Metabolism
Preliminary
determination of a molecular basis of chronic fatigue syndrome.
McGregor NR, Dunstan RH,
Zerbes M, Butt HL, Roberts TK, Klineberg IJ
Collaborative Pain Research Unit,
University of Sydney, Westmead Hospital, NSW, Australia.
Biochem Mol Med 1996
Apr;57(2):73-80
Chronic fatigue syndrome (CFS/ME) is a debilitating fatigue illness that has an unknown etiology. We studied 20 chronic fatigue syndrome (CFS) patients, who complied with the Oxford and American CDC definitions, and 45 non-CFS subjects. Participants completed questionnaires, were clinically examined, and had first morning urine specimens collected, which were screened by gas chromatography-mass spectrometry for changes in metabolite excretion. Multivariate analysis of the urinary metabolite profiles differed significantly in the CFS patients compared to the non-CFS patients (P < 0.004). The CFS patients had increases in aminohydroxy-N-methylpyrrolidine (P < 0.00003, referred to as chronic fatigue symptom urinary marker 1, or CFSUM1), tyrosine (P < 0.02), beta-alanine (P < 0.02), aconitic acid (P < 0.05), and succinic acid (P < 0.05) and reductions in an unidentified urinary metabolite, CFSUM2 (P < 0.0007), alanine (P < 0.005), and glutamic acid (P < 0.02). CFSUM1, beta-alanine, and CFSUM2 were found by discriminant function analysis to be the first, second, and third most important metabolites, respectively for discriminating between CFS and non-CFS subjects. The abundances of CFSUM1 and beta-alanine were positively correlated with symptom incidence (P < 0.01 and P < 0.001, respectively), symptom severity, core CFS symptoms, and SCL-90-R somatization (P < 0.00001), suggesting a molecular basis for CFS.
PMID: 8733884, UI: 96316008
Preliminary determination of
the association between symptom expression and urinary metabolites in
subjects with chronic fatigue syndrome.
McGregor
NR, Dunstan RH, Zerbes M,
Butt HL, Roberts TK, Klineberg IJ
Collaborative Pain Research Unit,
University of Sydney, Australia.
Biochem Mol Med 1996
Jun;58(1):85-92
Chronic fatigue syndrome (CFS) patients have a
urinary metabolite labeled CFSUM1 with increased incidence (P < 0.004) and
relative abundance (P < 0.00003). The relative abundances of urinary CFSUM1
and beta-alanine were associated with alterations in metabolite excretion and
symptom incidence. In 20 CFS patients and 45 non-CFS subjects,
symptom/metabolite associations were investigated by assessing symptom
sensitivity and specificity, and symptom indices of total symptom incidence,
CFS core symptoms, cognitive, neurological, musculoskeletal, gastrointestinal,
infection-related and genitourinary symptom indices, as well as a visual
analogue pain scale of average pain intensity. Thirty-three symptoms had
significant (P < 0.005) sensitivity and specificity in the CFS patients
compared to that in the non-CFS controls. Severe fatigue was the only symptom
with 100% sensitivity and specificity and CFSUM1 excretion was the primary
metabolite for expression of this symptom. All nine symptom indices had
elevated responses in the CFS patients (all P < 0.0000001). Multiple
regression analyses indicated that all the symptom indices had significant
correlations (R) with changes in the urinary excretion of metabolites (P <
0.0001). CFSUM1 and beta-alanine were the first and second metabolites
correlated with the CFS core symptom index and CFSUM1 was primarily associated
with infection-related and musculoskeletal indices whereas beta-alanine was
primarily associated with gastrointestinal and genitourinary indices. The strong
associations of CFSUM1 and beta-alanine with CFS symptom expression provide a
molecular basis for developing an objective test for CFS.
Publication Types: Clinical
trial PMID: 8809350, UI: 96405210
Free radicals in chronic fatigue syndrome.
Richards, RS., Roberts,
TK., Dunstan, RH., McGregor, NR and Butt, HL.
Redox
Report, 2000, 5, 2-3, 146-147.
The findings from 24 patients with CFS (Oxford and CDC criteria '88), 36
people with rheumatoid arthritis (RA) and 20 controls revealed raised levels in
erythrocyte 2,3-DPG and methaemoglobin in the patient groups. Erythrocyte
reduced glutathione was increased in RA patients only. Erythrocyte
malondialdehyde was increased in CFS but not in RA. The researchers suggest
that free radical formation may contribute to the pathology of CFS.
The
Development of Laboratory-Based Tests in Chronic Pain and Fatigue:
1. Muscle Catabolism and Coagulase Negative
Staphylococci Which Produce Membrane Damaging Toxins
R.H.Dunstan, DPhil; N.R. McGregor, MDSc;
T.K.Roberts, PhD; H.Butt, PhD; S.H.Niblett, BSc; T.Rothkirch, Dip App Sc
Collaborative Pain Research Unit,
Department of Biological Sciences, University of Newcastle, Callaghan, NSW
2308, Australia
Background: The diagnosis of chronic fatigue syndrome (CFS) requires the
exclusion of other known fatigue-related diseases because the core symptoms of
CFS represent a general host response to many well-defined diseases. The patient set derived by this process is
heterogeneous in their polysymptomatic presentation and has proved very
difficult to study clinically and scientifically.
Objectives: To investigate the alterations in urine
excretion and microbiology in patients with CFS.
Results: CFS patients had multiple anomalies in their
amino and organic acid homeostasis.
Sub-groups of CFS patients could be delineated on the basis of their
urine excretion and their symptom presentation. The most common feature was an active muscle catabolism resulting
in a depletion of amino acids and associated organic and keto-acids. The extent of muscle catabolism was directly
correlated to pain severity. The
carriage of toxin-producing coagulase negative staphylococci (MDT-CoNS) was
strongly correlated with the catabolic response and pain severity.
Conclusions: An hypothesis has been
constructed where an occult pathogen, such as MDT-CoNS, may be an aetiological
agent contributing to the sustenance of a chronic fatigue/pain disorder, a
comorbid pathogen. Urine analysis
offers an opportunity for assessment of muscle catabolism and
sub-classification of chronic fatigue patients leading to a number of
management options. The detection of
MDTCoNS identifies potentially treatable agents that contribute to the fatigue
and pain condition.
Impaired oxygen delivery to
muscle in chronic fatigue syndrome.
McCully KK,
Natelson BH
Department of Medicine, Medical College
of Pennsylvania and Hahnemann University, Philadelphia, PA 19129, USA.
kmccully@coe.uga.edu
Clin Sci (Colch) 1999 Nov;97(5):603-8
The purpose of this study was to determine if
chronic fatigue syndrome (CFS) is associated with reduced oxygen delivery to
muscles. Patients with CFS according to
CDC (Center for Disease Control) criteria (n=20) were compared with normal
sedentary subjects (n=12). Muscle
oxygen delivery was measured as the rate of post-exercise and post-ischaemia
oxygen-haem resaturation. Oxygen-haem
resaturation was measured in the medial gastrocnemius muscle using continuous-wavelength
near-IR spectroscopy. Phosphocreatine
resynthesis was measured simultaneously using (31)P magnetic resonance
spectroscopy. The time constant of
oxygen delivery was significantly reduced in CFS patients after exercise
(46.5+/-16 s; mean+/-S.D.) compared with that in controls (29.4+/-6.9 s). The time constant of oxygen delivery was
also reduced (20.0+/-12 s) compared with controls (12.0+/-2.8 s) after cuff
ischaemia. Oxidative metabolism was
also reduced by 20% in CFS patients, and a significant correlation was found
between oxidative metabolism and recovery of oxygen delivery. In conclusion, oxygen delivery was reduced
in CFS patients compared with that in sedentary controls. This result is
consistent with previous studies showing abnormal autonomic control of blood
flow. Reduced oxidative delivery in CFS
patients could be specifically related to CFS, or could be a non-specific
effect of reduced activity levels in these patients. While these results suggest that reduced oxygen delivery could result
in reduced oxidative metabolism and muscle fatigue, further studies will be
needed to address this issue.
PMID: 10545311
* Biochemical Abnormalities in Chronic Fatigue
Syndrome
Phillip Clifton Bligh 2,
Suzanne Niblett 1, Leigh Hoskin 2, R Hugh Dunstan 1,
Greg Fulcher 2, Neil McGregor 1,4, Julie Dunsmore 3,
Timothy K Roberts 1, Henry L Butt 1, Katrina King 1,
Iven Klineberg 4
1
Collaborative Pain Research Unit, Bioanalytical Research Group, Dept of
Biological Sciences, University of Newcastle, Callaghan, NSW 2308
Australia
2 Royal North Shore Hospital, CFS Research
Unit, Dept of Endocrinology, Royal North Shore Hospital, St Leonards, NSW
2065
3
Royal North Shore Hospital, CFS Research Unit, Dept of Health Promotion and
Education, Royal North Shore Hospital, St Leonards, NSW 2065
4
Neurobiology Research Unit, Centre for Oral Health Research, University of
Sydney, Westmead Hospital Westmead, NSW 2084
Chronic fatigue syndrome is defined as a disorder in which the subject has unexplained prolonged fatigue, often worse after minimal exercise, frequently associated with impaired sleeping, painful muscles, intermittently swollen lymph glands and impaired cognitive function. The pathogenesis has eluded explanation. The bioanalytical research group of the University of Newcastle has developed methodology for examining excretion of amino acids and organic acids into the urine. In collaboration with the Department of Endocrinology at the Royal North Shore Hospital, the overnight urine excretion rate of a number of amino acids and organic acids was measured in 100 patients with chronic fatigue syndrome, and in 83 age- and sex-matched normal controls.
The excretion rate of the metabolites was measured in units/minute. The most striking differences between patients with chronic fatigue syndrome and controls was a reduction in urine asparagine (p<0.0001) and a reduction in urine succinic acid (p<0.0003) in patients with chronic fatigue syndrome.
The excretion of urinary asparagine and succinic acid was highly correlated (p<0.00001). Urinary tyrosine (p<0.04) and urinary 3-methyl histidine (p<0.03) were significantly increased in patients with chronic fatigue syndrome. The urinary excretion of tyrosine, a protein catabolism marker, was associated with symptoms of fatigue, muscle pain, lymph node pain and cognitive disturbance.
The overnight excretion of succinic acid was correlated with the fasting plasma glucose (p<0.002). It is not known at present whether urine excretion rates of succinic acid and asparagine are correlated with serum concentrations of these metabolites or whether renal tubular function independently influences the urine excretion rates, and if so, whether renal tubular function is itself altered in chronic fatigue syndrome.
It is possible that urine asparagine excretion rates are low because of reduced entry of asparagine into the circulation, and thence into the urine. If the rate of entry of asparagine into the circulation is reduced, this could come about because of more rapid metabolism of asparagine in cells or because total body stores of asparagine are depleted. Further work is necessary to define these issues.
BIOCHEMICAL ABNORMALITIES in CFS
Dr Clifton Bligh,
Royal Northshore Hospital CFS Unit, Department of Endocrinology, St Leonards, NSW 2065, Australia in conjunction with C P R Unit, Bioanylytical Research Group, Dept.
Biological Sciences, University of Newcastle, Callaghan, NSW 2308.
One hundred CFS patients plus 83 age/sex matched controls had urinary amino acids and organic acids measured at the CPRU Unit at the University of Newcastle. The most striking difference between CFS patients and controls was a reduction in urine asparginine (p<0.0001) and a reduction in urinary succinic acid (p<0.0003) in patients with CFS. Both of those correlated together (p<0.00001). Fasting plasma glucose was not low enough for hypoglycemia but it did correlate with succinic acid (p<0.002)[succinic acid is the one of the end products of glycolysis] UM17 and phenalanine were also significantly reduced. Also urinary tyrosine (p<0.04) and urinary 3-methyl histidine (p<0.03) were significantly increased in CFS. Increased tyrosine was associated with fatigue, muscle pain, lymph node pain and cognitive disturbance.
The discussion then considered why the reductions in particular? Was it because of depleted body stores or was it because of some other independent reason eg that renal tubular function/ reabsorption could itself be altered in CFS?. Other correlations showed reduced cognitive function correlated with low urinary glycine and UM14.
Pain correlated with UM 15b which is thought to be a metabolite of Paracetamol.
SERUM
POTASSIUM and HORMONE RESPONSES to EXERCISE in CFS
Dr Richard Burnet,
Endocrine Unit, Royal Adelaide Hospital, North
Terrace, Adelaide, SA 5000, Australia
Ten years ago Dr Burnet became interested in CFS after seeing a lady with whom he decided to try the drug Spirinolactone. Her fatigue improved on it, off it she relapsed. Amongst other things the drug causes potassium retention.
Last year he presented a study of 23 patients. 2/3rd of the patients showed Total Body Potassium reductions - up to 10% or more, these were 'fatigue only' patients. In the other 1/3 with 'myalgia and fatigue' total body potassium levels were high. They postulated that for the 'fatigue only' subgroup potassium handling problems could be at fault. Potassium is primarily an intracellular ion with 80% being present in muscle, 10% in the brain and 10% in other tissues.
This year, in a small study of 11 CFS patients (6F, 5M) and 11 age sex matched controls they studied the effects of exercise on plasma ACTH, growth hormone, prolactin, cortisol , sodium, potassium and bicarbonate. Subjects were exercised for 10 mins on a cycle ergometer at a work load of 75% maximal oxygen consumption. Blood was taken at one minute intervals for ten mins and 5mins thereafter for 70 mins.
At rest all values were similar between the two groups, except that patients had significant increases in ACTH levels.
The response to exercise of growth hormone, prolactin and sodium was normal.
The 3 key findings were:
1.
During exercise ACTH release increased cf with controls, but
cortisone release increase remained at similar levels to controls. ie Excess
ACTH release on exercise does not have a concomitant cortisone increase. This
suggests that the there is no abnormality of the pituitary hormonal response,
but a diminished adrenal -cortisone response [Ted Dinan (Ireland) has shown
that the adrenal gland is smaller in volume in CFS].
2.
Potassium release in patients was delayed and the peak level
was lower. This suggests that there is an abnormality in potassium handling
which could be due to the reduced total body potassium or due to some other
reason for reduced potassium flux across cell
membranes. [This finding dovetails with the
Channelopathy concept]
3.
Bicarbonate followed a similar curve, which equates with
excess lactate production.
Wilhelmina M. H. Behan, Ian
J. Holt, David H. Kay, and Pamela Moonie
Journal of Chronic Fatigue Syndrome, Vol. 5( 1)
1999 page 3-16
The purpose of this study was to establish if muscle aerobic metabolism is abnormal in chronic fatigue syndrome (CFS). Myoblast cultures from muscle biopsies of 16 patients with CFS and 10 healthy controls were established. Micromethods were used to determine the lactate/pyruvate (L/P) ratio, respiratory chain function and cytochrome oxidase and lactic dehydrogenase activities. Mitochrondrial DNA (mtDNA) volume was measured and mtDNA rearrangements sought. The results showed that myoblasts from ten of 16 cases of CFS had defects in aerobic metabolism: two had increased L/P ratios, suggestive of a defect in oxidative phosphorylation while eight had decreased ratios, consistent with a deficiency in pyruvate dehydrogenase. There was a statistically significant broader range of L/P ratios in the patients' cultures, compared to controls (p=0.011). No mtDNA rearrangements were present. This in vitro study confirms that there is convincing evidence of mild aerobic defects in skeletal muscle in some cases of CFS.
Muscle metabolites
detected in urine in fibromyalgia and chronic fatigue syndrome may suggest
ongoing muscle damage.
Richards, SCM, Bell, J.,
Cheung, Y-L, Cleare, A and Scott, DL.
Conference Proceedings of the British Society of Rheumatologists,
April 2001, Scotland. Abstract 382
Richards et al measured creatine and other
metabolites known to be released from damaged muscle in morning urine samples
collected from 60 patients with fibromyalgia (FM) and 60 people with CFS
(undefined but likely to be Oxford or CDC criteria '94). Controls included 12
healthy individuals and 60 people with a variety of diseases.
Significant levels of creatine were detected in the
urine of 29 (48%) of the patients with FM and 32 (53%) of the patients with CFS
compared with none of the healthy controls (both p<.01) and 2 of the disease
controls. There were also significantly higher levels of urinary
excretion of choline, taurine, citrate and trimethyl amine oxide in FM compared
to controls (all p<.05) and of choline and glycine in CFS compared to
controls (both p<.05).
"This study reveals that approximately half
these patients with FM and CFS were excreting creatine and other muscle related
metabolites in their urine in detectable levels compared to healthy and disease
controls. This may well represent ongoing muscle damage in FM and CFS and
suggests a potential therapeutic target for dietary supplementation."
Low Urinary Serine Output is Associated with an
Altered Faecal Microbial Flora in Chronic Fatigue/Pain Patients
Butt
HL1,2, Dunstan RH2, McGregor NR2,3,
Roberts TK2, Harrison TL2, and Grainger JR2
1 Collaborative Pain Research Unit (CPRU), Division
of Microbiology & Infectious Disease, Hunter Area Pathology Service, John
Hunter Hospital
2 Department of Biological Sciences,
University of Newcastle, Newcastle 3
Faculty of Dentistry, University of Sydney, Westmead Hospital, Westmead
Australia
Serine is an important precursor of tryptophan and serotonin. Previous studies of patients with chronic fatigue syndrome (CFS) demonstrated that serine (CFSUM2) was an important urinary metabolite discriminating between CFS from control subjects, and was negatively correlated with CFS neurological symptom index and total symptom index. Serine synthesis requires both alanine and glycine as precursors, and also as a result of microbial metabolism. The aim of this study is to determine if faecal microorganisms can produce serine, and how these organisms are quantitatively related to the total gastrointestinal microbial flora in CFS patients.
Three clinical faecal coliforms (Escherichia coli, Enterobacter cloacae and Proteus mirabilis) were incubated in defined broth and their metabolites were analyzed by a gas chromatogram (GC-MS). Serine was produced by the three organisms at varying concentrations. Other amino acids including serine precursors (alaine & glycine), leucine, phenylalanine and succinic acid, an organic acid, were also detected suggesting that the contribution of microbial metabolites by enteric organisms to achieve a balanced diet may be more important as previously thought.
Faecal samples from 27 CFS patients and four age and sex matched control subjects were studied. Quantitative bacteriology was performed on all samples. Seventeen (62.9%) CFS patients had a low % distribution of E.coli (<80% of total aerobic faecal count). In contrast none all four control subjects had a low % distribution of E.coli ( p < 0.03).
These studies showed that the low urinary excretion of serine in CFS patients reported in previous study was associated with a disturbed gastrointestinal microbial flora. Alteration in the aerobic microbial flora, particularly the Gram negative enteric organisms, may change the exogenous supply of serine and contribute to the increased symptoms expression of patients with CFS.
TOTAL BODY POTASSIUM IN THE CHRONIC FATIGUE SYNDROME.
Richard
B. Burnet, Barry E. Chatterton, Robert D. Gaffney, Garry C. Scroop.
Endocrine and Metabolic Unit, Royal Adelaide Hospital
(R.B.B), Exercise Physiology Research Unit, Department of Physiology,
University of Adelaide (G.C.S), Department of Nuclear
Medicine Royal Adelaide Hospital (B.E.C, R.D.G)
Normal potassium levels (both intra and extracellular) are essential for initiating a full muscle contraction and neural transmission. Approximately 80% of the body potassium is found in muscle and a further 10% in the brain. The remainder is in the blood stream and other organs. Potassium is primarily an intra cellular ion.
A number of medical conditions that cause low potassium are associated with fatigue. Previous studies in Chronic Fatigue Syndrome (CFS) have not demonstrated an abnormality in the level of serum potassium but the present studies have concentrated on intra-cellular potassium and its relationship with CFS.
An initial study of Total Body Potassium (TBK) measured by whole body counting in 20 matched pairs of patients and controls matched for age weight and sex showed that there was a significant decrease in the values of the those persons who had CFS as defined by the British, Australian and American clinical criteria. Eight pairs subjects in this study had a whole body DEXA scan which showed no significant difference in the amount of lean body mass or total bone mass. There was overlap in the levels of TBK in patients with CFS and controls so further investigations were undertaken to define the abnormality.
Patents with CFS were divided into two groups, those with fatigue symptoms only and those patients who had a mixed symptomatology of fatigue and myalgia. This was defined by patient assessment of their disability at the medical consultation.
Fifty-one subjects with CFS only (29) or myalgia/fatigue (22) were studied with a TBK a full biochemical profile and the results were analysed for these 2 groups. The CFS group with fatigue only, showed a significant reduction in the level of TBK and in one half of these the reduction in TBK was greater than 10% of the normal estimated for age weight and sex. The serum potassium levels were normal in all subjects.
In the maylgic group there was no reduction in TBK. There was no correlation of the TBK with age, sex, duration of illness, reduction in daily living activities and time for recovery from exercise. Nor was there any correlation with any allergic symptomatology or recurrent chronic infections. There was a strong inverse correlation of the TBK and the total time spent resting (p=0.02).
These investigations show that in approximately 50% of subjects with CFS where fatigue is the primary symptom there is a significant reduction in the level of TBK. This decrease in TBK is not found if there are myalgic symptoms even if there is associated fatigue.
Longer term studies are needed to define this abnormality further, whether it fluctuates with the disease and its progression is unknown.
This finding of a lowered TBK has great significance as a possible marker of CFS with fatigue and also points a way to improving therapy by determining the effects of normalising the intracellular potassium.
Cassarino
DS, Bennett JP Jr.
University
of Virginia Health Sciences Center, Charlottesville 22908, USA.
Brain
Research Reviews, 1999, Vol 29, Iss 1, pp 1-25
There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's, Parkinson's, and Lou Gehrig's Disease (ALS). Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP (energy) production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death. Although protective nuclear responses such as antioxidant enzymes may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This article's hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and points out many potential therapeutic targets for preventing or ameliorating these diseases.
PMID: 9974149
The
role of mitochondria in the pathogenesis of neurodegenerative diseases.
Manfredi G, Beal MF
Department of Neurology and
Neuroscience, Weill Medical College of Cornell University and the New York
Hospital, Cornell Medical Center, New York 10021, USA.
gim2004@mail.med.cornell.edu
Brain Pathol
2000 Jul;10(3):462-72
A growing body of evidence
indicates that mitochondrial dysfunction may play an important role in the
pathogenesis of many neurodegenerative disorders. Because mitochondrial metabolism is not only the principal source
of high energy intermediates, but also of free radicals, it has been suggested
that inherited or acquired mitochondrial defects could be the cause of neuronal
degeneration as a consequence of energy defects and oxidative damage. Mitochondrial respiratory chain dysfunction
has been reported in association with primary mitochondrial DNA abnormalities,
and also as a consequence of mutations in nuclear genes directly involved in
mitochondrial functions, such as SURF1, frataxin, and paraplegin. Defects of oxidative phosphorylation and
increased free radical production have also been observed in diseases that are
not due to primary mitochondrial abnormalities. In these cases, the mitochondrial dysfunction is likely to be an
epiphenomenon, which, nevertheless, could be of importance in precipitating a
cascade of events leading to cell death.
In either case, understanding the role of mitochondria in the
pathogenesis of neurodegenerative diseases could be important for the
development of therapeutic strategies in these disorders.
PMID: 10885665 Publication
Types: Review, Review, tutorial
Raised Plasma Adenosine Associated with Chronic Fatigue Syndrome: A Preliminary StudyJohn A. Duley, PhD; D. Paul Garrick, MA, FRC Path; David A. Pratt, BCom (Ace)Purine Research Laboratory and Guy’s & St. Thomas’ Hospitals, London, UKJournal of Chronic Fatigue Syndrome, Vol. 7(3) 2000, pp. 77-85Plasma adenosine levels were measured in a small trial study of eighteen volunteers, aged 36-85 years. Volunteers comprised nine with chronic fatigue syndrome (CFS), four with ‘other fatigue’ illnesses, and five with no history of fatigue illnesses but some of whom were related to chronic fatigue sufferers. Plasma adenosine was slightly raised above the minimum detectable level (approx. 1 micromole/L) in one healthy non-fatigued volunteer and grossly raised (greater than 5 micromoles/L) in two non-fatigued volunteers, both of whom were related to CFSs. Among the nine CFSs, all had plasma adenosine raised above baseline, and seven were grossly raised. High adenosine levels were also seen in two of the volunteers with ‘other fatigue.’ Raised adenosine occurred among certain families, suggesting a genetic metabolic element. Instability of adenosine in frozen stored plasma was noted. High levels of adenosine probably do not exist freely within peripheral plasma but may be released from blood cells locally within tissues or in response to venipuncture stress or other factors. The results may be highly relevant to other pathologies such as heart disease.
Increased
Resting Energy Expenditure in the Chronic Fatigue Syndrome
Walter
S. Watson, PhD
Donald C. McMillan, PhD Abhijit Chaudhuri, DM,
MD Peter O. Behan,
MD,
DSc
Journal of Chronic Fatigue Syndrome Vol.4 (4) 1998
It has been suggested that resting energy expenditure may be raised in chronic fatigue syndrome due to an upregulation of transmembrane ion transport. We measured resting energy expenditure by indirect calorimetry in 11 women with chronic fatigue and in 11 healthy women. Total body potassium, by whole body counting, and total body water, extracellular water and intracellular water, by a bioelectrical impedance method, were also measured.
When individual resting energy expenditure was predicted on the basis of total body potassium values for the chronic fatigue group, 5 out of 11 of these subjects had resting energy expenditure above the upper limit of normal as defined by the control group data. This is consistent with the hypothesis that there is upregulation of the sodium-potassium pump in chronic fatigue syndrome.
Antioxidant status and lipoprotein
peroxidation in chronic fatigue syndrome.
Manuel
y Keenoy B, Moorkens G, Vertommen J, De Leeuw I.
University Hospital, University of
Antwerp, Belgium. mailto:begona@uia.ua.ac.be
Life Sci 2001 Mar
16;68(17):2037-49
The aetiology and pathogenesis of the Chronic
Fatigue Syndrome (CFS) are still largely unresolved.
Accompanying metabolic disorders such as selective n-6 fatty acid depletion
suggest that oxidative stress and
more specifically lipid peroxidation might play a role in its pathogenesis.
In order to investigate this hypothesis, oxidant-antioxidant status and its
impact on lipoprotein peroxidation in vitro was examined in 61 patients with
unexplained fatigue lasting more than 1 month.
They were subdivided into 2 groups: group CFS+ (33 subjects) fulfilled the 1988
Center of Disease Control
criteria for CFS and group CFS- did not but was similar as regards age, sex
distribution and clinical characteristics.
Antioxidant status was similar in the 2 groups except for lower serum
transferrin in the CFS + (mean (95 % CI) 2.41 (2.28-2.54) versus 2.73
(2.54-2.92) g/L in the CFS-, p = 0.009) and higher lipoprotein peroxidation in
vitro: 6630 (5949-7312) versus 5581 (4852-6310) nmol MDA/mg LDL and VLDL
cholesterol x minutes, p = 0.035). CFS intensified the influence of LDL
cholesterol (p = 0.012) and of transferrin (p = 0.045) on peroxidation in
vitro, suggesting additional pro-oxidant effects.
These results indicate that patients with CFS have increased susceptibility of
LDL and VLDL to copper-induced peroxidation and that this is related both to
their lower levels of serum transferrin and to other unidentified pro-oxidising
effects of CFS.
PMID: 11388705
W
Droge and E Holm
Division of
Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
The combination of abnormally low plasma cystine and glutamine levels, low natural killer (NK) cell activity, skeletal muscle wasting or muscle fatigue, and increased rates of urea production defines a complex of abnormalities that is tentatively called "low CG syndrome." These symptoms are found in patients with HIV infection, cancer, major injuries, sepsis, Crohn's disease, ulcerative colitis, chronic fatigue syndrome, and to some extent in overtrained athletes. The coincidence of these symptoms in diseases of different etiological origin suggests a causal relationship. The low NK cell activity in most cases is not life-threatening, but may be disastrous in HIV infection because it may compromise the initially stable balance between the immune system and virus, and trigger disease progression. This hypothesis is supported by the coincidence observed between the decrease of CD4+ T cells and a decrease in the plasma cystine level. In addition, recent studies revealed important clues about the role of cysteine and glutathione in the development of skeletal muscle wasting. Evidence suggests that 1) the cystine level is regulated primarily by the normal postabsorptive skeletal muscle protein catabolism, 2) the cystine level itself is a physiological regulator of nitrogen balance and body cell mass, 3) the cyst(e)ine-mediated regulatory circuit is compromised in various catabolic conditions, including old age, and 4) cysteine supplementation may be a useful therapy if combined with disease- specific treatments such as antiviral therapy in HIV infection.
Bone formation impairment noted in Gulf War vets
(Reuters Health) TORONTO Wednesday September 27 By Pam Harrison
Impaired bone formation has been identified in Gulf War veterans who have symptoms attributed to Gulf War syndrome, British researchers report. Their findings were presented here during the 22nd annual meeting of the American Society for Bone and Mineral Research.
Dr. Juliet Compston, of the University of Cambridge School of Clinical Medicine in the UK, and multicenter colleagues assessed eight sections of bone obtained through hipbone biopsy from 17 British Gulf War veterans. Thirteen healthy, age-matched males served as 'control' subjects.
``Basically, what we found is that the cells which make bone are forming less well than normal, and the rate at which bone is turning over is also very low (among veterans compared with controls),'' Compston told Reuters Health in an interview. These changes may or may not predispose veterans to osteoporosis over the next few decades, she said. Of interest, however, is that 14 out of the 17 Gulf War veterans reported a history of fracture, she pointed out.
While some of these fractures were definitely traumatic, ''some seemed to be related to fragility, even though it's hard to be absolutely certain about this from history alone,'' Compston commented.
Compston cautioned that the reduced bone formation observed in these veterans may have more to do with changes in lifestyle than exposure to multiple chemicals during the Gulf War.
Veterans involved in the British study, for example, were not working, some of them drank quite heavily and some smoked, and they had little in the way of physical activity. ``All of these factors in themselves could lead to abnormalities in bone,'' Compston explained, ``so we cannot say from this work that the abnormalities we defined are directly related to the multiple chemical insults we know soldiers had in the Gulf War.''
Nevertheless, it is theoretically possible that chemical exposure could interfere with cellular mechanisms that produce normal bone formation. Organophosphates, among other chemicals to which veterans were exposed during the war, can impair bone cell formation.
Other investigators have reported that farmers exposed to organophosphates show histologic changes associated with reduced bone formation.
Bone density and body composition in young women with chronic fatigue
syndrome. Hoskin, L., Clifton-Bligh, P., Hansen, R., Fulcher, G
and Gates, F.
Annals
of the New York Academy of Sciences, 2000, 904, 625-627.
This study
compared 37 nulliparous women with CFS (Oxford criteria, mean age 25) with 25
healthy controls, all of whom were screened for bone density.
Patients with CFS had
significantly lower lean muscle mass (LMM) than control subjects (34.52kg vs
38.15kg p < 0.01) and significantly lower bone mineral density at the
trochanter (0.71 ± 0.09 vs 0.81 ± 0.15 p < 0.002), and almost reached
significance at the Wards triangle (0.79 ± 0.11 vs 0.89 ± 0.22 p <
0.07). Bone density at other sites measured was not significantly different.
Grazyna
Piec,1 Jelena Mirkovitch,1 Silvia Palacio,1
Peter F. Mühlradt,2 and Rolf Felix1,
Department
of Clinical Research, Bone Biology, University of Bern, CH-3010 Bern,
Switzerland,1 and Immunobiology Research Group, Gesellschaft für
Biotechnologische Forschung, D-38124-Braunschweig, Germany2
Mycoplasmas may be associated with rheumatoid
arthritis in various animal hosts. In
humans, mycoplasma arthritis has been recorded in association with
hypogammaglobulinemia. Mycoplasma
fermentans is one mycoplasma species considered to be involved in
causing arthritis. To clarify which
mycoplasmal compounds contribute to the inflammatory,
bone-destructive processes in arthritis, we used a well-defined
lipopeptide, 2-kDa macrophage-activating lipopeptide (MALP-2) from M. fermentans,
as an example of a class of macrophage-activating compounds
ubiquitous in mycoplasmas, to study its effects on bone
resorption. MALP-2 stimulated
osteoclast-mediated bone resorption in murine calvaria cultures,
with a maximal effect at around 2 nM. Anti-inflammatory drugs inhibited MALP-2-mediated bone
resorption by about 30%. This finding
suggests that MALP-2 stimulates bone resorption partially by
stimulating the formation of prostaglandins. Since interleukin-6 (IL-6) stimulates bone
resorption, we investigated IL-6 production in cultured calvaria. MALP-2 stimulated the liberation of
IL-6, while no tumor necrosis factor was detectable. Additionally, MALP-2 stimulated low levels
of NO in calvaria cultures, an effect which was strongly increased in
the presence of gamma interferon, causing an inhibition of bone
resorption. MALP-2 stimulated the
bone-resorbing activity of osteoclasts isolated from long bones of
newborn rats and cultured on dentine slices without affecting their
number. In bone marrow cultures,
MALP-2 inhibited the formation of osteoclasts. It appears that
MALP-2 has two opposing effects: it increases the bone resorption in
bone tissue by stimulation of mature osteoclasts but inhibits the
formation of new ones.
Chronic fatigue syndrome:objective criteria of metabolic defects
Gil'miiarova
FN, Radomskaia VM, Kretova IG, Vinogradova LN, Samykina LN, Sheshunov IV,
Babichev AV, Sharafutdinova IuM, Ponomareva LA [Article in Russian]
Klin
Lab Diagn 1999 Feb;(2):9-11
Multi-level
system of defense mechanisms is studied in 206 normal subjects living in an
ecologically unfavorable region and working at chemical plants. Control group
consisted of 24 subjects living in en ecologically safe region. The content of
total protein and albumin and its effective and binding capacity were
decreased, while the content of medium molecular weight peptides increased in
the blood of subjects exposed to technogenic environmental pollution. The
detected shifts are regarded as a mechanism of development of chronic fatigue
syndrome.
PMID: 10876679, UI: 20335411
Vitamin B status in patients
with chronic fatigue syndrome.
Heap LC, Peters TJ, Wessely S
Department of Clinical Biochemistry, King's College School of Medicine,
London, UK.
J R Soc Med
1999 Apr;92(4):183-5
Some patients with chronic fatigue syndrome say they benefit from taking vitamin supplements. We assessed functional status for the B vitamins pyridoxine, riboflavin and thiamine in 12 vitamin-untreated CFS patients and in 18 healthy controls matched for age and sex. Vitamin-dependent activities--aspartate aminotransferase (AST) for pyridoxine, glutathione reductase (GTR) for riboflavin, transketolase (TK) for thiamine--were measured in erythrocyte haemolysates before and after in-vitro addition of the relevant vitamin. For all three enzymes basal activity (U/g Hb) was lower in CFS patients than in controls: AST 2.84 (SD 0.62) vs 4.61 (1.43), P < 0.001; GTR 6.13 (1.89) vs 7.42 (1.25), P < 0.04; TK 0.50 (0.13) vs 0.60 (0.07), P < 0.04. This was also true of activated values: AST 4.91 (0.54) vs 7.89 (2.11), P < 0.001; GTR 8.29 (1.60) vs 10.0 (1.80), P < 0.001; TK 0.56 (0.19) vs 0.66 (0.08), P < 0.07. The activation ratios, however, did not differ between the groups. These data provide preliminary evidence of reduced functional B vitamin status, particularly of pyridoxine, in CFS patients.
PMID: 10450194, UI: 99378688
EVIDENCE FOR GLUTATHIONE
DEFICIENCY IN CHRONIC FATIGUE SYNDROME
Paul R Cheney MD, PhD conference presentation at
London, April 1999
Chronic Fatigue Syndrome has recently been linked to activation of a novel, low molecular weight (37 Kda) Rnase L (1). Such activity would be expected to significantly impair key enzyme systems important to human function. Recent studies have also suggested that xenobiotic toxicity plays a substantial role in the symptoms of chronic fatigue syndrome (2). Urinary xenobiotics which are likely of gut microbial origin, correlate with the severity of and types of symptoms associated with chronic fatigue syndrome. We will present evidence of impairment of glutathione synthesis and function in chronic fatigue syndrome. Dysfunction in this key detoxification system would be expected to cause portal circulation toxicity as well as other xenobiotic toxicity now reported for chronic fatigue syndrome.
1. Suhadolnik, JR; Peterson, DL; O'Brien, K; Cheney PR et al. "Biochemical
Evidences for a Novel Low Molecular Weight 2-SA-Dependent RnaseL in Chronic
Fatigue Syndrome"
Journal of lnterferon and Cytokine Research, 17:377-385 (1997)
2. McGregor,
NR; Dunstan, RN et al. "Preliminary Determination of a
Molecular Basis to Chronic Fatigue Syndrome" Biochemical and Molecular Medicine,
57:73-80 (1996)
Serum concentrations of some
metals and steroids in patients with chronic fatigue syndrome with reference to
neurological and cognitive abnormalities.
van
Rensburg SJ, Potocnik FC, Kiss T, Hugo F, van Zijl P, Mansvelt E, Carstens ME,
Theodorou P, Hurly PR, Emsley RA, Taljaard JJ.
Department of Chemical
Pathology, University of Stellenbosch Medical School, Tygerberg Hospital,
Tygerberg, South Africa
Brain Res Bull 2001 May 15;55(2):319-25
Chronic fatigue syndrome is defined by the Atlanta
Centers for Disease Control (Atlanta, GA, USA) as debilitating fatigue lasting
for longer than 6 months. Symptoms include disturbances of cognition. Certain
factors have in the past been shown to influence cognition, including metals
such as aluminum, iron, and zinc; and steroids such as dehydroepiandrosterone.
In the present study, concentrations of these
factors were determined in the serum and plasma of patients and their age- and
gender-matched healthy controls (10 women and 5 men in each group). In
addition, copper, dehydroepiandrosterone sulphate, cortisol, cholesterol,
hemoglobin, ferritin and transferrin concentrations, as well as transferrin
genetic subtypes were determined in both groups.
The results indicate that patients had significantly
increased serum aluminum and decreased iron compared to controls. In the
females, serum iron and dehydroepiandrosterone sulphate were significantly
decreased and correlated. Total cholesterol was significantly increased, and
significantly negatively correlated with dehydroepiandrosterone sulphate. There
were no differences in zinc, copper, cortisol, hemoglobin, transferrin and ferritin
concentrations, or in transferrin genetic subtypes
NLM
Citation: PMID: 11470334
Elevated apoptotic cell population in patients with chronic fatigue syndrome:
the pivotal role of protein kinase RNA
Vojdani
A; Ghoneum M; Choppa PC; Magtoto L; Lapp CW
Immunosciences Laboratory Inc., Beverly Hills, California, USA.
J
Intern Med 1997 Dec;242(6):465-78 (ISSN:
0954-6820)
OBJECTIVES: A prominent feature of chronic fatigue syndrome (CFS) is a disordered immune system. Recent evidence indicates that induction of apoptosis might be mediated in a dysregulated immune system by the upregulation of growth inhibitory cytokines. Therefore, the purpose of this study was to evaluate the apoptotic cell population, interferon-alpha (IFN-alpha) and the IFN-induced protein kinase RNA (PKR) gene transcripts in peripheral blood lymphocytes (PBL) of CFS individuals, as compared to healthy controls. SUBJECTS AND METHODS: PBL were isolated from CFS (n = 29) and healthy control individuals (n = 15) and subjected to quantitative analysis of apoptotic cell population and cell cycle progression by flow cytometry. Quantitative competitive polymerase chain reaction (Q/C PCR) and Western blot analysis were used to assess the levels of PKR mRNA and protein in control and CFS individuals. In addition, circulating IFN-alpha was measured by ELISA assay. RESULTS: Increased apoptotic cell population was observed in CFS individuals, as compared to healthy controls (26.6 +/- 12.9% and 9.9 +/- 4.2%, respectively). The increased apoptotic subpopulation in CFS individuals was accompanied by an abnormal cell arrest in the S phase and the G2/M boundary of the cell cycle as compared to the control group (8.6 +/- 1.2 to 22.8 +/- 2.4 and 3.6 +/- 0.82 to 24.3 +/- 3.4, respectively). In addition, CFS individuals exhibited enhanced PKR mRNA and protein levels (mean basal level 3538 +/- 1050 and 2.7 +/- 0.26, respectively) as compared to healthy controls (mean basal level 562 +/- 162 and 0.89 +/- 0.18, respectively). In 50% of the CFS samples (n = 29) treated with 2-aminopurine (2-AP) (a potent inhibitor of PKR) the apoptotic population was reduced by more then 50%. CONCLUSIONS: PKR-mediated apoptosis in CFS individuals may contribute to the pathogenesis and the fatigue symptomatology associated with CFS.
Unique NLM Identifier: 98100060
Increased concentrations of
homocysteine in the cerebrospinal fluid in patients with fibromyalgia and
chronic fatigue syndrome.
Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE,
Gottfries CG.
Institute of Clinical Neuroscience,
Goteborg University, Sweden.
Scand J
Rheumatol 1997;26(4):301-7
Twelve outpatients, all women, who fulfilled the
criteria for both fibromyalgia and chronic fatigue syndrome were rated on 15
items of the Comprehensive Psychopathological Rating Scale (CPRS-15). These
items were chosen to constitute a proper neurasthenic subscale. Blood
laboratory levels were generally normal. The most obvious finding was that, in
all the patients, the homocysteine (HCY) levels were increased in the
cerebrospinal fluid (CSF). There was a significant positive correlation between
CSF-HCY levels and fatiguability, and the levels of CSF-B12 correlated
significantly with the item of fatiguability and with CPRS-15. The correlations
between vitamin B12 and clinical variables of the CPRS-scale in this study
indicate that low CSF-B12 values are of clinical importance. Vitamin B12
deficiency causes a deficient remethylation of HCY and is therefore probably
contributing to the increased homocysteine levels found in our patient group.
We conclude that increased homocysteine levels in the central nervous system
characterize patients fulfilling the criteria for both fibromyalgia and chronic
fatigue syndrome.
PMID: 9310111 [PubMed - indexed for MEDLINE]
Epstein-Barr virus infection
associated with interstitial nephritis and chronic fatigue.
Lopez-Navidad
A, Domingo P, Lopez-Talavera JC, Rabella N, Verger G.
Scandanavian
Journal of Infectious Diseases 1996; 28: 185-187.
Abstract: Severe renal disease in the setting of
Epstein-Barr virus (EBV) infection is exceedingly rare. We report here the case of a 22-year-old man
with acute EBV infection associated with severe interstitial nephritis. The patient developed chronic fatigue and
chronic renal failure with a serological profile typical of primary EBV
infection. Clinical improvement with
anti-EBNA seroconversion occurred after acyclovir therapy. Our patient illustrates that chronic fatigue
with major organ dysfunction and a serological profile of primary infection can
be seen in chronic EBV infection. In
such a case, acyclovir may prove beneficial.