Accelerated speed Rest
Figure 1 Sequence of walking and resting periods according to each week
of exercise program.
Table 2 Intragroups comparison (x, s.d.) of upper extremities
strength performance variation, between rst and third trials
Muscle group CG P TG P
Shoulder DM
Abductors 0.78 (0.150)d 0.002* 0.94 (0.138)d 0.231
Flexors 0.77 (0.142)d 0.001* 1.01 (0.254)i 0.878
Shoulder NDM
Abductors 0.71 (0.130)d 0.000* 0.93 (0.096)d 0.066
Flexors 0.78 (0.134)d 0.001* 1.08 (0.301)i 0.448
Elbow DM
Flexors 0.78 (0.127)d 0.001* 1.00 (0.196)i 0.979
Extensors 0.75 (0.168)d 0.154 0.89 (0.205)d 0.145
Elbow NDM
Flexors 0.76 (0.129)d 0.000* 0.95 (0.202)d 0.537
Extensors 0.76 (0.159)d 0.002* 1.01 (0.223)i 0.860
DM=dominant; NDM=nondominant; d=decrease, i=increase.
Table 3 Intragroups comparison (x, s.d.) of lower extremities
strength performance variation, between rst and third trials
Muscle Group CG P TG P
Hip DM
Flexors 0.91 (0.225)d 0.277 1.03 (0.232)i 0.734
Abductors 0.88 (0.164)d 0.055 1.09 (0.186)i 0.176
Hip NDM
Flexors 0.90 (0.210)d 0.194 1.01 (0.160)i 0.903
Abductors 0.91 (0.205)d 0.236 1.04 (0.181)i 0.503
Knee DM
Flexors 0.66 (0.295)d 0.008* 0.82 (0.211)d 0.033*
Extensors 0.84 (0.209)d 0.052 0.97 (0.166)d 0.649
Knee NDM
Flexors 0.66 (0.257)d 0.004* 0.83 (0.097)d 0.001*
Extensors 0.87 (0.180)d 0.057 0.98 (0.206)d 0.792
Ankle DM
Flexors 0.81 (0.145)d 0.005* 0.96 (0.270)d 0.668
Ankle NDM
Flexors 0.78 (0.149)d 0.002* 1.03 (0.255)i 0.737
DM=dominant; NDM=nondominant; d=decrease, i=increase.
Exercise program after allogeneic BMT
M Mello et al
725
Bone Marrow Transplantation
Figures 2 and 3, respectively, illustrate the shoulder
exors and hip abductors group strength, collected from
trials 1 to 3.
The ANOVA for the CG showed that the averages for
trial 2 were closer to trial 3 than trial 1. Therefore, in TG,
ANOVA showed that the averages of trial 2 were closer to
trial 1 than to trial 3.
Discussion
Allogeneic BMT is a well-based therapy for treating
oncohematological diseases resistant to conventional ther-
apy. Further research into human histocompatibility has
increased the success of engraftment, and the development
of new immunosuppressive drugs has also allowed a greater
control of adverse reactions, such as GVHD, making this
procedure less aggressive.
Clinical experience of the authors has shown the need for
a broader evaluation of physical conditions with muscle
strength tests to quantify the losses in each phase of BMT.
The maximum voluntary isometric strength test was chosen
for this study because it is similar to manual tests regarding
the standardization of measurement location, the stable
maintenance of the lever arm and the capacity to detect
changes in strength without requiring excessive effort.
Moreover, the chosen method allowed the decisive advan-
tage of applicability considering the severe clinical condi-
tions of this group of patients.
The maximum voluntary isometric strength test can
be performed with any kind of dynamometer, but the
hand-held dynamometers afford several clinical advantages
compared with isokinetic ones. They are portable, easy
to use, can be performed in outpatient settings and enable
the measurement of major muscle groups. The applicability
is also superior when one wishes to evaluate the perfor-
mance of the same patient in several phases of the
treatment.
29,20
Absolute values alone are of limited usefulness without
normal strength values for comparison; for example, 20 N
of elbow exion may be strong or weak depending on the
gender, age and size of the individual tested.
29
The normalized ratio of strength was used to make
possible the interpretation of absolute strength values
related to the values foreseen in the literature.
21,19
It also
made possible data comparison among patient groups of
different sexes and weights and at different ages, and the
evaluation of the BMT effect itself.
The results obtained in trial 1 represent the condition of
the groups prior to BMT. The similarity among the groups
was observed, referring to the nature of the disease, general
and nutritional status (BMI) as well as muscle strength.
However, both groups showed values o1, below the
literature standard.
Such ndings make one think that, although the patients
all had good general status and no functional complaints,
the presence of hematological disease can cause subclinical
alterations in motor function, with disturbance of other
mechanisms related to the voluntary recruitment of motor
units.
Tilignac
30
inductively related effects of cytostatic agents
on skeletal muscle protein turnover to a negative nitrogen
balance, downregulated muscle proteosome dependent on
proteolyis by a mechanism that includes reduced m-RNA
levels, which is associated with a decrease in the bulk of
muscle proteolysis to the major contractile compounds,
actin and myosin. These effects were also observed in adult
cancer patients after the administration of vinblastine,
cisplatin and bleomycin.
31
In addition to this, Glaus
6
noted that fatigue is more
frequent in periods of active neoplasic disease, when the
patients cachectic status compromises the energy con-
sumption required to perform muscular contraction. It
can, nevertheless, persist beyond the remission phase, in
the absence of physiological mechanisms of fatigue, as the
psychological mechanisms of nonmotivation, related to the
severity of the disease prognosis.
The existential outlook of a person suffering from a
potentially fatal disease may require him or her to
withdraw, and use a coping mechanism expressed as a
feeling of depression. On the other hand, if there is evidence
for physical causes of fatigue, the unanswered question is
whether this tiredness is a symptom of the disease or a
symptom of a coping mechanism and depression, or
whether it is a combination of both.
Dominant Nondominant
1.0
0.8
0.6
0.4
0.2
N
o
r
m
a
l
i
z
e
d

r
a
t
i
o

o
f

s
t
r
e
n
g
t
h
1 2 3 1 2 3
TG GC
Trial
Figure 3 Normalized ratio of hip abductors strength in three trials.
Dominant Nondominant
1.0
0.8
0.6
0.4
0.2
N
o
r
m
a
l
i
z
e
d

r
a
t
i
o

o
f

s
t
r
e
n
g
t
h
1 2 3 1 2 3
GT GC
Trial
Figure 2 Normalized ratio of shoulders exor strength in three trials.
Exercise program after allogeneic BMT
M Mello et al
726
Bone Marrow Transplantation
The muscle strength decrease prior to BMT does not
represent a pathologic state or a serious risk during life, but
it reinforces the need for careful follow-up of these patients,
considering that the use of some drugs, which are indirectly
involved in this decrease, are necessary and fundamental
for the success of the procedure.
In trial 2, there was a similar decrease in muscle strength
in the upper and lower limb muscles with no statistical
difference between the two groups. This nding shows that
the change is global, compatible with the side effects of
BMT itself. These symptoms have already been related in
our previous study.
2
The authors consider that muscle
weakness may not be related to drug effects. Cyclosporine
and corticosteroids are the most common drugs used for
GVHD prophylaxis and treatment. An acute form of
corticosteroid-induced myopathy has been observed in
patients with acutely severe asthma being treated with
34 mg/kg day, who show diffuse muscle weakness,
rhabdomyolisis and marked elevation of creatinokinase as
the main clinical features.
32
The chronic form of corticos-
teroid-induced myopathy was reported in patients with
pathologic cardiac and pulmonary conditions who had
received long-term corticosteroids. There is a wide time
variation between the appearance of myopathy and
administration, so the correlation is poor. The muscle
weakness is insidious, symmetric, and has variable grades
from no objective fall in muscle strength to difculties in
raising upper or lower limbs.
32,12
In trial 3, there was an increase in muscle strength in the
CG as well as in the TG. The absence of a signicant
difference in the intergroup comparison shows that the
strength increase occurred in all patients, and could be
attributed to the stabilization of their general clinical status
by that time.
After discharge some patients may need weeks or months
to regain their pretreatment level of tness. The studies of
DIMEO
7
show that the loss of performance observed after
high-dose chemotherapy (HDC) can be at least partially
prevented with exercise, and that starting rehabilitation
immediately after HDC is possible without increasing
morbidity.
The intragroup comparison of muscle strength change
between trials 1 and 3 of the same group, represents the real
gain or loss of values obtained at the post BMT, as related
to the pre BMT. The greater number or the most expressive
number of muscles with decreased strength in CG, as
related to TG, concurs in that there has been a strength
improvement in the latter. Such ndings demonstrate the
inuence of exercises in TG rehabilitation, the subjects of
which achieved a performance closer to the one obtained
pre-BMT than did the CG.
Braith
33
had already associated the improvement in
muscle strength with the use of early exercises in patients
undergoing cardiac transplantation. This author demon-
strated a 12% increase in the strength of knee extensor
muscles in the training group against 2.1% in the control
group, when compared to the pre- and post-transplant
results.
The benecial effects of exercises on muscular fatigue or
weakness could be related to a greater release of androgens,
corticoid antagonists; reduction of protein degradation and
change in cell receptor capacities. The stimulus to normal
metabolism acts in all sorts of bers, even though it does
not cause objective muscular hypertrophy.
16
Gait is the
physical activity most known and better adapted to
improvement in physical status, and it is considered safe
from the cardiovascular and orthopedic point of view.
Dimeo
28
has already successfully used a treadmill gait
program for patients in post BMT, demonstrating an
improvement in physical capacity, but to show their
efciency, that author supported his study with parameters
other than muscle strength.
We have chosen to use a similar program, adapted to its
purpose, adding exercises for the upper limbs and stretch-
ing. The intensity used in the exercise, which ranged from
mild to moderate, proved to be adequate for the immediate
post BMT phase, and for the muscle strength decrease
observed in trial 2. This decrease in muscle strength could
interfere with gait performance, regardless of the stable
levels of hemoglobin required to perform the exercises.
We believe that the activity programs used in this
treatment protocol acted as functional stimuli to muscle
contraction, covering the summation of factors that
produce strength decreases in patients in post BMT.
In spite of a direct comparison of these study data with
those of Dimeo
28
being impaired owing to differences in
method, it is complemented by the decrease in complaints
of fatigue and the good tolerance to early exercise
performance, making it possible to conclude that the
proposed treatment program proved effective in promoting
increased muscle strength after allogeneic BMT, consider-
ing that TG presented an earlier return to strength values
similar to those obtained pre-BMT.
Acknowledgements
We thank Patr cia Ramos for her useful suggestions regarding
statistics, to Sidney Philocreon for the drawing of the gures and
FAPESP, Fundaca o de Amparo a` Pesquisa do Estado de Sa o
Paulo, for funding this project.
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